Legumes, Nuts & Seeds - ImmunoCAP Explorer€¦ · Legumes Both grain legumes and nuts consist of a...

Allergy – Which allergens?

Legumes, Nuts & Seeds

Design: RAK Design AB, 2008Printed by: X-O Graf Tryckeri AB, Uppsala, SwedenISBN 91-970475-5-4

Author: Dr Harris Steinman,Allergy Resources International, P O Box 565, Milnerton 7435, South Africa,[email protected] rights reserved. No part of this publication may be reproduced in any formwithout the written consent of Phadia AB.©Phadia AB, 2008

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Contents

Introduction ............................................................................. 5f20 Almond (Amygdalus communis) ..................................... 9f6 Barley (Hordeum vulgare) ............................................ 15f310 Blue vetch (Lathyrus sativus) ....................................... 22f18 Brazil nut (Bertholletia excelsa) ................................... 26f11 Buckwheat (Fagopyrum esculentum) ............................ 32f202 Cashew nut (Anacardium occidentale) .......................... 41f309 Chick pea (Cicer arietinus) .......................................... 49f36 Coconut (Cocos nucifera) ............................................. 54f55 Common millet (Panicum milliaceum) .......................... 59f305 Fenugreek (Trigonella foenum-graecum) ........................ 64f56 Foxtail millet (Setaria italica) ....................................... 67f79 Gluten (from Triticum aestivum) ................................... 70f315 Green bean (Phaseolus vulgaris) ................................... 77f17 Hazel nut (Corylus avellana) ........................................ 81f57 Japanese millet (Echinochloa crus-galli) ....................... 89f235 Lentil (Lens esculenta) ................................................ 92f182 Lima bean (Phaseolus lunatus) .................................... 97f333 Linseed (Linum usitatissimum) .................................. 100f335 Lupin seed (Lupinus albus) ....................................... 103f345 Macadamia nut (Macadamia spp.) .............................. 111f8 Maize/Corn (Zea mays) .............................................. 114f7 Oat (Avena sativa) ..................................................... 122f12 Pea (Pisum sativum) ................................................. 126f13 Peanut (Arachis hypogaea) ........................................ 132f201 Pecan nut (Carya illinoensis) ...................................... 150f253 Pine nut, pignoles (Pinus edulis) ................................ 153f203 Pistachio (Pistacia vera) ............................................ 157f224 Poppy seed (Papaver somniferum) .............................. 161f226 Pumpkin seed (Cucurbita pepo) ................................. 165f347 Quinoa (Chenopodium quinoa) ................................... 167f316 Rape seed (Brassica napus) ....................................... 168f287 Red kidney bean (Phaseolus vulgaris) ......................... 172f9 Rice (Oryza sativa) .................................................... 175f5 Rye (Secale cereale) ................................................. 184f10 Sesame seed (Sesamum indicum) .............................. 192f14 Soybean (Glycine max) .............................................. 200f124 Spelt wheat (Triticum spelta) ..................................... 216f227 Sugar-beet seed (Beta vulgaris) .................................. 218f299 Sweet chestnut (Castanea sativa) ............................... 220f256 Walnut (Juglans spp.) ................................................ 227f4 Wheat (Triticum aestivum) ......................................... 235f15 White bean (Phaseolus vulgaris) ................................. 251Mixes fx1, fx3, fx5, fx8, fx9 ................................................ 254

fx11, fx12, fx13, fx18, fx20, fx22, fx24 .................... 255fx25, fx26, fx27, fx28 .............................................. 256

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Legume, nut and seed allergens

This reference book describes the 42allergens categorized as Legumes, Nuts andSeeds available as ImmunoCAP® allergensfor in vitro testing. A number of allergenscustomarily listed in these categories do notin the strict sense fulfil the definition of thatcategory either in the botanical sense orbecause they may easily fit into twocategories. For example, Lupin seed couldappear to belong to the seed category, andhere is preferentially categorised as a legume.Whether Peanut is a nut or a legume maynot always be immediately obvious, inparticular as Peanut has characteristics ofboth. A number of foods classified here, havepollen counterparts that are recognized asaeroallergens resulting in asthma andrhinoconjuctivitis, e.g., Wheat and Rye.

Legumes

Both grain legumes and nuts consist of asimple dry fruit carried inside a pod or shell.In the strict botanical use of the term, a nutwill usually have only one seed and at mosttwo compared to legumes which containmultiple seeds. Most legumes are dehiscent,opening naturally along a seam on two sides,compared to a true nut that is alwaysindehiscent, i.e., does not open on its own.Legumes often contain seeds attached totheir pods unlike a true nut which is neverattached to the ovary wall. Peanut, classifiedas a legume, clearly has features of both nutsand legumes but has overriding legumecharacteristics, e.g., its high protein yield andthe capacity to replenish nitrogen in the soil.

The legumes are members of the Fabaceae(Leguminosae) botanical family. Theprincipal unifying feature of the family is thefruit, a pod, technically known as a Legume.The Fabaceae is a very large family consistingof 650 genera and over 18,000 species. Thefamily is often divided into three sub-families:Papilionoideae, Caesalpinioideae andMimosoideae. These sub-families aresometimes recognised as three separatefamilies: Papilionaceae, Caesalpiniaceae andMimosaceae.

The Papilionoideae contains most of theimportant leguminous crop species such asthe Soya Bean (Glycine max), Common Pea(Pisum sativum), Chickpea (Cicerarietinum), French Bean (Phaseolusvulgaris), Lentil (Lens culinaris) and Peanut(Arachis hypogaea). A legume is a simpledry fruit which develops from a simple carpeland usually opens along a seam (dehisces)on two sides. Peanut is an indehiscentlegume.

The majority of the Caesalpinioideae aretropical or subtropical trees and shrubs. Themajority of the Mimosoideae are tropical orsubtropical trees and shrubs, of which thegenera Acacia and Mimosa have species thatare extremely important economically, e.g.,bark of the Golden Wattle (Acaciapycnantha) and Acacia Senegal which yieldscommercial gum arabic which is used in awide range of industrial processes.

The legumes consist of the grain andforage legumes. More than forty species andcountless varieties of grain legumes arecultivated throughout the world. The legumefamily is characterised by flowers that havefive petals (papilionaceous flower with abutterfly form), a superior ovary that ripensto form a fruit, the specialised pod whichcontains seeds, and the ability to useatmospheric nitrogen to produce their ownprotein compounds, as a result of thesymbiosis with nitrogen-fixing bacteriawithin organs known as nodules developedon the plant roots, for nearly all of itsmembers. Unlike other cultivated plants,legume crops do not need nitrogenfertilisation for optimal growth in general.

The “forage” legumes are customarilygrown for whole crop use for animal feedor for industrial purposes. For animal feed,the crop may be grown for grazing or forthe production of silage or hay. Alfalfa(Lucerne) is an example of a forage legume.Conversely, “grain” legumes are cultivatedprimarily for their seeds which are rich inprotein and energy and therefore used forhuman consumption or animal feed. The

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grain legumes are commercially termed“pulses”, but exclude the “leguminousoilseeds” that are used primarily for theirhigh oil content. Soybean is an example ofthis group.

Legume species may preferable thrive intemperate climates and other prefer tropicalregions. The major grain legumes growninclude species belong to a number of tribes.For example, Pea (Pisum sativum) and Lentil(Lens culinaris), which are members of theFabeae tribe. The tribe Phaseoleae, includeSoybean (Glycine max) and White bean(Phaseolus vulgaris). Chickpea (or Garbanzobean) (Cicer arietinum), a member of theCicereae tribe, is a very important grain inthe Spanish diet. Lupin seed (tribeGenisteae), is preferentially classified as alegume. Of the legumes, Soybean is the mostimportant grain crop with around 185million tonnes being produced, grownprimarily in the USA, Brazil, Argentina,Paraguay and Uraguay. The worldproduction of grain legumes other thanSoybeans amounts to approximately 57million tonnes.

Individuals may become sensitized to thelegumes as a result from inhalation ofaerosolized proteins from the cooking of thefruit/seed/grain of the plant, fromoccupational contact with the dust or actualfruit/seed/grain, or following its ingestion.Respiratory allergy as a result of inhalationof the pollen of the plant, e.g., Wheat(Cultivated Wheat g15), is discussed in thereference book, ImmunoCAP® Grass pollensin this series.

Nuts

Nut is a general term for the dry seed orsimple dry fruit of some plants carried insidea pod or shell (ovary wall) which becomesvery hard (stony or woody) at maturity, andwhere the seed remains unattached orunfused with the ovary wall. In the strictbotanical use of the term, a nut will usuallyhave only one seed and at most it will havetwo. A true nut is always indehiscent,meaning it won't open on its own at maturityand a true nut is never attached to the ovarywall. While a wide variety of dried seeds andfruits are called nuts, only a certain number

of them are considered by biologists to betrue nuts. Nuts are an important source ofnutrition for both humans and wildlife. Anut is the seed of a tree. When we eat thesoft layer, we call it a fruit. When we eat theseed we call it a nut. A nut is a seed, but aseed is not necessarily a nut.

True nuts may be edible or inedible;common examples are Acorn, Beechnut,Chestnut, and Hazel nut. Fruits or seeds thatare incorrectly and popularly termed nutinclude Almond and Coconut which areactually drupes with the fleshy outer layerremoved. Brazil nut are seeds contained incapsules. Traditionally a distinction has beenmade between Peanut and Tree nuts. Peanutis actually a legume, belonging to the familyFabaceae. In common parlance, the culinarydefinition of a nut may carry more weightthan the botanical definition. In culinaryterms, a nut is any large seed which is usedin food and comes from a shell. This groupincludes drupes, fruit that contain a hard pit,e.g., Almond and Coconut, seeds which arenot nuts, such as Cashew and Peanut.

True nuts are produced, for example, bysome plants – families of the order Fagales:

• Family Juglandaceae: e.g., Walnut,Pecan nut

• Family Fagaceae: e.g., Chestnut

• Family Betulaceae:, e.g., Hazel nut

Some fruits and seeds that are nuts in theculinary sense, but not in the botanical sense:

• Almond is the edible seed of a drupe– the leathery “flesh” is removed atharvest

• Brazil nut is the seed from a capsule

• Cashew nut is a seed

• Coconut is a dry, fibrous drupe

• Macadamia nut is a creamy whitekernel

• Peanut is a legume and a seed

• Pine nut is the seed of several speciesof Pine

• Pistachio nut is the seed of a thin-shelled drupe

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Seeds

A seed is a small embryonic plant of a seedplant before germination enclosed in acovering called the seed coat, usually withsome stored food. It is the product of theripened ovule of gymnosperm andangiosperm plants which occurs afterfertilization and some growth within themother plant. The seeds listed here are“edible” seeds. Many seeds are edible andthe majority of human calories come fromseeds, especially from cereals such as Wheatand Rice. Seeds also provide cooking oils,beverages and spices. Edible seeds containstorage proteins which may be found in theembryo or endosperm and differ in theiramino acid content and physical properties.For example Wheat gluten, important inproviding the elastic property to breaddough, is strictly an endosperm protein. Ofcourse, seeds are used to propagate manycrops. Seeds are also eaten by animals, fedto livestock and used as birdseed.

Pine nuts suggest classification as nuts,but are in fact the edible seeds of Pines(family Pinaceae, genus Pinus).

Further reading• AEP - Grain legumes portal. What are grain

legumes? http://www.grainlegumes.com/aep/crops_species/what_are_grain_legumes.(Accessed May 9, 2008)

• ILDIS - International Legume Database &Information Service. http://www.ildis.org/(Accessed May 9, 2008)

• LegumeChef.com. Legume classes. http://www.legumechef.com/English/Variedades_en.htm. (Accessed May 9, 2008)

• Hymowitz, T. 1990. Grain legumes. p. 54-57. In: J. Janick and J.E. Simon (eds.),Advances in new crops. Timber Press,Portland, OR. http://www.hort.purdue.edu/newcrop/proceedings1990/V1-154.html(Accessed May 9, 2008)

• Wikipedia contributors, "Seed," Wikipedia,The Free Encyclopedia, http://en.wikipedia.org/w/index.php?title=Seed&oldid=210679585(accessed May 9, 2008)

• Wikipedia contributors, "Nut (fruit),"Wikipedia, The Free Encyclopedia, http://en.wikipedia.org/w/index.php?title=Nut_%28fruit%29&oldid=210567542(accessed May 9, 2008)

• Wayne's Word. Fruits Called Nuts. http://waynesword.palomar.edu/ecoph8.htm(accessed May 9, 2008)

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Legume, nut and seed ImmunoCAP® Allergens available for IgE antibody testing

f7 Oat (Avena sativa)

f12 Pea (Pisum sativum)

f13 Peanut (Arachis hypogaea)

f201 Pecan nut (Carya illinoensis)

f253 Pine nut, pignoles (Pinus edulis)

f203 Pistachio (Pistacia vera)

f224 Poppy seed (Papaver somniferum)

f226 Pumpkin seed (Cucurbita pepo)

f347 Quinoa (Chenopodium quinoa)

f316 Rape seed (Brassica napus)

f287 Red kidney bean (Phaseolusvulgaris)

f9 Rice (Oryza sativa)

f5 Rye (Secale cereale)

f10 Sesame seed (Sesamum indicum)

f14 Soybean (Glycine max)

f124 Spelt wheat (Triticum spelta)

f227 Sugar-beet seed (Beta vulgaris)

f299 Sweet chestnut (Castanea sativa)

f256 Walnut (Juglans spp.)

f4 Wheat (Triticum aestivum)

f15 White bean (Phaseolus vulgaris)

Mixes: fx1, fx3, fx5, fx8, fx9, f11fx12, fx13, fx18, fx20, fx22,fx24, fx25, fx26, fx27, fx28

f20 Almond (Amygdalus communis)

f6 Barley (Hordeum vulgare)

f310 Blue vetch (Lathyrus sativus)

f18 Brazil nut (Bertholletia excelsa)

f11 Buckwheat (Fagopyrumesculentum)

f202 Cashew nut (Anacardiumoccidentale)

f309 Chick pea (Cicer arietinus)

f36 Coconut (Cocos nucifera)

f55 Common millet (Panicummilliaceum)

f305 Fenugreek (Trigonella foenum-graecum)

f56 Foxtail millet (Setaria italica)

f79 Gluten (from Triticum aestivum)

f315 Green bean (Phaseolus vulgaris)

f17 Hazel nut (Corylus avellana)

f57 Japanese millet (Echinochloacrus-galli)

f235 Lentil (Lens esculenta)

f182 Lima bean (Phaseolus lunatus)

f333 Linseed (Linum usitatissimum)

f335 Lupin seed (Lupinus albus)

f345 Macadamia nut (Macadamia spp.)

f8 Maize, Corn (Zea mays)

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Amygdalus communisFamily: RosaceaeGenus: PrunusSubgenus: AmygdalusCommonnames: Almond, Sweet Almond,

Bitter AlmondSynonymes: A. dulcis, Prunus

amygdalus and P. dulcisSourcematerial: Shelled almondsThe fruit and seeds of several otherplants are known as Almonds. Theseeds of the African shrub Brabeiumstellatifolium are known as AfricanAlmonds. Country Almonds is a namegiven to the fruit of the East Indiantree Terminalia Catappa. The fruit ofCanarium commune is known as JavaAlmondsFor continuous updates:www.immunocapinvitrosight.com

f20 Almond

Allergen Exposure

Geographical distribution

The Almond is the fruit of a vigorous, deep-rooted deciduous small tree belonging to theRose family, which grows best in areas withdry, warm summers. The plant is believedto be a native of northern Africa and theMiddle East. It occurs wild in Sicily andGreece and is extensively cultivated innorthern Africa, southern Europe, Australiaand the warmer parts of the United States,particularly California.

The fruit is a drupe or kernel stone fruit,resembling the Peach in its general structuralcharacteristics. It is, however, much smaller,measuring about 4 cm in length. As in thePeach, the outer portion of the fruit coat(sarcocarp) is fleshy, while the inner portion(endocarp or putamen) is hard and enclosesthe kernel or seed, to which the term Almondis commonly applied.

Almonds come in many varieties, but the2 major, universally recognised ones are theSweet (Prunus amygdalus var. dulcis) andthe Bitter (Prunus amygdalus var. amara).They appear very similar but are differentin chemistry. In the Bitter variety, substantialamounts of amygdalin (or “laetrile”),containing hydrocyanic (or “prussic”) acid,are found. The Bitter almond is banned fromretail sale in the US because of the toxicityof unprocessed amygdalin. Only Sweetalmonds are readily edible.

Environment

Almonds have always been an importantingredient in Arabic dishes and Indiancurries. Sweet almonds (fresh, blanched,roasted, candied, and smoked; whole, sliced,chopped, and in paste form) are readilyavailable in markets and are used in a varietyof recipes, especially for sweets andconfectionery. Heat-processed Bitteralmonds are used to flavour extracts,flavourings, liqueurs and syrups. Thepurified fixed oil from both varieties ofAlmonds has food uses, particularly as acondiment. Almonds are a nutritionalpowerhouse, packed with calcium, fibre,folic acid, magnesium, potassium, riboflavinand vitamin E.

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f20 AlmondMedicinally, externally applied Almond

oil is an emollient; taken internally, alaxative, nutritional substitute andsupplement (particularly in cases ofdiabetes), and a remedy for nervous systemdisorders such as whooping cough andspasmodic troubles.

Almond oil and paste often feature incosmetics and toiletries.

Unexpected exposure

See under Environment.

Allergens

A number of allergens of various molecularweights have been isolated: 12, 30, 37, 45,50, and 62 kDa proteins. Several of theseproteins were shown to be similar to a 7Sglobulin and a 2S albumin (1-2). Twoallergens isolated were reported to be majorallergens - 1 heat-labile and the other heat-stable. The Almond major protein (AMP oramandin), the primary storage protein inAlmonds, is the major allergen recognisedby Almond-allergic patients and is probablythe 2S albumin identified previously andshown to be a heat-stabile allergen (3). Theantigenicity of processed Almond proteinshas been shown to be very stable whencompared with that of the unprocessedcounterpart (4).

To date, the following allergens have beencharacterised:

Pru du 2S Albumin, a 2S albumin (1).

Pru du Conglutin, a conglutin (1).

Pru du LPT, a lipid transfer protein. (5-7).

Pru du Amandin, a 360 kDa hexamericprotein, an 11S legumin-like protein (8-9).

Pru du 4, a profilin (10-12).

Pru du 5, an acid ribosomal protein P2(11,13).

Amandin is a legumin-type protein andis composed of 2 major types ofpolypeptides, with estimated molecularweights of 42-46 and 20-22 kDa, linked viadisulfide bonds. Amandin is not aglycoprotein (7).

Pru du 4, a profilin, is a minor allergen:6 of 18 patient sera (33%) were shown toreact with the recombinant Pru du 4 protein,and 8 of 18 (44%) reacted with the nativePru du 4. More than 1 native Almondprofilin isoform was isolated (9).

Potential cross-reactivity

An extensive cross-reactivity among thedifferent members of the family, and inparticular of the genus, could be expected(14). Potential clinical allergy to otherRosaceae should not be overlooked. If thereported reaction is confirmed, currenttolerance to other Rosaceae should beprecisely established, unless there has beeningestion without symptoms after thereaction (15).

A major Almond allergen, a 2S albumin,can be expected to result in cross-reactionswith other foods containing this protein, e.g.,Walnut, Sunflower seed and Peanut (1,16-17).Ara h 2, a major Peanut allergen, is a conglutin/2S albumin. In a study evaluating serum fromPeanut-allergic patients, Ara h 2 specific serumIgE antibodies bound to proteins present inAlmond and Brazil nut extracts, indicatingthat Ara h 2 shares IgE-binding epitopes withAlmond and Brazil nut allergens (18). Thebiological activity of cross-reactive IgEantibodies between Peanut, Brazil nut andAlmond has been demonstrated (19).

The Lipid Transfer Proteins are majorallergens of Rosaceae fruits and will resultin varying degrees of cross-reactivity withother family members, as well as betweenAlmond and non-family-related foodcontaining LPT allergens (20-21). Forexample, Apricot LTP has a sequence identityof 91% and 94% with Peach and AlmondLTPs, respectively. (22) Hazel nut LTP has a62% amino acid homology with the LTPfrom Almond, 59% with Peach LTP and 59%with Cherry LTP. (5) Apricot LTP has asequence identity of 91% and 94% withPeach and Almond LTP, respectively (7).

Pru du 4 is a profilin, and cross-reactivitybetween Almond profilin and other profilin-containing plants is possible (10). Almondand Ryegrass profilin were shown to bemutually inhibitable, so there must be cross-

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f20 Almondreactivity with grass pollen profilin (9). Asprofilin is susceptible to denaturation,variable reactivity will result (10).

The existence of common antigenic bandsbetween Pine nut and Almond has beenreported, and this may result in cross-reactivity between these foods (23-24).

In an in vitro study, Pru du Amandin hasbeen reported to be cross-reactive with aminor 50 kDa protein of Maize (a gamma-zein), as well as having low cross-reactivitywith the 27 kDa gamma-zein. The 50 kDaMaize gamma-zein also reacted with IgEfrom pooled human sera of patients withself-reported severe Almond allergy (25).

An association between pollen allergy andAlmond allergy has been reported. Almost33% of Birch pollen-allergic patients werereported to also be hypersensitive to Almondand Cherry (26-27). Among 120 patientswith pollen allergy and 80 patients withpollen-associated food allergy (as evaluatedby skin prick tests, IgE antibodydeterminations, and HLA genotyping),monovalent pollen allergy was observed in57% of the pollinosis patients, but in only15% of patients with food allergy. Hazel nut(71%), Almond (65%), Walnut (44%) andApple (41%) were the most common foodallergens and were frequently associatedwith allergy to Birch pollen allergy (28).

In a study of 61 patients with adocumented history of IgE-mediatedreactions to Grape or its products (wine, juice,and wine vinegar), 81.9% were co-sensitisedto Apple, 70.5% to Peach, 47.5% to Cherry,32.8% to Strawberry, 49.2% to Peanut,42.6% to Walnut, 31.1% to Hazel nut,26.2% to Almond, and 29.5% to Pistachio.Whether this was due to the presence ofpanallergens was not elucidated (29).

Clinical Experience

IgE-mediated reactions

Almond may frequently result insensitisation (30) and may commonly inducesymptoms of food allergy (7,11,23,31-36).In general, nut allergies are potentially life-threatening and uncommonly outgrown,and appear to be increasing in prevalence.

In studies of patients with nut allergy (adultsand children), Peanuts are usually found tobe the commonest cause, followed by Brazilnut, Almond, and Hazelnut (37). Otherreports have indicated that the mostcommon tree nut allergies are to Walnut,Almond, and Pecan nut. Initial reactions arereported to usually occur at home and inchildren, at 5 years of age on average.Adverse effects result from a first exposurein 72% of cases. Eighty-nine percent of thereactions involved the skin (urticaria,angioedema), 52% the respiratory tract(wheezing, throat tightness, repetitivecoughing, dyspnoea), and 32% thegastrointestinal tract (vomiting, diarrhoea).Two organ systems were affected in 31% ofinitial reactions, and all 3 in 21% ofreactions. Approximately 1/3 of Peanut-allergic individuals will have a co-existingtree nut allergy.

In a retrospective study of 213 Australianchildren with Peanut or tree nut allergy, 177patients (83.1%) had Peanut allergy, 27(12.6%) had Cashew allergy, and 9 hadallergy to other tree nuts (4.2%; 2 each toAlmond and Pecan, 1 each to Hazel nut andWalnut, and 3 to a mixture of nuts) (38). Across-sectional, descriptive, questionnaire-based survey conducted in schools inToulouse, France, found that of 2,716questionnaires returned, 192 reported a foodallergy. Tree nut allergy was self-reportedin 19 (7.8%), with 10 for Hazel nut, 6 forWalnut, 2 for Almond and 1 to Cashew. (39)In an American study of 115 patients aged4-19.5 years, 37% reported an allergy to 1or more Tree nuts; 19% reported mildadverse reactions to Almond, and 1 patientexperienced severe adverse effects (40). Anearlier study, by the Food Allergy andAnaphylaxis Network (FAAN) Peanut andTree Nut Allergy Registry in the USA,collected data on 5,149 patients (mainlychildren) and reported Walnut as the firstcause of allergic reactions to Tree nuts in34%, followed by Cashew (20%), Almond(15%), Pecan (9%), and Pistachio (7%) (41).

Accidental ingestion occurs frequentlyoutside of the home. As rather low levels ofAlmond proteins can provoke an allergicreaction in sensitised individuals, thesereactions often require emergency treatment

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f20 Almond(42). Kiss-induced allergy, a form of allergyby proxy, may occur with Almond, andsymptoms may be local or general, mild,moderate or severe. A careful history willdetermine that the symptoms appeared withinminutes after a kiss, the time between eatingthe allergen and the kiss being quite variable,from a few minutes up to 2 hours (43).Even traces of residual Almond protein inAlmond nut oil may pose a threat to patientswith allergy, depending on the method ofmanufacture and processing (44).Anaphylaxis may thus be a commonpresenting complaint (1,45). An Italian studydescribes 5 patients with Almond allergy,who were shown to have skin reactivity forAlmond. Four patients experienced oralallergy symptoms and anaphylaxis, whereas1 only experienced oral allergy syndrome,with itching of the oral cavity and rhino-conjunctivitis (1).

A review was done of 601 patients aged1 to 79 years of age who had experiencedanaphylaxis. Of the 133 food reactions,Peanut was responsible in 25, tree nuts in13, and Almond or Peach in 5 (46).

The sudden and unexpected death of anindividual following the ingestion of Hazelnuts and Almonds, to which the individualhad not been previously known to beallergic, was described. After eating a dessertcontaining these nuts, he experiencedsymptoms of his throat closing and swellingof his lips. He had previously experiencedsimilar symptoms after ingesting Peanuts buthad thought nothing of it after being assuredthat no contact with Peanut was possible.He suddenly collapsed during vigorousdancing. The death was not associated withcutaneous or laryngeal manifestations ofanaphylaxis (47).

Other cutaneous symptoms describedinclude acne vulgaris (48) and atopicdermatitis (49). A 5-month-old child withatopic dermatitis developed contactdermatitis to Almond. Persistent eczemacorrelated with the application of Almondoil on the cheeks and buttocks. The childhad not ingested Almond, and her motherdid not report Almond intake during herbreast-feeding. IgE antobodies to Almondwas detectable. Sensitisation appeared tooccur from a percutaneous route.

Asthma may occasionally be associatedwith Almond. In the evaluation of 163 food-allergic asthmatic children for food-inducedasthma, using DBPCFC, 1.5% of the groupdemonstrated Almond as a culprit (25).

Other reactions

Cyanide poisoning after Bitter almond(Prunus amygdalus var. amara) ingestion hasbeen reported (50).

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f20 AlmondReferences

1. Poltronieri P, Cappello MS, Dohmae N, Conti A,Fortunato D, Pastorello EA, Ortolani C,Zacheo G. Identification and characterisationof the IgE-binding proteins 2S albumin andconglutin gamma in almond (Prunus dulcis)seeds. Int Arch Allergy Immunol2002;128(2):97-104

2. Pasini G, Simonato B, Giannattasio M,Gemignani C, Curioni A. IgE binding toalmond proteins in two CAP-FEIA-negativepatients with allergic symptoms to almond ascompared to three CAP-FEIA-false-positivesubjects. Allergy 2000;55(10):955-8

3. Roux KH, Teuber SS, Robotham JM, Sathe SK.Detection and stability of the major almondallergen in foods.J Agric Food Chem 2001;49(5):2131-6

4. Venkatachalam M, Teuber SS, Roux KH,Sathe SK. Effects of roasting, blanching,autoclaving, and microwave heating onantigenicity of almond (Prunus dulcis L.)proteins.J Agric Food Chem 2002;50(12):3544-8

5. Schocker F, Lüttkopf D., Scheurer S.,Petersen A., Vieths S., Becker W. M. Cloningand sequencing of the lipid transfer proteinfrom hazelnut (corylus avellana) [Poster] 8thInternational Symposium on Problems ofFood Allergy 2001,ch 11-13, Venice

6. Diaz-Perales A, Lombardero M, Sanchez-Monge R, Garcia-Selles FJ, et al. Lipid-transfer proteins as potential plantpanallergens: cross-reactivity among proteinsof Artemisia pollen, Castanea nut andRosaceae fruits with different IgE-bindingcapacities.Clin Exp Allergy 2000;30(10):1403-10

7. Conti A, Fortunato D, Ortolani C, et al.Determination of the primary structure of twolipid transfer proteins from apricot (Prunusarmeniaca). J Chromatogr B Biomed Sci Appl2001;756(1-2):123-9

8. Sathe SK, Wolf WJ, Roux KH, Teuber SS,Venkatachalam M, Sze-Tao KW. Biochemicalcharacterization of amandin, the majorstorage protein in almond (Prunus dulcis L.).J Agric Food Chem 2002;50(15):4333-41

9. Gaur V, Sethi DK, Salunke DM. Purification,identification and preliminarycrystallographic studies of Pru du amandin,an allergenic protein from Prunus dulcis.Acta Crystallogr Sect F Struct Biol CrystCommun 2008;64(Pt 1):32-5

10. Tawde P, Venkatesh YP, Wang F, Teuber SS,Sathe SK, Roux KH. Cloning andcharacterization of profilin (Pru du 4), across-reactive almond (Prunus dulcis)allergen.J Allergy Clin Immunol 2006;118(4):915-22

11. van Ree R, Voitenko V, et al. Profilin is across-reactive allergen in pollen andvegetable foods.Int Arch Allergy Immunol 1992;98(2):97-104

12. International Union of ImmunologicalSocieties Allergen Nomenclature: IUISofficial list http://www.allergen.org/List.htm2007

13. Jacquenet S, Moneret-Vautrin DA. Lesallergènes de l'arachide et des fruits à coque/ Allergy to peanut and all kinds of nutsRevue francaise d allergologie2007;47(8):487-91

14. Yman L. Botanical relations and immuno-logical cross-reactions in pollen allergy. 2nded. Pharmacia Diagnostics AB. Uppsala.Sweden. 1982: ISBN 91-970475-09

15. Rodriguez J, Crespo JF, Lopez-Rubio A,De La Cruz-Bertolo J, Ferrando-Vivas P, Vives R,Daroca P. Clinical cross-reactivity amongfoods of the Rosaceae family. J Allergy ClinImmunol 2000;106(1 Pt 1):183-9

16. Teuber SS, Peterson WR. Systemic allergicreaction to coconut (Cocos nucifera) in 2subjects with hypersensitivity to tree nut anddemonstration of cross-reactivity to legumin-like seed storage proteins: new coconut andwalnut food allergens. J Allergy Clin Immunol1999;103(6):1180-5

17. Asero R, Mistrello G, Roncarolo D, Amato S.Allergenic similarities of 2S albumins.Allergy 2002;57(1):62-3

18. de Leon MP, Drew AC, Glaspole IN,Suphioglu C, O'Hehir RE, Rolland JM. IgEcross-reactivity between the major peanutallergen Ara h 2 and tree nut allergens.Mol Immunol 2007;44(4):463-71

19. de Leon MP, Drew AC, Glaspole IN,Suphioglu C, Rolland JM, O'Hehir RE.Functional analysis of cross-reactiveimmunoglobulin E antibodies: peanut-specific immunoglobulin E sensitizesbasophils to tree nut allergens.Clin Exp Allergy 2005;35(8):1056-64

20. Garcia-Selles FJ, Diaz-Perales A, Sanchez-Monge R, Alcantara M, Lombardero M,Barber D, Salcedo G, Fernandez-Rivas M.Patterns of reactivity to lipid transfer proteinsof plant foods and Artemisia pollen: an invivo study.Int Arch Allergy Immunol 2002;128(2):115-22

21. Sanchez-Monge R, Lombardero M, Garcia-Selles FJ, Barber D, Salcedo G. Lipid-transferproteins are relevant allergens in fruit allergy.J Allergy Clin Immunol 1999;103(3 Pt1):514-9

22. Conti A, Fortunato D, Ortolani C, Giuffrida MG,Pravettoni V, Napolitano L, Farioli L, PeronoGaroffo L, Trambaioli C, Pastorello EA.Determination of the primary structure of twolipid transfer proteins from apricot (Prunusarmeniaca). J Chromatogr B Biomed Sci Appl2001;756(1-2):123-9

23. A MA, Maselli JP, Sanz Mf ML, Fernandez-Benitez M. Allergy to pine nut. AllergolImmunopathol (Madr) 2002;30(2):104-8

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24. de las Marinas D, Vila L, Sanz ML. Allergy topine nuts. Allergy 1998;53(2):220-2

25. Lee SH, Benmoussa M, Sathe SK, Roux KH,Teuber SS, Hamaker BR. A 50 kDa Maizegamma-Zein Has Marked Cross-Reactivitywith the Almond Major Protein.J Agric Food Chem. 2005;53(20):7965-70

26. Eriksson NR, Formgren H, Svenonius E. Foodhypersensitivity in patients with pollenallergy. Allergy 1982;37:437-43

27. Ortolani C, Ispano M, Pastorello EA, Ansoloni R,et al. Comparison of results of skin pricktests (with fresh foods and commercial foodextracts) and RAST in 100 patients with oralallergy syndrome.J Allergy Clin Immunol 1989;83:683-90

28. Boehncke WH, Loeliger C, Kuehnl P,Kalbacher H, Bohm BO, Gall H.Identification of HLA-DR and -DQ allelesconferring susceptibility to pollen allergy andpollen associated food allergy.Clin Exp Allergy 1998;28(4):434-41

29. Kalogeromitros DC, Makris MP, Gregoriou SG,Katoulis AC, Straurianeas NG. Sensitizationto other foods in subjects with reportedallergy to grapes.Allergy Asthma Proc 2006;27(1):68-71

30. Amat Par P, Sanosa Valls J, Lluch Perez M,Malet Casajuana A, Garcia Calderon PA.Dried fruit hypersensitivity and its correlationwith pollen allergy. Allergol Immunopathol(Madr) 1990;18(1):27-34

31. Crespo JF, Rodriguez J, James JM, Daroca P,Reano M, Vives R. Reactivity to potentialcross-reactive foods in fruit-allergic patients:implications for prescribing food avoidance.Allergy 2002;57(10):946-9

32. Rance F, Dutau G. Asthma and food allergy:report of 163 pediatric cases. [French] ArchPediatr 2002;9 Suppl 3:402s-407s

33. Garcia Ortiz JC, Cosmes PM, Lopez-Asunsolo A.Allergy to foods in patients monosensitized toArtemisia pollen.Allergy 1996;51(12):927-31

34. Gillespie DN, Nakajima S, Gleich GJ.Detection of allergy to nuts by theradioallergosorbent test.J Allergy Clin Immunol 1976;57(4):302-9

35. Kakemizu N, Yamakawa Y, Aihara M, Ikezawa Z.A case of cashew nut allergy followed byalmond allergy. [Japanese] Arerugi2003;52(10):1022-6

36. Sporik R, Hill D. Allergy to peanut, nuts, andsesame seed in Australian children. [Letter]BMJ 1996;313(7070):1477-8

37. Ewan PW. Clinical study of peanut and nutallergy in 62 consecutive patients: newfeatures and associations.BMJ 1996;312(7038):1074-8

38. Davoren M, Peake J. Cashew nut allergy isassociated with a high risk of anaphylaxis.Arch Dis Child 2005;90(10):1084-5

39. Rance F, Grandmottet X, Grandjean H.Prevalence and main characteristics of school-children diagnosed with food allergies inFrance. Clin Exp Allergy 2005;35(2):167-72

40. Fleischer DM, Conover-Walker MK, Matsui EC,Wood RA. The natural history of tree nutallergy. J Allergy Clin Immunol2005;116(5):5-1093

41. Sicherer SH, Furlong TJ, Munoz-Furlong A,Burks AW, Sampson HA. A voluntary registryfor peanut and tree nut allergy:characteristics of the first 5149 registrants.J Allergy Clin Immunol 2001;108(1):128-32

42. Sicherer SH, Burks AW, Sampson HA.Clinical features of acute allergic reactions topeanut and tree nuts in children.Pediatrics 1998;102(1):e6

43. Dutau G, Rancé F. Le syndrome des allergiesinduites par le baiser / Kiss-induced allergyRevue francaise d allergologie2006;46(2):80-84

44. Teuber SS, Brown RL, Haapanen LA.Allergenicity of gourmet nut oils processed bydifferent methods.J Allergy Clin Immunol 1997;99(4):502-7

45. Armentia A, Barber D, Lombardero M, MartinSantos JM, Martin Gil FJ, Arranz Pena ML,Callejo A, Salcedo G, Sanchez-Monge R.Anaphylaxis associated with antiphospholipidsyndrome. Ann Allergy Asthma Immunol2001;87(1):54-9

46. Webb LM, Lieberman P. Anaphylaxis: areview of 601 cases. Ann Allergy AsthmaImmunol 2006;97(1):39-43

47. Flannagan LM, Wolf BC. Sudden deathassociated with food and exercise.J Forensic Sci 2004;49(3):543-5

48. Wüthrich B, Much Th. NahrungsmittelAllergen-Testung bei Acne vulgaris?Dermatologica 1978;157:294-5

49. Guillet G, Guillet MH. Percutaneoussensitization to almond oil in infancy andstudy of ointments in 27 children with foodallergy. [French] Allerg Immunol (Paris)2000;32(8):309-11

50. Shragg TA, Albertson TE, Fisher CJ Jr.Cyanide poisoning after bitter almondingestion. West J Med 1982;136(1):65-9

f20 Almond

15

Hordeum vulgareFamily: Poaceae (Gramineae)Commonnames: Barley, BarleycornSourcematerial: Untreated planting seedsSee also: Barley g201, Malt f90,

and Gluten f79For continuous updates:www.immunocapinvitrosight.com

f6 Barley

Allergen Exposure


This hardy cereal grain is native toMesopotamia, and its use dates back to theStone Age. Barley is the fourth mostimportant grain in the world, after Wheat,Maize and Rice. Most of the Barley nowgrown in the Western world is used eitherfor animal fodder or, when malted, in thebrewing and distilling industries. Barley isan erect annual grass, producing grain inbristly-bearded terminal spikes.

Environment

About half of the total US production is usedfor malting, but because of Barley's mildflavour and soft texture, the grain is oftenfound in soups and baby foods. Malt is usedin making several kinds of alcoholicbeverages, most prominently beer andwhiskey. Other products are flour, flakes andbran. Scotch and Hulled barley are typeswith only the outer husk removed. Pearlbarley is rounded and polished after the huskis removed. Barley flour is ground from Pearlbarley and must be combined with a Gluten-containing flour for use in yeast breads.When combined with water and lemon,Pearl barley is used to make Barley water,an old-fashioned restorative for invalids.Barley is a good source of B vitamins andsome minerals.

Allergens

A number of allergens have been isolatedfrom Barley. In 132 Pig farm-workers, 43showed IgE reactivity to 15 components ofBarley with molecular masses ranging from14 kDa to 148 kDa. The major allergenappeared to be a 37 kDa protein and wasfound in 32 (74.4%) of the 43 immunoblot-positive serum samples. Components ofabout 55 and 67 kDa reacted with 26(60.5%) and 18 (41.9%) of the positiveserum samples, respectively (1). Theseproteins may be similar to those in a studyreporting that Barley flour proteins of 69,52 and 10 kDa had been identified in serumfrom Wheat-hypersensitive individuals andappeared to be major allergens (2).

A number of allergens have beencharacterised:

Hor v 15, a 16 kDa protein, previouslyknown as Hor v 1, an alpha-amylase/trypsininhibitor (3-12).

Hor v 16, an alpha-amylase (3,13)

Hor v 17, a beta-amylase (3).

Hor v 21, also known as hordein (3,14-15).

Hor v LTP, a 10 kDa protein, a lipid transferprotein (7,9,14,16).

Hor v Z4, a 45 kDa protein (9,14).

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f6 BarleyThe allergens Hor v 1, Hor v 2, Hor v 4,

Hor v 5, Hor v 9 (now known as Hor v 5),Hor v 12 and Hor v 13 have been isolatedand characterised from Barley pollen.

Barley seed proteins that could beinvolved in the foaming properties of beerwere investigated. From Barley to Malt andto beer, most of the heat-stable proteins werereported to be disulfide-rich defenceproteins, e.g., serpin-like chymotrypsininhibitors (protein Z), amylase and amylase-protease inhibitors, and lipid transferproteins (14). The main residual allergensin beer that may result in allergic reactionsare the residual lipid transfer protein allergenor Hor v Z4 from Barley (7,9). In individualswho experienced urticaria from beer,analysis of their sera demonstrated that IgEbound only a 10 kDa protein (found also inMalt). In sera of the control patient group,individuals with baker's asthma from Barleyflour, a 16 kDa allergen was implicated.Because of the severity of the allergicmanifestations to beer, the researchersrecommend testing for sensitivity to thisbeverage those atopic patients who arepositive to Malt/Barley and/or who exhibiturticarial reactions after drinking beer (7).

In the case of a 21-year-old atopic womanwho developed urticaria, angioedema of theface, a wheeze and dyspnoea shortly afterdrinking beer and after eating a Maize snack,immunoblotting demonstrated several IgE-binding bands at 31-56 kDa in Malt andBarley extracts, and a major band at 38 kDain the beer extract (17).

Furthermore, Gluten from Barley can bepresent in beer, as a result of the addition ofMalt. However, a study demonstrated thatGluten levels decreased due to precipitationduring the mashing process, during primaryand secondary fermentation and, lastly, as aresult of adsorption during beer stabilisation.The Gluten content in beer wasapproximately 3 orders of magnitude lowerthan in the raw Malt (18).

In baker's asthma, where Barley isimplicated, Hor v 15, an alpha-Amylase/Trypsin inhibitor has been shown to be amajor allergen (6,8,12).

The major Wheat allergen associated withexercise-induced anaphylaxis is an omega-5gliadin. Gamma-70 and gamma-35 secalinsin Rye and gamma-3 hordein, or Hor v 21,in Barley have been shown to cross-react withomega-5 gliadin, suggesting that Rye andBarley may also elicit symptoms in patientswith Wheat-dependent, exercise-inducedanaphylaxis (15).

Barley lipid transfer protein (LTP1) is aheat-stable and protease-resistant albuminthat concentrates in beer, where itparticipates in the formation and stabilityof beer foam. Whereas Barley LTP1 does notdisplay any foaming properties, thecorresponding beer protein is surface-activeas a result of glycation by Maillard reactionson malting, acylation on mashing, andstructural unfolding on brewing (19). BarleyLTP (and protein Z(4)) have been identifiedas the main beer allergens (9).


An extensive cross-reactivity among thedifferent individual species of the genuscould be expected (20). Cross-reactivity withother species within the Poaceae family canbe expected, as well as with other specieswithin the genus Triticum.

RAST inhibition tests have demonstratedcross-antigenicity among different cerealgrains. The degree of cross-reactivity closelyparalleled their taxonomic relationship andappeared to be in the following order ofdecreasing closeness: Wheat, Triticale, Rye,Barley, Oat, Rice and Maize (21). Otherstudies have demonstrated cross-allergenicity between Rye and Barley, andamong Wheat, Rye and Barley. The majorallergen was thought to be Gluten, although16 similar protein bands were detected thatwere common to all 3 (22-23). Similarly, inpatients sensitised to Wheat and Rye flour,IgE antibody investigation indicated thatthere is significant cross-reaction with seedextracts of Wheat, Durum wheat, Triticale,Rye, Barley, Rye grass, Oats, Canary grass,Rice, Maize, Sorghum and Johnson grass,compared with non-related plants. Inparticular, significant cross-reactivity wasshown among grain extracts of Wheat, Rye,Barley and Oats. Results of this study

17

f6 Barleysuggested that the bran layers of cerealgrains are at least as allergenic as the flour(24). The clinical relevance of this isdemonstrated in a study of 5 patients withcereal-dependent exercise-induced ana-phylaxis and IgE antibodies to Wheat, Rye,Barley and Oats. Wheat gliadin and thecorresponding ethanol-soluble proteins oftaxonomically closely related cereals werefound to be the causative allergens (25).However, in a study examining the IgEspecificity of Wheat, Barley and Rye proteinsthrough the use of 2 sera as representativeof patients with either Wheat-dependentexercise-induced anaphylaxis (WDEIA) orhypersensitivity to hydrolysed Wheatproteins (HHWP), IgE from a patient withboth contact urticaria and food allergy toGluten hydrolysates cross-reacted withgamma 3-hordein. The pattern of reactivitywith Wheat, Barley and Rye proteinsdiffered from that of a WDEIA patient testedunder the same conditions (26).

Furthermore, although pollen from thesecereals contains unique and specificallergens, the existence of cross-reactivitybetween Barley and Wheat flour, andbetween Rye and Wheat flour, as well asamong the pollens of cereals and cerealflours, has been suggested (27).

Cross-reactivity among plants containinglipid transfer protein (LTP) is possible butwould depend on the specific plants. Forexample, the lipid transfer protein fromMaize was shown to completely cross-reactwith Rice and Peach lipid transfer proteinsbut not with Wheat or Barley lipid transferproteins (17). Rice nonspecific lipid transferprotein closely resembles nonspecific LTPsof Wheat, Barley and Maize, exhibiting anearly identical pattern of the numeroussequence-specific interactions (28).

A number of Wheat and Barley flourproteins that belong to the cereal alpha-amylase/trypsin inhibitor family have beenidentified as major allergens associated withbaker's asthma. There is complete cross-reactivity among grass, Wheat, Barley, andRice trypsin inhibitors (13,17,29). However,different allergenic behaviours have beenreported to occur among such homologousallergens from Rye, Barley, and Wheat (30).

Cereal alpha- and beta-amylase appearto be important allergens in patients withallergy to flour. RAST inhibition studies haveshown minimal cross-reactivity betweenBarley alpha- or beta-amylase and Barleyand fungal alpha-amylase. An associationwas demonstrated between IgE antibodiesto Wheat flour and to Barley alpha-amylaseand Barley beta-amylase, but a poorassociation with fungal alpha-amylase (31).

Gamma-70 and gamma-35 secalins inRye, and gamma-3 hordein (probablyrepresenting Hor v 21) in Barley, have beenshown to cross-react with omega-5 gliadin,a major allergen in Wheat-dependent,exercise-induced anaphylaxis (WDEIA).These findings suggest that Rye and Barleymay also elicit symptoms in patients withWheat-dependent, exercise-induced ana-phylaxis (15). Due to this cross-reactivity,treatment with a Gluten-free diet, i.e., a dietexcluding Wheat, Rye, and Barley, isindicated for all patients with WDEIA (32).

Prolamines extracted from Wheat(gliadin), Rye (secalin), Barley (hordein) andOats (avenin) were used to raise antibodiesin rabbits. The close botanical relationshipbetween Wheat and Rye, and, to a lesserextent, between these and Barley, is clearlyestablished. The cross-reactivity of gliadin,secalin and hordein with anti-avenin serumwas found to be weak. In contrast, aveninshows a strong cross-reactivity with anti-gliadin serum (33).

A degree of homology among amylase/protease inhibitors, acyl-CoA oxidase andfructose-bisphosphate-aldolase from Wheat,Barley, Maize, and Rice has been reportedbut requires further elucidation (34).

Clinical Experience


Barley may commonly induce symptoms offood allergy in sensitised individuals. (1)Symptoms may include gastrointestinaldistress, atopic dermatitis and urticaria,angioedema, anaphylaxis and food-dependant, exercise-induced anaphylaxis,wheezing and baker's asthma. Cough,wheezing, shortness of breath, fever, stuffy

18

f6 Barleynose, and skin itching/rash on exposure tograin dust have also been reported, as wellas “grain fever” (35).

In a study of cereal allergy and atopicdermatitis, on oral provocation, 18 childrenexhibited a positive response to Wheat, 3 toRye, 1 to Barley, and 1 to Oats. Symptomswere dermatologic, gastrointestinal, ororopharyngeal, and their onset afterprovocation was immediate in 8, delayed in14, and both immediate and delayed in 1. Acombination of SPT, IgE antibodydetermination and histamine-release testsdetected all those with immediate reactionsand 9/14 with delayed reactions. Of 5subjects negative to these tests, 3 werepositive on patch or lymphocyteproliferation tests (36).

In a study evaluating the allergicreactivity to ingested and inhaled cerealallergens at different ages among 66 patients,40 children aged 3 to 6 months experienceddiarrhoea, vomiting, eczema or weight lossafter the introduction of cereal formula intotheir diet. Coeliac disease was excluded inall. The most important allergen was Wheat,followed by Barley and Rye. Among adultswith cereal allergy, sensitisation to otherallergens was common, especially to Loliumperenne (Rye grass) pollen (37).

Anaphylaxis following the ingestion ofBarley may occur. These reactions may beto residual Barley proteins in beer. In 2 casesof severe systemic reactions due to beeringestion, 1 required emergency care, andthe other presented with generalisedurticaria and angioedema (38). A 21-year-old woman is described who developedurticaria, angioedema of the face, a wheezeand dyspnoea shortly after drinking beer andafter eating a Maize snack. She was shownon immunoblotting studies of her serum tohave antibodies to allergens in Malt andBarley extracts present in the beer. Theauthors concluded that the patient haddeveloped type I hypersensitivity to Barley,Malt and Maize (18).

Food-dependent exercise-induced ana-phylaxis may result from ingestion of Barley(15,39). In 5 patients with cereal-dependentexercise-induced anaphylaxis and IgEantibodies to Wheat, Rye, Barley and Oats,

Wheat gliadin and the correspondingethanol-soluble proteins of taxonomicallyclosely related cereals were found to be thecausative allergens (26). Thus, Rye andBarley may elicit these symptoms in patientswith Wheat-dependent, exercise-inducedanaphylaxis, and vice versa (15). Due to thiscross-reactivity, treatment with a Gluten-freediet, i.e., a diet excluding Wheat, Rye, andBarley, is indicated for all patients withWDEIA. In an evaluation of sera of 2patients with either Wheat-dependentexercise-induced anaphylaxis (WDEIA) orhyper-sensitivity to hydrolysed wheatproteins, in the latter patient, whoexperienced both contact urticaria and foodallergy to Gluten hydrolysates, IgE wasshown to also cross-react with gamma 3-hordein (Hor v 21) (27).

Barley may also result in occupationalallergy in bakery and other food industryworkers, liqueur and spirit manufacturers,and farmers. Barley may commonly resultin baker's asthma (28). Barley alpha-amylase/trypsin inhibitors have beenidentified as major allergens associated withbaker's asthma (30). Asthma related toexposure to cereal flour contained in animalformula feeds has been reported (40).Similarly, flour made from Barley resultedin IgE-mediated occupational respiratorysymptoms in Pig farm workers in southernTaiwan (1).

Occupational asthma paired with asthmafollowing oral ingestion of Barley flour andbeer made from Barley has also beenreported. A 50-year-old man developedasthma both after exposure to feeding stuffsand flours and after ingestion of beveragesmade of cereal flour. Allergy to Barley flour(and Maize flour and mites) wasdemonstrated by skin reactivity and allergen-specific IgE. A bronchial challenge test withBarley flour resulted in an immediatepositive response (41).

Cereal flours are used in the woodindustry to improve the quality of the gluesnecessary to produce veneer panels in woodmanufacturing. Three workers were foundto be allergic to cereal alpha-amylaseinhibitors, proteins cross-reactive proteinsfound in Rye, Barley and Wheat (4).

19

f6 BarleyOccupational asthma may also occur to

Barley grain dust. A report was made of a32-year-old storeman who dealt with thepackaging of Wheat flour, Barley andPeanuts. He developed immediate symptomsof sneezing, cough and dyspnoea onexposure to Barley (42).

Alpha-amylase allergens have beenidentified as a major allergen in baker'sasthma (12).

Other reactions

Barley may result in or exacerbate atopicdermatitis (24) or contact dermatitis (43).

Barley may also cause coeliac disease, anautoimmune disease resulting in a food-induced enteropathy, which occurs followingexposure to prolamins (Gluten) in Wheat,Rye, and Barley (44-45).

Infantile food protein-inducedenterocolitis syndrome (FPIES) is a severe,cell-mediated gastrointestinal foodhypersensitivity typically provoked byCow's milk or Soy but sometimes by otherfoods, including Barley. Symptoms of typicalFPIES are delayed (median: 2 hours) andinclude vomiting, diarrhoea, lethargy anddehydration. Initial presentation is severe in79% of patients, prompting evaluation forsepsis and hospitalisation for dehydrationor shock. FPIES appears not to occur tomaternally ingested foods throughbreastfeeding, but does occur if the offendingfood is fed directly to the infant (46).

The ingestion, by a largely illiteratepopulation in Iraq, of Wheat and Barley seedtreated with an alkyl mercury fungicide forsowing led to a major outbreak of poisoningwith a high fatality rate (47).

Six cases of acute exogenous allergicalveolitis after loading mouldy Barley havebeen reported (48).

Malt, a product of Barley, may result inimmediate-type reactions. (See Malt f90.)Malt extract is made from germinating Barley.In a patient allergic to Malt, the allergicreactions usually occurred after consumptionof Malt-containing chocolate drinks andMalt-containing snack products (18,49).

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8. Mena M, Sanchez-Monge R, Gomez L,Salcedo G, Carbonero P. A major barleyallergen associated with baker's asthmadisease is a glycosylated monomeric inhibitorof insect alpha-amylase: cDNA cloning andchromosomal location of the gene.Plant Mol Biol 1992;20(3):451-8

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21. Block G, Tse KS, Kijek K, Chan H, Chan-Yeung M. Baker's asthma. Studies of thecross-antigenicity between different cerealgrains. Clin Allergy 1984;14(2):177-85

22. Guenard-Bilbault L, Kanny G, Moneret-Vautrin D. Food allergy to wheat flour inadults. [French] Allerg Immunol (Paris)1999;31(1):22-5

23. Varjonen E, Savolainen J, Mattila L, Kalimo K.IgE-binding components of wheat, rye, barleyand oats recognized by immunoblottinganalysis with sera from adult atopicdermatitis patients.Clin Exp Allergy 1994;24(5):481-9

24. Baldo BA, Krilis S, Wrigley CW.Hypersensitivity to inhaled flour allergens.Comparison between cereals.Allergy 1980;35(1):45-56

25. Varjonen E, Vainio E, Kalimo K. Life-threatening, recurrent anaphylaxis caused byallergy to gliadin and exercise.Clin Exp Allergy 1997;27(2):162-6

26. Snégaroff J, Bouchez-Mahiout I, Pecquet C,Branlard G, Laurière M. Study of IgEantigenic relationships in hypersensitivity tohydrolyzed wheat proteins and wheat-dependent exercise-induced anaphylaxis. IntArch Allergy Immunol 2006;139(3):201-8

27. Valero Santiago A, Amat Par P, Sanosa Valls J,Sierra Martinez P, Malet Casajuana A, GarciaCalderon PA. Hypersensitivity to wheat flourin bakers. Allergol Immunopathol (Madr)1988;16(5):309-14

28. Poznanski J, Sodano P, Suh SW, Lee JY, Ptak M,Vovelle F. Solution structure of a lipidtransfer protein extracted from rice seeds.Comparison with homologous proteins.Eur J Biochem 1999 Feb;259(3):692-708

29. Nakamura R, Matsuda T. Rice allergenicprotein and molecular-genetic approach forhypoallergenic rice. [Review] Biosci BiotechBiochem 1996;60(8):1215-21

30. Garcia-Casado G, Armentia A, Sanchez-Monge R, Malpica JM, Salcedo G. Rye flourallergens associated with baker's asthma.Correlation between in vivo and in vitroactivities and comparison with their wheatand barley homologues.Clin Exp Allergy 1996;26(4):428-35

31. Sandiford CP, Tee RD, Taylor AJ. The role ofcereal and fungal amylases in cereal flourhypersensitivity.Clin Exp Allergy 1994;24(6):549-57

32. Palosuo K, Alenius H, Varjonen E, Kalkkinen N,Reunala T. Rye gamma-secalin and barleygamma-hordein are cross-reactive allergensin wheat-dependent, exercise-inducedanaphylaxis.AAAAI 56th Annual Meeting 2000,ch

33. van Twist-de Graaf MJ, Wieser H, Hekkens WT.Immunocrossreactivity of antisera againstgrain prolamines of wheat, rye, barley andoats. Z Lebensm Unters Forsch1989;188(6):535-9

34. Weiss W, Huber G, Engel KH, Pethran A,Dunn MJ, Gooley AA, Gorg A. Identificationand characterization of wheat grain albumin/globulin allergens.Electrophoresis 1997;18(5):826-33

35. Manfreda J, Holford-Strevens V, Cheang M,Warren CP. Acute symptoms followingexposure to grain dust in farming.Environ Health Perspect 1986;66:73-80

36. Rasanen L, Lehto M, Turjanmaa K,Savolainen J, Reunala T. Allergy to ingestedcereals in atopic children.Allergy 1994;49(10):871-6

37. Armentia A, Rodriguez R, Callejo A, Martin-Esteban M, Martin-Santos JM, Salcedo G,Pascual C, Sanchez-Monge R, Pardo M.Allergy after ingestion or inhalation of cerealsinvolves similar allergens in different ages.Clin Exp Allergy 2002;32(8):1216-22

21

38. Bonadonna P, Crivellaro M, Dama A, Senna GE,Mistrello G, Passalacqua G. Beer-inducedanaphylaxis due to barley sensitization: twocase reports. J Investig Allergol Clin Immunol1999;9(4):268-70

39. Mathelier-Fusade P, Vermeulen C, Leynadier F.Responsibility of food in exercise-inducedanaphylaxis: 7 cases. [French] Ann DermatolVenereol 2002;129(5 Pt 1):694-7

40. Valdivieso R, Pola J, Zapata C, Puyana J,Cuesta J, Martin C, Losada E. Farm animalfeeders: another group affected by cerealflour asthma. Allergy 1988;43(6):406-10

41. Vidal C, Gonzalez-Quintela A. Food-inducedand occupational asthma due to barley flour.Ann Allergy Asthma Immunol1995;75(2):121-4

42. Yap JC, Chan CC, Wang YT, Poh SC, Lee HS,Tan KT. A case of occupational asthma due tobarley grain dust.Ann Acad Med Singapore 1994;23(5):734-6

43. Pereira F, Rafael M, Lacerda MH. Contactdermatitis from barley.Contact Dermatitis 1998;39(5):261-2

44. Kitts D, Yuan Y, Joneja J, Scott F, Szilagyi A,Amiot J, Zarkadas M. Adverse reactions tofood constituents: allergy, intolerance, andautoimmunity. Can J Physiol Pharmacol1997;75(4):241-54

45. Ansaldi N, Tavassoli K, Forni M, Lerro P, Poli E.Up-date on the etiopathogenesis of celiacdisease. [Italian] Pediatr Med Chir1988;10(1):7-11

46. Nowak-Wegrzyn A, Sampson HA, Wood RA,Sicherer SH. Food protein-inducedenterocolitis syndrome caused by solid foodproteins.Pediatrics 2003;111(4 Pt 1):829-35

47. Kazantzis G. Mercury exposure and earlyeffects: an overview.Med Lav 2002;93(3):139-47

48. Gatzemeier U. Acute exogenous allergicalveolitis--6 cases after loading mouldybarley. [German] Prax Klin Pneumol1981;35(9):400-2

49. Wuthrich B. Acute recurring Quincke edemain allergy to malt extract. [German] SchweizMed Wochenschr 1984;114(8):269-71

f6 Barley

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Lathyrus sativusFamily: Fabaceae (Leguminosae)Commonnames: Blue vetch, Grasspea,

Chickling pea,Chickling vetch

Sourcematerial: Dried seedsFor continuous updates:www.immunocapinvitrosight.com

f310 Blue vetch

Allergen Exposure


Blue vetch is found in Eurasia, NorthAmerica, temperate South America and EastAfrica. But the geographical origin ofLathyrus sativus is unknown.

Blue vetch is a many-branched stragglingor climbing herbaceous winter annual withstems up to 90 cm tall. It produces a drought-resistant, high-yielding, nitrogen-rich pulsewith high-quality protein and carbohydrate.The seeds are used for food (which may bean exclusive food during times of droughtor famine) and livestock feed, and the plantas green manure and a cold-weather foragecrop, and for erosion control.

Environment

Lathyrus sativus is a high-yielding, drought-resistant legume consumed as a food innorthern India and neighbouring countries,as well as in Ethiopia. Its development intoan important food legume, however, hasbeen hindered by the presence of theneurotoxin beta-N-oxalyl-L-alpha,beta-diaminopropionic acid (beta-ODAP), which,if consumed in large quantities for prolongedperiods, can cause irreversible paralysis (1).The flour is used in cattle feeding andindustrial processing in some countries (2).

The plant is found in cultivated beds oras a relict of cultivation; no truly wild standsexist. The immature seed can be eaten likeGreen peas. The mature seed is eaten roastedor boiled, after soaking or parching, and theyoung shoots can also be cooked. The seedis often used in making dhal, paste balls forcurry, or beverages. It can also be groundinto a powder and mixed with Wheat tomake protein-enhanced bread. The seeds areused locally in homeopathic medicine.

Unexpected exposure

See under Environment. Blue vetch as a driedlegume is used in some regions of Spain inthe form of flour for cooking and has beenresponsible for some cases of allergicreactions through food intake or contact (3).

Allergens

No allergens from this plant have yet beencharacterised.

More than 60% of the seed comprisesglobulin proteins, and 30% albumins. Asingle 24 kDa polypeptide comprises morethan half of the protein present in thealbumin fraction. The globulins may befractionated into 3 main components, whichare named alpha-lathyrin (the majorglobulin), beta-lathyrin, and gamma-lathyrin (4).

Blue vetch flour shows a complexallergenicity. Most allergens are said to bethermostable (3), but researchers in otherstudies suggest that some or all allergens inBlue vetch may be heat-labile, resulting inBlue vetch-allergic individuals being able toingest cooked Blue vetch products (13).

23

f310 Blue vetchIn a study of sera from 38 Spanish legume-

sensitised patients, 77% were shown to haveskin reactivity to Blue vetch flour; 4 of whomhad developed clinical symptoms to Bluevetch, and 2 of whom, in addition, to otherlegumes. No protein bands were identifiedby IgE antibodies to extracts boiled for 15minutes, whereas 20 protein bands wereidentified to raw Blue vetch extracts. SerumIgE bound most frequently to protein bandsof 50.9 and 27.7 kDa. Only 2 allergens ofmolecular weights 27.7 and 12.9 kDa wereidentified by sera from the subjects who weresensitive only to Blue vetch (3). Other studieshave indicated the presence of allergens of46, 32 and 28 kDa (2).

A 24 kDa protein was purified from theseeds of Lathyrus sativus. The N-terminalamino-acid sequence showed significanthomology with the 2S albumin class of seedstorage proteins. The protein showed 85%sequence homology with the seed albuminof Pisum sativum (5). However, itsallergenicity was not evaluated.


An extensive cross-reactivity among thedifferent individual species of the genuscould be expected but in fact is not seenfrequently (6). In an in vitro study, thespecific IgE binding by protein extracts of11 food legumes was examined by IgEantibody determination and RAST inhibition.Cross-allergenicity was demonstrated to bemost marked among the extracts of Peanut,Garden pea, Chick pea, and Soybean (7-8). However, clinical studies have foundthat there is little cross-reactivity amongmembers of the Fabaceae (Leguminosae)(9-11).

Cross-reactivity and/or co-sensitivityhave been reported among Blue vetch, Chickpea, and Lentil (12).

Clinical Experience


Blue vetch may uncommonly inducesymptoms of food allergy and occupationalallergy in sensitised individuals.

Sera from 38 Spanish legume-sensitisedpatients were used to assess the allergeniccomposition of Blue vetch. Seventy-sevenpercent of patients showed a positive skintest to Blue vetch flour; 4 of these patientshad developed clinical symptoms in relationto Blue vetch, and 2 of them, in addition, toother legumes (3).

A study reports on a 10-year-old childwith asthmatic attacks related to Lathyrussativus flour inhalation. This child had ahistory of perennial rhinitis, and bronchialasthma was reported. In the previous year,shortly after exposure to Blue vetch flour inthe family store, he had experiencedsneezing, rhinorrhoea, wheezing anddyspnoea attacks. Avoiding exposureresulted in a marked reduction of symptoms,and he became asymptomatic. He toleratedthe ingestion of foodstuffs prepared fromthis legume, as well as exposure to othertypes of flours. Skin test with the raw extractwas positive, and negative for the heatedextract. Specific bronchial provocationchallenge was markedly and immediatelypositive. IgE antibodies to Lathyrus sativusflour were demonstrated by indirect enzymeimmunoassay. The authors suggest that theloss of allergenic sensitivity observed in thecutaneous test with heated Blue vetch mayindicate the reason this patient was able toingest cooked foodstuffs prepared with thisflour without reacting (13).

Two young women experiencedsymptoms after eating Blue vetch. Theyreported previous hypersensitivity to otherlegumes (14).

Generalised urticaria and facial oedemain a 5-year-old, occurring a few minutes afteringestion, have been reported (15).

24

Occupational asthma has been reportedfollowing exposure to flour made from Bluevetch. This flour is used in the industrialprocessing of parquet (wood flooring). A 55years old man is described, who reported aone year long history of rhinorrhoea,paroxysmal sneezing, eyes and nasalpruritus, and wheezing dyspnea withcoughing and chest tightness, symptomswhich were related to his working with Bluevetch flour. Symptoms abated duringholidays and weekends. He had worked indirect contact with Blue vetch flour for 15years, which involved the production of asealant for wooden floor panels. He hadnever eaten Blue vetch and did notexperience adverse effects ingesting otherlegumes. Skin prick test with the extractshowed a positive immediate response. IgEantibody level to grass pea was 9.57 kUA/l.Specific bronchial challenge test elicited animmediate response, both clinically (rhinitis,cough, dyspnoea, chest tightness) and witha 20% decrease in FEV1 at 5 minutes (2).

A 42-year-old man was described whohad worked as a carpenter for 6 years andwho reported a history of rhinorrhoea,paroxysmal sneezing, nasocular pruritus,lacrimation, wheezing and dyspnoea attackswhile preparing a mixture to seal thejunctures between wooden panels. Skin pricktests with Blue vetch and Lentil extracts werepositive. IgE antibody level to Blue vetch was0.62 kUA/l. Histamine release tests werepositive. Bronchial challenge with Blue vetchwas positive within 5 minutes, with adecrease in FEV1 of 20%. He also developedrhinoconjunctivis. The authors point outthat in cases of occupational asthma to Bluevetch flour, patients tolerate the cooked food(16). As suggest by other authors as well,some or all allergens in Blue vetch are heat-labile, resulting in Blue vetch-allergicindividuals being able to ingest cooked Bluevetch products (13).

Occupational asthma to a close relative,Sweet pea (Lathyrus odoratus), has also beendescribed (17).

Other reactions

Neurolathyrism is a neurological conditionseen among people who eat the seeds ofLathyrus sativus as a principal source offood energy for 2 months or more. It ischaracterised by severe muscular rigidity andirreversible spastic paralysis of the lowerlimbs, spinal hyperreflexia, and structuralchanges of the skeleton and connective tissue(18-19). Once prevalent throughout Europe,N. Africa, the Middle East and parts of theFar East, the disease is presently restrictedto India, Bangladesh and Ethiopia (20). Thebiochemical mechanism involves beta-N-Oxalyl amino-L-alanine (L-BOAA); asynonym is beta-N-oxalyl-alpha,beta-diaminopropionic acid (beta-ODAP). Thisis a naturally occurring non-protein aminoacid present in Blue vetch. Ingestion of L-BOAA in a staple diet results in a progressiveneurodegenerative condition, a form ofmotor neuron disease that affects the uppermotor neurons and anterior horn cells of thelumbar spinal cord. L-BOAA is an excitatoryacid and acts as an agonist at the AMPAreceptor (21-22).

The oil from the seeds is a powerful anddangerous cathartic that contains apoisonous principle, probably an acid saltof phytic acid.

f310 Blue vetch

25

References1. Yan ZY, Spencer PS, Li ZX, Liang YM, Wang YF,

Wang CY, Li FM. Lathyrus sativus (grass pea)and its neurotoxin ODAP.Phytochemistry 2006 Jan;67(2):107-21

2. Porcel S, Leon F, Martin Calderin P, Valero A,Botello A, Alvarez Cuesta E. Occupationalasthma caused by grass pea used in theindustrial processing of parquet. AllergolImmunopathol (Madr) 2001;29(5):207-11

3. Martinez San Ireneo M, Ibanez Sandin MD,Elices Apellaniz A, Maranon Lizana F,Fernandez Caldas E, Laso Borrego MT.Allergenicity of vetchling (Lathyrus sativus).Rev Esp Alergol Inmunol Clin1998;13(5):282-6

4. Rosa MJ, Ferreira RB, Teixeira AR. Storageproteins from Lathyrus sativus seeds.J Agric Food Chem 2000;48(11):5432-9

5. Qureshi IA, Sethi DK, Salunke DMPurification, identification and preliminarycrystallographic studies of an allergenicprotein from Lathyrus sativus.Acta Crystallograph Sect F Struct Biol CrystCommun 2006; 62(0):869-72


7. Barnett D, Bonham B, Howden ME.Allergenic cross-reactions among legumefoods – an in vitro study.J Allergy Clin Immunol 1987;79(3):433-8

8. Bardare M, Magnolfi C, Zani G.Soy sensitivity: personal observation on 71children with food intolerance.Allerg Immunol (Paris) 1988;20(2):63-6

9. Bernhisel Broadbent J, Sampson HA. Cross-allergenicity in the legume botanical familyin children with food hypersensitivity.J Allergy Clin Immunol 1989;83:435-40

10. Bernhisel-Broadbent J, Taylor S, Sampson HA.Cross-allergenicity in the legume botanicalfamily in children with food hypersensitivity.II. Laboratory correlates. J Allergy ClinImmunol 1989;84(5 Pt 1):701-9

11. Eigenmann PA, Burks AW, Bannon GA,Sampson HA. Identification of unique peanutand soy allergens in sera adsorbed withcross-reacting antibodies. J Allergy ClinImmunol 1996;98(5 Pt 1):969-78

12. Huertas AJ, Iriarte P, Polo P, Ayuso R.Urticaria during prick by prick skin test withlegumes. [Abstract] Allergy 1995;50S:230

13. Valdivieso R, Quirce S, Sainz T. Bronchialasthma caused by Lathyrus sativus flour.Allergy 1988;43(7):536-9

14. Sainza T, Zapatero L, Martinez MI, Lozano M,Zubeldia JM, Baera ML. Hypersensitivity toLathyrus sativus. [Abstract] Allergy1995;50S:230

15. Ortiz GG, Conde-Salazar L, Guimaraens D, dela Hoz C, Agustin MC. Occupational proteincontact dermatitis from fruits.Contact Dermatitis 2000;43:43

16. Anton GM, de la Hoz CB, Munoz MT,Cuevas AM, Sanchez-Cano M. Occupationalrhinoconjunctivitis and asthma by exposureto Lathyrus sativus flour.Allergol Immunopathol (Madr ) 2005Nov;33(6):6-328

17. Jansen A, Vermeulen A, van Toorenenbergen AW,Dieges PH. Occupational asthma inhorticulture caused by Lathyrus odoratus.Allergy Proc 1995;16(3):135-9

18. Jahan K, Ahmad K.Studies on neurolathyrism.Environ Res 1993;60(2):259-66

19. Carod-Artal FJ. Neurological syndromeslinked with the intake of plants and fungicontaining a toxic component (I). Neurotoxicsyndromes caused by the ingestion of plants,seeds and fruits. [Spanish] Rev Neurol 2003May 1-15;36(9):860-71

20. Getahun H, Mekonnen A, TekleHaimanot R,Lambein F. Epidemic of neurolathyrism inEthiopia.Lancet 1999 Jul 24;354(9175):306-7

21. Ravindranath V. Neurolathyrism:mitochondrial dysfunction in excitotoxicitymediated by L-beta-oxalyl aminoalanine.Neurochem Int 2002;40(6):505-9

22. Spencer PS. Food toxins, ampa receptors,and motor neuron diseases.Drug Metab Rev 1999;31(3):561-87

f310 Blue vetch

26

Bertholletia excelsaFamily: LecythidaceaeCommonnames: Brazil nut, Para-nut,

Cream nutSourcematerial: Shelled nutsFor continuous updates:www.immunocapinvitrosight.com

f18 Brazil nut

Allergen Exposure


The Brazil nut is actually the seed of a gianttree that grows wild in South America'sAmazon jungle. The seeds, about 6 cm long,come in clusters of 8 to 25 inside a large,hard, thick-walled globular pod thatresembles a Coconut and weighs up to 2 kg.The extremely hard shell of each seed isdark-brown and 3-sided. The kernel is whiteand high in oil, containing about 70% oiland 17% protein. When fresh it is highlyesteemed for its rich flavour, but it becomesrancid in a short time from the great quantityof oil it contains. Except for its close relativethe Paradise nut, it is not closely related toany other food.

Brazil nut exportation from the Amazonwas begun in the 1600s by Dutch andPortuguese traders. The monetary value ofthe nuts (nearly all from wild trees) is secondonly to that of rubber.

Environment

In the Amazon, indigenous tribes eat the nutsraw, or grate them and mix them into gruels,often along with Manioc flour. The plentifuloil is used in cooking. Exported, the nutsare a snack food, and their oil is prized. Inaddition to protein and fat, Brazil nuts are asubstantial source of selenium, an important

antioxidant. The proteins, though makingup only 15-17% of the nuts' fresh weight,comprise 50% of the defatted flour. Storageproteins are the most important ones, andthe 12S globulin legumin-like protein andthe 2S albumin have been identified as themost representative. The 2S protein is highin sulfur-rich amino acid (3-8% cysteine and18% methionine) (1). The proteins are alsoextremely rich in glutamine, glutamic acid,and arginine.

The tree bark is brewed into tea to treatliver ailments. The husks of the seed podshave also been brewed to treat stomachaches.

Unexpected exposure

Brazil nut may be a “hidden” allergen incookies, etc. The oil extracted from the nutsis commonly used in Peru and other SouthAmerican countries to manufacture soap,and for lighting, and the empty pods are usedas implements and burned to repel insects.Worldwide, Brazil nut oil is often used insoaps, shampoos, hair conditioning/repairproducts, and skin moisturisers, and extractsof the pods can figure in insect repellents.

Allergens

A number of allergenic proteins has beenisolated from Brazil nut. These range in sizefrom 4 kDa to 58 kDa. In a study of a groupof patients with IgE antibodies to Brazil nut,comprising 11 patients with anaphylaxis toeating Brazil nuts and 10 asymptomaticsubjects, sera from all the symptomaticpatients recognised a 9 kDa allergencorresponding to 2S albumin of Brazil nut,whereas the other allergens each bound IgEantibodies from less than 50% of sera. No

27

f18 Brazil nutIgE binding to the 9 kDa allergen occurredin sera from asymptomatic subjects, butallergenic proteins of 25 to 58 kDa wererecognised and were identified as minorallergens (5). Other minor allergens havebeen detected: of 18, 25, 33, and 45 kDa(2), including a 12S globulin protein, whichis a legumin-like storage globulin (1).

The allergens characterised to date are:

Ber e 1, a 9 kDa protein, a 2S albumin,resistant to digestion by pepsin, and a majorallergen (3-14).

Ber e 2, an 11S globulin-like protein(10,13,15).

The main immunoglobulin E epitoperegion of the 2S albumin, Ber e 1, is verystable to gastric digestion (3,8,16).

The Brazil nut 2S albumin has beenrecognised as a methionine-rich protein thatcould be used to increase the nutritionalvalue of certain foods through geneticengineering techniques. However, the 2Salbumin of the Brazil nut is also the majorallergen of Brazil nuts (Ber e 1) and showsIgE-reactivity with more than 80% of thesera from Brazil nut-allergic subjects. Thiswas demonstrated in transgenic Soybean: thenewly expressed protein retained itsallergenicity (17-18).


An extensive cross-reactivity within thefamily can be expected (19).

Brazil nut contains a 2S albumin storageprotein, a protein common to many seeds,which displays similarity to the 2S albuminof Cotton, Cocoa bean, Sunflower seed, Rapeseed, Castor bean, English walnut (Jug r 1),Mustard seed (Sin a 1) and Sesame seed(Ses i 2). Comparison of the amino acidsequence shows high sequence similarity,from 34% between Sunflower seed andBrazil nut, to >52% similarity and >38%identity between Brazil nut and many otherplant 2S albumins (20-24). The Englishwalnut allergen (Jug r 1) exhibits a 46.1%identity with the Brazil nut 2S albumin seedstorage protein, Ber e 1 (24-25).

The 2S albumins have been shown to playa significant role in cross-reactivity betweenWalnut Jug r 1 and Pecan nut Car i 1, as aresult of the high degree of structuralhomology of the 2S albumins in these 2 treenuts. However, a study of the con-formational analysis of the linear IgE-binding epitopes mapped on the molecularsurface of Ara h 2, a 2S albumin, showedno structural homology with thecorresponding region of Brazil nut Ber e 1;this indicates that allergenic cross-reactivityobserved between Peanut and Brazil nut maydepend on other ubiquitous seed storageprotein allergens, e.g., the vicilins (26).

However, a recent study evaluatingcloned Peanut Ara h 2 reported that whenserum from Peanut-allergic patients is pre-incubated with increasing concentrations ofAlmond or Brazil nut extract, IgE bindingto rAra h 2 is inhibited. Purified rAra h 2-specific serum IgE antibodies also bound toproteins present in Almond and Brazil nutextracts through immunoblotting, whichindicates that the Peanut allergen Ara h 2shares IgE-binding epitopes with bothAlmond and Brazil nut allergens (27). Thesame authors had previously reported thatPeanut-specific antibodies from sera ofPeanut-allergic subjects became activatedfollowing stimulation with Peanut, Almondand Brazil nut extracts, demonstratingbiological activity of cross-reactive IgEantibodies (28).

A 2S albumin has been isolated from theseed of Tomato and was found to cross-reactwith antiserum to the fruit lectin. The sequenceof the fruit lectin was shown to be similar tothat of 2S albumins from different plants, suchas Brazil nut and Castor beans (29). Theallergenicity of the Tomato seed 2S albuminwas not evaluated.

Walnut-induced anaphylaxis has beenreported, with cross-reactivity to Hazel nutand Brazil nut described (30).

28

f18 Brazil nut

Clinical Experience


Allergy to Brazil nut is common, frequentlyhas an onset in the first few years of life,generally persists, and accounts for severeand potentially fatal allergic reactions. Theubiquity of this food in the modern dietmakes avoidance difficult, and accidentalingestions, with reactions, are common(1,31-36). Symptoms include vomiting,diarrhoea and other manifestationsassociated with food allergy: laryngealoedema, atopic dermatitis, urticaria andanaphylaxis (1, 36-37).

The probability of patients with nut allergyhaving IgE antibodies to a particularcombination of Peanut, Hazel nut and Brazilnut is similar, whatever the patients' age orsex. The apparent increase in multiple nutreactivity with increasing age may thereforebe due to exposure of previouslyunchallenged sensitivity. The frequency ofmultiple-nut specificity is sufficiently highthat patients should always be tested forallergy to a range of nuts if they have a historyof reacting to any nut (38). In a study of 62patients (adults and children) with nut allergy,Peanuts were the commonest cause of allergy(n=47), followed by Brazil nut (n=18),Almond (n=14), and Hazel nut (n=13) (35).

In an American study of 115 patientsaged 4-19.5 years, 2% (n=1) were gradedas mildly allergic to Brazil nut, and 4% (n=2)were graded as severely allergic. The studyalso concluded that around 9% of childrenwith tree nut allergy outgrow their allergy.(39) An earlier American study by the FoodAllergy and Anaphylaxis Network (FAAN)Peanut and Tree Nut Allergy Registrycollected information on 5,149 patients(mainly children) and found that 34% wereallergic to Walnut, followed by Cashew(20%), Almond (15%), Pecan (9%), andPistachio (7%). Less than 5% each wereallergic to Hazel, Brazil, Pine, Macadamiaand Hickory nuts (40). It is evident that thefrequency of reported allergy depends on thepopulation group being studied and that incountries where the consumption of Brazilnut is low, the prevalence of reported allergyto this nut will be low.

A study reports on 11 patients withanaphylaxis after eating Brazil nuts and on10 subjects with no symptoms to this food,although both groups had IgE antibodies toBrazil nut. A number of allergeniccomponents with molecular weights rangingfrom 4 to 58 kDa were isolated. All serafrom symptomatic patients recognised theBrazil nut 2S albumin, whereas the otherallergens each bound IgE antibodies fromless than 50% of sera. No sera fromasymptomatic subjects showed IgE antibodybinding to the 2S albumin, but sera didrecognise 25 to 58 kDa components, whichare minor allergens (5). Therefore, minorBrazil nut allergens were thought to resultonly in sensitisation to Brazil nut and not inallergic symptoms (5). However, this iscontradicted by a study of a 15-year-old boywho experienced 2 distinct episodes ofgeneralised urticaria about 30 minutes aftereating Brazil nut. An IgE antibody test wasvery positive to Brazil nut. Serum IgE waspositive to Brazil nut but negative toMustard, Poppy seed, Sesame seed andSunflower seed, suggesting no sensitisationto the 2S albumin allergen (2). The 2Salbumins may be very important in food-induced anaphylaxis (6).

Anaphylaxis to Brazil nut has beenreported. A British report from the Isle ofWight (population 125,000) described 12cases of allergy to Brazil nut recorded over8 years from 1983 to 1991. Eleven patientsdeveloped angioedema, 7 generalisedurticaria, 5 bronchospasm, 2 stridor, 2 throattightness, 2 itchy mouth and 1 syncope.Onset of symptoms was less than 1-3 minutesin all. Eight patients were shown to havesignificant skin reactivity for Brazil nut. In 6out of 8 patients, Brazil nut IgE antobodieswere demonstrated (> 0.7 kUA/l). In 3patients there was no definite evidence ofIgE-mediated hypersensitivity. Total IgE wasnormal in 5 patients with severe reactions.Ten out of 12 patients had other atopicdiseases such as asthma, eczema or allergicrhinitis, usually from infancy or earlychildhood. Seven out of 8 patients werepositive to several food and/or inhalantallergens on skin test (36).

29

Anaphylaxis to Brazil nut may occur evenwith no previous history of ingestion of thisnut. This was reported from SPTinvestigation for Brazil nut sensitisation ina young adult who had experienced anadverse reaction presumed to be a result ofallergy to Walnut. Immediately after the skinwas pricked with fresh Brazil nut, an episodeof severe anaphylaxis occurred, requiringepinephrine and intravenous steroids. Theauthors thought this might have resultedfrom cross-reactivity, as occurs with othertree nuts (41).

Anaphylaxis was also reported in a 31-year-old woman, known to haverhinoconjunctivitis and asthma, whodeveloped pharyngeal itching, lip swelling,dysphonia, dyspnoea, wheezing, andgeneralised macular exanthema 10 minutesafter eating a Brazil nut. She had previouslydeveloped oral allergy syndrome after eatingAlmond, Walnut, Sunflower seed, and Hazelnut. She had suffered from abdominal painafter eating Chestnut. She tolerated Peanutand Pistachio. Skin reactivity was detectedfor Brazil nut, Almond, Peanut, Chestnut,Sunflower seed, Pistachio, Hazel nut, Walnut,and Cashew nut. Serum IgE was raised forAlmond, Peanut, Chestnut, Pistachio, Hazelnut and Sunflower seed. IgE antibody levelto Brazil nut was 2.37 kUA/l (37).

Patients sensitised to minor Brazil nutallergens are reported to not have allergicsymptoms (5), but this is contradicted by areport on a 15-year-old boy who experienced2 distinct episodes of generalised urticariaabout 30 minutes after eating Brazil nut. SPTand serum IgE was present for Brazil nut.As serum IgE was present for Brazil nut butnot for Mustard, Poppy seed, Sesame seedor Sunflower seed, the authors concludedthat no reactivity was therefore shown to2S albumins, which suggests that a minorallergen was involved (2).

Food allergens have been reported to bepresent in breast milk. A study also reportson a 20-year-old woman with documentedBrazil nut allergy who developed widespreadurticaria and mild dyspnoea after intercoursewith her boyfriend, who had earlierconsumed Brazil nuts. SPT evaluation withthe boyfriend's semen after Brazil nutconsumption confirmed significantreactivity, whereas a sample before nutconsumption was negative (42).

In a study to find the best approach tothe diagnosis of Brazil nut allergy, 56children and adults with a history of anallergic reaction to Brazil nut or otherevidence of sensitisation were evaluated byquestionnaire, SPT and serum IgE antibodiesto Brazil nut, and by double-blind, placebo-controlled labial and, if necessary, oralchallenges. The study concluded that acombination of history, SPT and IgEantibodies was adequate for achieving adiagnosis in the approximately 77% ofpatients with suspected Brazil nut allergy.However, a doubtful history combined withSPT result (between 1 and 5 mm), or a IgEantibody level less than 3.5 kUA/l, mayrequire an oral challenge to help determinethe risk of a Brazil nut allergic reaction (43).

f18 Brazil nut

30

References1. Bartolome B, Mendez JD, Armentia A,

Vallverdu A, Palacios R. Allergens from Brazilnut: immunochemical characterization.Allergol Immunopathol (Madr)1997;25(3):135-44

2. Asero R, Mistrello G, Roncarolo D, Amato S.Allergy to minor allergens of Brazil nut.Allergy 2002;57(11):1080-1

3. Murtagh GJ, Dumoulin M, Archer DB,Alcocer MJ. Stability of recombinant 2 Salbumin allergens in vitro.Biochem Soc Trans 2001;30(6):913-5

4. Alcocer MJ, Murtagh GJ, Bailey K, Dumoulin M,Meseguer AS, Parker MJ, Archer DB. Thedisulphide mapping, folding andcharacterisation of recombinant Ber e 1, anallergenic protein, and SFA8, two sulphur-rich 2S plant albumins.J Mol Biol 2002;324(1):165-75

5. Pastorello EA, Farioli L, Pravettoni V, Ispano M,Conti A, Ansaloni R, Rotondo F, Incorvaia C,Bengtsson A, Rivolta F, Trambaioli C, Previdi M,Ortolani C. Sensitization to the major allergenof Brazil nut is correlated with the clinicalexpression of allergy. J Allergy Clin Immunol1998;102(6 Pt 1):1021-7

6. Pastorello EA, Pompei C, Pravettoni V,Brenna O, Farioli L, Trambaioli C, Conti A.Lipid transfer proteins and 2S albumins asallergens. Allergy 2001;56 Suppl 67:45-7

7. Alcocer MJ, Murtagh GJ, Wilson PB, Progias P,Lin J, Archer DB. The major human structuralIgE epitope of the Brazil nut allergen Ber e 1:a chimaeric and protein microarray approach.J Mol Biol 2004;343(3):759-69

8. Moreno FJ, Mellon FA, Wickham MS,Bottrill AR, Mills EN. Stability of the majorallergen Brazil nut 2S albumin (Ber e 1) tophysiologically relevant in vitrogastrointestinal digestion.FEBS J 2005;272(2):341-52

9. Koppelman SJ, Nieuwenhuizen WF, Gaspari M,Knippels LM, Penninks AH, Knol EF, Hefle SL,de Jongh HH. Reversible denaturation ofBrazil Nut 2S albumin (Ber e1) andimplication of structural destabilization ondigestion by pepsin.J Agric Food Chem 2005; 53(1):123-31


11. Moreno FJ, Rubio LA, Olano A, Clemente A.Uptake of 2S albumin allergens, Ber e 1 andSes i 1, across human intestinal epithelialCaco-2 cell monolayers.J Agric Food Chem 2006;54(22):8631-9

12. Tengel T, Alcocer MJ, Schleucher J, Larsson G.Complete Assignment and SecondaryStructure of the Brazil Nut Allergen Ber e 1.J Biomol NMR 2005;32(4):336

13. Roux KH, Teuber SS, Sathe SK. Tree nutallergens. Int Arch Allergy Immunol2003;131(4):234-44

14. Gander ES, Holmstroem KO, De Paiva GR, DeCastro LA, Carneiro M, et al. Isolation,characterization and expression of a genecoding for a 2S albumin from Bertholletiaexcelsa (Brazil nut). Plant Mol Biol1991;16(3):437-48

15. Guo F, Jin T, Howard A, Zhang YZ.Purification, crystallization and initialcrystallographic characterization of brazil-nutallergen Ber e 2. Acta Crystallogr Sect FStruct Biol Cryst Commun 2007;63(Pt11):976-9.

16. Murtagh GJ, Archer DB, Dumoulin M, Ridout S,Matthews S, Arshad SH, Alcocer MJ. In vitrostability and immunoreactivity of the nativeand recombinant plant food 2S albumins Bere 1 and SFA-8.Clin Exp Allergy 2003;33(8):1147-52

17. Nordlee JA, Taylor SL, Townsend JA,Thomas LA, Bush RK. Identification of aBrazil-nut allergen in transgenic soybeans.N Engl J Med 1996;334(11):688-92

18. Oommen A, Kelly J, Benson A, Hefle SIdentification of IgE-binding epitopes of theBrazil nut 2S albumin allergen. AAAAI 56thAnnual Meeting 2000;March 3-8


20. Kochhar S, Gartenmann K, Guilloteau M,McCarthy J. Isolation and characterization of2S cocoa seed albumin storage polypeptideand the corresponding cDNA.J Agric Food Chem 2001;49(9):4470-7

21. Kelly JD, Hlywka JJ, Hefle SL. Identificationof sunflower seed IgE-binding proteins. IntArch Allergy Immunol 2000;121(1):19-24

22. Kortt AA, Caldwell JB, Lilley GG, Higgins TJ.Amino acid and cDNA sequences of amethionine-rich 2S protein from sunflowerseed (Helianthus annuus L.).Eur J Biochem 1991;195(2):329-34

23. Menendez-Arias L, Moneo I, Dominguez J,Rodriguez R. Primary structure of the majorallergen of yellow mustard (Sinapis alba L.)seed, Sin a I.Eur J Biochem 1988;177(1):159-66

24. Teuber SS, Dandekar AM, Peterson WR,Sellers CL. Cloning and sequencing of a geneencoding a 2S albumin seed storage proteinprecursor from English walnut (Juglansregia), a major food allergen. J Allergy ClinImmunol 1998 Jun;101(6 Pt 1):807-14

25. Beyer K, Bardina L, Grishina G, Sampson HA.Identification of sesame seed allergens by 2-dimensional proteomics and Edmansequencing: seed storage proteins ascommon food allergens.J Allergy Clin Immunol 2002;110(1):154-9

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26. Barre A, Borges JP, Culerrier R, Rouge P.Homology modelling of the major peanutallergen Ara h 2 and surface mapping of IgE-binding epitopes.Immunol Lett 2005;100(2):153-8

27. de Leon MP, Drew AC, Glaspole IN,Suphioglu C, O'Hehir RE, Rolland JM. IgEcross-reactivity between the major peanutallergen Ara h 2 and tree nut allergens.Mol Immunol 2007;44(4):463-71

28. de Leon MP, Drew AC, Glaspole IN,Suphioglu C, Rolland JM, O'Hehir RE.Functional analysis of cross-reactiveimmunoglobulin E antibodies: peanut-specific immunoglobulin E sensitizesbasophils to tree nut allergens.Clin Exp Allergy 2005;35(8):1056-64

29. Oguri S, Kamoshida M, Nagata Y, Momonoki YS,Kamimura H. Characterization and sequenceof tomato 2S seed albumin: a storage proteinwith sequence similarities to the fruit lectin.Planta 2003;216(6):976-84

30. Asero R, Mistrello G, Roncarolo D, Amato S.Walnut-induced anaphylaxis with cross-reactivity to hazelnut and Brazil nut.J Allergy Clin Immunol 2004;113(2):358-60

31. Sicherer SH, Sampson HA. Peanut and treenut allergy.Curr Opin Pediatr 2000;12(6):567-73

32. Hide DW. Clinical curio: allergy to Brazil nut.Br Med J (Clin Res Ed) 1983;287(6396):900


34. Dutau G, Rittie JL, Rance F, Juchet A,Bremont F. New food allergies. [French]Presse Med 1999;28(28):1553-9


f18 Brazil nut

36. Arshad SH, Malmberg E, Krapf K, Hide DW.Clinical and immunological characteristics ofBrazil nut allergy.Clin Exp Allergy 1991;21(3):373-6

37. Borja JM, Bartolome B, Gomez E, Galindo PA,Feo F. Anaphylaxis from Brazil nut.Allergy 1999;54(9):1007-8

38. Pumphrey RS, Wilson PB, Faragher EB,Edwards SR. Specific immunoglobulin E topeanut, hazelnut and brazil nut in 731patients: similar patterns found at all ages.Clin Exp Allergy 1999;29(9):1256-9



41. Senna G, Bonadonna P, Crivellaro M,Schiappoli M, Passalacqua G. Anaphylaxisdue to Brazil nut skin testing in a walnut-allergic subject. J Investig Allergol ClinImmunol 2005;15(3):225-7

42. Bansal AS, Chee R, Nagendran V, Warner A,Hayman G. Dangerous liaison: sexuallytransmitted allergic reaction to Brazil nuts.J Investig Allergol Clin Immunol2007;17(3):189-91

43. Ridout S, Matthews S, Gant C, Twiselton R,Dean T, Arshad SH. The diagnosis of Brazilnut allergy using history, skin prick tests,serum-specific immunoglobulin E and foodchallenges.Clin Exp Allergy 2006;36(2):226-32

32

Fagopyrum esculentumFamily: PolygonaceaeCommonnames: Buckwheat, Beechwheat,

Fagopyrum,French wheat,Garden buckwheat

Sourcematerial: Whole seedsFor continuous updates:www.immunocapinvitrosight.com

f11 Buckwheat

Allergen Exposure


Buckwheat is grown almost worldwide, butis especially common in China and Iraq. Itsoriginal habitat is obscure. It is a memberof the Polygonaceae group of weeds. InChina another type of Buckwheat, Tartarybuckwheat (Fagopyrum tartaricum) isgrown and consumed (1). Buckwheat isconsumed mainly in Asian countries, inparticular in Japan, where it is a major foodallergen due to the popularity of soba(Buckwheat noodles).

Buckwheat is a large-leafed, herbaceousspecies and not a grass, and thus not a truecereal. The only other common food plantin this family is Rhubarb. Buckwheat isuseful as a substitute for Wheat and othersmall grains (Rice, Barley, Oats, Rye), inparticular as an alternative for peopleallergic to Wheat.

Environment

Buckwheat grows in cultivated beds and,where it has escaped from cultivation, onwaste ground. Buckwheat flour is used forbread and other baked products. The seedis processed to make noodles (termed “soba”in Japan) and is used in soups, cakes,biscuits, etc. The grain can produce ediblesprouts and excellent beer. The leaves can

be eaten raw or cooked like Spinach.Buckwheat is high in fibre, minerals,vitamins and essential amino acids,especially lysine. It also contains rutin, whichis believed to improve cardiovascular healthby dilating the blood vessels, reducingcapillary permeability, and lowering bloodpressure.

Buckwheat is used internally in thetreatment of high blood pressure, gout,varicose veins, chilblains, radiation damage,etc. It is best used in conjunction withvitamin C, since this aids absorption. Oftencombined with Lime flowers (Tilia species),it is a specific treatment for haemorrhageinto the retina. A poultice made from theseeds has been used for restoring the flowof milk in nursing mothers. An infusion ofthe herb has been a treatment of erysipelas(an acute infectious skin disease). Ahomeopathic remedy has been made fromthe leaves and used in the treatment ofeczema and liver disorders.

Unexpected exposure

The hulls of Buckwheat are used as cushionfillings in some Asian countries. A blue dyeis obtained from the stems, while a browndye is obtained from the flowers.

Allergens

Buckwheat is a very potent allergen, causingboth food and inhalant allergy.Approximately 30% of total Buckwheatproteins are 2S albumins. These polypeptidesrange from 8 to 16 kDa, and are water-soluble. (2) However, the allergenicity of theseproteins was not evaluated. Using sera from

33

f11 Buckwheat9 Buckwheat-allergic subjects, major IgE-reactive bands of 73, 70, 62, 58 and 54 kDawere isolated under non-reducing conditions.Under reducing conditions, the 73, 70, 62 and58 kDa bands split to 56 and 24, 52 and 24,45 and 24, and 43 and 24 kDa molecules,respectively. The 24 kDa molecule was themost prominent band recognised with IgE aswell as IgG and IgA (3).

In a study of 19 Buckwheat-allergic subjectswith symptoms after Buckwheat ingestion, and15 asymptomatic control subjects with positiveSPT to Buckwheat, the prevalence of IgEbinding to 24 kDa (Fag e 1), 16kDa(Fag e 16kD), and 9 kDa (presumably nowrecognised as Fag e TI) allergens was assessed.IgE antibodies to split 19 kDa allergens wasmore often found in Buckwheat-allergicpatients than in asymptomatic subjects (78%vs. 7%). The amino acid sequence of the19 kDa and 16 kDa allergens showedmoderate and weak homology to the 19 kDaglobulin protein of Rice and the alpha-amylase/trypsin inhibitor of Millet,respectively. The 9 kDa isoallergens weresimilar to each other and were identified astrypsin inhibitors. The authors concluded thatthe allergens of 24, 19, 16, and 9 kDa werestrong major allergen candidates forBuckwheat, and that the 19 kDa allergen wasrelatively specific for Buckwheat-allergicpatients (4). Studies by other researchers havesuggested that 14 and 18 kDa Buckwheatallergens are major allergens (5), and an earlierstudy reported the isolation of 22 kDa, 36 kDa,39 - 40 kDa and 70 - 72 kDa allergens thatwere identified from water-soluble fractionsof Buckwheat (6).

An 8S storage globulin from Buckwheat,with the structure common to the vicilin-like family of seed storage proteins, wasisolated; its increase precedes that of the 13Sglobulin (the main Buckwheat storageprotein) and starts from an early stage ofBuckwheat seed development, continuing toaccumulate throughout seed development tocontribute approximately 7% of total seedproteins. A 13S Buckwheat legumin of 23-25 kDa, reported to be a major Buckwheatallergen, was also isolated. A partial cDNAshowed high homology with cDNAs codingfor vicilin-like storage proteins from variousplant species (7).

The following allergens have beencharacterised:

Fag e 1, previously known as BW24KD, a22 - 24 kDa protein, an 11S Globulin-likelegumin (3,6,8-11).

Fag e 10kD, a 8-17 kDa protein, a 2Salbumin (12-13).

Fag e 16kD, a 16 kDa protein, a 2S Albumin.(9,12,14-15).

Fag e 19kD, a 19 kDa vicilin-like protein. (9,15).

Fag e TI, a trypsin inhibitor (4,16-17).

Studies have elaborated on thecharacterised allergens, and a number ofother proteins have been isolated but notcharacterised.

Fag e 10kD is also a major allergen ofBuckwheat and was reported to sensitiseapproximately 57% of Buckwheat-allergicpatients (13). Interestingly, not all species ofBuckwheat contain the major allergen foundin F. esculentum. F. lineare and F. urophyllumhave been shown to lack the 22 kDa majorallergenic protein (18).

The 16 kDa protein of Buckwheat, alsoa major allergen, has 50% homology to thereported 8 kDa Buckwheat allergen whichis a 2 S storage albumin. Using a re-combinant 16 kDa allergen, it was foundthat approximately 77.8% of 18 patientswith Buckwheat allergy had raised IgEantibody level to this allergen, compared tonone of 20 asymptomatic Buckwheat-sensitised subjects (14).

In an assessment of the 19 kDa allergen,about 83.3% of Buckwheat-allergic patientswere shown to have IgE antibodies raisedto the recombinant 19 kDa protein,compared to only 1 of the 19 asymptomaticBuckwheat-sensitised subjects, suggestingthat the 19 kDa Buckwheat allergen may bea major allergen (15).

Allergens of 14 and 18 kDa have beenisolated and shown to share some homologywith Rice proteins. Both are major allergens(5). Another major allergen, a 24 kDa protein,bound to IgE antibodies in sera from everyBuckwheat-allergic patient in a study (1,19).

34

f11 BuckwheatA16 kDa Buckwheat protein that was

isolated has been shown to be resistant topepsin digestion and was reported to beresponsible for immediate hypersensitivityreactions, including anaphylaxis. Allergen-specific IgE was detected to a pepsin-sensitive 24 kDa protein but was not thoughtto play a role in immediate hypersensitivityreactions. However, the 24 kDa protein,previously reported to be a major allergenand now recognised as Fag e 1, reacted toIgE antibodies present in sera from almostall subjects (19/20) regardless of symptoms.On the other hand, 16 and 19 kDa proteinsbound with IgE antibodies present in serafrom 9 of the 10 patients with immediatehypersensitivity reactions, including 8patients with anaphylaxis; but not with serafrom Buckwheat-specific IgE-positivesubjects without immediate hypersensitivityreactions. After pepsin treatment, the 16kDa protein but not the 19 and 24 kDaproteins remained undigested and preservedthe capacity of IgE binding (9).

In an analysis of Buckwheat-specific IgEantibodies in an 8-year-old with fatal food-dependent exercise-induced anaphylaxis, 7protein bands were found that reacted withthe IgE of the patient's serum. Four bandsof 16, 20, 24, and 58 kDa were specific tothe patient, compared to subjects not allergicto Buckwheat (20).

Buckwheat seed contains a thiamin-binding protein. The protein has homologywith the thiamin-binding proteins from Riceseeds and Sesame seeds (21). A 230 kDathiamin-binding protein has been isolatedfrom Sunflower seeds; its properties aresimilar to those in proteins from Buckwheatseeds, but not to those from Rice seeds andSesame seeds; and similar to those ofhelianthinin (22). The clinical significanceof this protein has not been established.Similarly, the significance of the inhibitor oftrypsin and chymotrypsin is unknown (23).


An extensive cross-reactivity among thedifferent individual species of the genuscould be expected (24). Importantly,Buckwheat is not taxonomically closelyrelated to Wheat or other cereal grains. The24 kDa allergenic protein in Tartarybuckwheat shares a greater than 93%homology with the allergenic storage proteinand a legumin-like protein from Commonbuckwheat (25).

Immediate hypersensitivity reactionsinduced by the ingestion of Buckwheat areconsidered to be IgE-mediated. In 28subjects without immediate hypersensitivityreactions to Buckwheat ingestion, out of 46subjects in whom IgE antibodies to bothBuckwheat and Rice allergens were detected,results led to the conclusion that there iscross-reactivity with IgE antibodies betweenBuckwheat and Rice and that IgE antibodiesfrom subjects without immediate hyper-sensitivity reactions might recognise theepitopes on Buckwheat antigens whichcross-react with Rice antigens, whereas IgEantibodies from subjects with immediatehypersensitivity reactions might bind toBuckwheat-specific epitopes (26-27).

Cross-reactivity between Buckwheat andNatural rubber latex has been reported;therefore, allergy to fruits and vegetablesthat cross-react with Latex should beconsidered in patients who are proven to beallergic to Buckwheat (28-29). Immuno-chemical cross-reactivity between theglobulins from Buckwheat and Indigo seedshas been documented (30).

The 19 kDa Buckwheat allergen has a weakhomology to the vicilin-like allergens ofCashew (Ana o 1), English walnut (Jug r 2)and 7 S globulin from Sesamum indicum.(15) Cross-sensitisation of Poppy seed withBuckwheat has been reported (31).

35

f11 Buckwheat

Clinical Experience


Buckwheat has been recognised as acommon food allergen in Korea, Japan, andother Asian countries, but not in Taiwan (32-33). In these countries, Buckwheat mayfrequently induce sensitisation or symptomsof food allergy or inhalant allergy insensitised individuals (3,34-43). Approxi-mately 5% of Korean children were reportedto have IgE antibodies to Buckwheat (44).Similarly, food allergy was noted in 5.2%of Japanese students, with a higherprevalence in female students. Buckwheatwas reported to be the second-most-frequentcause after Egg, followed by Shrimp, Crab,Mackerel and Cow's milk (33). In a studyof the incidence of anaphylaxis in a Koreantertiary care hospital, radio-contrast mediaand Buckwheat were respectively the leadingcauses of drug and food anaphylaxis (45).

Despite being a potent allergen wheningested or inhaled, Buckwheat has beenincreasingly popular, in particular as a healthfood, in the United States, Canada, andEurope (46-47). Researchers have suggestedthat allergy to Buckwheat will become alarger problem as a result of its increaseduse in the food processing industry.Buckwheat is also used as a substitute cerealfor children with coeliac disease (43).

Some authors have stated that Buckwheatcan cause allergic reactions much moresevere than Wheat and its relatives do, andthat allergy to Buckwheat should thereforebe considered in patients with classicsymptoms of food allergy, where the signsare often severe (43). Symptoms includegastrointestinal distress, urticaria, Quinckeoedema (angioedema), dyspnoea, rhinorrhoea,wheezing, asthma, rhinitis, anaphylaxis andshock (48-51).

Among adult asthmatics in a Japanesestudy, 625 of 3102 (20.1%) had a positivetest to 1 or more food allergens, accordingto skin-specific IgE evaluation. Thecommonest food allergens were Shrimp(27.7%), Crab (27.7%), Yeast (23.8%) andBuckwheat (15.8%). Positive food challengeresponses occurred in 30/60 subjects (50%).

The foods which most often provoked areaction were Buckwheat, Shrimp, Crab andBread (52). In a Japanese study, moreseverely asthmatic children had a higherincidence of positive intracutaneous skintests to house dust, molds, Japanese cedartree, Ragweed, Cat dander, Silk andBuckwheat (53). An earlier study reportedthe opposite in children with asthma (54).

From the results of a questionnaire sentto 341 elementary school nurses inYokohama, the incidence of Buckwheatallergy in of 92,680 children was determinedto be 0.22% (140 boys and 54 girls).Symptoms were urticaria (37.3%), skinitching (33.3%), and wheezing (26.5%).Anaphylaxis was reported in 4 children(3.9%). The incidence of anaphylaxis dueto Buckwheat was higher than that due toEgg and Milk allergy. Seven pupils hadallergic reactions to Buckwheat noodleserved at school lunch (55).

The French Allergy Vigilance Network,which monitors adverse allergy reactions inthat country, reported that in 2002, 107cases were reported, of which 59.8% werecases of anaphylactic shock, 18.7% ofsystemic reactions, 15.9% of laryngealangioedema, and 5.6% of serious acuteasthma. The most frequent causal allergenswere Peanut (n=14), Nuts (n=16) andShellfish (n=9). Severe adverse reactions toBuckwheat were reported in 3, in contrastto 4 to Sesame, 3 to Cow's milk, and 3 toFish (56).

In 34 Finish children with atopic dermatitis,33 were SPT positive to Wheat and 18 to Oats,whereas Rice, Maize, Millet or Buckwheat waspositive in 16/34 patients (57).

Inhalation of very small amounts ofBuckwheat allergen can initiate severeallergic symptoms (19). A 20% reductionin lung function after inhalation ofaerosolised Buckwheat allergens has beendocumented (58). In 12 children with IgE-mediated food allergy who developedasthma on inhalational exposure to food, theimplicated foods were Fish, Chick pea, Milk,Egg and Buckwheat. Bronchial foodchallenge resulted in 5 children showingobjective clinical features of asthma and 2

36

f11 Buckwheatdeveloping late-phase symptoms (59). Aninteresting report described a young womanwho experienced anaphylaxis after enteringa pancake restaurant but before consumingany food or drink. Investigationdemonstrated sensitisation to both Dustmites and Buckwheat, and airborneBuckwheat allergens were incriminated inthe anaphylactic reaction, with a Buckwheat2S albumin implicated as the responsibleallergen (60).

In Switzerland reactions to Buckwheatare uncommon and reported to be mostlydue to ingested Buckwheat in the form ofpizoccheri (dumplings) and Buckwheatbread. A study described 6 individuals whoexperienced allergic reactions due toBuckwheat. Symptoms of urticaria wereexperienced by 6, angioedema in 4 andasthma in 5. Four patients reacted toingestion of Buckwheat and 2 to inhaledBuckwheat allergens in an occupationalsetting. All were shown to have positive SPTand raised allergen-specific IgE toBuckwheat (49).

Exposure to Buckwheat may also resultin anaphylaxis (61-62). An anaphylacticreaction was reported in a 19-year-old-manafter he ate “poffertjes” (small Dutchpancakes), the principal ingredient beingBuckwheat. The authors suggest that it washighly likely that this patient had beensensitised to Buckwheat by sleeping on apillow stuffed with Buckwheat husk (63).Similarly, an individual developed asthmaand worsening allergic rhinitis afterexposure to Buckwheat present in his pillow.SPT and IgE in vitro test were stronglypositive, and the later was reported to beclass 4 (64). Indeed, nocturnal asthma fromsleeping on Buckwheat chaff-stuffed pillows,a common type in Korea, has been reportedas a result of Buckwheat allergy (65-66).However, House dust mite (D. farinae) mayalso be an important allergenic substance inBuckwheat-husk pillows (67).

A woman with asthma is described whohad anaphylaxis, generalised urticaria, andan acute exacerbation of asthma 5 minutesafter ingesting Buckwheat. She wasmarkedly SPT positive for Buckwheat, andserum Buckwheat-specific IgE was reportedas class 6 (32).

A 36-year-old man is described whoexperienced nausea, vomiting, urticaria, asensation of throat closing, inability tospeak, dyspnoea, and dizziness shortly afteringesting a large portion of Buckwheat. Inthe previous 2 years, he had experiencedasthma, contact urticaria, allergicconjunctivitis, and allergic rhinitis fromsleeping with a Buckwheat pillow. Sixmonths after the first ingestion reaction, thepatient again experienced anaphylaxisrequiring emergency treatment when heaccidentally ate crackers with a smallamount of Buckwheat in them. SPT and IgEin vitro test were markedly positive forBuckwheat. The authors postulated thatinhaled Buckwheat, provoking asthma, hadsensitised the patient prior to the 2 episodesof ingestion anaphylaxis (46).

A 37-year-old woman twice developed alife-threatening anaphylactic reaction aftereating galettes, a special French pancake fromBrittany. She had tolerated ordinary pancakesand crêpes for many years. Investigationconfirmed Buckwheat as the causativeallergen, and found it in the galettes. SPT andIgE in vitro test was positive for Buckwheat.The authors suggested that whenever apatient experiences allergic reactions due topastries, Buckwheat allergy should beconsidered (68).

Food-dependent exercise-inducedanaphylaxis caused by Buckwheat may alsooccur, as reported in an 8-year-old girl. Thepatient consumed Buckwheat noodles called“zaru soba” and swam vigorouslyimmediately thereafter. Approximately 30minutes later, she complained of abdominalpain, vomiting, coughing, and chestdiscomfort, followed 10 minutes later by adeterioration of consciousness andcardiorespiratory arrest. An exaggeratedhematemesis that occurred immediately afterhospital admission indicated aninflammatory condition of the digestive tractthat was caused by Buckwheat. Markedulceration accompanied with hemorrhageand necrosis was noted at the ileum.Extensive hemorrhage involving theendotracheal pulmonary field andlymphocyte infiltration of the alveolar spacelikely appeared after the inflammation. The

37

f11 Buckwheatserum IgE antibody level was raised forBuckwheat (20).

Buckwheat may also be a “hidden”allergen. Anaphylaxis as a result ofBuckwheat used as filler in pepper has beenreported (69); and to “hidden” Buckwheatin a Wheatburger (70).

Occupational rhinitis, conjunctivitis,asthma or urticaria may occur to Buckwheator Buckwheat dust in animal husbandry andother food industry workers (1). Thesesymptoms have occurred after exposure tocomparatively low levels of Buckwheat dustresulting from the grinding and packagingof Buckwheat (71-72), to Buckwheat flour(73), and in a noodle maker (74-75).Occupational asthma has also been reportedin an individual working in a pancakerestaurant, and was confirmed by specificbronchial challenge with aerolisedBuckwheat (39,50).

Other reactions

Pulmonary haemosiderosis as a result of non-immediate Buckwheat protein hypersensitivityhas been reported. The patient had no skinreactivity or IgE antibodies, but was positiveto a patch test (76).

Immediate hypersensitivity reactionsinduced by Buckwheat ingestion areconsidered to be IgE-mediated. Somesubjects, however, develop no immediateadverse reactions after Buckwheat ingestion,despite high levels of Buckwheat-specific IgEantibodies. To elucidate the possiblemechanisms, RAST inhibition between theseantigens were performed using sera from 23Buckwheat-sensitive subjects and 30Buckwheat-tolerant subjects who had IgEantibodies for both Buckwheat and Rice.The authors report that there was cross-reactivity with IgE antibodies betweenBuckwheat and Rice, and that IgE antibodiesfrom Buckwheat-tolerant subjects with highlevels of IgE antibodies to Buckwheat mightrecognise the epitopes on Buckwheatantigens which cross-react with Riceantigens, whereas IgE antibodies from theBuckwheat-sensitive subjects might bind toBuckwheat-specific epitopes. (77)

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6. Nair A, Adachi T Immunodetection andcharacterization of allergenic proteins incommon buckwheat (Fagopyrumesculentum).Plant Biotechnol 1999;16(3):219-24

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10. Fujino K, Funatsuki H, Inada M, Shimono Y,Kikuta Y. Expression, cloning, andimmunological analysis of buckwheat(Fagopyrum esculentum Moench) seedstorage proteins.J Agric Food Chem 2001;49(4):1825-9

11. Yoshioka H, Ohmoto T, Urisu A, Mine Y,Adachi T. Expression and epitope analysis ofthe major allergenic protein Fag e 1 frombuckwheat.J Plant Physiol 2004;161(7):761-7

12. Koyano S, Takagi K, Teshima R, Sawada JI.Molecular Cloning of cDNA, Recombinantprotein expression and characterization of abuckwheat 16-kDa major allergen. Int ArchAllergy Immunol 2006;140(1):73-81

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13. Matsumoto R, Fujino K, Nagata Y,Hashiguchi S, Ito Y, Aihara Y, Takahashi Y,Maeda K, Sugimura K. Molecularcharacterization of a 10-kDa buckwheatmolecule reactive to allergic patients' IgE.Acta allergologica 2004;59(5):533-8

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27. Wada E, Urisu A, Kondo Y, Horiba F, Tsuruta M,Yasaki T, Masuda S, Yamada K, Kozawa T,Hida Y, et al. Relationship betweenimmediate hypersensitive reactions bybuckwheat ingestion and specific IgE for ricein subject with positive IgE-RAST forbuckwheat. [Japanese] Arerugi1991;40(12):1493-9

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31. Oppel T, Thomas P, Wollenberg A. Cross-sensitization between poppy seed andbuckwheat in a food-allergic patient withpoppy seed anaphylaxis. Int Arch AllergyImmunol 2006;140(2):170-3

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35. Nakamura S, Murohisa B, Kawasaki T, Mori M.Case of occupational buckwheat allergy.[Japanese] Naika 1970;26(6):1169-71

36. Horesh AJ. Buckwheat sensitivity in children.Ann Allergy 1972;30(12):685-9

37. Nakamura S, Yamaguchi MY. Studies on thebuckwheat allergose report 2: clinicalinvestigation on 169 cases with thebuckwheat allergose gathered from the wholecountry of Japan. Allerg Immunol (Leipz)1974-1975;20-21(4):457-65

38. Wieslander G, Norback D. Buckwheat allergy.[Editorial] Allergy 2001 Aug;56(8):703-4

39. Choudat D, Villette C, Dessanges JF,Combalot MF, Fabries JF, Lockhart A,Dall'Ava J, Conso F. Occupational asthmacaused by buckwheat flour. [French] Rev MalRespir 1997 Sep;14(4):319-21

40. Wieslander G. Review on buckwheat allergy.Allergy 1996;51(10):661-5

41. Varjonen E, Vainio E, Kalimo K, Juntunen-Backman K, Savolainen J. Skin-prick testand RAST responses to cereals in childrenwith atopic dermatitis. Characterization ofIgE-binding components in wheat and oats byan immunoblotting method.Clin Exp Allergy 1995;25(11):1100-7

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42. Nukada S, Minagawa H, Shigeno S, Yasuda K,Hirano K. A case study of buckwheat allergy--purification of buckwheat antigen andinvestigation on the sensitivity tomultiantigens. [Japanese] Nippon HifukaGakkai Zasshi 1987;97(13):1551-4

43. Baruteau J, Sadani G, Jourdan C, Morelle K,Broué-Chabbert A, Rancé F. Allergie ausarrasin : à propos d'une observation chezl'enfant et revue de la littérature Revuefrancaise d allergologie 2005;45(5):422-5

44. Sohn MH, Lee SY, Kim KE. Prediction ofbuckwheat allergy using specific IgEconcentrations in children.Allergy 2003;58(12):1308-10

45. Yang MS, Lee SH, Kim TW, Kwon JW, Lee SM,Kim SH, Kwon HS, Park CH, Park HW, Kim SS,Cho SH, Min KU, Kim YY, Chang YS.Epidemiologic and clinical features ofanaphylaxis in Korea. Ann Allergy AsthmaImmunol 2008 Jan;100(1):31-6

46. Stember RH. Buckwheat allergy.Allergy Asthma Proc 2006 Jul;27(4):393-5

47. Bourrier T, Noormahomed T, Coache M,Albertini M, Boutte P. A case of buckwheatallergy in a child. [French] Revue francaise dallergologie 2003;43(8):530-2

48. Takahashi Y. Analysis of immune responses inbuckwheat allergy. [Japanese] Arerugi1996;45(12):1244-55

49. Schumacher F, Schmid P, Wuthrich B.Sarrazin allergy: a contribution to buckwheatallergy. [German] Schweiz Med Wochenschr1993;123(33):1559-62

50. Davidson AE, Passero MA, Settipane GA.Buckwheat-induced anaphylaxis: a casereport. Ann Allergy 1992;69(5):439-40

51. Blumstein GI. Buckwheat sensitivity.J Allergy 1935;7:7-9

52. Arai Y, Sano Y, Ito K, Iwasaki E, Mukouyama T,Baba M. Food and food additiveshypersensitivity in adult asthmatics. I. Skinscratch test with food allergens and foodchallenge in adult asthmatics. [Japanese]Arerugi 1998;47(7):658-66

53. Yamaguchi H. Evaluation of immediatehypersensitivity and environmental factors byintracutaneous skin tests and specific IgEantibodies in allergic children. Part 1. Theannual change of immediate hypersensitivitymeasured by intracutaneous skin tests andradioallergosorbent test. [Japanese] Arerugi1993;42(4):571-81

54. Kuno-Sakai H. Total serum IgE and specificIgE antibodies in children with bronchialasthma. Ann Allergy 1986;56(6):488-91

55. Takahashi Y, Ichikawa S, Aihara Y, Yokota S.Buckwheat allergy in 90,000 school childrenin Yokohama. [Japanese] Arerugi1998;47(1):26-33

56. Moneret-Vautrin DA, Kanny G, Morisset M,Rance F, Fardeau MF, Beaudouin E. Severefood anaphylaxis: 107 cases registered in2002 by the Allergy Vigilance Network.Allerg Immunol (Paris) 2004;36(2):46-51

57. Varjonen E, Vainio E, Kalimo K, Juntunen-Backman K, Savolainen J. Skin-prick testand RAST responses to cereals in childrenwith atopic dermatitis.Clin Exp Allergy 1995;25(11):1100-7

58. Golder N, Roberts G, Lack G Aerosolised foodcan provoke asthma in childhood AAAAI 56thAnnual Meeting 2000;March 3-8

59. Roberts G, Golder N, Lack G. Bronchialchallenges with aerosolized food inasthmatic, food-allergic children.Allergy 2002;57(8):713-7

60. Mittaine M, Sordet C, Culerrier R, Barre A,Rouge P, Didier A. Anaphylaxie au sarrasinpar voie inhalée / Buckwheat anaphylaxis byinhalation Revue francaise d allergologie2008;48(2):106-8

61. Leynadier F. Anaphylaxis. 3 clinical cases.[French] Allerg Immunol (Paris)2001;33(10):409-11

62. Schiffner R, Przybilla B, Burgdorff T,Landthaler M, Stolz W. Anaphylaxis tobuckwheat. Allergy 2001;56(10):1020-1

63. van Ginkel CJ. Sensitisation to 'poffertjes' asa result of sleeping on a pillow containingbuckwheat. [Dutch] Ned Tijdschr Geneeskd2002;146(13):624-5

64. Fritz SB, Gold BL. Buckwheat pillow-inducedasthma and allergic rhinitis. Ann AllergyAsthma Immunol 2003;90(3):355-8

65. Matsumura T, Tateno K, Yugami S, Fujii H,Kimura T. Detection of allergens in bronchialasthma in childhood and its therapy. Bronchialasthma induced by buckwheat flour attachedto buckwheat chaff in the pillow. [Japanese]Arerugi 1969;18(11):902-11

66. Lee SY, Lee KS, Hong CH, Lee KY. Threecases of childhood nocturnal asthma due tobuckwheat allergy. Allergy 2001;56(8):763-6

67. Hong CS, Park HS, Oh SH.Dermatophagoides farinae, an importantallergenic substance in buckwheat-huskpillows. Yonsei Med J 1987;28(4):274-81

68. Plaza T, Mahler V. Anaphylactic shock due toFrench galette. Type I allergic reaction tobuckwheat. [German] Hautarzt2005;56(2):2-163

69. Yuge M, Niimi Y, Kawana S. A case ofanaphylaxis caused by buck-wheat as anaddition contained in pepper. [Japanese]Arerugi 2001;50(6):555-7

70. Wüthrich B, Trojan A. Wheatburgeranaphylaxis due to hidden buckwheat.Clin Exp Allergy 1995;25(12):1263

71. Gohte CJ, Wieslander G, Ancker K, Forsbeck M.Buckwheat allergy: health food, an inhalationhealth risk. Allergy 1983;38(3):155-9

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72. Valdivieso R, Moneo I, Pola J, Munoz T,Zapata C, Hinojosa M, Losada E.Occupational asthma and contact urticariacaused by buckwheat flour.Ann Allergy 1989;63(2):149-52

73. Obase Y, Shimoda T, Mitsuta K, Matsuse H,Kohno S. Two patients with occupationalasthma who returned to work with dustrespirators.Occup Environ Med 2000;57(1):62-4

74. Park HS, Nahm DH. Buckwheat flourhypersensitivity: an occupational asthma in anoodle maker.Clin Exp Allergy 1996;26(4):423-7

75. Okumura E. A case of bronchial asthma frombuckwheat in a housewife whose husband isworking in a buckwheat flour mill (author'stransl). [Japanese] Sangyo Igaku1980;22(5):382-3

76. Agata H, Kondo N, Fukutomi O, Takemura M,Tashita H, Kobayashi Y, Shinoda S, Nishida T,Shinbara M, Orii T. Pulmonary hemosiderosiswith hypersensitivity to buckwheat. AnnAllergy Asthma Immunol 1997;78(2):233-7

77. Yamada K, Urisu A, Morita Y, Kondo Y, Wada E,Komada H, Yamada M, Inagaki Y, Torii S.Immediate hypersensitive reactions tobuckwheat ingestion and cross allergenicitybetween buckwheat and rice antigens insubjects with high levels of IgE antibodies tobuckwheat. Ann Allergy Asthma Immunol1995;75(1):56-61

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Anacardium occidentaleFamily: AnacardiaceaeSourcematerial: Shelled nutsFor continuous updates:www.immunocapinvitrosight.com

f202 Cashew nut

Allergen Exposure


The Cashew nut comes from the Cashew nuttree, a member of the Anacardiaceae family,which includes a number of dermatitis-inducing plants such as poison ivy, poisonoak, poison sumac and lacquer sumac. Thetree is native to Brazil but is grown in otherparts of the world, and the nut is now alsoexported from southern India, Mozambique,Tanzania and Kenya. This is a smallperennial evergreen tree growing to 12 mtall, with a short, often irregularly-shapedtrunk. The leaves are simple, alternate,spirally arranged, leathery, elliptic orobovate, up to 22 cm long and 15 cm broad,with a smooth margin.

The buds grow on terminal panicleswhich are up to 26 cm long. The flowerschange from pale green to reddish as theydevelop and have 5 slender, pointed petals7-15 mm long. The Cashew tree flowers oncea year and pollination is mainly by insects.In the northeast region of Brazil, where thetree grows in great numbers, it flowers oncea year between August and October.

The pear-shaped accessory fruit or falsefruit is called the Cashew apple. Thismeasures 4-8 cm by 10-20 cm and is yellowor red, soft and juicy, and rich in vitamin C.But the 3 cm, edible, smooth-kernelled,kidney-shaped nut (botanically defined, aseed) that grows at the end of the Cashewapple is the real fruit.

The Cashew nutshell has 3 layers. Theouter leathery exocarp and the thin, hard,inner endocarp enclose a honeycombedmesocarp which is filled with an oily fluidcontaining substances that are themselvesallergens: cardol, cardanol, 2-methylcardoland anacardic acid. This oily brown Cashewnut shell oil causes an immediate vesicantreaction because of its high concentrationof phenols. Cashew wood exudes a yellowgum that also can cause vesicant reactions.It is used in the production of varnish, insectrepellents, and adhesives. The tree barkproduces thick resinous latex that turnsblack on contact with air and may result inblistering reactions on contact (1-3).

The oily substance in the shells must beremoved before the nut is processed forconsumption. Unaided shelling of the nutscan easily produce painful dermatitis (similarto poison-ivy rashes). The nuts are thereforeusually first put through a hot bath for easyremoval of the shells. The heating processcauses the pericarp to burst, releasing theCashew nutshell liquid (CNSL) and at thesame time decarboxylating the anacardic

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acids into less allergenic cardanols. The nutsare then centrifuged in sawdust to removethe endocarp and residual phenols. Heating,water washing and agitation constitute analternative process (4). Next, the endocarpis removed to yield an edible nut. RawCashews are not processed to the sameextent and may be contaminated with theshell oil (1).

The resorcinol cardol is both an irritantand an allergen, with side chains similar tothe side chains of poison ivy and poison oak.Early oral exposure to resorcinols such ascardol appears to protect against contactdermatitis to catechols (present in poisonivy), whereas early cutaneous exposure tocatechols predisposes to an allergic reactionto resorcinols. The concentration of phenolsin the Cashew nutshell and bark is so highthat contact with them causes immediatevesicant reactions. Africans have used CNSLand Cashew bark in ritual scarification andkeloid formation, and it has been used forwart removal (1).

Therefore, Cashew nuts generate bothallergy to Cashew nut shell oil and allergyto the nut itself. As far as the shell isconcerned, roasting diffuses irritatingvapours, but unless roasting is complete, notall the allergens are inactivated. Problemsalso arise when children play with the rawshells or when improperly shelled Cashewnuts are sold (5).

Environment

Cashew nuts are edible and popular snacks.They are also used as an ingredient in manyprocessed foods such as nut "butters",bakery and confectionery products, andpesto. They are a common component oforiental foods.

The Cashew apple is used for its juicy butacidic pulp, which can be eaten raw or usedin the production of jam, chutney, or variousbeverages. Its juice can also be processed anddistilled into liquor or consumed diluted andsugared as a drink.

Unexpected exposure


Allergens

Cashew food allergy is associated with thepresence of IgE antibodies directed against themajor seed storage proteins in Cashew,including the 13S globulin proteins (legumingroup) and 2S albumins, both of whichrepresent major allergen classes in several plantseeds. The 13S globulin proteins are in the 31-35 kDa range, whereas the 2S albumins arelow-molecular-weight polypeptides (6). In 3individuals who experienced anaphylaxis toCashew nut, a number of other allergens of15, 30 and 60 kDa were shown to beinvolved, the 15 kDa one possibly being a 2Salbumin (7).

The following allergens have beencharacterised to date:

Ana o 1, a 7S vicilin-like globulin, a majorallergen. (6,8-11).

Ana o 2, an 11S globulin, a 33 kDa, legumin-like protein, and a major allergen (9,11-12).

Ana o 3, a 2S albumin, a 12.6 kDa proteinand a major allergen (6, 9,11,13-14).

Ana o Profilin (15).

Two isoforms of Ana o 1, Ana o 1.0101and Ana o 1.0102, have been characterised.Ana o 1 and Ana o 3 have been expressed asrecombinant allergens.

Ana o 1, a vicilin-like protein, has beenshown not to share linear epitopes withPeanut vicilin. Recombinant Ana o 1 boundwith 50% of sera from 20 patients withCashew nut allergy, and with sera of 25%of 8 Cashew-tolerant patients with allergiesto other tree nuts (8).

Ana o 2, a legumin-like protein, showson immunoblots as a major band atapproximately 33 kDa and a minor band atapproximately 53 kDa. Legumins representthe main storage proteins in Cashew,accounting for approximately 50% of thetotal seed protein. Thirteen of 21 sera (62%)from Cashew-allergic patients were reactiveto Ana o 2 (12).

Ana o 3 was shown to bind with sera of21 (81%) of 26 Cashew-allergic patients (13).

A profilin has been detected in Cashewnut, at levels which may result in no clinicaladverse effects (15). Its clinical relevance wasnot evaluated.

f202 Cashew nut

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f202 Cashew nutPotential cross-reactivity

Significant cross-reactivity has been reportedbetween Pistachio nut and Cashew nut(13,16-17).

Cross-reactivity between Cashew nut andWalnut is possible, as a result of Ana o 2, thelegumin protein which is a major allergen inCashew nut and present in Walnut (13); andthe cross-reactivity is also suggested by invitro studies. A recent study describedsignificant sequence homology between therecombinant Jug r 4 from Walnut, and Hazelnut and Cashew legumin allergens (18).

An early study reported little cross-reactivity between Cashew and Peanut orBrazil nut. (19) Although Cashew nut andPeanut vicilins share 27% identity, they werereported to not share linear epitopes, andhence did not appear to be cross-reactive(8,12,20). However, a recent study arguedthat the vicilin allergens of Peanut (Ara h 1),Walnut (Jug r 2), Hazel nut (Cor a 11) andCashew nut (Ana o 1) share structurallyrelated IgE-binding epitopes; that thisepitopic community creates a risk of cross-sensitisation; and that a restriction oravoidance of tree nuts should berecommended to Peanut-sensitisedindividuals (10).

A 19 kDa protein from Buckwheat wasreported to have weak homology to the vicilin-like allergens of Cashew, Walnut (Jug r 2), and7S globulin from Sesamum indicum (21).

Conformational analysis of the leguminallergens of Peanut (Ara h 3), Walnut (Jug r 4),and Hazel nut (Cor a 9), along with Ana o 2of Cashew nut, showed that consensualsurface-exposed IgE-binding epitopesexhibited some structural homology. Theauthors suggested that individuals allergicto Peanut should avoid the other 3 nuts toprevent possible allergic reactions (14).

Pectin has been shown to contain all ofthe allergen epitopes of Cashew nut, whereasCashew nut does not exhibit all of theepitopes of pectin. The clinical significanceof this fact has not yet been established, andfurther studies are required to characterisethese cross-reacting allergens (22). However,a recent study reported that Cashew nut

allergy, and possibly Pistachio nut allergy,may be associated with pectin allergy, andthe possibility of pectin allergy should beconsidered in Cashew- or Pistachio-allergicpatients who have unexplained allergicreactions. The study described a 3 1/2-year-old boy who developed anaphylaxis aftereating Cashew nut and later after eating apectin-containing fruit “smoothie”. Thechild had skin reactivity to pectin and a highlevel of IgE antibodies to Cashew nut andPistachio nut, as well as a low level of IgEto Grapefruit, to which he had previouslyalso reacted. The pectin in the smoothie wasconfirmed to be of citrus origin (23).

Cardol, found in the Cashew nut shell, isnot usually present in the nut unlesscontamination occurs. An early studyreported cross-reactivity of poison ivy andCashew nut as a result of the nut beingcontaminated with cardol (24).

Clinical Experience


Cashew nut may commonly inducesymptoms of food allergy, atopic dermatitisand other hypersensitivity reactions insensitised individuals (7,25-29). Tree nutsand Peanuts are among the most commonfoods responsible for causing IgE-mediatedfood hypersensitivity. Tree nut and Peanutallergy is usually lifelong. Cashew nut allergymay present as a singular event or inconjunction with allergy to other tree nuts.

Although typically very severe, Cashewnut allergy was initially thought to be veryrare; 1 out of 1,218 in a paediatric populationon the Isle of Wight, UK, was found to beCashew nut-allergic. (26) However, Cashewnut, initially regarded as a novel food but nowincreasing in popularity as a snack, isregarded as an “emerging” allergen, (30) andhypersensitivity reactions are expected toincrease (27). In particular, with the increasingconsumption of Asian cuisine, containingfoodstuffs such as Sesame, Brazil nuts andCashew nuts, the associated allergies are morefrequent than they were formerly (31).

Cashew nut allergy is now the secondmost commonly reported tree nut allergy in

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f202 Cashew nutthe United States (13). Besides the proteinallergens, Cashew nuts contain oleoresinswhich can cause contact dermatitis and arethought to cause gastrointestinal, systemicand allergic manifestations. In a Frenchstudy that evaluated, using DBPCFC, 163asthmatic and food-allergic children forfood-induced asthma, Cashew nut was theninth most frequent offending food andaffected 2.1% of the group (32). Theprevalence of Cashew nut hypersensitivityhas also been reported to be increasing inChina, as attested in a study of 30 patientswith Cashew nut allergy (33). Aretrospective review of 213 Australianchildren with Peanut or tree nut allergyreported that anaphylaxis to Cashew nutwas more common than to Peanut (74.1%vs. 30.5%) (34).

Cashew nut allergy may span a wide agerange, and age of onset may vary widely. Ina study of 21 Cashew nut-allergic subjectsranging from 25 to 62 years of age, age ofonset varied between 1 year and 15 years,with 15 subjects experiencing onset at lessthan 3 years of age (12).

In a study of 42 children with Cashewnut allergy, the mean age at the first reactionwas 2 years, and the mean age at diagnosiswas 2.7 years. One in 5 children (12%) hada prior history of exposure to Cashew nuts.Fifty-six per cent had skin symptoms, 25%had respiratory symptoms, and 17% hadgastrointestinal symptoms. Eighteenchildren had proven associated food allergies(Pistachio [7], Hen's egg [5], Mustard [3],Shrimp [2], Cow's milk [1]). Eight childrenhad positive food challenges. The studyconcluded that the increase in Cashewallergy is worrying because it affects youngchildren who may have a reaction withoutever having been exposed to Cashews. Theauthors also point out that a clinical historymay be sufficiently suggestive to allowdiagnosis of Cashew allergy withoutrecourse to food challenges (35).

Significantly, minimal contact may berequired to precipitate symptoms. In a studyof Cashew-allergic individuals, 48% reactedto minimal contact with Cashew, i.e.,smelling, touching, or tasting, but not eating

Cashew. The authors point out that reactionscould be as severe as those from Peanutallergy (36).

Oral allergy has been described in a 26-year-old woman, who experienced tinglingon her tongue and itching both in the throatand on the face immediately after she put aCashew nut onto her tongue. SPT and serumIgE antibody tests were positive for Cashewnuts and negative for Peanuts and other treenuts. Skin reactivity for Cashew nutsnormalised one year after she began avoidingCashew nuts (37).

Life-threatening anaphylactic reactions toCashew nut have been reported, and onestudy reported on 15 subjects (6).Anaphylaxis to Cashew nut was reported ina 20-month-old girl who developed facialangioedema and generalised urticariaimmediately after eating a Cashew nut; in a12-year-old girl who experienced oralitching, generalised urticaria, wheezing,dyspnoea, and dizziness 15 minutes aftereating a single Cashew nut; and in a 36-year-old woman who developed generalisederythema, rhinorrhoea, dyspnoea,dysphagia, nausea, vomiting and diarrhoeaimmediately after eating ice creamcontaining Cashew nut. SPT and IgEantibodies to Cashew and Pistachio nutswere positive in all 3 patients (7). A 42-year-old patient allergic to Pistachio who hadanaphylaxis to Cashew nuts was described.Symptoms included mouth and lip itching,slurred voice, dyspnoea and vomiting a fewminutes after eating some Cashew nuts.History disclosed 3 previous episodes ofadverse reactions to Pistachio. Allergen-specific IgE was negative for both (38).

A 2007 report from Holland points outthat in recent years there has been anincreasing number of patients with ananaphylactic reaction after eating smallamounts of Cashew nut. The reportdescribes a boy aged 7 and 2 girls aged 9and 10 years, with heterogeneous casehistories involving allergic upper airway andconjunctival symptoms and constitutionaleczema, who presented with anaphylacticsymptoms after ingestion of nuts. Allergy toCashew nut was diagnosed in the first 2 andfor Peanut in the third (29).

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f202 Cashew nutCashew nut is reported to cause more

severe reactions than Peanut. In a study toconfirm this, children whose worst-everreaction was to Cashew nut were matchedwith 2 children each whose worst-everreaction was to Peanut, resulting in a totalof 47 children in the Cashew group beingmatched to 94 in the Peanut group. Therewere no differences in overall clinicalfeatures between groups, except for asthma,which was more prevalent in the Peanutgroup. Wheezing and cardiovascularsymptoms were reported more frequentlyduring reactions in the Cashew group,compared with the Peanut group.Furthermore, the Cashew group hadreceived intramuscular adrenaline morefrequently. The authors concluded, by usingcase-matching, that severe clinical reactionsoccur more frequently in Cashew than inPeanut allergy (39).

Inhalation of pectin has been identifiedas a cause of occupational asthma. Thefollowing study describes the first knowncase of allergy to ingested pectin. A 3 1/2-year-old boy developed anaphylaxis onceafter eating Cashew nut and later after eatinga pectin-containing fruit “smoothie”.Significant levels of IgE antibodies forCashew and Pistachio were demonstrated,along with skin reactivity for pectin. Thepectin in the smoothie was confirmed to beof citrus origin, and the authors report cross-reactivity between pectin and Cashew (23).

Anaphylactic reactions may not alwaysbe obviously attributable to Cashew nut, inparticular when the nut is hidden in acompound food. For example, fatalanaphylactic reactions reported in 2adolescents had very different but in bothcases cryptic causes: a sandwich containingCashew nut, and candy. (40) A report wasmade of an allergic reaction to Cashew thatresulted in upper airway obstruction andwas initially misdiagnosed as foreign bodyaspiration. (41) Cases of “idiopathic”anaphylaxis may in fact result frominadvertent contact with Cashew nut (42).

An anaphylactic reaction to Cashew nutwas reported in a non-atopic 60-year-oldman 25 days after he received a liver

allograft from a 15-year-old atopic boy whodied of anaphylaxis after Peanut ingestion.The liver recipient had no history of nutallergy. Post-transplantation skin prick testresults were positive for Peanut, Cashew nut,and Sesame seed, and the donor hadallergen-specific IgE antibodies to the same3 allergens. The authors stated that this caseillustrated that transfer of IgE-mediatedhypersensitivity can occur after livertransplantation, with potentially seriousconsequences (43).

Atopic dermatitis and allergic contactdermatitis (3-4,44-48) from ingestion of orcontact with Cashew nut have frequentlybeen reported, as well as from contact withthe nut shell (49). Hypersensitivity mayresult from contact with the urushiol presentin the shell and contaminating the nut, orfrom the Cashew nut protein. Allergiccontact dermatitis to Cashew nut maysimulate photosensitivity eczema (50).Furthermore, Cashew nut dermatitis shouldbe a consideration for individuals travellingto countries where Cashew nut is a frequentingredient in food (51).

In an American study of 165 patients aged4 months to 22 years with atopic dermatitis,7 foods (Cow's milk, Hen's egg, Peanut, Soy,Wheat, Cod/Catfish, Cashew) accounted for89% of the positive challenges (25).

Other reactions

Pollen from the Cashew nut tree may resultin sensitisation, asthma and allergic rhinitis.In a study of 80 Brazilian subjects withallergic asthma, as documented by previouspositive skin test reactions to various pollens,all 80 were shown to have significant skinreactivity to pollen from this tree. Theauthors suggested a correlation between theCashew tree flowering period and anincreased number of allergic asthma cases(52). Similarly, in an Indian study of 65subjects with allergic asthma, 26 (40%) hadpositive SPT to pollen of this tree. Bronchialprovocation tests were performed in 22 ofthe 26 patients, and 20 (90.9%) had apositive result. Allergen-specific IgE forCashew tree pollen was raised (53).

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f202 Cashew nutThe urushiol dermatitis caused by plants

of the Anacardiaceae family is the mostcommon cause of acute allergic contactdermatitis and systemic dermatitis. Urushiol,containing cardol and ancardic acid, is foundin Cashew nut shell oil. A study of 54individuals who developed a poison ivy-likedermatitis 1 to 8 days after eating importedCashew nuts (contaminated by urushiolfrom the Cashew shell oil) described howthe patients had a very pruritic,erythematous, maculopapular eruption thatwas accentuated in the flexural areas of thebody. Three had blistering of the mouth, and4 had rectal itching. Nine who reacted tothe Cashew extract also reacted to poisonivy urushiol (54).

Systemic contact dermatitis to rawCashew nut found in imported pesto saucehas been described. In this instance, the causewas attributed to the nut shell oil's cardoland anacardic acid. The clinical expressionswere dermatitis with flexural accentuation,typically distributed on the extremities,groin, and buttocks, and occurring generally1 to 3 days after ingestion of raw Cashewnuts contaminated with allergenic oil (3).

Urushiol dermatitis has been describedfollowing the ingestion of homemadeCashew nut butter contaminated by Cashewnut shell oil, which resulted also in perianalcontact dermatitis. The severe systemicdermatitis required 3 weeks of systemicsteroid therapy. The authors state thatperianal eruptions may be due to materialsdeliberately applied to the anogenital regionor to ingested antigens that remainsufficiently intact within the faeces to affectperianal skin (55).

In a series of patients with Cashew nutdermatitis, patch tests were positive tomoistened, crushed raw Cashews but not toroasted Cashews in patients with an internal-external contact type of hypersensitivity toraw Cashews purchased from organic foodstores. Control patients without a history ofpoison ivy sensitivity did not react to theraw Cashew patch test and did not developthe rash on ingestion of large amounts ofraw Cashews. Affected patients had eatenbetween 150 and 450 g of Cashews,prompting the authors to conclude that large

quantities of allergen in raw Cashews wouldprovoke the syndrome in highly sensitivepeople (3). (Other studies have demonstratedthat very low levels of allergen are requiredas a trigger, suggesting that these casesinvolve a protein allergen, whereas in thecases in which high levels are required for areaction, the reaction is to a substance suchas cardol (4)).

With the precautions taken today toavoid contamination of food products withCashew urushiols, it is rare to find a case ofCashew nut dermatitis as a result of urushiolin the United States (55).

47

f202 Cashew nutReferences

1. McGovern TW. Botanical briefs: The cashewtree – Anacardium occidentale L.Cutis 2001;68(5):321-2

2. Lampe KF. Dermatitis-producingAnacardiacea of the Caribbean area.Clin Dermatol 1986;4:171-82

3. Ratner JH, Spencer SK, Grainge JM Cashewnut dermatitis. An example of internal-external contact-type hypersensitivity.Arch Dermatol 1974;110(6):921-3

4. Hamilton TK, Zug KA. Systemic contactdermatitis to raw cashew nuts in a pestosauce.Am J Contact Dermat 1998;9(1):51-54

5. DermNet NZ. Cashew nut.www.dermnetnz.org/dermatitis/plants/cashew.html. Accessed October 2006

6. Teuber SS, Sathe SK, Peterson WR, Roux KH.Characterization of the soluble allergenicproteins of cashew nut (Anacardiumoccidentale L.).J Agric Food Chem 2002;50(22):6543-9

7. Garcia F, Moneo I, Fernandez B, Garcia-Menaya JM, Blanco J, Juste S, Gonzalo.Allergy to Anacardiaceae: description ofcashew and pistachio nut allergens.J Investig Allergol Clin Immunol2000;10(3):173-7.

8. Wang F, Robotham JM, Teuber SS, Tawde P,Sathe SK, Roux KH. Ana o 1, a cashew(Anacardium occidental) allergen of thevicilin seed storage protein family.J Allergy Clin Immunol 2002;110(1):160-6


10. Barre A, Sordet C, Culerrier R, Rancé F,Didier A, Rougé P. Vicilin allergens of peanutand tree nuts (walnut, hazelnut and cashewnut) share structurally related IgE-bindingepitopes.Mol Immunol 2008;45(5):1231-40.


12. Wang F, Robotham JM, Teuber SS, Sathe SK,Roux KH. Ana o 2, a major cashew(Anacardium occidentale L.) nut allergen ofthe legumin family. Int Arch Allergy Immunol2003;132(1):27-39

13. Robotham JM, Wang F, Seamon V, Teuber SS,Sathe SK, Sampson HA, Beyer K, Seavy M,Roux KH. Ana o 3, an important cashew nut(Anacardium occidentale L.) allergen of the2S albumin family. J Allergy Clin Immunol2005;115(6):6-1290

14. Barre A, Jacquet G, Sordet C, Culerrier R,Rouge P. Homology modelling andconformational analysis of IgE-bindingepitopes of Ara h 3 and other leguminallergens with a cupin fold from tree nuts.Mol Immunol 2007;44(12):3243-55

15. van Ree R, Voitenko V, et al. Profilin is across-reactive allergen in pollen andvegetable foods. Int Arch Allergy Immunol1992;98(2):97-104

16. Fernandez C, Fiandor A, Martinez-Garate A,Martinez Quesada J. Allergy to pistachio:crossreactivity between pistachio nut andother Anacardiaceae.Clin Exp Allergy 1995;(25):1254-9

17. Parra FM, Cuevas M, Lezaun A, et al.Pistachio nut hypersensitivity: identificationof pistachio nut allergens.Clin Exp Allergy 1993;23:996-1001

18. Wallowitz M, Peterson WR, Uratsu S,Comstock SS, Dandekar AM, Teuber SS.Jug r 4, a Legumin Group Food Allergen fromWalnut (Juglans regia Cv. Chandler).J Agric Food Chem 2006;54(21):8369-75

19. Gillespie DN, Nakajima S, Gleich G.Detection of allergy to nuts by theradioallergosorbent test.J Allergy Clin Immunol 1976;(57):302-9


21. Choi SY, Sohn JH, Lee YW, Lee EK, Hong CS,Park JW. Characterization of Buckwheat 19-kDAllergen and Its Application for DiagnosingClinical Reactivity. Int Arch Allergy Immunol2007;144(4):267-74

22. Rasanen L, Makinen-Kiljunen S, Harvima RJ.Pectin and cashew nut allergy: cross-reactingallergens? Allergy 1998;53:626-8

23. Ferdman RM, Ong PY, Church JA. Pectinanaphylaxis and possible association withcashew allergy. Ann Allergy Asthma Immunol2006;97(6):759-60

24. Keil H, Wasserman D, Dawson CR. Therelation of hypersensitiveness to poison ivyand to the pure ingredients in cashew nutshell liquid and related substances.Indust Med 1945;14:825-30

25. Burks AW, James JM, Hiegel A, et al. Atopicdermatitis and food hypersensitivityreactions. J Pediatr 1998;132(1):132-6

26. Tariq SM, Stevens M, Matthews S, Ridout S,Twiselton R, Hide DW. Cohort study of peanutand tree nut sensitisation by age of 4 years.BMJ 1996;313(7056):514-7


28. Kakemizu N, Yamakawa Y, Aihara M, Ikezawa Z.A case of cashew nut allergy followed byalmond allergy. [Japanese] Arerugi2003;52(10):1022-6

29. de Groot H. Allergy to cashew nuts andpeanuts. [Dutch] Ned Tijdschr Geneeskd2007 May 5;151(18):997-1001

48

f202 Cashew nut30. Dutau G, Rittie JL, Rance F, Juchet A,

Bremont F. New food allergies. [French]Presse Med 1999;28(28):1553-9

31. Senti G, Ballmer-Weber BK, Wuthrich B.Nuts, seeds and grains from an allergist'spoint of view. [German] Schweiz MedWochenschr 2000;130(47):1795-804

32. Rance F, Dutau G. Asthma and food allergy:report of 163 pediatric cases. [French] ArchPediatr 2002;9 Suppl 3:402s-407s

33. Li H, Zhang H. Hypersensitivity of cashewnut. Chin Med Sci J 1997;12(3):189-92


35. Rance F, Bidat E, Bourrier T, Sabouraud D.Cashew allergy: observations of 42 childrenwithout associated peanut allergy.Allergy 2003;58(12):1311-4

36. Hourihane JO, Harris H, Langton-Hewer S,Kilburn SA, Warner Clinical features ofcashew allergy. Allergy 2001;56(3):252-3

37. Inomata N, Osuna H, Ikezawa Z. Oral allergysyndrome due to cashew nuts in the patientwithout pollinosis. [Japanese] Arerugi2006;55(1):38-42

38. Quercia O, Rafanelli S, Marsigli L, Foschi FG,Stefanini GF. Unexpected anaphylaxis tocashew nut. Allergy 1999;54(8):895-7

39. Clark AT, Anagnostou K, Ewan PW. Cashewnut causes more severe reactions thanpeanut: case-matched comparison in 141children. Allergy 2007;62(8):913-6

40. Sampson HA, Mendelson L, Rosen JP. Fataland near-fatal anaphylactic reactions to foodin children and adolescents.N Eng J Med 1992;(327):380-4

41. Nguyen AD, Gern JE. Food allergymasquerading as foreign body obstruction.Ann Allergy Asthma Immunol2003;90(2):271-2

42. Stricker WE, Anorve-Lopez E, Reed CE. Foodskin testing in patients with idiopathicanaphylaxis. J Allergy Clin Immunol1986;(77):516-9

43. Phan TG, Strasser SI, Koorey D,McCaughan GW, Rimmer J, Dunckley H,Goddard L, Adelstein S. Passive transfer ofnut allergy after liver transplantation.Arch Intern Med 2003;163(2):237-9

44. Orris L. Cashew nut dermatitis. N Y State JMed 1958;58(17 Part 1):2799-800

45. Cueva J. A case of contact dermatitis causedby cashew nuts. [Spanish] Alergia1965;12(4):133-5

46. Centers for Disease Control (CDC). Dermatitisassociated with cashew nut consumption--Pennsylvania. MMWR Morb Mortal Wkly Rep1983;32(9):129-30

47. Bedello PG, Goitre M, Cane D, Roncarolo G,Alovisi V Allergic contact dermatitis tocashew nut.Contact Dermatitis 1985;12(4):235

48. Behl PN Dermatitis from cashew nuts.J Am Acad Dermatol 1985;12(1 Pt 1):117

49. McNairy DJ. Contact dermatitis from cashewnut shell novelties.Ariz Med 1959;16(5):361-2

50. Criado RF, Criado PR, Malaman F, Ensina LF,Vasconcellos C, Aun WT, Mello JF, Pires MC.Nonoccupational allergic contact dermatitisto cashew nut simulating photosensitivityeczema.Am J Contact Dermat 2002;13(2):85-6

51. Maje HA, Freedman DO. Cashew nutdermatitis in a returned traveler.J Travel Med 2001;8(4):213-5

52. Menezes EA, Tome ER, Nunes RN, Nunes AP,Freire CC, Torres JC, et al. Extracts ofAnacardium occidentale (cashew) pollen inpatients with allergic bronchial asthma.J Investig Allergol Clin Immunol2002;12(1):25-8

53. Fernandes L, Mesquita AM. Anacardiumoccidentale (cashew) pollen allergy inpatients with allergic bronchial asthma.J Allergy Clin Immunol 1995;95(2):501-4

54. Marks JG Jr, DeMelfi T, McCarthy MA, Witte EJ,et al. Dermatitis from cashew nuts.J Am Acad Dermatol 1984;10(4):627-31

55. Rosen T, Fordice DB Cashew nut dermatitis.South Med J 1994;87(4):543-6

49

Cicer arietinusFamily: Fabaceae (Leguminosae)Commonnames: Chick pea, Garbanzo

bean, Bengal GramSourcematerial: Dried peasFor continuous updates:www.immunocapinvitrosight.com

f309 Chick pea

Allergen Exposure


Chick pea is a leguminous plant whichproduces hazel nut-shaped, nut-flavouredseeds. Chick pea is an important source ofproteins, carbohydrates, B-group vitaminsand certain minerals, particularly to thepopulations of developing nations. Indiacontributes over 75% of the Chick peaproduction in the world. In India itself, thislegume is consumed mostly as dhal, wholeseeds, and several types of traditional,fermented, deep fried, sweetened, and puffedproducts. Chick peas are a staple food inthe Middle East. Chick peas are also usedextensively in the Mediterranean, especiallyin Spain. The use of Chick peas has spreadalong with ethnic cuisines.

Environment

The Chick pea is unknown in the wild,though there are some related wild species.Chick peas are available canned, dried andsometimes fresh. Chick pea seeds are eatenfresh as green vegetables; parched, fried,roasted, and boiled; and as a snack food,sweet and condiment. Hummus is anespecially popular Chick pea recipe. Seedsare roasted and ground and the flour can beused in soup, as dhal (which has a numberof uses as an ingredient), and to make bread.Sprouted seeds are eaten as a vegetable oradded to salads. Young shoots and greenpods are eaten like spinach (but may betoxic: see under Other reactions). A smallproportion of Chick pea is used to producefermented food. The roasted seed or rootcan be used as a coffee substitute. Acidexudate from the seedpod can be eaten as atype of vinegar.

The acid exudate is astringent. It has beenused in the treatment of a number ofailments, including diarrhea.

Unexpected exposure

Parts of the plant can serve as animal feed,and can be made into adhesive, dye, andstarch.

Allergens

Immunoblot analysis has demonstrated that70, 64, 35, and 26 kDa proteins are majorallergens (1-2). Other studies have detectedmultiple allergens in both raw and boiledChick pea extracts in the molecular weightrange of 10-106 kDa, of which the majoritywere heat-stable (3-4).


Cic a 2S Albumin, a 10-12 kDa protein (5).

Cic a IFR, an Isoflavone Reductase (6).

The presence of an allergen belonging tothe profilin family has been suggested by astudy examining the possible association of

50

f309 Chick peaoral allergy syndrome with Plane tree pollen(Platanus acerifolia) (7). This has beenquestioned by another study (8).

A beta-1,3-glucanase and two chitinaseshave been isolated from Chick pea. One ofthe chitinases, a 32 kDa protein, was shownto be a class I chitinase, and the second, a28 kDa protein, showed homology to classIII chitinases (9). The allergenic significanceof these proteins has not yet beendetermined.

Infection of the Chick pea plant wasshown to initiate the formation of athaumatin-like protein in Chick pea leaves(10). Whether this protein occurs in the seedof the plant or whether it has allergenicpotential has not been determined yet. Also,a trypsin and chymotrypsin inhibitor hasbeen isolated in Chick pea (11). The clinicalsignificance of this has not yet beendetermined.


An extensive cross-reactivity among thedifferent individual species of the Fabaceae(legume family) could be expected but in factdoes not occur frequently (12). In an earlystudy, an in vitro study, the specific IgEbinding by protein extracts of 11 foodlegumes was examined by IgE antibodydetermination and RAST inhibition. Cross-allergenicity was demonstrated to be mostmarked between the extracts of Peanut,Garden pea, Chick pea, and Soybean (13.)Legumes have a high degree ofimmunological cross-reactivity, at least in invitro studies. The allergenicity of legumes ismainly is mainly related to allergens fromthe storage proteins of seeds. Vicilins fromthis group of proteins could be an importantcommon allergen in clinical allergy tolegumes. Other panallergens of increasingimportance are lipid transfer proteins (14).However, some clinical studies have reportedthat there is little cross-reactivity betweenmembers of the legume family (15-16).

In fact, although the different legumeshave structurally homologous proteins, theyare not all equally allergenic, thus making itdifficult to distinguish in vitro and in vivocross-reactivity. Studies in Spanish patients,

in whom a high prevalence of chick peaallergy occurs, have shown that most of thepatients are sensitised to more than onespecies. A great degree of cross-reactivitywas demonstrated among Lentil, Chick pea,Pea and Peanut by inhibition studies. Theauthors report that unlike the Anglo-Saxonpopulation, this phenomenon implies clinicalsensitisation for many Spanish children andthat the majority of these patients have hadsymptoms with more than one legume(median 3 legumes). Of 39 patientschallenged with two or more legumes, 32 (82%) reacted to two or more legumes: 43,5 %to 3, 25,6 % to 2, 13 % to 4 legumes. Seventythree per cent of the patients challenged withLentil and Pea had positive challenge to both,69,4 % to Lentil and Chick pea, 60 % toChickpea and 64,3 % to Lentil, Chick-Peaand Pea simultaneously. Peanut allergy wasassociated with to allergy to Lentil, Chick peaand Pea but less frequently, whereas Whitebean and Green bean and Soybean were welltolerated by children allergic to otherlegumes. The authors stressed that in spite ofan evident clinical and immunological cross-reactivity, the diagnosis of legume allergyshould not be based only on allergen-specificIgE tests (17).

Nevertheless, some reports of specificcross-reactivity between certain members ofthis family have been published. Lentilsappear to be cross-reactive with Chick peaand beans (4,18-19), and cross-reactivitywas shown between Pea, Soybean, Whitebean, Peanut, Lentil, Fennel, Guar gum,Carob bean, Tragacanth, Chick pea andLiquorice (20).

Of 720 patients evaluated for oral allergysyndrome (OAS), and sensitisation to Planetree (P. acerifolia) pollen, 61 (8.48%) weresensitised to pollen from this tree, and foodallergy was reported in 32 (52.45%) of these61 patients. The food allergens mostfrequently implicated were Hazel nuts,Peach, Apple, Peanuts, Maize, Chick pea andLettuce. The study concluded that cross-reactivity was observed between P. acerifoliapollen and plant-derived foods, and thatOAS in these patients may have been causedby primary respiratory sensitisation to Planetree pollen. The authors suggested thatprofilin may be the responsible allergen (7).

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f309 Chick peaCross-reactivity between allergens from

Latex and Chick pea was recently describedin a boy with spina bifida with allergy toChick pea, which developed after theappearance of Latex allergy symptoms. IgEantibodies to Latex and Chick pea weredemonstrated by SPT and serum IgEantibodies (21).

In a Spanish study, symptomatichypersensitivity to Chick peas wasfrequently associated with Lentil allergy(22). In another Spanish study, aimed atdetermining the prevalence of Lupinsensitisation in 1,160 subjects consultingallergologists, a 4,1 % sensitisation rate (28patients) was found, with 75% co-sensitisation between Lupin and legumes. Of28 patients, 13 were shown to have skinreactivity to Chick pea, 8 to Pea, 12 toPeanut, 13 to Bean, and 7 to Lentil (but 18were not tested for Lentil) (23).

Clinical Experience


Chick pea may commonly induce symptomsof food allergy in sensitised individuals, inparticular in communities where this legumeforms part of the staple diet such as India,in the Mediterranean area and Middle East.The clinical manifestations of the allergy toChick pea are similar to that for all legumesranging from oral allergy syndrome,urticaria, angioedema, rhinitis, asthma, toanaphylaxis and death (13,24).

Legumes are an important ingredient inthe Mediterranean diet. In theMediterranean area and Middle East, themost commonly consumed legumes areLentils and Chickpea. (In the United States,United Kingdom and south-east Asia, themajor legumes involved in food allergy areconsidered to be Peanut and Soy bean) (13).Among Spanish children, sensitivity tolegumes is the fifth most prevalent foodallergy. Lentil and Chick pea are the mostfrequent cause of allergic reactions tolegumes in Spanish children (16) but thismay vary from one geographical area toanother: in a study of food allergy in 674patients referred to an Allergy Unit in Spain,

the prevalence of food legume allergy was9.1%. Two patients were challenge-positiveto Chick pea (25).

Chick pea has been reported to be animportant allergen in India. Of 1,400patients screened for Chick pea allergy, 142were food allergy-positive on history, ofwhich 59 implicated Chick peas. Subsequentchallenges demonstrated that 31 wereDBPCFC-positive for Chick pea (2). Furtherreports from India indicate that Chick peais an important source of allergens that cancause IgE-mediated hypersensitivityreactions ranging from rhinitis toanaphylaxis. The ELISA results did notcorrelate well with the DBPCFC results;however, the skin test results correlated withDBPCFC in 75% of patients (1).

Other symptoms reported from Chick peaallergy include urticaria, angioedema,abdominal symptoms, rhinoconjunctivitisand/or asthma, which may follow ingestionor inhalation of vapours from cooked Chickpea and other cooked legumes (Lentil, bean).Lentil was found to induce the most severereactions (26). Other studies have alsoimplicated Chick pea in the genesis ofallergic symptoms following inhalation.Twelve children with an IgE-mediated foodallergy who developed asthma oninhalational exposure to food were identifiedin one study. The implicated foods were Fish,Chick pea, Milk, Egg and Buckwheat. Nineout of the 12 children consented to undergoa bronchial food challenge, of which 5challenges were positive, with objectiveclinical features of asthma. Additionally, twochildren developed late-phase symptoms,with a decrease in lung function. Positivereactions were seen with Fish, Chick pea andBuckwheat (27). Allergic reactions tolegumes through inhalation have also beendescribed in adults, notably a 20-year-oldman who experienced asthmatic attackswhen exposed to the steam from cookingeither Chick pea or Lentil. Type Ihypersensitivity to the antigens in theselegumes was demonstrated by means ofimmediate skin reactivity, histamine releasetests, IgE antibody determinations andRAST inhibition. Specific bronchialchallenges with the heated (75 °C for 30 min)

52

f309 Chick peaextracts of Chick pea and Lentil elicitedisolated immediate responses (4). A 20%reduction in lung function after inhalationof aerosolised Fish, Buckwheat and Chickpea has been reported (28).

Importantly, Chick pea allergens appearto be heat-stable. Sera of 29 children with ahistory of allergic reactions after ingestionof Chick pea, and positive skin tests to thislegume, were used to study the allergeniccomposition of raw and boiled Chick peaextracts. There were no significantdifferences between IgE antibody levels tothe raw and boiled extracts. Patients with acurrent clinical allergy to Chick pea wereshown to have statistically higher IgEantibody levels than tolerant patients andcontrols (3).

Reactions to Chick pea may be severe. An8-year-old girl suffered with contact urticariafrom raw Chick peas and an anaphylacticreaction after ingestion of cooked Chick peas(29). Anaphylactic reactions have beendescribed by other authors (1). Features ofanaphylaxis including severe wheezing andurticaria occurring 1 hour after the ingestionof Chick pea were reported in an 8 year oldIndian girl. She had a previous history ofwheezing following inhalation of chick peaflour or its vapours emitted while beingcooked. External application of chickpeapaste had resulted in urticaria. Specific IgEto Chick pea was detected both in serum andin skin (30).

Occupational exposure may result inallergic reactions. Asthma has been reportedin individuals exposed to vapours fromcooking of some kinds of legumes (Peas,Chick peas, beans, Lentils) (31). Also reportedwas the case of a 20-year-old man whoexperienced asthmatic attacks when exposedto the steam from cooking either Chick peaor Lentil. Type I hypersensitivity to theantigens in these legumes was demonstratedby means of immediate skin reactivity,histamine release tests, IgE antibodydeterminations and RAST inhibition (4).

Other reactions

The foliage and seedpods contain oxalic acidand can irritate the skin. Oxalic acid canlock up certain nutrients in the diet,especially calcium, and therefore heavy useof foods that contain this substance can leadto nutritional deficiencies. Cooking willgreatly reduce the oxalic acid content. Peoplewith a tendency to rheumatism, arthritis,gout, kidney stones or hyperacidity shouldtake especial caution if including this plantin their diet, since the oxalic acid canaggravate their condition.

References1. Patil SP, Niphadkar PV, Bapat MM. Chickpea:

a major food allergen in the Indiansubcontinent and its clinical andimmunochemical correlation. Ann AllergyAsthma Immunol 2001;87(2):140-5

2. Niphadkar, PV Patil, SP, Bapat, MM.Legumes the most important food allergen inIndia. Allergy 1992;47:318

3. Martinez San Ireneo M, Ibanez Sandin MD,Fernandez-Caldas E, Maranon Lizana F,Rosales Fletes MJ, Laso Borrego MT. SpecificIgE levels to Cicer arietinum (Chick pea) intolerant and nontolerant children: evaluationof boiled and raw extracts. Int Arch AllergyImmunol 2000;121(2):137-43

4. Martin JA, Compaired JA, de la Hoz B, Quirce S,Alonso MD, Igea JM, Losada E. Bronchialasthma induced by chick pea and lentil.Allergy 1992;47(2 Pt 2):185-7

5. Vioque J, Sanchez-Vioque R, Clemente A,Pedroche J, Bautista J, Millan F. Purificationand partial characterization of chickpea 2Salbumin.J Agric Food Chem 1999;47(4):1405-9

6. Karamloo F, Wangorsch A, Kasahara H,Davin LB, Haustein D, Lewis NG, Vieths S.Phenylcoumaran benzylic ether andisoflavonoid reductases are a new class ofcross-reactive allergens in birch pollen, fruitsand vegetables.Eur J Biochem 2001;268(20):5310-20

7. Enrique E, Cistero-Bahima A, Bartolome B,Alonso R, San Miguel-Moncin MM, Bartra J,Martinez A. Platanus acerifolia pollinosis andfood allergy. Allergy 2002;57(4):351-6

8. Enrique E, Alonso R, Bartolome B,San Miguel-Moncin M, Bartra J, Fernandez-Parra B, Tella R, Asturias JA, Ibarrola I,Martinez A, Cistero-Bahima A. IgE reactivityto profilin in Platanus acerifolia pollen-sensitized subjects with plant-derived foodallergy. J Investig Allergol Clin Immunol2004;14(4):4-342

53

9. Vogelsang R, Barz W. Purification,characterization and differential hormonalregulation of a beta-1,3-glucanase and twochitinases from chickpea (Cicer arietinum L.).Planta 1993;189(1):60-9

10. Hanselle T, Ichinoseb Y, Barz W. Biochemicaland molecular biological studies on infection(Ascochyta rabiei)-induced thaumatin-likeproteins from chickpea plants (Cicerarietinum L.). Z Naturforsch [C]2001;56(11-12):1095-107

11. Smirnoff P, Khalef S, Birk Y, Applebaum SW.A trypsin and chymotrypsin inhibitor fromchick peas (Cicer arietinum).Biochem J 1976;157(3):745-51



14. Pereira MJ, Belver MT, Pascual CY, MartinEsteban M. The allergenic significance oflegumes. [Spanish] Allergol Immunopathol(Madr) 2002;30(6):346-53



17. Ibanez MD, Martinez M, Sanchez JJ,Fernandez-Caldas E. Legume cross-reactivity.[Spanish] Allergol Immunopathol (Madr)2003;31(3):151-61

18. Martin MA, Compaired JA, de la Hoz B, et.al.Bronchial asthma induced by legumes(abstract). CH Schweiz med Wschr1991;121:2297.S40

19. Sanchez-Monge R, Pascual CY, Diaz-PeralesA, Fernandez-Crespo J, et al. Isolation andcharacterization of relevant allergens fromboiled lentils. J Allergy Clin Immunol2000;106(5 Pt 1):955-61

20. European Federation of Asthma and AllergyAssociations Food Allergy Brochure EFABrochure, Box 5, 3830 Leusden, Netherland1997

21. Branco Ferreira M, Pedro E, Meneses Santos J,Pereira dos Santos MC, Palma Carlos ML,Bartolome B, Palma Carlos AG. Latex andchickpea (Cicer arietinum) allergy: firstdescription of a new association. Allergie etimmunologie 2004;36(10):366-71

22. Pascual CY, Fernandez-Crespo J, SanchezPastor S, Ayuso R, Garcia Sanchez G, Martin-Esteban M. Allergy to lentils in Spain.Pediatr Pulmonol 2001;Suppl 23:41-3

23. Reis AM, Fernandes NP, Marques SL, Paes MJ,Sousa S, Carvalho F, Conde T, Trindade M.Lupin sensitisation in a population of 1,160subjects. Allergol Immunopathol (Madr )2007;35(4):162-3

24. Asero R, Mistrello G, Roncarolo D, Amato S.Detection of some safe plant-derived foodsfor LTP-allergic patients. Int Arch AllergyImmunol 2007;144(1):57-63

25. Alvarado MI, Perez M. Study of food allergyon Spanish population. AllergolImmunopathol (Madr ) 2006;34(5):185-93

26. Carrillo Diaz T, Cuevas Agustin M, Luz DiezGomez M, Losada Cosme E, Moneo Goiri.In vitro immunologic diagnosis ofhypersensitivity to vegetables. [Spanish]Allergol Immunopathol (Madr)1986;14(2):139-46

27. Roberts G, Golder N, Lack G. Bronchialchallenges with aerosolized food inasthmatic, food-allergic children.Allergy 2002;57(8):713-7

28. Golder N, Roberts G, Lack G Aerosolised foodcan provoke asthma in childhood.AAAAI 56th Annual Meeting 2000, March

29. Kalogeromitros D, Armenaka M, Galatas I,Capellou O, Katsarou A. Anaphylaxis inducedby lentils. Ann Allergy Asthma Immunol1996;77(6):480-2

30. Niphadkar PV, Patil SP, Bapat MM. Chickpea-induced anaphylaxis.Allergy 1997;52(1):115-6

31. Garcia Ortiz JC, Lopez Asunsolo A, Cosmes P,Duran AM. Bronchial asthma induced byhypersensitivity to legumes. Allergologia etImmunopathologia 1995;23(1):38-40

f309 Chick pea

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Cocos nuciferaFamily: ArecaceaeCommonnames: Coconut, Common

CoconutSourcematerial: Fresh coconut meatThere have in the past been 60 otherspecies classified under the genusCocos, but the Coconut palm isactually monotypic, meaning thatwithin the genus Cocos only onespecies, nucifera, is now recognised,though within this species arenumerous varietiesFor continuous updates:www.immunocapinvitrosight.com

f36 Coconut

Allergen Exposure


The Coconut is native to tropical easternregions, but today it is also grown in thetropical parts of the United States, in Centraland South America, and in Africa. Thelargest-producing countries are Mozambique,Tanzania and Ghana. Coconut is a staplefood in Asia. Coconuts are both a main sourceof income for many producing countries, anda source of many important products used inthe industrialised world.

The Coconut palm is a long-lived, single-trunk plant up to 30 m tall, with a spiky todrooping crown of long leaves at the top.The fruit, as big as a man's head and 1-2 kgin weight, is a drupe with a thin, smooth,grey-brownish epicarp, a fibrous mesocarpand a woody endocarp. Inside, it contains asingle seed, which is partly liquid (Coconutmilk) and partly solid (Coconut meat).

Environment

Man can use every part of the Coconut.Coconut can be harvested when young, butthe mature fruit is more familiar to the West.

The white nut-meat can be eaten either rawor cooked, alone or in a great variety ofdishes. The sap produces palm wine andvinegar. The apical buds are eaten as “palm-cabbage”. Coconut milk derives from theunripe nuts and is used fresh or fermented.Desiccated Coconut consists of dried andshredded endosperm. Though desiccatedCoconut meat in sweets and pastries is themost visible use of Coconut in the West, theoil is very widely used in processed foodssuch as margarine. Coconut is sensitive tooxidation due to the high oil content andshould be stored in well-sealed containers.

At one time, Coconut oil receivednegative press because of its high level ofsaturated fat. However, recent research hasshown that the fatty acids inunhydrogenated Coconut oil, the medium-chain triglycerides, do not raise serumcholesterol or contribute to heart disease,as do the long-chain triglycerides found inseed oils.

Coconuts are high in protein.Additionally, they have been classified as a“functional food”, providing health benefitsbeyond those from the basic nutrients. Thelauric acid in Coconut oil is converted intomonolaurin in the body. Monolaurin is theantiviral, antibacterial, and antiprotozoalmonoglyceride that destroys lipid-coatedviruses and various pathogenic bacteria inthe body. Studies have also shown some

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f36 Coconutantimicrobial effects of free lauric acid.Coconut oil is also used by hypothyroidsufferers to increase body metabolism andto lose weight.

Non-edible parts of the plant are used forthatch, fertiliser, charcoal, lumber, caulking,components of furniture, tools, gas masksand air filters, and material for basket-weaving and many other handicrafts.Coconut oil may be burned for illuminationand is often used for making natural soapsand other health products, detergents, etc.

Unexpected exposure

See under Environment and Other reactions.

Allergens

Coconut allergens appear to be 55, 35, and36.5 kDa in size. The 35 kDa Coconutprotein was shown to be immunologicallysimilar to Soy glycinin (in the legumin groupof seed storage proteins) (1).

In a 28-year-old man who experiencedanaphylaxis following ingestion of Coconutice-cream, protein bands of 15, 20, 35, 45and 200 kDa were detected. IgE immunoblotshowed intense reactivity to a 78 kDaprotein, and weaker bands for 15-20, 22 and30 kDa proteins (2).

In a study of a patient with anaphylaxisto Coconut and oral symptoms to tree nuts,IgE binding to 35 and 50 kDa protein bandsin Coconut and Hazel nut extracts,respectively, was demonstrated (3).

The serum of a 64-year-old woman, whowas monosensitised to Coconut, demonstratedmultiple allergen-specific IgE-reacting bandsto Coconut milk and Coconut pulp, as well asto dry commercial Coconut powder. The mostprominent proteins involved had an apparentmolecular weight of 18, 22 and 28 kD (4).

An IgE binding protein of about 18 kDaand 2 weaker bands of about 25 and 75 kDawere demonstrated in the serum of a 3-year-old boy who presented with abdominal pain,vomiting, oral allergy syndrome, andoedema of the eyelids immediately afteringesting a Coconut (5).

The following allergens have been isolated:

Coc n 7S globulin (6-7).

Coc n 11S globulin, known as Cocosin (6,8).

Coc n Profilin has been isolated from Coconuttree pollen (9).

A report was made of 2 Coconut-allergicpatients, a 30-year-old man who experiencedsevere oropharyngeal itching, throathoarseness, and gastric pain; and a 4-year-old girl who experienced anaphylaxis. Analmost identical profile of IgE bindingproteins in the Coconut extract wasdemonstrated in both patients. Both reactedstrongly to a band of approximately 29 kDa,shown to be a 7S globulin (7). The 29 kDaband was digested by pepsin in less than 1minute.

Coconut water contains the proteinsglutelin and prolamin (10). Their allergenicpotential has not been assessed.


An extensive cross-reactivity among thedifferent individual species of the genus couldbe expected (11).

A 35 kDa Coconut protein is immuno-logically similar to Soy glycinin (in thelegumin group of seed storage proteins). In2 patients allergic to Coconut, the clinicalreactivity was reported to likely be due tocross-reacting IgE antibodies primarilydirected against Walnut, the original clinicalallergy reported, and most likely against aWalnut legumin-like protein (1). Coconutonly partially inhibited IgE reactivity to 35and 36 kDa bands on a Walnut immunoblot,suggesting that IgE resulting from primaryWalnut exposure was responsible for asecondary cross-reaction to Coconut (12).Even though Coconut is a monocot andWalnut a dicot, a quite distant relationship,evidence of substantial IgE cross-reactivitybetween the 2 nuts was detected (12).Similarly, cross-reactive allergens betweenHazel nut (a tree nut) and Coconut (adistantly related palm family member) havebeen reported (3).

56

f36 CoconutIn a report on 2 Coconut-allergic patients, a

30-year-old man who experienced severeoropharyngeal itching, throat hoarseness, andgastric pain, and a 4-year-old girl whoexperienced anaphylaxis, both reacted stronglyto a band of approximately 29 kDa shown tobe a 7S globulin, a protein with a highcorrelation with a 7S globulin from Elaeisguineensis (Oil Palm). Cross-reactivity wasdemonstrated among Coconut, Walnut, andHazel nut by inhibition studies in patient 2 (7).

There may be a weak association betweenLatex allergy and allergy to Coconut.Among 137 patients with Latex allergy, 49potential allergic reactions to foods werereported in 29 (21.1%). Foods responsiblefor these reactions included Banana (n=9,or 18.3%), Avocado (n=8, or 16.3%),shellfish (n=6, or 12.2%), fish (n=4, or8.1%), Kiwi (n=6, or 12.2%), and Tomato(n=3, or 6.1%); Watermelon, Peach, andCarrot (n=2, or 4.1% each); and Apple,Chestnut, Cherry, Coconut, Apricot,Strawberry, and Loquat (n=1, or 2.0% each).Reactions to foods included local mouthirritation, angioedema, urticaria, asthma,nausea, vomiting, diarrhoea, rhinitis, andanaphylaxis (13).

Clinical Experience


Coconut may uncommonly induce symptomsof food allergy in sensitised individuals (1,14-16). The prevalence of Coconut allergy hasnot been studied; however, the Food Allergyand Anaphylaxis Network (FAAN) Peanutand Tree Nut Allergy Registry in the USA,which collected data on 5,149 patients(mainly children), records that 4 individualsreported allergy to Coconut (17).

A baby of 8 months, fed from birth withmaternal milk, developed severe gastro-intestinal symptoms due to the presence ofCoconut oil in an infant formula. Diagnosiswas made using SPT and oral challenges (18).

A report described 2 Coconut-allergicpatients: a 30-year-old pollen-allergic manmonosensitised to Coconut who presentedwith severe oropharyngeal itching, throathoarseness, and gastric pain 10 minutes after

the intake of fresh Coconut; and a 4-year-old girl with a previous allergy to Walnut(intense oropharyngeal itching and facialpruritic erythema after ingesting a smallamount of Walnut), but not allergic topollen, who developed anaphylaxis onCoconut ingestion. Within 15 minutes ofeating a piece of fresh Coconut, sheexperienced intense oropharyngeal itching,followed by facial angioedema, cough,wheezing and dyspnoea requiring emergencytreatment. Both patients were shown to haveskin reactivity and serum IgE to Coconut.The adult patient did not report any adversereactions Peanut or tree nuts. For him,Coconut-specific IgE was 18 kUA/l. Theyoung girl's IgE was 18.3 kUA/l for Coconut,and IgE for Almond, Hazel nut, and Walnutwere 2.40, 19.70, and 49.0 kUA/l,respectively, with cross-reactivity beingdemonstrated between these (7).

Monosensitisation to Coconut wasdescribed in a 64-year-old woman whoexperienced generalised urticaria, facial anduvula oedema, dysphagia and dyspnoea afew minutes after eating a Coconut biscuit.She also experienced bronchoconstriction,hypotension and hypoxemia minutes aftereating a Spanish sweet containing, amongother ingredients, Coconut. She was notsensitised to the other ingredients. SPT wasstrongly positive for Coconut pulp andCoconut milk, and a skin reaction (oedemaand erythema) developed 4-6 hours later. Noskin reactivity was demonstrated for, amongother substances, Date, Palm pollen, Peanut,Almond, Pistachio nut, Walnut, Hazel nut,Sweet chestnut, Soybean, Cocoa, Chick pea,Lentil, Mustard or Latex. Coconut IgEantibody level was 20.8 kUA/l, but not detectedfor Tree nuts, legumes or Soybean (4).

A 3-year-old boy was described asexperiencing abdominal pain, vomiting, oralallergy syndrome, and oedema of the eyelidsimmediately after ingesting a Coconut sweet.A year after this episode, he experienced thesame symptoms after eating a small portionof fresh Coconut. SPT to Coconut with freshCoconut was strongly positive. SPT wasweakly positive for Almond, and an oralchallenge with Almond was negative. Apatch test with Coconut was negative.Coconut-specific IgE was Class 3 (5).

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f36 CoconutTwo patients aged 50 and 21, with tree nut

allergy manifested by life-threatening systemicreactions, reported systemic reactions after theconsumption of Coconut. The clinicalreactivity in these 2 patients was ascribed tocross-reacting IgE antibodies directedprimarily against Walnut, the original clinicalallergy reported, and most likely against aWalnut legumin-like protein (1).

Anaphylaxis following the ingestion ofCoconut has been reported in a 28-year-oldatopic man following ingestion of Coconutice cream. The reaction consisted of oralpruritis, vomiting and intense angioedemaof the lips and uvula (2).

Concomitant anaphylaxis to Coconutand oral symptoms to Hazel nut have beenreported, with positive SPT to Coconut (3).

Contact dermatitis to Coconut has beenmore commonly reported than Coconutfood allergy. Coconut-derived productsinclude Coconut diethanolamide, cocamidesulphate, cocamide DEA, and CDEA. Theseare commonly present in cosmetics,moisturisers, soaps, hand washing liquidsand other cleansers, and shampoo. An itchy,blistering rash may arise a day or two aftercontact with the allergen and take severaldays to resolve - unless ongoing contact withthe allergen is made, in which case it willpersist (19).

It has been proposed that sensitisation tofoods may occur through topical exposure.A study sought to describe the prevalenceof allergenic foods and herbs in pediatricskin care products and found that Coconutwas the most common food present. It wasfound in 44.4% of the products examined,and was particularly often used in soaps andbody washes (75.9%) and in shampoos(76.9%) (20).

Other reactions

Various substances, e.g., Coconut diethanol-amide (CDEA), are manufactured fromCoconut and Coconut oil. These substancesare widely used as surface-active agents inhand gels, hand-washing liquids, shampoosand dish-washing liquids, and may result incontact dermatitis (19,21).

Pollen from the Coconut tree has beenreported to result in rhinitis and asthma inCoconut pollen-sensitised individuals (22-24).

Occupational allergic conjunctivitis dueto Coconut fibre dust was reported in a 46-year-old who had worked for 10 years in aCoconut fibre mattress factory.Conjunctivitis would develop 20-30 minutesafter he began tufting mattress with Coconutfibre (25).

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f36 CoconutReferences

1. Teuber SS, Peterson WR. Systemic allergicreaction to coconut (Cocos nucifera) in 2subjects with hypersensitivity to tree nut anddemonstration of cross-reactivity to legumin-like seed storage proteins: new coconut andwalnut food allergens.J Allergy Clin Immunol 1999;103(6):1180-5

2. Rosado A, Fernandez-Rivas M, Gonzalez-Mancebo E, Leon F, Campos C, Tejedor MA.Anaphylaxis to coconut.Allergy 2002;57(2):182-3

3. Nguyen SA, More DR, Whisman BA, Hagan LL.Cross-reactivity between coconut andhazelnut proteins in a patient with coconutanaphylaxis. Ann Allergy Asthma Immunol2004;92(2):281-4

4. Martin E, Tornero P, De Barrio M, Pérez CI,Beitia J M, Baeza ML. Monosensitization tococonut.J Allergy Clin Immunol 2004:113:S315

5. Tella R, Gaig P, Lombardero M, Paniagua MJ,Garcia-Ortega P, Richart C. A case of coconutallergy. Allergy 2003;58(8):825-6

6. Balasundaresan D, Sugadev R,Ponnuswamy MN. Purification andcrystallization of coconut globulin cocosinfrom Cocos nucifera.Biochim Biophys Acta 2002;1601(1):121-2

7. Benito C, Gonzalez-Mancebo E, de D, Tolon RM,Fernandez-Rivas M. Identification of a 7Sglobulin as a novel coconut allergen.Ann Allergy Asthma Immunol2007;98(6):580-584

8. Carr HJ, Plumb GW, Parker ML, Lambert N.Characterization and crystallization of an 11Sseed storage globulin from coconut (Cocosnucifera). Food Chemistry 1990;38(1):11-20

9. Liu ZG, Wu YL., Zhang HY. Cloning,expression and immunocharacterization ofpan-allergen profilin in Cocos nucifera.http://www.expasy.org/uniprot/A1Z292 2007:February 6

10. Birosel DM, de Oliveira Ferro V, Holcberg IB,Pitelli AC. Isolation of proteins in coconutwater. [Portuguese] Rev Farm Bioquim UnivSao Paulo 1976;14(1):35-42



13. Kim KT, Hussain H. Prevalence of foodallergy in 137 latex-allergic patients.Allergy Asthma Proc 1999;20(2):95-7

14. Sastre J, Olmo M, Novalvos A, Ibanez D,Lahoz C. Occupational asthma due todifferent spices. Allergy 1996;51(2):117-20


16. Agarkhedkar SR, Bapat HB, Bapat BN.Avoidance of food allergens in childhoodasthma.Indian Pediatr. 2005;42(4):362-6


18. Couturier P, Basset-Stheme D, Navette N,Sainte-Laudy J. A case of coconut oil allergyin an infant: responsibility of “maternalized”infant formulas. [French] Allerg Immunol(Paris) 1994;26(10):386-7

19. Fowler JF Jr. Allergy to cocamide DEA.Am J Contact Dermat 1998;9(1):40-1

20. Newhall KK, Amoruso LS, Sinacore JM,Pongracic JA. Presence of common foodallergens in commercially available pediatricskin care products.J Allergy Clin Immunol 2004:113:S235

21. Pinola A, Estlander T, Jolanki R, Tarvainen K,Kanerva L. Occupational allergic contactdermatitis due to coconut diethanolamide(cocamide DEA).Contact Dermatitis 1993;29(5):262-5

22. Karmakar PR, Chatterjee BP. Cocos nuciferapollen inducing allergy: sensitivity test andimmunological study.Indian J Exp Biol 1995;33(7):489-96

23. Chowdhury I, Chakraborty P, Gupta-Bhattacharya S, Chanda S. Antigenicrelationship between four airborne palmpollen grains from Calcutta, India Ann AgricEnviron Med. 1999; 6(1):53-56

24. Pumhirun P, Towiwat P, Mahakit P.Aeroallergen sensitivity of Thai patients withallergic rhinitis. Asian Pac J Allergy Immunol1997;15(4):183-5

25. Wittczak T, Pas-Wyroslak A, Palczynski C.Occupational allergic conjunctivitis due tococonut fibre dust.Allergy 2005;60(7):970-1

59

Panicum milliaceumFamily: Poaceae (Gramineae)Commonnames: Common millet, Prove

millet, BroomcornMillet, Broom-cornmillet, Hog millet,Russian millet, Browncorn

Sourcematerial: Peeled seedsSee also: Foxtail millet f56 and

Japanese millet f57For continuous updates:www.immunocapinvitrosight.com

f55 Common millet

Allergen Exposure


The name Millet is used to describe seedsfrom several taxonomically divergent speciesof grass. They are grown mostly in marginalareas and under agricultural conditions inwhich major cereals fail to give sustainableyields (3).

See common background for Millets onnext page.

Common millet and the other Millets arenot closely related to Wheat. Common milletwas grown in prehistoric Europe. Becauseof its ability to mature quickly, it is oftencultivated by nomads. This shallow-rootedplant varies in height between 30 and 100cm. The grain contains a comparatively highpercentage of indigestible fibre because theseeds are enclosed in the hulls and aredifficult to remove by conventional millingprocesses (1).

Environment

See common background for Millets on nextpage.

The Millets are important sources of foodfor humans and animals. But in the West,with the exception of natural food stores,Millet is sold mainly as bird feed.

Unexpected exposure

See common background for Millets on nextpage.

Allergens


In a study of 7 patients who experiencedallergic symptoms after ingestion of Millet,immunoblotting detected 3 major allergensin Millet extract, directed to serum IgEantibodies of 6 of the patients. In the controlgroup, 10 of 16 (63%) of Millet-exposedatopic bird keepers were shown to have IgEantibodies directed at allergens in Milletextract. A protein of approximately 36 kDawas recognised by 94% of the patients. Anallergen of approximately 70 kDa wasrecognised by 62% of the patients, and anallergen of approximately 90 kDa by 75%of the patients (4).

In a study, the antigenic relationshipsamong “minor Millets” (Barnyard, Littleand Foxtail millets) and other cereals

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Common background for MilletsThe Millets are not a taxonomic class, but rather a functional one. They are all small-seededgrasses viable in harsh climates, and they are often used for fodder and food.

The Millet species span several genera, most notably in the subfamily Panicoideae, of thegrass family Poaceae. The following are the most widely cultivated species, shown in these tablesin order of worldwide production volume (1).

Table 1a. Origins and common names of Millets.Common name Crop Other Common names Suggested origin

Sorghum Sorghum bicolor Great millet, guinea corn, Northeast quadrantkafir corn, aura, mtama, of Africa (Ethiopia-jowar, cholam. kaoliang, Sudan border)milo, milo-maize

Pearl millet Pennisetum glaucum, Cumbu, spiked millet, Tropical West Africasynonym Pennisetum bajra, bulrush millet,americanum candle millet, dark millet

Foxtail millet Setaria italica Italian millet, German Eastern Asia (China)millet, Hungarian millet,Siberian millet

Common millet Panicum miliaceum Proso millet, hog millet, Central and easternbroom-corn millet, AsiaRussian millet, brown corn,white millet

Finger millet Eleusine coracana African millet, koracan, Uganda orragi, wimbi, bulo, telebun neighbouring region

Table 1b. Minor millets include:Barnyard millet Echinochloa crus-galli Sawa millet, Japanese Japan

barnyard milletKodo millet Paspalum scrobiculatum IndiaLittle millet Panicum sumatrense Southeast AsiaGuinea millet Brachiaria deflexa, Guinea

synonym Urochloa deflexaBrowntop millet Urochloa ramose, synonyms South East Asia

Brachiaria ramose,Panicum ramosum

Modified from: Food and Agriculture Organization of the United Nations Sorghum and millets in humannutrition. ISBN 92-5-103381-1. www.fao.org/DOCREP/T0818e/T0818E01.htm Accessed April 2008.

Teff (Eragrostis tef) and Fonio (Digitaria exilis) are also often classed as Millets; more rarely,Sorghum (Sorghum spp.) and Job's tears (Coix lacrima-jobi) are called Millets. Teff, however,which is common in Ethiopia, is not a true Millet. Fonio (Digitaria exilis), though a Millet, is ofminor importance (1). Some experts regard Sorghum as a Millet; this would make it the mostproductive Millet variety (2).

For centuries, Sorghum and Millet have been staple foods in the semi-arid Asian and Africantropics. For millions of the poorest inhabitants of these places, there is no more important sourceof energy, protein, vitamins and minerals. The crops grow in harsh climates and poor soil, withlittle fertiliser or other inputs. As classic subsistence crops, they are usually consumed by thegrowers rather than traded. However, in the West they are increasingly valued as “natural foods”,which has meant wider commercial availability and a greater variety of uses worldwide.

The basic kernel structure, with pericarp, germ or embryo, and endosperm, is the same forSorghum and the various Millets. The largest part of the kernel is the endosperm, used forstorage. In Foxtail and a few other Millets, the pericarp is like a bag, attached to the endospermat a single point. In Millets and Sorghum, the aleurone layer of the pericarp, located just belowthe seed coat, is rich in minerals, B vitamins and oil, and includes some hydrolysing enzymes.Alcohol-soluble prolamins are the most abundant proteins. There are also albumin and globulin,cross-linked prolamin and other glutelin-like proteins. Millet and sorghum do not contain gluten.

f55 Common millet

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(Wheat, Maize, Rice, Sorghum, Finger milletand Pearl millet) were evaluated using anantibody raised against a 20 kDa prolaminfrom Kodo millet. It was demonstrated thatthis prolamin was related to the prolaminsfrom the other foods. Rice was the onlycommon cereal that did not cross-reactimmunologically with the 20 kDa prolaminof Kodo millet (5). Common millet was notassessed, and it is possible that a similarprotein is present in Common millet.

A Rice protein of 16 kDa was reportedto be involved in cross-allergenicity amongantigens in Rice, Wheat, Corn, Japanesemillet and Foxtail millet (6). This proteinwas subsequently shown to have sequencehomology to Wheat alpha-amylase inhibitorand Barley trypsin inhibitor (7). Commonmillet was not assessed, and it is possiblethat a similar protein is present in Commonmillet.

A beta-amylase of 58 kDa, belonging toa protein family that has allergenic members,was isolated from germinating Commonmillet seed (8). The allergenicity of thisprotein was not evaluated.


Studies have not reported cross-reactivitybetween Millet and Barley, Maize, Oats,Wheat, or grass pollen (Rye, Orchard, andJune grass) (2,9-10). A study found thatthough cross-reactivity to these cereals maybe suggested by the presence of IgEantibodies directed to them, this was notclinically relevant (11).

A Rice protein of 16 kDa has been shownto be involved in cross-allergenicity amongantigens in Rice, Wheat, Maize, Japanesemillet and Foxtail millet (4). However,Common millet was not assessed, andwhether a similar protein can be found inthis Millet is unknown.

Clinical Experience


Hypersensitivity to cereals may occur viainhalation or ingestion. But in spite ofCommon millet being regarded as a potent

allergen, allergy is uncommon, with reportsgenerally confined to case studies (12).

With the increasing popularity of“natural foods”, Millet is more frequentlyincluded in various dishes, which might raisethe incidence of Millet-related allergicreactions. Patients with adverse effects toGluten may substitute Millet for gluten-containing cereals.

Allergic reactions have been describedafter ingestion of Millet, and after inhalationof bird seed dust by people who keep cagedbirds (10,13). Case reports of asthma and/or anaphylaxis after ingestion of foodcontaining Millet have been documented(7,8,10-11,14-17).

Individual cases are most instructive.

The first report of an adverse reaction toCommon millet was described in a 25-yearold clerk who developed anaphylaxis afterthe ingestion of Millet seed. Symptomsdeveloped approximately 30 minutes after a“natural food” dinner, which included aDate-Millet pudding. The symptoms includedperiorbital angioedema, ocular injection,tightness of the throat, shortness of breath,wheezing, intense generalised pruritus, andlower abdominal distress. Significantintradermal skin-test reactivity to Milletextract was shown. IgE antibodies to Milletwere elevated. Histamine release tests werepositive. No cross-allergenicity betweenMillet seed and other grains and grasses (Rye,Orchard, and June grass pollen; Wheat, Oat,and Barley grain) was shown (8).

A meal containing Millet triggered ananaphylactic reaction in a young womanwho kept a Parrot in a cage in her bedroom.Millet seeds were major constituents of thebird's feed (12).

A few minutes after ingestion of a cookiecontaining Millet, a 32-year-old womandeveloped laryngeal pruritus and oedemawith stridor, tightness of the throat, pruritusof the palms and soles, conjunctivitis, facialswelling, and, a few minutes later,bronchospasm and hypotension. She hadpreviously complained of laryngeal itchingafter ingestion of a pastry containing Millet,as well as of an episode of swelling of the

f55 Common millet

62

tongue in her childhood related to ingestionof a particular but unidentified cereal. Noadverse effects were reported to othercommon cereals, including Barley andWheat. Skin reactivity was determined forBarley seed and Wheat flour, but wasnegative for Barley flour, Maize seed andflour, and Oat seed and flour. Skin reactivitywas present for fresh Millet seed extract. IgEantibody determination for Barley, Maize,Oats, and Wheat were negative but raisedfor Common millet (1.7, class 2). Theauthors highlighted the fact that, althoughskin reactivity was found for Wheat andBarley seed, she tolerated them well (7).

Anaphylaxis after ingestion of foodcontaining Millet was reported in a 51-year-old woman who, after ingesting a Milletdumpling, immediately developed generalisedurticaria, mucosal swelling, shortness ofbreath, and “hypotonic” reactions. She hadnot eaten Millet before. She had kept aBudgerigar years before and described havinghad asthmatic attacks while cleaning the birdcage. Skin reactivity was found only to Millet,which was strongly positive. Intradermaltesting was positive for Rye, Oats, Maize, andBarley. SPT for Budgerigar allergens wasnegative. IgE antibody levels were raised fornearly all the cereals evaluated and inparticular for Millet (9).

A study evaluated 7 individuals who allkept caged birds and had experiencedallergic reactions after ingestion of Millet-containing food, with adverse reactionsranging from oral allergy syndrome toanaphylaxis. Symptoms includedconjunctivitis (n=1), collapse (n=1),dyspnoea (n=3), hypotension (n=2), nausea(n=2), oral allergy syndrome (n=2), rhinitis(n=2), and urticaria (n=3). The individualprofiles of these patients were the following:a 13-year-old male (nausea, hypotension), a28-year-old female (oral allergy syndrome),a 32-year-old female (conjunctivitis,dyspnoea, urticaria), a 46-year-old female(rhinitis, dyspnoea, urticaria), a 62-year-oldfemale (nausea, dyspnoea, urticaria,hypotension), a 30-year-old female (rhinitis),and a 40-year-old female (oral allergysyndrome). IgE antibody levels varied fromImmunoCAP classes of 2 to 4. As all of these

subjects kept birds at home and used Milletas birdseed, the authors assumed that thesensitisation to Millet occurred via theinhalant route. Sixty-three percent of thebird keepers had IgE antibodies directed atMillet. Several patients reported respiratorysymptoms while cleaning the bird cage. Theauthors suggested that sensitisation to Milletmay subsequently also elicit food allergy (2).

Anaphylaxis was described in a bird-keepersensitised to Millet via inhalation; theanaphylaxis occurred after oral ingestion (18).

Other reactions

Crude extracts of Millet may containaflatoxins (19).

Some varieties of Millet appear to containcyanide. (20) Fonio millet (Digitaria exilis)contains flavanoids with antithyroidproperties and was reported to have resultedin an epidemic of severely iodine-depletedgoiter, as a result of the presence of apigeninand of luteolin. Other Millets contain C-glycosylflavones (21). Millet diets rich in C-glycosylflavones are goitrogenic (22).

Jimson weed poisoning due tocontamination of Millet porridge with thisseed has been reported (23).

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References1. Food and Agriculture Organization of the

United Nations. Relative importance of milletspecies, 1992-94. Annex II. The WorldSorghum and Millet Economies: Facts,Trends and Outlook. 1996. ISBN 92-5-103861-9. www.fao.org/DOCREP/T0818e/T0818E01.htm Accessed April 2008

2. Alkaemper J, Sorghum and Millet Sorghum.Scientific Centre for the Tropics, Justus-Liebig-Universitaet Giessen, Giessen,Germany. http://www.fertilizer.org/ifa/publicat/html/pubman/sorg&mil.pdf.Accessed April 2008

3. Food and Agriculture Organization of theUnited Nations Sorghum and millets inhuman nutrition. ISBN 92-5-103381-1www.fao.org/DOCREP/T0818e/T0818E01.htm 2008

4. Bohle B, Hirt W, Nachbargauer P, Ebner H,Ebner C. Allergy to millet: another risk foratopic bird keepers.Allergy 2003;58(4):325-8

5. Parameswaran KP, Thayumanavan B.Isolation and characterization of a 20 kDprolamin from kodo millet (Paspalumscrobiculatum L.): homology with othermillets and cereals.Plant Foods Hum Nutr 1997;50(4):359-73

6. Yamada K, Urisu A, Komada H, Inagaki Y,Yamada M, Nakamura R, Torii S. Theinvolvement of rice protein 16KD in cross-allergenicity between antigens in rice, wheat,corn, Japanese millet, Italian millet.[Japanese] Arerugi 1991;40(12):1485-92

7. Izumi H, Adachi T, Fujii N, Matsuda T,Nakamura R, Tanaka K, Urisu A, Kurosawa Y.Nucleotide sequence of a cDNA cloneencoding a major allergenic protein in riceseeds. Homology of the deduced amino acidsequence with members of alpha-amylase/trypsin inhibitor family.FEBS Lett 1992;302(3):213-6

8. Yamasaki Y. Beta-amylase in germinatingmillet seeds.Phytochemistry 2003 Nov;64(5):935-9

9. Olivieri J, Hauser C. Anaphylaxis to millet.Allergy 1998;53(1):109-10

10. Parker JL, Yunginger JW, Swedlund HA.Anaphylaxis after ingestion of millet seeds.J Allergy Clin Immunol 1981;67:78-80

11. Stuck BA, Blum A, Klimek L, Hormann K.Millet, a potentially life-threatening allergen.Allergy 2001;56(4):350

12. Voit C, Kalveram CM, Merkel M, Gall H.Soforttypallergie auf Hirse.Allergologie 1996;19:379-81

13. Eckstein G, Huszar A, Kägi M, Wüthrich B.Hirse: ein seltenes nutritives und inhalativesAllergen? Allergo J 1994;4(3):189

14. Schlacke Kh, Fuchs T. Soforttypallergie aufHirse und Bohne. Anaphylactic reaction dueto millet and beans.Allergologie 1989;12:64-5

15. Steurich F, Feyerabend R. Anaphylaxis tomillet seed. Allergologie 1997;20:69-71

16. Etsamifar M, Wüthrich B. IgE-vermittelteNahrungsmittel-allergien bei 383 Patientenunter Berücksichtigung des oralen. Allergie-Syndroms. Allergologie 1998;21:451-7

17. Wüthrich B. Zur Nahrungsmittelallergie.Häufigheit der symptome und derallergieauslösenden Nahrungsmittel bei 402patienten - Kuhmilchallergie -Nahrungsmittel und Neurodermitis atopica.Allergologie 1993;16:280-7

18. Takahama H, Shimazu T. Common milletanaphylaxis: a case of a bird-keepersensitized to millet via inhalation, whodeveloped anaphylaxis after oral ingestion.Clin Exp Dermatol 2008 May;33(3):341-2

19. Gupta SK. Venkitasubramanian, TA.Production of aflatoxin on soybeans.Applied Micro 1975;29:834-6

20. Shayo NB, Nnko SA, Gidamis AB, Dillon VM.Assessment of cyanogenic glucoside(cyanide) residues in Mbege: an opaquetraditional Tanzanian beer.Int J Food Sci Nutr 1998 Sep;49(5):333-8

21. Sartelet H, Serghat S, Lobstein A, Ingenbleek Y,Anton R, Petitfrère E, Aguie-Aguie G, MartinyL, Haye B. Flavonoids extracted from Foniomillet (Digitaria exilis) reveal potentantithyroid properties.Nutrition 1996 Feb;12(2):100-6

22. Gaitan E, Cooksey RC, Legan J, Lindsay RH.Antithyroid effects in vivo and in vitro ofvitexin: a C-glucosylflavone in millet. J ClinEndocrinol Metab 1995 Apr;80(4):1144-7

23. Rwiza HT. Jimson weed food poisoning. Anepidemic at Usangi rural governmenthospital.Trop Geogr Med 1991;43(1-2):85-90

f55 Common millet

64

Trigonella foenum-graecumFamily: Fabaceae (Leguminosae)Commonnames: Fenugreek, Greek Hay,

Greek Fennel, Bird'sFoot, Greek Hay-seed

Sourcematerial: Dried seedsSynonym: T. foenumgraecumFor continuous updates:www.immunocapinvitrosight.com

f305 Fenugreek

Allergen Exposure


Native to western Asia and south-easternEurope, this aromatic legume plant is wellknown almost worldwide for its pleasantlybitter, slightly sweet seeds, sometimesdescribed as having a suggestion of burntsugar. Fenugreek grows today in many partsof the world, including India, northernAfrica and the United States. The seed, driedfor use, is about 3mm long, about 10 - 20seeds being produced in each long pod. Itsleaves are less widely in use. The seedscomprise of mucilaginous fibre (± 50% byweight) and steroid saponins (± 50% byweight) (1). It was primarily an animalfodder.

Environment

Fenugreek may grow wild, but forcommercial purposes is generally cultivated.The very aromatic leaves (not generallyavailable in the United States) can be usedin salads, as a potherb or a flavoring,especially in curries. Pods may be cookedwhole. Fenugreek seeds, which come wholeand ground, are used to flavor many foods,including curry powders, spice blends andteas. The sprouted seeds can be added tosalads or cooked. An essential oil obtained

from the seed is used as food flavouring inimitation maple syrup, vanilla compositions,liquorice, pickles, etc. The roasted seed is acoffee substitute.

Fenugreek has many uses as an herbalmedicine (both topical and ingested),especially in North Africa, the Middle Eastand India (2). Western pharmacological useshave borne out reports of the plant's efficacy.For example, Fenugreek and isolatedFenugreek fractions have been shown to actas hypoglycaemic and hypocholesterolaemicagents in both animal and human studies(1,3). Fenugreek has been purported to beeffective in initiating and maintainingadequate milk production (4). Research hasalso shown that the seeds can inhibit cancer,lower blood cholesterol levels and have anantidiabetic effect. The seeds are verynourishing and are given to convalescentsand to encourage weight gain, especially inanorexia nervosa. The seeds should not beprescribed medicinally for pregnant women,since they can induce uterine contractions.

Unexpected exposure

The plant is employed as a green manurecrop, for cosmetic purposes, and as a dyeingredient.

Allergens

No allergens from this plant have yet beencharacterised, but allergens between 20 kDato 70 kDa have been detected (2).

65

f305 FenugreekPotential cross-reactivity

An extensive cross-reactivity among thedifferent individual species of the genuscould be expected but in fact is not seenfrequently (5). In an in vitro study, thespecific IgE binding by protein extracts of11 food legumes was examined by IgEantibody determination and RAST inhibition.Cross-allergenicity was demonstrated to bemost marked between the extracts of Peanut,Garden pea, Chick pea, and Soybean (6).However, clinical studies have found thatthere is little cross-reactivity betweenmembers of the legume family (7).

Clinical Experience


Fenugreek has not commonly reported toinduce symptoms of food allergy in sensitisedindividuals.

Reactions may follow ingestion,inhalation or external application ofFenugreek seed powder. Two cases ofimmediate severe allergy to Fenugreek havebeen described. In the first case, inhalationof the Fenugreek seed powder resulted inrhinorrhea, wheezing, and fainting. Thesecond case was of a patient with chronicasthma who developed numbness of thehead, facial angioedema, and wheezing afterapplication of Fenugreek paste to her scalpas a treatment for dandruff. Skin reactivitywas detected to Fenugreek and Chickpeas.During double-blind-placebo-controlled-food-challenge, both patients showed a> 20% drop in peak flow rate afterconsumption of Fenugreek and chickpea (2).

Anaphylaxis to curry powder wasdescribed in a 26-year-old nurse whopresented with bronchospasm. Her initialsymptoms were generalised itching,diarrhoea and stridor which werereproduced 20 minutes later following anoral challenge of curry and rice. Thecausative allergens were narrowed down toCardamom and Fenugreek. Serum IgEantibodies to both were high (8).

An Algerian student using Fenugreekpowder orally as an appetite stimulant andtopically as a healing agent was reported tohave rhinitis and asthma as a result ofhandling the powder. A prick test withFenugreek powder was strongly positive (9).

Fenugreek has also been reported to resultin occupational asthma (10).

This study describes a patient, working ina spice factory, with anaphylaxis fromcoriander in a meal. He also demonstratedurticaria, angioedema, rhinoconjunctivitisand bronchospasm during handling corianderand fenugreek. SPT, serum IgE antibodies andbasophil activation tests were clearly positivein the patient. No cross-reactivity betweenfenugreek and coriander was demonstrableby inhibition experiments (11).

Other reactions

See also under Environment. The seedcontains 1% saponins. Although poisonous,saponins are poorly absorbed by the humanbody and so most pass through withoutharm. Only large amounts tend to bedangerous. Leaching or thorough cookingwill remove most saponins.

Non-steroidal anti-inflammatory drugs,particularly aspirin, have the potential tointeract with herbal supplements containingcoumarin, e.g., Fenugreek, resulting inbleeding (12) or potentiation of the effectsof warfarin therapy (13-14).

Fenugreek, maple syrup, and the urine ofmaple syrup urine disease patients all sharea characteristic odour (“maple-syrup” urineodour), originating from a commoncomponent, sotolone (15-18). Maple syrupurine disease is an autosomal recessiveinherited disorder of amino acid metabolism.The disease gives a characteristic sweetaroma, reminiscent of maple syrup, to thebody fluids, e.g., urine, of affected patients.The substance responsible for the odour is4,5-dimethyl-3-hydroxy-2[5H]-furanone(sotolone), a compound also present inFenugreek and Lovage (19). Ingestion ofFenugreek by mothers during labour resultedin a maple syrup-like odour in their newborninfants, leading to a false suspicion of maplesyrup urine disease (15).

66

f305 FenugreekReferences

1. Mohan V, Balasubramanyam M. Fenugreekand Insulin Resistance. [Editorial] JAPI2001;49:1055-1056

2. Patil SP, Niphadkar PV, Bapat MM. Allergy tofenugreek (Trigonella foenum graecum).Ann Allergy Asthma Immunol1997;78(3):297-300

3. Madar Z, Stark AH. New legume sources astherapeutic agents.Br J Nutr 2002;88 Suppl 3:287-92

4. Gabay MP. Galactogogues: medications thatinduce lactation.J Hum Lact 2002;18(3):274-9


6. Barnett D, Bonham B, Howden ME.Allergenic cross-reactions among legumefoods – an in vitro study. J Allergy ClinImmunol 1987;79(3):433-8


8. Ohnuma N, Yamaguchi E, Kawakami YAnaphylaxis to curry powder.Allergy 1998;53(4):452-4

9. Bessot JC, Gourdon C, Pauli G. Respiratoryallergy to Fenugreek. Rev Fr AllergolImmunol Clin 1996;36(5):510-2

10. Dugue P, Bel J, Figueredo M. Fenugreekcausing a new type of occupational asthma.[Letter] [French] Presse Med1993;22(19):922

11. Ebo DG, Bridts CH, Mertens MH, Stevens WJ.Coriander anaphylaxis in a spice grinder withundetected occupational allergy.Acta Clin Belg 2006;61(3):152-6

12. Abebe W. Herbal medication: potential foradverse interactions with analgesic drugs.J Clin Pharm Ther 2002;27(6):391-401

13. Heck AM, DeWitt BA, Lukes AL. Potentialinteractions between alternative therapiesand warfarin Am J Health Syst Pharm2000;57(13):1221-7

14. Lambert JP, Cormier J. Potential interactionbetween warfarin and boldo-fenugreek.Pharmacotherapy 2001;21(4):509-12

15. Korman SH, Cohen E, Preminger A. Pseudo-maple syrup urine disease due to maternalprenatal ingestion of fenugreek.J Paediatr Child Health 2001;37(4):403-4

16. Bartley GB, Hilty MD, Andreson BD,Clairmont AC, Maschke SP. “Maple-syrup”urine odor due to fenugreek ingestion.N Engl J Med 1981;305(8):467

17. Yalcin SS, Tekinalp G, Ozalp I. Peculiar odorof traditional food and maple syrup urinedisease. Pediatr Int 1999;41(1):108-9

18. Monastiri K, Limame K, Kaabachi N, Kharrat H,Bousnina S, Pousse H, Radhouane M,Gueddiche MN, Snoussi N. Fenugreek odourin maple syrup urine disease.J Inherit Metab Dis 1997;20(4):614-5

19. Podebrad F, Heil M, Reichert S, Mosandl A,Sewell AC, Bohles H. 4,5-dimethyl-3-hydroxy-2[5H]-furanone (sotolone) – theodour of maple syrup urine disease.J Inherit Metab Dis 1999;22(2):107-14

67

Setaria italicaFamily: Poaceae (Gramineae)Commonnames: Foxtail millet, Italian

millet, German millet,Hungarian millet,Siberian millet

Sourcematerial: Peeled seedsSee also: Common millet f55 and

Japanese millet f57For continuous updates:www.immunocapinvitrosight.com

f56 Foxtail millet

Allergen Exposure



See common background for Millets onpage 60.

Foxtail millet and the other Millets arenot closely related to Wheat.

Foxtail millet is used mainly in animalfodder and for bird seed. The mainproduction area is China, but this is the mostimportant Millet in Japan and is widelycultivated in India. Because of its fastmaturation, it is a suitable crop for growingby nomads. The height of the plants variesfrom 1 to 1.5 m, and the colour of the grainvaries from pale yellow through orange, red,brown and black (1).

Environment



Unexpected exposure


Allergens


A number of proteins have been isolatedand described as occurring in Foxtail millet.The allergenic potential of these proteinswas, however, not evaluated.

Barnyard millet, Common millet, Littlemillet, Foxtail millet and Kodo millet werestudied. The protein contents of the selecteddecorticated Millets were found to be 11.0,12.3, 12.9, 10.5 and 10.6%, respectively.Prolamin is a major storage protein inFoxtail millet, whereas glutelin is a majorstorage protein in all the other Millets. Aprotein band at the molecular weight rangeof 20 kDa was found to be homologous inall except Proso millet (2).

A Foxtail millet glutelin of 60 kDa(MG60) has been isolated. The primarystructure at the N-terminal end was almostidentical to those of the granule-bound

68

starch synthase (GBSS) proteins from Rice,Barley, Maize, Wheat and Potato. Commonepitopes from these starch-storing cerealswere corroborated by immunoblot analysis,strongly suggesting a close relationship (3).

In a study, the antigenic relationshipsamong “minor Millets” (Barnyard, Littleand Foxtail millets) and other cereals(Wheat, Maize, Rice, Sorghum, Finger milletand Pearl millet) were evaluated using anantibody raised against a 20 kDa prolaminfrom Kodo millet. It was demonstrated thatthe prolamin was related to the prolaminsfrom the other plants. Rice was the onlycommon cereal that did not cross-reactimmunologically with the 20 kDa prolaminof Kodo millet (4).

A subtilisin inhibitor has been isolatedfrom seeds of Foxtail millet (5).

Proteinase inhibitors (trypsin/chymo-trypsin) have been demonstrated to bepresent in Finger millet, Sorghum, Pearlmillet, Foxtail millet, and Japanese millet (6).The amino acid sequence of an isolatedtrypsin inhibitor (7) had a high degree ofhomology to Bowman-Birk type inhibitorsfrom leguminous and gramineous plants (8).

Cross-allergenicity among Rice, Wheat,Maize, Japanese and Foxtail millet wasexamined by IgE antibody determinationand RAST inhibition studies, demonstratingsignificant close correlations among the 5cereal grain extracts. A Rice protein of16KDa was shown to be one of major allergensin Rice grain extracts (9-10). The proteinshowed sequence homology to Wheat alpha-amylase inhibitor and Barley trypsininhibitor (11). The clinical relevance of thisprotein was not assessed.


A Rice protein of 16 kDa has been shownto be involved in cross-allergenicity amongantigens in Rice, Wheat, Maize, Japanesemillet and Foxtail millet (10). The clinicalrelevance of this allergen was not examined.

In a study, the antigenic relationshipsamong “minor Millets” (Barnyard, Littleand Foxtail millets) and other cereals(Wheat, Maize, Rice, Sorghum, Finger millet

and Pearl millet) were evaluated using anantibody raised against a 20 kDa prolaminfrom Kodo millet. It was demonstrated thatthe prolamin was related to the prolaminsfrom the other plants. Rice was the onlycommon cereal that did not cross-reactimmunologically with the 20 kDa prolaminof Kodo millet (4). The clinical significanceof this was not evaluated.

Clinical Experience


Hypersensitivity to cereals may occur viainhalation or ingestion, but reported allergyto Foxtail millet is rare.

With the increasing popularity of“natural foods”, Millet is more frequentlyincluded in various dishes, which might raisethe incidence of Millet-related allergicreactions. Patients with adverse reaction toGluten may substitute Millet for gluten-containing cereals.

Little information is available on theallergens causing symptoms in patients withatopic dermatitis. One study analysed theIgE immune response to various cereals andto specific protein fractions of Wheat andOats in children with severe atopicdermatitis (AD) and correlated the resultswith challenge studies. In SPT studies, 33children were positive for Wheat and 18 forOats. SPT for Rice, Maize, Millet orBuckwheat were positive in 16 of the 34patients (12).

IgE antibodies against Foxtail milletwere found in serum of patients with atopicdermatitis with or without bronchialasthma (9).

Other reactions


Millet diets rich in C-glycosylflavones aregoitrogenic (14).

f56 Foxtail millet

69


United Nations Sorghum and millets inhuman nutrition. ISBN 92-5-103381-1www.fao.org/DOCREP/T0818e/T0818E01.htm 2008

2. Parameswaran KP, Thayumanavan B.Homologies between prolamins of differentminor millets. Plant Foods Hum Nutr 1995Sep;48(2):119-26

3. Takumi K, Udaka J, Kimoto M, Koga T, Tsuji H.Structural and immunochemical homologiesbetween foxtail millet glutelin 60 kDa andstarch granule-bound starch synthaseproteins from rice, barley, corn and wheatgrains. J Nutr Sci Vitaminol (Tokyo) 2000Apr;46(2):109-12


5. Tashiro M, Asao T, Nakano H, Takahashi K,Kanamori M. Purification andcharacterization of a subtilisin inhibitor fromseeds of foxtail millet, Setaria italica.Agric Biol Chem 1991 Jan;55(1):265-7

6. Pattabiraman TN. Trypsin/chymotrypsininhibitors from millets.Adv Exp Med Biol 1986;199:439-48

7. Tashiro M, Asao T, Hirata C, Takahashi K.Purification, characterization, and amino acidsequence of foxtail millet trypsin inhibitor III.Agric Biol Chem 1991 Feb;55(2):419-26

8. Tashiro M, Asao T, Hirata C, Takahashi K,Kanamori M. The complete amino acidsequence of a major trypsin inhibitor fromseeds of foxtail millet (Setaria italica).J Biochem 1990 Oct;108(4):669-72

9. Urisu A, Yamada K, Masuda S, Komada H,Wada E, et al. 16-kilodalton rice protein isone of the major allergens in rice grainextract and responsible for cross-allergenicitybetween cereal grains in the Poaceae family.Int Arch Allergy Appl Immunol1991;96(3):244-52






f56 Foxtail millet

70

Commonnames: Gluten, Tri a Gluten,

Gliadin, Gamma-Gliadin, Omega-gliadin

Sourcematerial: Gluten from WheatSee also: Wheat f4, Barley f6,

Rye f5, Oat f7,rTri a 19; Omega-5Gliadin f416

For continuous updates:www.immunocapinvitrosight.com

f79 Gluten

Allergen Exposure


Gluten is the elastic rubbery protein presentin Wheat, Rye, Barley and to a lesser degreein Oats. It binds the dough in bread andother baked goods. It contributes toconsistency and sponginess.

Only Gluten from Wheat (and close familymembers), Barley, Rye and Oats may resultin symptoms of coeliac disease (CD) insusceptible individuals. Although Oatscontains Gluten, studies have reported thatlevels are too low to warrant exclusion byindividuals with CD. In contrast, Wheatstarch with a 0.3% protein level has an actualGluten content of around 200 ppm (mg/Kg).

Environment

Food derived from Wheat, Barley and Ryecontains gliadin and is toxic to individualswith CD. Because the type and proportionof prolamin proteins in grains vary, the kindof reaction (if any) they are likely to causealso varies. Corn, Rice, other cereal grainssuch as sorghum, millet, teff, ragi and Job'stears as well as Buckwheat, quinoa andamaranth can safely be ingested by a personwith CD. Wheat, Rye, Barley, Spelt and

kamut, however, should be avoided in CD.Although Oats contain Gluten, studies havereported that levels are too low to warrantexclusion by individuals with CD. However,there are concerns among some authoritieson coeliac disease that even if Oats themselvesare safe, they nonetheless may becontaminated with Wheat, Rye, or Barley (1).

Unexpected exposure

Some foods contain gliadin because they aredirect derivatives from Wheat, such asglucose and maltose syrups. Also posingdangers are Wheat germ oil, and alcoholicbeverages obtained from various gliadin-containing grains, such as beer made fromBarley. In other foods, the residual Wheatproteins may derive from productionpractices; blue cheeses or mold-coveredcheeses, for example, should not be allowedin a Gluten-free diet, since Penicilliuminocula are grown on bread, and thereforeare thought to contain residual gliadin (2).

Allergens

The Gluten allergen has been identifiedand characterized:

The gliadin and glutenin proteins form a“complex” and have been termed Gluten;i.e., Gluten is composed of gliadin andglutelin. Wheat flour contains between 7%and 12% Gluten proteins by weight. Glutenis also known as Tri a Gluten, Gliadin,Gamma-gliadin and Omega-gliadin. SeeWheat f4 for details on the individualgliadins (e.g., Tri a alphabeta-gliadin, Tri aalpha-gliadin, Tri a beta-gliadin, Tri aomega-2 gliadin), and glutelin.

71

f79 GlutenGluten consists mainly of proteins (~ 90%),

which can be divided into alcohol-solublegliadins and alcohol-insoluble glutenins.Wheat flour contains between 7% and 12%Gluten proteins by weight. All glutenproteins are high in proline and glutaminecontents, and that is the predominant basisfor calling them prolamins. Cereal prolaminshave no known function apart from storageand are the major storage proteins in mostcereal seeds (3-4). Prolamins consist of aheterogeneous mixture of proteins of amolecular weight 30-90 kDa (5). There arespecific names for individual prolamins fromdifferent species: secalins from Rye, hordeinsfrom Barley, zeins from Maize, and aveninsfrom Oats.

The following is a list of the type ofprolamin in each grain and the percentagethat the prolamin contributes to the grain'sprotein content:

Wheat: Gliadin 69%Corn: Zein 55%Barley: Hordein 46-52%Sorghum: Kafirin 52%Rye: Secalinin 30-50%Millet: Panicin 40%Oats: Avenin 16%Rice: Orzenin 5%

The 70% ethanol-soluble gliadins of asingle Wheat grain can be separated into upto 50 components and are a heterogeneousmixture of single-chained polypeptides. Theyare divided into 4 groups, here in descendingorder of mobility in accordance with acid-PAGE studies: alpha-, beta-, gamma-, andomega-gliadins (6). Their molecular weightranges from around 30 to 75 kDa.

The 70% ethanol-insoluble glutenins aredivided into high-molecular-weight (HMW)and low-molecular-weight (LMW) glutenins.

The major difference between gluteninsand gliadins is in their functionality. Whilegliadins are single polypeptide chains(monomeric proteins), the glutenins aremultichained structures of polypeptides thatare held together by disulfide bonds.

Data suggest that the different prolaminsmay share regions of amino acid sequencehomology with each other and with someof the water/salt soluble albumin/globulinproteins (7).

Another classification of the glutenproteins is based on the amino acidsequences and does not correspond preciselyto the gliadin/glutenin classification forWheat prolamins discussed above, which isbased on the ability of the proteins to forminter-molecular disulphide bonds. Incontrast, this further classification dividesthe proteins into 3 groups: sulphur-poor (S-poor), S-rich, and high-molecular-weight(HMW) prolamins.

The S-poor prolamins comprise theomega-gliadins of Wheat, the omega-secalinsof Rye, and C hordeins of Barley. The S-richprolamins are the major group of prolaminspresent in Wheat, Barley and Rye, accountingfor approximately 80% of the total fractions.They comprise the alpha-gliadins, thegamma-gliadins and LMW glutenin subunitsof Wheat, the gamma and B hordeins ofBarley and the 40 kDa and 75 kDa gamma-secalins of Rye. The HMW subunits of Wheatglutenin play an important role indetermining the breadmaking quality ofWheat. HMW prolamins are also present inBarley and Rye, where they are called Dhordein and HMW secalins, respectively.

Early studies demonstrated that a numberof Wheat allergens play diverse roles inallergy to Wheat (8-14). Although thealbumin and globulin fractions are the mostprevalent allergens in Wheat-allergicindividuals, IgE binding has beendemonstrated to the water/salt-insolublefractions (gliadin and glutenin) of Wheatflour (5,15).

The alpha- and fast omega- are the mostimmuno-reactive gliadins, with the totalglutenins also being highly immuno-reactive.The development of IgE antibodies to alpha-gliadin and total glutenins is to a moderatedegree associated with the development ofIgE antibodies to water/salt-soluble Wheatallergens and may be due to the presence ofcross-reacting epitopes in the prolamins andthe water/salt-soluble albumins/globulins, inparticular enzyme inhibitors. The develop-ment of allergen-specific IgE to the majorityof gliadins is independent of both the levelsof total IgE and the development of IgEantibodies to water/salt-soluble proteins,suggesting that 2 or more populations of IgEmay be involved in hypersensitivity to cereal

72

f79 Glutenprolamins: those which bind to epitopeshomologous to those found in water/salt-soluble proteins, and those which bind to the-rich repetitive domains of prolamins (16).

Similarly, in a study assessing theallergenicity of the protein fractionsextracted from Wheat flour with indicatedsolvents, the gliadins (ethanol) were thestrongest allergens, followed by glutenins(acetic acid), albumins (water), and globulins(salt water). Of the gliadins, the alpha andbeta fractions were most potent, followedby the gamma and omega types (17).

LMW glutenin, alpha-gliadin, andgamma-gliadin have been identified asallergens in Wheat-allergic patients (18).Alpha-gliadin and fast omega-gliadin havebeen reported to be the allergens associatedwith baker's asthma (5). Low-molecular-weight (LMW) glutenin, one of the water/salt-insoluble proteins, has been reported tobe the major allergen for patients allergic toWheat (19-20). Other researchers haveshown that alpha-gliadin and -gamma-gliadin, in addition to LMW glutenin, arethe allergens for patients with Wheatallergies (18).

Although glutenins usually occur in Wheatas polymers with molecular weights of up to1000 kDa and are held together by disulphidebonds, low-molecular-weight gluteninsubunits have been identified (4-16).

Individual types of gliadin found inGluten have been characterised and mayeach individually or in various combinationsresult in sensitisation. For example, omega-5 gliadin (Tri a 19) from Wheat, a gliadin,also known as fast omega-gliadin, has beenreported to be a major allergen in WDEIA(14,18,20-32). Approximately between 66%and 92% of Wheat-allergic patients arepositive to this allergen. In a study todetermine IgE binding against a panel ofpurified Gluten proteins by using sera from15 patients with WDEIA, approximately80% of the patients reacted to fast omega-gliadin, strongly confirming that thisallergen is a predominant allergen forWDEIA (14). Further information onomega-5 gliadin will be found at Wheat f4in this reference book, and recombinantomega-5 gliadin at rTri a 19; Omega-5Gliadin f416 (Separate reference book).

Potential cross-ReactivityStudies of Wheat allergens have reportedvarious degrees of cross-reactivity. Wheatwater/salt-soluble proteins were reported tocross-react with alpha-gliadin and totalglutenins, the water/salt-soluble proteinssharing cross-reacting epitopes with water/salt-insoluble proteins. The authorssuggested that the development of IgEantibodies to alpha-gliadin may in partdepend on the presence of cross-reactingantibodies to water/salt-soluble Wheatallergens (5). Clear cross-reactivity was alsoreported between gliadin and otherfractions; the authors concluded thatidentical epitopes are found in severaldifferent allergenic molecules of the cerealflours despite their different solubility (5).

Fast omega-gliadin is a major allergenamong water/salt-insoluble proteins in thecase of Wheat-dependent exercise-inducedanaphylaxis in Japanese patients, and IgEagainst fast omega-gliadin cross-reacts togamma-gliadin and slow omega-gliadin (32).Further studies have reported that gamma-70 and gamma-35 secalins in Rye andgamma-3 hordein in Barley cross-react withomega-5 gliadin, suggesting that Rye andBarley may elicit symptoms in patients withWheat-dependent exercise-induced ana-phylaxis. In immunoblotting, anti-omega-5gliadin antibodies bound to 70 kDa and 32kDa proteins in Rye and to a 34-kDa proteinin Barley, but not to proteins in Oats. Theseproteins were identified as Rye gamma-70secalin, Rye gamma-35 secalin and Barleygamma-3 hordein, respectively. In ELISAstudies, 21/23 (91%) patients with Wheat-dependent exercise-induced anaphylaxisshowed IgE antibodies to purified gamma-70 secalin, 19/23 (83%) to gamma-35secalin and 21/23 (91%) to gamma-3hordein. Skin prick testing gave positivereactions to gamma-70 secalin in 10/15(67%) patients, to gamma-35 secalin in 3/15 (20%) patients and to gamma-3 hordeinin 7/15 (47%) patients (24).

Although extensive cross-reactivity canbe expected among the varieties of Wheat,Einkorn Wheats, particularly T.monococcum, are suspected to be less toxicthan bread and pasta Wheats to patientswith coeliac disease (33).

73

f79 Gluten

Clinical Experience


Gluten is among the most important foodcomponents accounting for hypersensitivityreactions in children. Adverse reactions toGluten protein include:

1. Food allergy,

2. Food-dependant exercise-inducedasthma or anaphylaxis,

3. Coeliac disease, a non-IgE-mediatedenteropathy caused by gliadin.

The onset of adverse reactions in the first 2conditions may be immediate, delayed, orboth immediate and delayed (34).

Sensitisation and allergic reactions todistinct gliadins and glutelin are discussedin detail at Wheat f4.

Overview of food allergy to Gluten

The majority of IgE-mediated reactions toWheat involve the albumin and globulinfractions. Gliadin and Gluten in Wheat,Barley and Rye may also induce IgE-mediated reactions. There is increasingevidence that components of gliadin areinvolved in baker's asthma. See Wheat f4,Barley f6 and Rye f5 for further information.

Sensitisation to Gluten by ingestion canlead to food allergy symptoms, whereassensitisation by inhalation causes baker'sasthma and rhinitis. For example, Wheatomega-5 gliadin (Tri a 19) has been shownto be a major allergen in children withimmediate allergy to ingested Wheat (21).

Gluten-dependent exercise-inducedanaphylaxis

The major allergen resulting in Gluten-dependant exercise-induced anaphylaxis(GDEIA) is a gliadin, a common and cross-reactive allergen found in Wheat, Barley andRye. The condition is more commonlydefined according to the predominant foodinvolved, i.e., Wheat-, or Barley-, or Rye-dependant exercise-induced anaphylaxis.GDEIA is a severe IgE-mediated allergicreaction provoked by the combination of theingestion of food containing Gluten withintensive physical exercise during the nextfew hours (26,28-30,35-39). Typical

symptoms are generalised urticaria andsevere allergic reactions such a shock orhypotension (14). GDEIA may occur tomultiple food intake (40).

The involvement of Gluten in thiscondition has been suggested from studies ofWheat. Of the Wheat proteins, omega-5gliadin (Tri a 19), one of the components offast omega-gliadin, has been reported to be amajor allergen in WDEIA (18). Although themechanism is not fully understood, a studyreports that omega-5 gliadin-derived peptidesare cross-linked by tissue transglutaminase(tTG), which causes a marked increase in IgEbinding both in vitro and in vivo. Activationof tTG, during exercise, in the intestinalmucosa of patients with WDEIA could leadto the formation of large allergen complexescapable of eliciting anaphylactic reactions(23). A study suggests that, in addition to IgEantibodies against omega-5 gliadin, IgAantibodies may be involved in thepathogenesis of WDEIA (27).

See Wheat f4 for more on this condition.

Atopic Dermatitis

Wheat, and in particular the Glutencomponent, may result in or exacerbateatopic dermatitis (AD) (41-42). The strongassociation between positive oral Wheatchallenge and positive SPT with ethanol-soluble gliadin suggests that gliadin is animportant allergen for Wheat-allergicchildren with AD (43).

SPT with a NaCl Wheat suspension andethanol-soluble Wheat gliadin wasperformed on 18 Wheat challenge-positiveor Wheat challenge-negative children withAD, 6 adult AD patients with suspectedcereal allergy, and 1 adult with Wheat-dependent exercise-induced urticaria/anaphylaxis. It was reported that 13 of theAD children were Wheat-challenge-positive,that 11 were SPT positive for gliadin andthat all had elevated Gluten-specific IgElevels. Those who were challenge-negativewere negative with both SPT to gliadin andGluten-specific IgE test. Four of the adultpatients responded to a cereal-free diet,although only 2 of them appeared to bepositive with gliadin SPT and Gluten-specificIgE test (43).

74

f79 GlutenOther IgE-mediated food reactions

Gluten may be a “hidden allergen” (44).

Baker's asthma

Baker's asthma is a frequent allergy in thebaking industry. In Germany, approximately1,800 bakers annually claim compensationfor baker's asthma (45). The prevalence ofasthma among bakers has been shown to bearound 10%, and the prevalence of cerealallergy 15-25% (46-47). Of those bakerswho have cereal allergy, up to 35%experience asthma (48). In Japan in recentyears, the number of patients suffering frombaker's asthma caused by bread Wheat hasbeen increasing, and includes not onlypeople engaged in food industries, but alsothose who live near a factory producingWheat flour products (49).

Several protein components of salt extractsof Wheat flour weighing from 10 to 100 kDahave been identified as major IgE-bindingproteins in occupational asthma (50). IgEantibodies to a number of flour componentshave been demonstrated in allergic bakers'sera, with the strongest reactivities occurringto water-soluble Wheat albumins andglobulins, with the former shown in inhibitionstudies to be more reactive than the latter (51-53). However, further analyses havedemonstrated that major IgE-binding proteinsare found in other fractions (gliadin andglutenin) as well (53).

Other reactions

Non-IgE immune reactions to Gluten mayresult in coeliac disease.

Coeliac disease is widespread, occurringin 0.5-1% of the population. Coeliac diseaseis traditionally associated with Europeancountries, particularly Scandinavia, but isnow commonly seen in populations ofEuropean ancestry (North and SouthAmericas, Australia), and in North Africa,the Middle East and South Asia (54). Inadults, the prevalence appears to be 1 in 250-300, while in children it may be as high as 1in 100 (54-55). The prevalence of coeliacdisease among school children from India isnot rare in Wheat-eating areas of NorthIndia (56).

CD disease may occur at any age. Ininfants, symptoms will usually appear onlya few months after the introduction of foodscontaining Gluten into the diet (6-12months); in adulthood, the onset is usuallybetween 30-40 years (57). After onset, it isa life-long disorder. It tends to affect twiceas many females as males.

CD is thought to be the result from aninappropriate T-cell-mediated immuneresponse against ingested Gluten ingenetically pre-disposed individuals. It iscaused by IgA- and IgG-mediated immuneresponses, and approximately 90-95% ofcases are linked to the HLA-DQ2 genecomplex, while 5-10% are seen in those withHLA DQ8 gene complexes. Sensitisation andactivation of the T-lymphocytes lead toinflammation and structural alteration of themucosal lining. The enzyme tissuetransglutaminase is one of the targets of theautoimmune response in coeliac sprue. Theenzyme converts particular glutamineresidues in Gluten peptides into glutamicacid, which results in a higher affinity ofthese peptides for HLA-DQ2 or HLA-DQ8(negative charges are preferred at anchorpositions in the peptide-binding groove ofthis molecule) (54,58-62).

References1. Thompson T. Oats and the gluten-free diet.

J Am Diet Assoc 2003;103(3):376-92. Iametti S, Bonomi F, Sironi E, Scafuri L.

Improved protocols for ELISA determinationof gliadin in some wheat-derived foods. In:Working group on prolamin analysis andtoxicity. Proceedings of the 18th meeting.Verlag Wissenschaftliche Scripten, Zwickau,Germany 2004

3. Osbome TB. The proteins of the wheatkernel. Washington, D.C., CarnegieInstitution 1907;84

4. Shewry PR, Tatham AS. The prolamin storageproteins of cereal seeds: structure andevolution. Biochem J 1990;267(1):1-12

5. Sandiford CP, Tatham AS, Fido R, Welch JA,Jones MG, Tee RD, Shewry PR, NewmanTaylor AJ. Identification of the major water/salt insoluble wheat proteins involved incereal hypersensitivity.Clin Exp Allergy 1997;27(10):1120-9

6. Tatham AS, Shewry PR. The conformation ofwheat gluten proteins. The secondarystructures and thermal stabilities of alpha-,beta-, gamma- and omega-gliadins.J Cereal Sci 1985; 3:103-13

75

f79 Gluten7. Shewry PR, Lafiandra D, Salcedo G et al. N-

terminal amino acid sequences ofchloroform/methanol-soluble proteins andalbumins from endosperms of wheat, barleyand related species.FEBS Letts 1984;175:359-63

8. Gomez L, Martin E, Hernandez D, Sanchez-Monge R, Barber D, del Pozo V, de Andres B,Armentia A, Lahoz C, Salcedo G, et al.Members of the alpha-amylase inhibitorsfamily from wheat endosperm are majorallergens associated with baker's asthma.FEBS Lett 1990;261(1):85-8

9. Pfeil T, Schwabl U, Ulmer WT, Konig W.Western blot analysis of water-soluble wheatflour (Triticum vulgaris) allergens. Int ArchAllergy Appi Immunol 1990:91:224-31


11. Sanchez-Monge R, Gomez L, Barber D,Lopez-Otin C, Armentia A, Salcedo G. Wheatand barley allergens associated with baker'sasthma. Glycosylated subunits of the alpha-amylase-inhibitor family have enhanced IgE-binding capacity.Biochem J 1992;281(Pt 2):401-5

12. Armentia A, Sanchez-Monge R, Gomez L,Barber D, Salcedo G. In vivo allergenicactivities of eleven purified members of amajor allergen family from wheat and barleyflour. Clin Exp Allergy 1993;23(5):410-5

13. Varjonen E, Vainio E, Kalimo K, Juntunen-Backman K, Savolainen J. Skin-prick testand RAST responses to cereals in childrenwith atopic dermatitis. Characterization ofIgE-binding components in wheat and oats byan immunoblotting method.Clin Exp Allergy 1995; 25:1100-7

14. Matsuo H, Morita E, Tatham AS, Morimoto K,Horikawa T, Osuna H, Ikezawa Z, Kaneko S,Kohno K, Dekio S. Identification of the IgE-binding epitope in omega-5 gliadin, a majorallergen in wheat-dependent exercise-induced anaphylaxis.J Biol Chem 2004;279(13):12135-40

15. Walsh BJ, Wrigley CW, Musk AW, Baldo BA.A comparison of the binding of IgE in thesera of patients with bakers' asthma tosoluble and insoluble wheat-grain proteins.J Allergy Clin Immunol 1985;76:23-8

16. Shewry PR, Miles MJ, Tatham AS. Theprolamin storage proteins of wheat andrelated cereals.Prog Biophys Molec Biol 1994;61:37-59

17. Buchanan BB, Adamidi C, Lozano RM, Yee BC,Momma M, Kobrehel K, Ermel R, Frick OL.Thioredoxin-linked mitigation of allergicresponses to wheat. Proc Natl Acad Sci U SA 1997;94(10):5372-7

18. Maruyama N, Ichise K, Katsube T, Kishimoto T,Kawase S, Matsumura Y, Takeuchi Y, Sawada T,Utsumi S. Identification of major wheatallergens by means of the Escherichia coliexpression system.Eur J Biochem 1998;255(3):739-45

19. Watanabe M, Tanabe S, Suzuki T, Ikezawa Z,Arai S. Primary structure of an allergenicpeptide occurring in the chymotryptichydrolysate of gluten. Biosci BiotechnolBiochem 1995;59(8):1596-7

20. Tanabe S, Arai S, Yanagihara Y, Mita H,Takahashi K, Watanabe M. A major wheatallergen has a Gln-Gln-Gln-Pro-Pro motifidentified as an IgE-binding epitope.Biochem Biophys Res Commun1996;219(2):290-3

21. Battais F, Pineau F, Popineau Y, Aparicio C,Kanny G, Guerin L, Moneret-Vautrin DA,Denery-Papini S. Food allergy to wheat:identification of immunogloglin E andimmunoglobulin G-binding proteins withsequential extracts and purified proteins fromwheat flour.Clin Exp Allergy 2003;33(7):962-70

22. Palosuo K, Alenius H, Varjonen E, Koivuluhta M,Mikkola J, Keskinen H, Kalkkinen N, Reunala T.A novel wheat gliadin as a cause of exercise-induced anaphylaxis. J Allergy Clin Immunol1999;103(5 Pt 1):912-7

23. Palosuo K, Varjonen E, Nurkkala J, Kalkkinen N,Harvima R, Reunala T, Alenius H.Transglutaminase-mediated cross-linking of apeptic fraction of omega-5 gliadin enhancesIgE reactivity in wheat-dependent, exercise-induced anaphylaxis. J Allergy Clin Immunol2003;111(6):1386-92

24. Palosuo K, Alenius H, Varjonen E, Kalkkinen N,Reunala T. Rye gamma-70 and gamma-35secalins and barley gamma-3 hordein cross-react with omega-5 gliadin, a major allergenin wheat-dependent, exercise-inducedanaphylaxis. Clin Exp Allergy2001;31(3):466-73

25. Palosuo K, Varjonen E, Kekki OM, Klemola T,Kalkkinen N, Alenius H, Reunala T. Wheatomega-5 gliadin is a major allergen inchildren with immediate allergy to ingestedwheat. J Allergy Clin Immunol2001;108(4):634-8

26. Varjonen E, Vainio E, Kalimo K. Lifethreatening anaphylaxis caused by allergy togliadin and exercise.Clin Exp Allergy 1997;27:162-6

27. Lehto M, Palosuo K, Varjonen E, Majuri ML,Andersson U, Reunala T, Alenius H. Humoraland cellular responses to gliadin in wheat-dependent, exercise-induced anaphylaxis.Clin Exp Allergy 2003;33(1):90-5

28. Morita E, Kameyoshi Y, Mihara S, Hiragun T,Yamamoto S. gamma-Gliadin: a presumptiveallergen causing wheat-dependent exercise-induced anaphylaxis. [Letter] Br J Dermatol2001;145(1):182-4

29. Morita E, Yamamura Y, Mihara S, Kameyoshi Y,Yamamoto S. Food-dependent exercise-induced anaphylaxis: a report of two casesand determination of wheat-gamma-gliadinas the presumptive allergen.Br J Dermatol 2000;143(5):1059-63

30. Gall H, Steinert M, Peter RU. Exercise-induced anaphylaxis to wheat flour.Allergy 2000;55(11):1096-7

76

f79 Gluten31. Seilmeier W, Valdez I, Mendez E, Wieser H.

Comparative investigations of gluten proteinsfrom different wheat species. II.Characterization of omega-gliadins.Eur Food Res Technol 2001;212:355-63

32. Morita E, Matsuo H, Mihara S, Morimoto K,Savage AW, Tatham AS. Fast omega-gliadin isa major allergen in wheat-dependentexercise-induced anaphylaxis.J Dermatol Sci 2003;33(2):99-104

33. Borghi B, Castagna R, Corbellini M, Henu M,Salamini F. Breadmaking quality of Einkornwheat (Triticum monococcum spp.monococcum). Cereal Chem 1996;73208-14

34. Räsänen L, Lehto M, Turjanmaa K,Savolainen J, Reunala T. Allergy to ingestedcereals in atopic children.Allergy 1994;49(10):871-6

35. Perkins DN, Keith PK. Food- and exercise-induced anaphylaxis: importance of history indiagnosis. Ann Allergy Asthma Immunol2002;89:15-23

36. Armentia A, Martin-Santos JM, Blanco M,Carretero L, Puyo M, Barber D. Exercise-induced anaphylactic reaction to grain flours.Ann Allergy 1990;65:149-51

37. Murakami R, Nakahara I, Kanemoto H,Suzuki T, Kasahara K, Mitusuchi M,Makiguchi Y, Takahashi H, Endo T, Imai K.Case of food-dependent exercise-inducedanaphylaxis caused by wheat. [Japanese]Nippon Naika Gakkai Zasshi1997;86(1):138-9

38. Guinnepain MT, Eloit C, Raffard M, Brunet-Moret MJ, Rassemont R, Laurent J. Exercise-induced anaphylaxis: useful screening of foodsensitization. Ann Allergy 1996;77(6):491-6


40. Caffarelli C, Cataldi R, Giordano S, Cavagni G.Anaphylaxis induced by exercise and relatedto multiple food intake.Allergy Asthma Proc 1997;18(4):245-8

41. Sampson HA, Ho DG. Relationship betweenfood-specific IgE concentrations and the riskof positive food challenges in children andadolescents. J Allergy Clin Immunol1997;100(4):444-51

42. Burks AW, James JM, Hiegel A, Wilson G,Wheeler JG, Jones SM, Zuerlein N. Atopicdermatitis and food hypersensitivityreactions. J Pediatr 1998;132(1):132-6

43. Varjonen E, Vainio E, Kalimo K. AntigliadinIgE – indicator of wheat allergy in atopicdermatitis. Allergy 2000;55(4):386-91

44. Steinman HA. Hidden Allergens in Foods.J Allergy Clin Immunol 1996;98(2):241-50

45. Baur X, Degens PO, Sander I. Baker'sasthma: still among the most frequentoccupational respiratory disorders. J AllergyClin Immunol 1998;102(6 Pt 1):984-97

46. Savolainen J. Baker's Asthma: diversity ofallergens. [Editorial] Clin Exp Allergy1997;27:1111-3

47. Armentia A, Martin-Santos JM, Quintero A,Fernandez A, Barber D, Alonso E, Gil I.Bakers' asthma: prevalence and evaluation ofimmunotherapy with a wheat flour extract.Ann Allergy 1990;65:265-72

48. Blands J, Diamant B, Kallos P, Kallos-Deffner L,Lowenstein H. Flour allergy in bakers. I.Identification of allergenic fractions in flourand comparison of diagnostic methods.Int Arch Allergy Appi Immunol1976;52:392-406

49. Kamidaira T, Suetsugu S, Umeda H. Clinicaland immunologic studies on patients withbaker's asthma. [Japanese] Arerugi1986;35(1):47-59

50. Sandiford CP. Cereal-induced occupationalasthma. Clin Exp Allergy 1996;26(2):128-31

51. Weiss W, Vogelmeier C, Görg A.Electrophoretic characterization of wheatgrain allergens from different cultivarsinvolved in baker's asthma.Electrophoresis 1993;14:805-16

52. Baldo, BA, Wrigley, CW. IgE antibodies towheat flour components.Clin Allergy 1978;8:109-24

53. Sutton R, Skerritt JH, Baldo BA, Wrigley CW.The diversity of allergens involved in baker'sasthma. Clin Allergy 1984;14:93-107.

54. Accomando S, Cataldo F. The global village ofceliac disease.Dig Liver Dis. 2004;36 (7):492-8

55. Bingley PJ, Williams AJ, Norcross AJ,Unsworth DJ, Lock RJ, Ness AR, Jones RW;Avon Longitudinal Study of Parents andChildren Study Team. Undiagnosed coeliacdisease at age seven: population basedprospective birth cohort study.2004;328(7435):322-3

56. Sood A, Midha V, Sood N, Avasthi G, Sehgal A.Prevalence of celiac disease among schoolchildren in Punjab, North India.J Gastroenterol Hepatol 2006;21(10):1622-5

57. Hill et al. Guideline for the Diagnosis andTreatment of Celiac Disease in Children:Recommendations of the North AmericanSociety for Pediatric Gastroenterology,Hepatology and Nutrition.J Ped Gastroenterol Nutr 2005;40(1):1-19

58. Raanan S. Advances in celiac disease.Gastroenterol Clin N Am 2003;32:931-947.

59. Vader LW, Stepniak DT, Bunnik EM, Kooy YM,de Haan W, Drijfhout JW, Van Veelen PA,Koning F. Characterisation of cereal toxicityfor celiac disease patients based on proteinhomology in grains.Gastroenterology 2003;125:1105-13

60. Ciclitira PJ. Recent advances in celiacdisease. Clin Med. 2003;3 (2):166-9.

61. McManus R, Kelleher D. Celiac disease- thevillain unmasked?N Engl J Med. 2003:348 (25) 2573-4

62. Louka AS, Sollid LM. HLA in celiac disease:unravelling the complex genetics of acomplex disorder.Tissue Antigens. 2003;61 (2):105-17

77

Phaseolus vulgarisFamily: Fabaceae (Leguminosae)Commonnames: Green bean, Common

bean, French bean,String bean, Snap bean,Wax bean, Haricot bean

Sourcematerial: Fresh beansSee also: White bean f15 and

Red kidney bean f287For continuous updates:www.immunocapinvitrosight.com

f315 Green bean

Allergen Exposure


The genus Phaseolus includes many varietiesof edible Beans. The Green bean, also knownas the French bean or Common bean, has along, slender green pod with small seedsinside. The entire pod is edible. The Waxbean is a pale yellow variety of Green bean.

The pods are usually harvested whenimmature, before the seeds inside havegrown too large. When the pods are left onthe plant to mature fully, the ripe seeds canthen be dried and used as Haricot beans.

Environment

The green pods are commonly used as avegetable. The young leaves can be eatenraw or cooked as a potherb.

The green or dried mature pods, or theseeds alone, are diuretic, hypoglycaemic andhypotensive. Ground into flour, the seeds areused as a homeopathic remedy.

Allergens

No allergens from this plant have yet beenfully characterised.

A 32 kDa IgE-binding protein, a class Ichitinase closely resembling the majorAvocado allergen Prs a 1, has been isolated.This reactive component was stronglyinduced by ethylene treatment. Immunoblotinhibition assays demonstrated cross-reactivity between the 2 allergens. The

purified allergen, designated PvChI, inducedpositive skin prick test responses in 7 of 8patients with Latex-fruit allergy. Thisallergen was completely inactivated byheating (1).

Green bean probably contains heat-labileand heat-stable allergens. A 35 kDa protein,probably a novel allergen and not a chitinase,was detected in a 20-year-old girl whoexperienced anaphylaxis to Green bean. Shereacted to boiled Green bean, which induceda stronger reaction than raw Green bean (2).That some allergens are differently sensitiveto heat was demonstrated in a second study,in which boiling completely abolished skinreactivity (3). In 3 women who developedasthma and rhinitis after exposure to rawGreen beans, but who tolerated ingestion ofcooked Green beans, immunoblots of rawand cooked Green bean extract showed 2 IgE-binding bands with apparent molecularweights of 41.1 and 70.6 kDa. A 47 kDa IgE-binding protein was detected only in rawGreen bean extracts (4).

A common feature of most legumeallergens is their natural resistance tothermal, chemical, and, in some respects,proteolytic denaturation (5).

78

f315 Green beanPotential cross-reactivity

An extensive cross-reactivity among thedifferent individual species of the genuscould be expected but in fact does not occurfrequently (6). In an in vitro study, thespecific IgE binding by protein extracts of11 food legumes was examined by IgEantibody determination and RAST inhibition.Cross-allergenicity was demonstrated to befrequent, and most marked between theextracts of Peanut, Garden pea, Chick pea,and Soybean (7). However, clinical studieshave found that there is little cross-reactivitybetween members of the legume family (8-10).

Nevertheless, legumes are an importantingredient in the Mediterranean diet, andamong Spanish children, sensitivity tolegumes is the fifth most prevalent foodallergy. Lentil and Chick pea are the mostfrequent causes of allergic reactions tolegumes in Spanish children. A high degreeof cross-reactivity has been demonstratedamong Lentil, Chick pea, Pea and Peanut.Unlike in other populations, in Spanishchildren this phenomenon implies clinicalsensitisation for many. In a study of 39 Spanishchildren challenged (open or simple blind) with2 or more legumes, 82% reacted to 2 or morelegumes: 43,5% to 3, 25,6% to 2, and 13%to 4 legumes. However, and surprisingly, thelegumes White bean and Green bean and Soywere well tolerated by children allergic to otherlegumes. Therefore the diagnosis of legumeallergy should not be based only on allergenspecific IgE tests (11).

PvChI, a class I chitinase closely resemblingthe major Avocado allergen Prs a 1, wasdemonstrated through immunoblot inhibitionassays to be cross-reactive (1).

A study investigated the in vitro cross-reactivity of allergens from Mesquite treepollen (Honey Locust tree; Prosopisjuliflora) and Lima bean (Phaseolus limensis/Phaseolus lunatus). Of 110 patients withasthma, rhinitis or both, as evaluated withintradermal skin test, 20 were highly positiveto Mesquite pollen extract. Of these, 12patients showed elevated IgE antibody levelsto Mesquite pollen extract alone, and 4 toboth Lima bean and pollen extract. Limabean extract could inhibit IgE binding to

Mesquite in a dose-dependent manner. Also,humoral and cellular cross-reactivity wasdemonstrated (12). Although cross-reactivity was not investigated betweenMesquite and Green bean per se, cross-reactivity may exist between pollen from thistree and other species of Phaseolus.

Clinical Experience


As a member of the legume family, the Greenbean may often result in symptoms of foodallergy. Allergic reactions caused by skincontact or by inhalation of vapor from rawor boiling Green bean have also beenreported (3-4).

Asthma and rhinitis were reported in 3women after exposure to raw Green bean(and 1 also when exposed to raw Chard). Allwomen tolerated ingestion of cooked Greenbeans. Multiple episodes while handling thesevegetables for cooking were reported. SPTand serum IgE antibody test were positive.Bronchial challenge tests with these allergensshowed positive responses to raw but notcooked Green bean and Chard. Oral foodchallenges with Green bean (raw and cooked)and Chard were negative in all patients (4).Similar symptoms were reported in ahomemaker, who experienced rhino-conjunctivitis, occupational asthma, andcontact urticaria while trimming raw Greenbeans or inhaling vapour from boiling Greenbeans. She was able to eat and touch cookedGreen beans without any ill effect and showedno reactivity to any other foods. Skinreactivity was detected to an allergen in rawGreen beans, but not to boiled Green beans.Rubbing the raw Green bean on the patient'sforearm elicited wheals and pruritus within10 minutes. Bronchial provocation test withboth Green bean extracts was positive andimmediate. Basophil histamine release testwas positive (3).

In an atopic housewife, rhino-conjunctivitis and acute asthma associatedwith unrelated family members, Green beanand Swiss Chard, have been reported. Skintests, histamine release test, IgE antibodydetermination, and bronchial responses after

79

f315 Green beanspecific bronchial challenges were positivefor both (13).

Reactions may be severe. Anaphylaxiswas described in a 20-year-old girl, whichoccurred 1 hour after ingestion of Greenbeans. Her symptoms included gastro-enteritis, generalised urticaria and collapse.SPT demonstrated a greater positivity toboiled Green bean, inducing a strongerreaction than raw Green bean (2).

A 7-year-old boy developed angioedemaassociated with inhalation of vapour fromcooked White bean. SPT evaluated using aprick-by-prick method with White bean waspositive. IgE antibody levels was raised forWhite bean and a closely related familymember, Green bean. The patient developedangioedema after ingestion of cooked Whitebean (14).

Recurrent otitis media with effusion wasreported to be associated with a variety offoods, including beans, but not specificallyGreen bean. Due to the close familyrelationship between these legumes, Greenbean may in future be shown to be similarlyresponsible (15).

Other reactions

Infantile food protein-induced enterocolitissyndrome (FPIES) is a severe cell-mediatedgastrointestinal food hypersensitivitytypically provoked by Cow's milk or Soy. Astudy reported on other foods causing thissyndrome: 14 infants with FPIES caused bygrains (Rice, Oat, and Barley), vegetables(Sweet potato, Squash, String beans, Pea),or poultry (Chicken and Turkey) wereidentified. Typical symptoms of FPIES aredelayed (median: 2 hours) and includevomiting, diarrhoea, and lethargy/dehydration. Eleven infants (78%) reactedto >1 food protein, including 7 (50%) whoreacted to >1 grain. Nine (64%) of allpatients with solid food FPIES also hadCow's milk and/or Soy FPIES. Initialpresentation was severe in 79% of thepatients, prompting sepsis evaluations(57%) and hospitalisation (64%) fordehydration or shock. None of the patientsdeveloped FPIES to maternally ingested

foods while breastfeeding unless the causalfood was fed directly to the infant (16).

Occupational contact dermatitis causedby the leaves of Phaseolus plants has beenreported in a farmer (17).

80

f315 Green beanReferences

1. Sanchez-Monge R, Blanco C, Perales AD,Collada C, Carrillo T, Aragoncillo C, Salcedo G.Class I chitinases, the panallergensresponsible for the latex-fruit syndrome, areinduced by ethylene treatment andinactivated by heating. J Allergy ClinImmunol 2000;106(1 Pt 1):190-5

2. Asero R, Mistrello G, Roncarolo D, Amato S,van Ree R. String bean-induced anaphylaxis.Allergy 2001;56(3):259-60

3. Igea Jm, Fernandez M, et al. Green beanhypersensitivity: an occupational allergy in ahomemaker J Allergy Clin Immunol1994;94:33-5

4. Daroca P, Crespo JF, Reano M, James JM,Lopez-Rubio A, Rodriguez J. Asthma andrhinitis induced by exposure to raw greenbeans and chards. Ann Allergy AsthmaImmunol 2000;85(3):215-8

5. Lalles JP, Peltre G. Biochemical features ofgrain legume allergens in humans andanimals. Nutr Rev 1996;54(4 Pt 1):101-7


7. Barnett D, Bonham B, Howden ME.Allergenic cross-reactions among legumefoods – an in vitro study. J Allergy ClinImmunol 1987;79(3):433-8





12. Dhyani A, Arora N, Jain VK, Sridhara S,Singh BP. Immunoglobulin E (IgE)-mediatedcross-reactivity between mesquite pollenproteins and lima bean, an edible legume.Clin Exp Immunol 2007;149(3):517-24

13. Parra FM, Lazaro M, Cuevas M, Ferrando MC,Martin JA, Lezaun A, Alonso MD, Sanchez-Cano M. Bronchial asthma caused by twounrelated vegetables.Ann Allergy 1993;70(4):324-7

14. Martinez AJ, Callejo MA, Fuentes Gonzalo MJ,Martin GC. Angioedema induced byinhalation of vapours from cooked white beanin a child. Allergol Immunopathol (Madr )2005;33(4):4-230

15. Arroyave CM. Recurrent otitis media witheffusion and food allergy in pediatricpatients. [Spanish] Rev Alerg Mex2001;48(5):141-4


17. Spiewak R, Dutkiewicz J. Occupationalcontact dermatitis to Phaseolus vulgaris in afarmer – a case report.Ann Agric Environ Med 2000;7(1):55-9

81

Corylus avellanaFamily: Betulaceae (Corylaceae)Commonnames: Hazel nut, Hazelnut,

Filbert, Cobnut, CobSourcematerial: Shelled nutsThe terms “Filbert” and “Hazel nut”are often used interchangeably for nutsfrom all plants in the genus Corylus,such as C. silvestris, C. maxima and C.colurnaSee also: Hazel t4For continuous updates:www.immunocapinvitrosight.com

f17 Hazel nut

Allergen Exposure


These wild nuts grow in clusters on the Hazeltree in temperate zones around the world.Hazel is an aggressive spreader and isparticularly common in Europe as a wildgrowth, where it has played a significant rolein the development of the present forestecology. Archaeology shows that the nutswere a prehistoric food and the wood abuilding material, and that tree populationswere not adversely affected by landclearance for Neolithic farming.

The tree grows up to 8 m and has asmooth, copper-coloured bark, which pealsoff in thin papery strips; and twigs coveredin thick, reddish, glandular hairs. Thefertilised flowers develop into clusters ofnuts. The fruit, a 2 cm nut, is surrounded bya leafy bract and ripens in late summer. Thefuzzy outer husk opens as the nut ripens,revealing a hard, smooth shell, inside ofwhich is a sweet, rich, grape-size nut withina bitter brown skin that is sometimesremoved. Italy, Spain, France and Turkeylead in Hazel nut production. The nutsgenerally fall in the autumn and areharvested from the ground and then shelledand dried.

Environment

Many Hazel trees grow wild, aggressivelyforming coppices and scrub. Particularlywhen cultivated, the nuts (often under thename “Filberts”) are used chopped, ground,roasted, blanched, sliced, and as flour andpaste in all manner of sweets. They are alsoeaten whole as a snack (often among “mixednuts”). During the Western holiday season,bowls of mixed nuts still in their shells aretraditionally served, to be cracked withnutcrackers; Hazel nuts are prominent inthese mixtures. Hazel nuts also add flavourand texture to savoury items such as saladsand main dishes.

Unexpected exposure

Hazel nut is widely used and can be a“hidden” allergen; for example, nougat, aningredient in secondary products such asconfections, is a Hazel nut product.

Allergens

Various allergens have been isolated andcharacterised in Hazel nut:

Cor a 1, a 18 kDa protein, a Bet v 1 homologueand a major Hazel nut allergen (1- 2).

Cor a 1.04, and variants (3-4).

Cor a 2, a 14 kDa protein, a profilin (5).

Cor a 8, a 9,4 kDa protein, a lipid transferprotein (2-3,6-7).

82

f17 Hazel nutCor a 9, a 40 kDa, 11S globulin-like protein,a major protein (8).

Cor a 11, a 7S vicilin-like globulin

Cor a Oleosin (9).

Cor a Heat Shock Protein (10).

The Hazel nut major allergens identifiedto date are an 18 kDa protein homologousto Bet v 1 and a 14 kDa allergen homologousto Bet v 2. A 47, a 32, and a 35 kDa allergenwere detected and reported to be majorallergens. The 18 kDa protein was abolishedin roasted Hazel nut. The 47 kDa allergenwas shown to be a sucrose-binding protein,the 35 kDa allergen a legumin, and the 32 kDaallergen a 2S albumin. Patients with severeanaphylactic reactions to Hazelnut showed IgEreactivity to a 9 kDa allergen that wascharacterised as a heat-stable lipid transferprotein (LTP) (6,11). The Bet v 1 homologueallergen may have been the allergen nowidentified as Cor a 1. Roasting of the nutsappears to significantly reduce allergenicactivity. Binding of Cor a 1 was severelydecreased after heating to 80 °C and higher.No activity of this allergen could be detectedin roasted Hazel nut meal.

Three isoforms have been described inHazel tree pollen, Cor a 1.01, 1.02, and 1.03;and 1, Cor a 1.04, in Hazel nut. Cor a 1.04shares greater identity with the Birch pollenallergen Bet v 1 (85%) than with its ownpollen homologue. A comparison of Birchand Hazel tree pollen extracts and Hazel nutCor a 1.04 suggests that in somepopulations, the majority of patients areprimarily sensitised by Birch Bet v 1 (13).

Cor a 1 isoforms of Hazel nut displaydifferent antigenic and allergenic properties,very likely due to few but significantvariations in their amino acid sequences(12). Cor a 1 isoforms appear to represent acomplex set of gene products, some of whichare more allergenic than others. Cor a 1.04is a 17.4 kDa protein expressed in at least 4sub-isoforms, Cor a 1.0401-1.0404, whichare 97-99% identical to each other but shareonly 63% and 71% identity with the Hazelpollen isoforms Cor a 1.0101 and Cor a 1.0301,respectively. Despite the high degree ofidentity between the 4 nut isoforms, and

despite the fact that between 91% and 95%of 43 Hazel nut-allergic patients werereactive with 3 of the 4 versions, 1 form,Cor a 1.0404, reacted with only 74% of thepatients (4).

Sensitisation to Cor a 1.04 wasdemonstrated in 16/17 patients, and to Cor a 2in 7/17 patients. None of this particulargroup of patients appeared to be sensitisedto the lipid transfer protein Cor a 8 (3). Thismay indicate that Cor a 8 is a minor allergenin some populations, but a major allergenin others (see below).

Cor a 1.04 has been identified as themajor Hazel nut allergen in 65 Europeanpatients with positive double-blind, placebo-controlled food challenges to Hazel nut. The11S globulin Cor a 9 was shown to be apollen-independent Hazel nut allergen in theUnited States, whereas the indications werethat Cor a 8, a lipid transfer protein (LTP),was an important Birch pollen-unrelatedHazel nut allergen in Europe. Twenty-sixSpanish patients allergic to Hazel nut withoutBirch pollen allergy, including 10 patientswith anaphylaxis, were evaluated forsensitisation to Cor a 8. The prevalence ofIgE antibody reactivity to this LTP (Cor a 8)was 62% in Hazelnut extract, and 77% tothe recombinant LTP. Natural Cor a 8 andrCor a 8 shared identical epitopes. Only 1patient had positive reactivity to Cor a 1.04,and no patients had positive reactivity toCor a 2. Two sera bound to high-molecular-weight allergens. Cor a 8 was thereforeshown to be a major allergen for a majorityof Spanish patients with Hazel nut allergy,and was responsible for severe allergicreactions (2).

Cor a 9 was recognised by IgE antibodiesfrom 86% (12/14) of patients with Hazelnut allergy and systemic reactions (8).

A low-molecular-weight (17 kDa) heatshock protein recognised by IgE from 10 of14 (71%) Hazel nut-allergic patients isdescribed (10,13).

83

f17 Hazel nutPotential cross-reactivity

An extensive cross-reactivity among thedifferent individual species of the genuscould be expected (14). Cross-reactivitybetween Hazel nut and Hazel tree pollenmay occur. IgE antibodies from all 25patients displaying type I allergic reactionsto the tree pollen as well as allergy to Hazelnuts bound to the major Hazel pollenallergen Cor a 1; and in 16% of the patientsthe IgE antibodies bound to the 14 kDaHazel tree pollen profilin. IgE binding toproteins of comparable molecular weightsin Hazel nut extracts (18 kDa and 14 kDa)was found, suggesting that proteins similarto Cor a 1 and Hazel profilin might also beexpressed in Hazel nuts (5,15).

Indeed, where trees of the familyBetulaceae (e.g., Birch, Alder, Hazel andHornbeam) are prevalent, the cross-reactivity between sensitising pollen and nutallergens can be the leading cause of foodallergies (13). Other authors have found arelationship between Birch pollinosis andsensitisation to Hazelnut, Apple, Kiwi,Carrot, Potato and other vegetables (16-17).

Of 196 Birch pollen-hypersensitivepatients with Oral Allergy Syndrome, 195had Apple and/or Hazel nut allergy, and 103were sensitised to food from the Apiaceaefamily, suggesting that most Apiaceaeallergens cross-react with Apple or Hazel nutallergens, whereas only some Apple or Hazelnut allergens cross-react with Apiaceaeallergenic proteins (18).

A 80.5-83% similarity was demonstratedbetween Cor a 1 isoforms and Bet v 1, themajor Birch pollen allergen (12). Allergy toHazel nuts can therefore be regarded as acommon example of Birch pollen-relatedfood allergy (3). Binding to Bet v 1 wasabolished in roasted Hazel nut (6).

A similarity of 83.6-85% appears to existbetween Cor a 1 isoforms and publishedsequences of Aln g 1, the major allergen fromAlder tree; and a 89.3-95% similaritybetween Car b 1 (and isoforms), the majorallergen from Hornbeam tree. IgE antibodiesfrom tree-pollen-allergic patients reacted withall 4 recombinant isoforms. However, markeddifferences in the IgE binding patterns of thedistinct isoforms were noted (12).

The presence of a Bet v 1-like allergenmay explain the association of Hazel nutallergy with other allergies. In individualswith Kiwi allergy, strong reactions to Appleand Hazel nut were reported and moderatereactions to Carrot, Potato and Avocado.RAST inhibition studies revealed cross-reacting antigens between Birch pollen andKiwi fruit (19).

A 45 and a 30 kDa protein were isolatedand shown to have a 60% homology to theconglutin gamma heavy chain from Lupinseed and to a 7S globulin from Soybean,respectively. A 12 kDa protein, probably a2S albumin, displayed a high degree ofhomology to the 2S albumin from Englishwalnut (Jug r 1). Immunoblot inhibition andIgE binding to Almond 2S albumin andconglutin gamma were demonstrated in thepresence of cross-reacting Walnut or Hazelnut antigens (20).

An important cross-reactivity among thepollen of Platanus acerifolia (London planetree), Hazel nut and Banana has beenreported (21).

Birch may not be the only source ofpollen-induced cross-reactivity, as Mugwort(Artemisia vulgaris) pollen has also beenshown to be cross-reactive with Hazelnutallergens and may also be a sensitising agent.In a pool of 28 individual sera with IgEantibodies to Mugwort pollen and Hazelnut, IgE antibodies to Hazel nut wasinhibited up to 63% by Mugwort pollen.However, the Mugwort pollen-specific IgEwas inhibited only up to 36% by Hazel nut.In immunoblotting inhibition experiments,Hazel nut partially inhibited all the Mugwortpollen bands, except that of the 19 kDaprotein, whereas Mugwort pollen produceda nearly total inhibition of all the Hazel nutallergens (22).

Besides the major role played by Bet v 1homologues in cross-reactivity among Birchpollen, Hazel nut and other foods and plantscontaining these substances, anotherallergen responsible for cross-reactivitybetween Birch pollen and Hazel nut is Hazelnut profilin (Cor a 2) – although the clinicalrelevance of this cross-reactivity has beenquestioned (15,23).

84

f17 Hazel nutIn some populations, the Hazel nut LTP

(Cor a 8) is the major allergen. A Hazel nutLTP allergen has been identified thatdemonstrated a 62% identity with LTPs fromAlmond, 59% with Peach, and 59% withCherry (7). Lipid Transfer Proteins have beenreported to be very relevant panallergens,resulting in adverse reactions after theingestion of botanically unrelated plant-derived foods. It has been suggested that, inview of the high prevalence and severity ofthe allergic reactions induced, Hazel nut,Walnut and Peanut should be regarded aspotentially hazardous to patients sensitisedto Lipid Transfer Protein allergens. (6,24-25).

Cor a 9, from Hazel nut, is an 11Sglobulin seed storage protein family member.This family comprises known food allergensin Peanut (Ara h 3) and Soya bean. Thehomology among these 3 proteins rangesfrom 45% to 50%. One known IgE-bindingepitope of Ara h 3 shares 67% ofhomologous amino acid residues with thecorresponding area of Cor a 9. The aminoacids that differ were previously shown notto be critical for IgE binding in Ara h 3 (8).

Partial cross-reactivity has been reportedto occur between Hazel nut and Macadamianuts (26).

In a study of a patient with anaphylaxisto Coconut and oral symptoms to tree nuts,the presence of cross-reactive allergensbetween Hazel nut (a tree nut) and Coconut(a distantly related palm family member)was shown (27).

Allergy to Kiwi, Poppy seeds and/orSesame seeds often occurs in patients with asimultaneous sensitisation to nuts and flour.In a study, the existence of both cross-reacting and unique components wasobserved; however, the cross-reacting andunique components could be different fordifferent patients (28).

Clinical Experience


Hazel nuts are a common cause of foodallergy (29-30). In a study of 62 patients(adults and children) with nut allergy,Peanuts were the commonest cause of allergy(47), followed by Brazil nut (18), Almond(14), and Hazel nut (13,31). Allergies toPeanut (a legume) and tree nuts (Walnut,Hazelnut, Brazil nut, Pecan) frequently havean onset in the first few years of life,generally persist, and may account for severeand potentially fatal allergic reactions.

Some patients with allergy to Hazel nutmay be allergic to the nut, others to the treepollen, and still others to both. The type ofallergic reaction and the specific allergensrecognised can vary considerably from onegeographic area to another (13).

Allergic reactions to Hazel nuts rangefrom Oral Allergy Syndrome to severeanaphylactic reactions (8,32). Allergy toHazel nut is most frequently observed inpatients with allergy to Birch pollen. Thiscan be explained largely by cross-reactivityof Bet v 1, the major Birch pollen allergen,with its homologue in Hazel nuts, Cor a 1.In addition, profilin and carbohydratestructures can be involved. Symptoms offood allergy in pollen-allergic patients areusually mild and restricted to the oral cavity,i.e., Oral Allergy Syndrome. Allergy to Hazelnuts without concomitant pollen allergy isless common, but symptoms tend to be moresevere and are often systemic (3,11,33-36).

The probability of patients with nut allergyhaving allergen-specific IgE to a particularcombination of Peanut, Hazel nut and Brazilnut is similar, whatever the patients' age andsex. Multiple nut reactivity appears toincrease with increasing age and may be dueto the exposure of previously unchallengedsensitivity. The risk of a patient beingsensitised to multiple nuts is sufficiently highthat patients should always be tested forallergy to a range of nuts if they have a historyof reacting to any nut (37).

85

f17 Hazel nutHazel nut-allergic individuals may react

to very low doses of Hazelnut. A studyreports that 29 Hazel nut-allergic patientshad a positive reaction to increasing-dosechallenges with Hazel nut. Itching of the oralcavity and/or lips was the first symptom inall cases. Additional gastrointestinalsymptoms were reported in 5 patients, anddifficulty in swallowing in 1 patient. Lipswelling was observed in 2 patients, followedby generalised urticaria in 1 of these.Threshold doses for eliciting subjectivereactions varied from 1 mg up to 100 mg ofHazel nut protein (which would be foundin 6.4 to 640 mg of Hazel nut meal) (38).Similar results have been reported in otherstudies. A study of a group of Hazel nut-allergic individuals indicated that 50% ofthe Hazel nut-allergic population will sufferfrom an allergic reaction after the ingestionof 6 mg (95% CI, 2-11 mg) of Hazel nutprotein (8). But roasting of Hazel nutssignificantly reduces their allergenicpotential (3).

Allergic sensitisation may occur early onin life. In 163 infants aged between 1 and12 months with symptoms of food allergy,IgE antibodies to Hazel nuts were detectedin 68 (41.7%) (39).

In a study of 86 subjects (from Milan,Zurich, and Copenhagen) with a history ofsymptoms after Hazel nut ingestion, thediagnosis was confirmed in 67 (77.9%) onthe basis of a DBPCFC. Of these subjects,87% also had positive SPT to Birch pollenextract (40). Hazel nut was reported to haveresulted in asthma in 2.7% of a study groupfollowing DBPCFC oral challenges to Hazelnut (41).

Grass allergy is the most commonpollinosis in Northern Italy. Some patientswith grass allergy show polysensitisationagainst other pollens and plant-derivedfoods. In these patients oral allergicsyndrome (OAS) is frequently associated. Ina study of 56 children suffering fromrespiratory allergy due to grass pollens, inthe 16 patients with food allergy, Hazel nutwas the major triggering food (50%),followed by Peanut (38%), Kiwi (31%),Apple and Walnut (19%) (42).

Severe systemic reactions such asanaphylaxis are possible with allergy toHazel nut. In contrast to IgE bindingpatterns that occur in sera from patients withpollen-related Hazel nut allergy, low-molecular-weight (below 10 kDa) heat-stable proteins are responsible, asdemonstrated in a young woman whoexperienced an anaphylactic reaction afterthe ingestion of Hazel nuts. She was not tree-pollen allergic. Suspect allergens in this sizerange include LTPs and 2S albumins (43). ASpanish study, evaluating 26 Hazel nut-allergic patients, including 10 who hadexperienced anaphylaxis, reported the lipidtransfer protein to be the major allergen inHazel nut allergy, including OAS and themore severe symptoms in the majority ofpatients (2). Food-dependant exercise-inducedanaphylaxis has also been reported (44).

Urticaria to commercial Hazel nut skincream has been reported in a 20-year-old girlwho presented with anaphylaxis to Stringbean (45).

Hidden Hazel nut is a threat to allergicpatients. (46) This may take the form ofHazel nut allergens in Hazel nut oil. Hazelnut or other nut oils may be used inchocolate manufacturing. The nut oil maypose a threat to patients with allergy, butthis would depend on the method ofmanufacture and processing (47).

Occupational allergy to Hazel nuts is alsoa possibility. In a study of workers in candyand pastry manufacturing, SPT with foodextracts used in the manufacturing of theseproducts demonstrated that the mostfrequent positive results occurred withextracts of Cacao (31%), followed byreactions to chocolate (9%), cocoa (6%),Hazel nut (6%), and sugar (2%) (48).

In a study of 37 children with symptomsonly of nocturnal enuresis who wereinvestigated for allergy, IgE antibodyevaluation showed that there may be arelationship between nocturnal enuresis andSoybean and Hazel nut food allergens. Theauthors cautioned that further studies werenecessary to explain the underlyingmechanisms and management of thisdisorder (49).

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f17 Hazel nutOther reactions

Nickel is abundant in Hazel nuts (50).

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Akkerdaas J.H., van Ree R. et al.Determination of threshold levels of patientswith hazelnut allergy using double-blindplacebo-controlled food challenges(DBPCFC"S) [Poster] 8th InternationalSymposium on Problems of Food Allergy2001,ch 11-13, Venice

2. Schocker F, Luttkopf D, Scheurer S, Petersen A,Cistero-Bahima A, Enrique E, San Miguel-Moncin M, Akkerdaas J, van Ree R, Vieths S,Becker WM. Recombinant lipid transferprotein Cor a 8 from hazelnut: a new tool forin vitro diagnosis of potentially severehazelnut allergy.J Allergy Clin Immunol 2004;113(1):141-7

3. Hansen KS, Ballmer-Weber BK, Luttkopf D,Skov PS, Wuthrich B, Bindslev-Jensen C,Vieths S, Poulsen LK. Roasted hazelnuts--allergenic activity evaluated by double-blind,placebo-controlled food challenge.Allergy 2003;58(2):132-8

4. Luttkopf D, Muller U, Skov PS, Ballmer-Weber BK, Wuthrich B, Skamstrup Hansen K,Poulsen LK, Kastner M, Haustein D, Vieths S.Comparison of four variants of a major allergenin hazelnut (Corylus avellana) Cor a 1.04 withthe major hazel pollen allergen Cor a 1.01.Mol Immunol 2002;38(7):515-25

5. Hirschwehr R, Valenta R, Ebner C, Ferreira F,Sperr WR, Valent P, Rohac M, et al.Identification of common allergenicstructures in hazel pollen and hazelnuts: apossible explanation for sensitivity tohazelnuts in patients allergic to tree pollen.J Allergy Clin Immunol 1992;90(6 Pt1):927-36

6. Pastorello EA, Vieths S, Pravettoni V, Farioli L,Trambaioli C, Fortunato D, Luttkopf D,Calamari M, Ansaloni R, Scibilia J, Ballmer-Weber BK, Poulsen LK, Wutrich B, Hansen KS,Robino AM, Ortolani C, Conti A.Identification of hazelnut major allergens insensitive patients with positive double-blind,placebo-controlled food challenge results.J Allergy Clin Immunol 2002;109(3):563-70

7. Frauke Schocker, Lüttkopf D., Scheurer S.,Petersen A., Vieths S., Becker W. M. Cloningand sequencing of the lipid transfer proteinfrom hazelnut (corylus avellana) [Poster] 8thInternational Symposium on Problems ofFood Allergy 2001,ch 11-13, Venice

8. Beyer K, Grishina G, Bardina L, Grishin A,Sampson HA. Identification of an 11Sglobulin as a major hazelnut food allergen inhazelnut-induced systemic reactions.J Allergy Clin Immunol 2002;110(3):517-23

9. Akkerdaas JH, Schocker F, Vieths S, Versteeg S,Zuidmeer L, Hefle SL, Aalberse RC, Richter K,Ferreira F, van Ree R. Cloning of oleosin, aputative new hazelnut allergen, using ahazelnut cDNA library. Mol Nutr Food Res2005 Nov 16;50(1):18-23

10. Beyer K, Bardina L, Grishina G, Sampson H.Identification of a heat shock protein as amajor hazelnut food allergen in hazelnut-induced systemic reactions.J Allergy Clin Immunol 2003;111:S249

11. Akkerdaas J., Wensing M., Knulst A.,Aalberse R., Hefle S., van Ree R.Identification and characterisation ofhazelnut allergens as LTP and 2S albumin[Poster] 8th International Symposium onProblems of Food Allergy 2001,ch 11-13,Venice

12. Breiteneder H, Ferreira F, Hoffmann-Sommergruber K, Ebner C, Breitenbach M,Rumpold H, Kraft D, Scheiner O. Fourrecombinant isoforms of Cor a I, the majorallergen of hazel pollen, show different IgE-binding properties.Eur J Biochem 1993 Mar 1;212(2):355-62


14. Yman L. Botanical relations and immuno-logical cross-reactions in pollen allergy.Pharmacia Diagnostics AB. Upsalla. Sweden.1978: ISBN 91-7260-511-1

15. Wensing M, Akkerdaas JH, van Leeuwen WA,Stapel SO, Bruijnzeel-Koomen CA, Aalberse RC,Bast BJ, Knulst AC, van Ree R. IgE to Bet v 1and profilin: cross-reactivity patterns andclinical relevance. J Allergy Clin Immunol2002;110(3):435-42

16. Caballero T, Martin-Esteban M. Associationbetween pollen hypersensitivity and ediblevegetable allergy: a review. J Investig AllergolClin Immunol 1998;8(1):6-16

17. Jankiewicz A, Aulepp H, Baltes W, Bogl KW,Dehne LI, Zuberbier T, Vieths S. Allergicsensitization to native and heated celery rootin pollen-sensitive patients investigated byskin test and IgE binding. Int Arch AllergyImmunol 1996;111(3):268-78

18. Asero R. Relevance of pollen-specific IgElevels to the development of Apiaceaehypersensitivity in patients with birch pollenallergy. Allergy 1997;52(5):560-4

19. Gall H, Kalveram KJ, Forck G, Sterry W. Kiwifruit allergy: a new birch pollen-associatedfood allergy. J Allergy Clin Immunol1994;94(1):70-6

20. Poltronieri P, Cappello MS, Dohmae N, Conti A,Fortunato D, Pastorello EA, Ortolani C,Zacheo G. Identification and characterisationof the IgE-binding proteins 2S albumin andconglutin gamma in almond (Prunus dulcis)seeds. Int Arch Allergy Immunol2002;128(2):97-104

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21. Miralles JC, Caravaca F, Guillen F,Lombardero M, Negro JM. Cross-reactivitybetween Platanus pollen and vegetables.Allergy 2002;57(2):146-9

22. Caballero T, Pascual C, Garcia-Ara MC,Ojeda JA, Martin-Esteban M. IgEcrossreactivity between mugwort pollen(Artemisia vulgaris) and hazelnut (Abellananux) in sera from patients with sensitivity toboth extracts.Clin Exp Allergy 1997;27(10):1203-11

23. Fah J, Wüthrich B, Vieths S. Anaphylacticreaction to lychee fruit: evidence forsensitization to profilin.Clin Exp Allergy 1995;25(10):1018-23

24. Asero R, Mistrello G, Roncarolo D, Amato S,Caldironi G, Barocci F, van Ree R.Immunological cross-reactivity between lipidtransfer proteins from botanically unrelatedplant-derived foods: a clinical study.Allergy 2002;57(10):900-6

25. Asero R, Mistrello G, Roncarolo D, Amato S,van Ree R. A case of allergy to beer showingcross-reactivity between lipid transferproteins. Ann Allergy Asthma Immunol2001;87(1):65-7

26. Sutherland MF, O'Hehir RE, Czarny D,Suphioglu C. Macadamia nut anaphylaxis:demonstration of specific IgE reactivity andpartial cross-reactivity with hazelnut.J Allergy Clin Immunol 1999;104(4 Pt1):889-90

27. Nguyen SA, More DR, Whisman BA, Hagan LL.Cross-reactivity between coconut andhazelnut proteins in a patient with coconutanaphylaxis. Ann Allergy Asthma Immunol2004;92(2):281-4

28. Vocks E, Borga A, Szliska C, Seifert HU,Seifert B, Burow G, Borelli S. Commonallergenic structures in hazelnut, rye grain,sesame seeds, kiwi, and poppy seeds.Allergy 1993;48(3):168-72

29. de Groot H, de Jong NW, Vuijk MH, Gerth vanWijk R. Birch pollinosis and atopy caused byapple, peach, and hazelnut; comparison ofthree extraction procedures with two applestrains. Allergy 1996;51(10):712-8

30. Molkhou P. The problems of the child withfood allergies. [French] Allerg Immunol(Paris) 2003;35(1):7-8


32. Ortolani C, Ispano M, Pastorello EA, Ansaloni R,Magri GC. Comparison of results of skin pricktests (with fresh foods and commercial foodextracts) and RAST in 100 patients with oralallergy syndrome.J Allergy Clin Immunol;83(3):683-90


34. Anhoej C, Backer V, Nolte H. Diagnosticevaluation of grass- and birch-allergicpatients with oral allergy syndrome.Allergy 2001;56(6):548-52

35. Kalyoncu AF, Demir AU, Kisacik G, Karakoca Y,Iskandarani A, Coplu L, Sahin AA, Baris YI.Birch pollen related food hypersensitivity: asa para-occupational syndrome. AllergolImmunopathol (Madr) 1995;23(2):94-5

36. Bindslev-Jensen C, Vibits A, Stahl Skov P,Weeke B. Oral allergy syndrome: the effect ofastemizole. Allergy 1991;46(8):610-3

37. Pumphrey RS, Wilson PB, Faragher EB,Edwards SR. Specific immunoglobulin E topeanut, hazelnut and brazil nut in 731patients: similar patterns found at all ages.Clin Exp Allergy 1999;29(9):1256-9

38. Wensing M, Penninks AH, Hefle SL,Akkerdaas JH, van Ree R, Koppelman SJ,Bruijnzeel-Koomen CA, Knulst AC. The rangeof minimum provoking doses in hazelnut-allergic patients as determined by double-blind, placebo-controlled food challenges.Clin Exp Allergy 2002;32(12):1757-62

39. Hofman T. Specific IgE antibodies for nuts ininfants. [Polish] Pol Tyg Lek 1994 Apr 4-11;49(14-15):328-9

40. Ortolani C, Ballmer-Weber BK, Hansen KS,Ispano M, Wuthrich B, Bindslev-Jensen C,Ansaloni R, Vannucci L, Pravettoni V, Scibilia J,Poulsen LK, Pastorello EA. Hazelnut allergy:a double-blind, placebo-controlled foodchallenge multicenter study.J Allergy Clin Immunol 2000;105(3):577-81

41. Rance F, Dutau G. [Asthma and food allergy:report of 163 pediatric cases. [French] ArchPediatr 2002;9 Suppl 3:402s-407s

42. Ricci G, Righetti F, Menna G, Bellini F,Miniaci A, Masi M. Relationship betweenBet v 1 and Bet v 2 specific IgE and foodallergy in children with grass pollenrespiratory allergy.Mol Immunol 2005;42(10):10-1257

43. Schocker F, Luttkopf D, Muller U, Thomas P,Vieths S, Becker WM. IgE binding to uniquehazelnut allergens: identification of nonpollen-related and heat-stable hazelnutallergens eliciting severe allergic reactions.Eur J Nutr 2000;39(4):172-80

44. Martin Munoz F, Lopez Cazana JM, Villas F,Contreras JF, Diaz JM, Ojeda JA. Exercise-induced anaphylactic reaction to hazelnut.Allergy 1994;49(5):314-6

45. Asero R, Mistrello G, Roncarolo D, Amato S,van Ree R. String bean-induced anaphylaxis.Allergy 2001;56(3):259-60

46. Wensing M, Koppelman SJ, Penninks AH,Bruijnzeel-Koomen CA, Knulst AC. Hiddenhazelnut is a threat to allergic patients.Allergy 2001;56(2):191-2


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48. Zuskin E, Kanceljak B, Mustajbegovic J,Schachter EN. Immunologic findings inconfectionary workers.Ann Allergy 1994;73(6):521-6

49. Mungan NA, Seckiner I, Yesilli C, Akduman B,Tekin IO. Nocturnal enuresis and allergy.Scand J Urol Nephrol 2005;39(3):237-41

50. Veien NK, Andersen MR. Nickel in Danish food.Acta Derm Venereol 1986;66(6):502-9

f17 Hazel nut

89

Echinochloa crus-galliFamily: Poaceae (Gramineae)Commonnames: Japanese millet,

Cockspur, Barnyardgrass, Sawa millet

Sourcematerial: Peeled seedsSee also: Common millet f55 and

Foxtail millet f56For continuous updates:www.immunocapinvitrosight.com

f57 Japanese millet

Allergen Exposure




Japanese millet and the other Millets arenot closely related to Wheat.

Japanese millet is the fastest growing ofall Millets and produces a crop in 6 weeks.It is grown in India, Japan and China as asubstitute for Rice when the paddy fails. Itis grown as a forage crop in the United Statesand can produce as many as 8 harvests peryear. The height of the plant varies between50 and 100 cm (1).

Environment



Unexpected exposure


Allergens


A number of proteins have been isolatedand described as occurring in Japanesemillet. The allergenic potential of theseproteins was, however, not evaluated.

Barnyard millet, Common millet, Littlemillet, Foxtail millet, and Kodo millet werestudied. The protein contents of the selecteddecorticated Millets were found to be 11.0,12.3, 12.9, 10.5 and 10.6% respectively.Prolamin is a major storage protein inFoxtail millet, whereas glutelin is a majorstorage protein in all the other Millets. Aprotein band at the molecular weight rangeof 20 kDa was found to be homologous inall except Proso millet (2).

A Foxtail millet glutelin of 60 kDa(MG60) has been isolated. The primarystructure at the N-terminal end was almostidentical to that of the granule-bound starchsynthase (GBSS) proteins from Rice, Barley,Maize, Wheat and Potato. Commonepitopes from these starch-storing cerealswere corroborated by immunoblot analysis,strongly suggesting a close relationship (3).

90

f57 Japanese milletIn a study, the antigenic relationships

among “minor Millets” (Barnyard, Littleand Foxtail millets) and other cereals(Wheat, Maize, Rice, Sorghum, Finger milletand Pearl millet) were evaluated using anantibody raised against a 20 kDa prolaminfrom Kodo millet. It was demonstrated thatthe prolamin was related to the prolaminsfrom the other plants. Rice was the onlycommon cereal that did not cross-reactimmunologically with the 20 kDa prolaminof Kodo millet (4).

A subtilisin inhibitor has been isolatedfrom seeds of Foxtail millet. (5)

Proteinase inhibitors (trypsin/chymotrypsin) have been demonstrated tobe present in Finger millet, Sorghum, Pearlmillet, Foxtail millet, and Japanese millet (6).The amino acid sequence of an isolatedtrypsin inhibitor (7) had a high degree ofhomology to Bowman-Birk type inhibitorsfrom leguminous and gramineous plants (8).

Cross-allergenicity among Rice, Wheat,Maize, Japanese millet and Foxtail milletwas examined by IgE antibody determinationand RAST inhibition studies, and significantclose correlations among the 5 cereal grainextracts were demonstrated. A Rice proteinof 16 KDa was shown to be one of the majorallergens in Rice grain extracts (9-10). Theprotein showed sequence homology toWheat alpha-amylase inhibitor and Barleytrypsin inhibitor (11). The clinical relevanceof this protein was not assessed.


A Rice protein of 16 kDa has been shownto be involved in cross-allergenicity amongantigens in Rice, Wheat, Maize, Japanesemillet and Foxtail millet (10). The clinicalrelevance of this allergen was not examined.

Clinical Experience


Hypersensitivity to cereals may occur viainhalation or ingestion. But reported allergyto Japanese millet is rare.

With the increasing popularity of“natural foods”, Millet is more frequentlyincluded in various dishes, which might raisethe incidence of Millet-related allergicreactions. Patients with adverse reactions toGluten may substitute Millet for gluten-containing cereals.

Several studies of adults and children withatopic dermatitis and/or respiratory diseaserevealed the presence of IgE antibodies toJapanese millet (9,12-15).

Other reactions


Millet diets rich in C-glycosylflavones aregoitrogenic (17).

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United Nations Sorghum and millets inhuman nutrition. ISBN 92-5-103381-1www.fao.org/DOCREP/T0818e/T0818E01.htm 2008

2. Parameswaran KP, Thayumanavan B.Homologies between prolamins of differentminor millets. Plant Foods Hum Nutr 1995Sep;48(2):119-26

3. Takumi K, Udaka J, Kimoto M, Koga T, Tsuji H.Structural and immunochemical homologiesbetween foxtail millet glutelin 60 kDa andstarch granule-bound starch synthaseproteins from rice, barley, corn and wheatgrains. J Nutr Sci Vitaminol (Tokyo) 2000Apr;46(2):109-12


5. Tashiro M, Asao T, Nakano H, Takahashi K,Kanamori M. Purification andcharacterization of a subtilisin inhibitor fromseeds of foxtail millet, Setaria italica.Agric Biol Chem 1991 Jan;55(1):265-7

6. Pattabiraman TN. Trypsin/chymotrypsininhibitors from millets.Adv Exp Med Biol 1986;199:439-48

7. Tashiro M, Asao T, Hirata C, Takahashi K.Purification, characterization, and amino acidsequence of foxtail millet trypsin inhibitor III.Agric Biol Chem 1991 Feb;55(2):419-26

8. Tashiro M, Asao T, Hirata C, Takahashi K,Kanamori M. The complete amino acidsequence of a major trypsin inhibitor fromseeds of foxtail millet (Setaria italica).J Biochem 1990 Oct;108(4):669-72

9. Urisu A, Yamada K, Masuda S, Komada H,Wada E, et al. 16-kilodalton rice protein isone of the major allergens in rice grainextract and responsible for cross-allergenicitybetween cereal grains in the Poaceae family.Int Arch Allergy Appl Immunol1991;96(3):244-52

f57 Japanese millet



12. Chiba T, et al. Clinical evaluation ofPharmacia CAP system new food allergens.Jap Soc Pediatric Allergol 1992 (paperpresented)

13. Konatsu H, Miyagawa K, Ikezawa Z. Study ofclinical efficacy of Pharmacia CAP Systemnew allergens in patients with atopicdermatitis. [abstract] Japanese Soc Allergol1992 (paper)

14. Matsumaru S, Artia M, et al. Clinicalevaluation of Pharmacia CAP System newallergens for fish, vegetables, fruits andgrains. Paper presented at Jap Soc FedAllergol 1992

15. Yamada M, Torii S. Clinical evaluation ofPharmacia CAP System new food andinhalant allergens. [Abstract] Japanese SocAllergol 1992 (paper d)



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Lens esculentaFamily: Fabaceae (Leguminosae)Commonname: LentilSourcematerial: Dried seedsSynonyms: Lens culinaris, Cicer

lens, Lentilla lensFor continuous updates:www.immunocapinvitrosight.com

f235 Lentil

Allergen Exposure


Lentils are annuals with flattened edibleseeds just a few millimetres in diameter.Lentils were cultivated by the Persians andEgyptians from 2500 BC. Lentils are nowcultivated in most warm and subtropicalregions of the world. Popular in parts ofEurope and a staple throughout much of theMiddle East and India, this tiny, lens-shaped,high-protein pulse, said to be the mostnutritious of the pulses, has long been usedas a meat substitute.

Environment

Lentils are usually dried for storage,transport and sale. They may be used insoups, salads and casseroles, and as dhal,and ground into cereal flour for enrichingother flours or infant food. Lentils need tobe boiled for 15 minutes to destroy harmfultoxins found in the skin.

The young seedpods can be eaten raw orcooked like Green beans. Lentils are moredigestible than many legumes. They are highin protein (but low in fat) and have a fairamount of minerals and vitamins.

The seeds are mucilaginous and laxative.They are considered helpful in the treatmentof a variety of intestinal afflictions. Madeinto a paste, they are used as a cleansingapplication for indolent ulcers.

Allergens

The following allergens have beencategorised:

Len c 1, a 12 to 16 kDa protein, a majorallergen, corresponding to gamma-vicilinstorage proteins (1-5).

Len c 2, a 66 kDa protein, corresponding toseed-specific biotinylated protein (1-2).

The isoforms Len c 1.0101, Len c 1.0102,Len c 1.0103 and Len c 2.0101 have beencharacterised.

Both Len c 1 and Len c 2 have beenisolated from boiled Lentils. Heat treatmentof Lentils was shown to result in drasticchanges in the electrophoretic pattern, astrong increase of low-molecular-weightbands of 12 to 16 kDa proteins, and adecrease or disappearance of protein bandsin the 25 to 45 kDa range. Len c 1 wasshown to bind to 68% of the individual seraof Lentil-allergic individuals tested, whereasLen c 2 reacted with 41% of individual seraof this group (1).

Len c 1.01, a 48 kDa protein, has beencharacterised. Two of its processingfragments, corresponding to subunits of 12to 16 kDa (previously named Len c 1) and26 kDa, were shown to also be relevant

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f235 LentilLentil IgE-binding proteins. The purifiedallergen was recognised by 77% (17/22) ofthe individual sera from patients with Lentilallergy. Three isoforms were isolated,varying in their degree of N-glycosylation.There was a greater than 50% amino acidhomology with Peanut and Soy vicillins (5).

Although many legumes appear to haveboth heat-labile and heat-stable allergens, acommon feature of most legume allergens istheir natural resistance to thermal, chemical,and, in some respects, proteolytic denaturation(6). The process of heating results in asignificant decrease in IgE antibody binding,and IgE inhibition studies showed that theboiled Lentil extract had a greater inhibitorycapacity than the crude extract. Immunoblotsrevealed no important differences in IgEbinding patterns between the 2 extracts.Multiple allergens have been detected in a widerange of molecular mass, and boiled Lentilextracts maintained strong allergenicity (7).But further evidence for the heat alteration ofthe allergenicity was demonstrated in studiesthat concluded that Lentil extracts for thediagnosis of Lentil hypersensitivity should beheated, since these best identify clinicallysensitive individuals (8).

Lentil-allergic patients who haddeveloped a tolerance to Lentil ingestionwere shown to have lower IgE antibodylevels than symptomatic patients (7).

A lipid transfer protein has been isolatedfrom germinated Lentil seed (9). Its potentialallergenicity was not evaluated.


An extensive cross-reactivity among thedifferent individual species of the genus couldbe expected but in fact is not seen frequently(10). In an in vitro study, the IgE antibodybinding by protein extracts of 11 food legumeswas examined by IgE antibody determinationand RAST inhibition. Cross-allergenicity wasdemonstrated to be immunochemicallyfrequent, and most marked between theextracts of Peanut, Garden pea, Chick pea,and Soybean (11). However, clinical studieshave found that there is little cross-reactivityamong members of the legume family (12-14).

In contrast with the typical diet of mostother Western countries, legumes are animportant ingredient in the Mediterraneandiet, and it is therefore not surprising thatamong Spanish children, sensitivity to legumesis the fifth most prevalent food allergy. Lentiland Chick pea are the most frequent causes ofallergic reactions to legumes in Spanishchildren. Legumes have structurallyhomologous proteins, but they are not allequally allergenic. In vitro and in vivo testsmay not predict cross-reactivity or clinicalrelevance. In a study of 39 Spanish childrenchallenged (open or simple blind) with 2 ormore legumes, the majority had symptomswith more than 1 legume. Thirty-two (82%)reacted to 2 or more legumes: 43,5% to 3,25,6% to 2, and 13% to 4 legumes. Seventy-three per cent of the patients challenged withLentil and Pea had positive challenges to both,69,4% to Lentil and Chick pea, 60% to Chickpea, and 64,3% to Lentil, Chick pea and Peasimultaneously. Peanut allergy can beassociated with allergy to Lentil, Chick peaand Pea, but less frequently. In contrast, Whitebean, Green bean and Soy were well toleratedby children allergic to other legumes. A highdegree of cross-reactivity appeared to existamong Lentil, Chick pea, Pea and Peanut, onevidence from inhibition experiments. In thisstudy, 82% of the children allergic to legumeswere also sensitised to pollen. Pea and Beanwere more likely to have in vitro cross-reactivity with Lolium perenne, Olea europeaand Betula alba; the authors suggested thatthis was a result of common antigenicdeterminants or the coexistence of pollen andlegume allergy (15).

Similarly, in another Spanish study,symptomatic hypersensitivity to Chick peawas frequently associated with Lentil allergy(16). Cross-reactivity or co-sensitivity wasalso observed among Blue vetch (Chicklingpea), Chick pea, and Lentil (17). Similarly,shared allergenicity has been shown amongblackgram, Lentil, Lima bean and Pea (18).

Panallergens or common protein families(e.g., vicilins) may result in cross-reactivityamong foods. Amino acid sequencesdeduced from 2 clones of the Lentil allergenLen c 1.02 were shown to have greater than50% identity with the major Peanut allergenAra h 1, and with Soybean (conglutinin

94

f235 Lentilsubunits), which are allergens belonging tothe vicilin family (5). Similarly, in a study of18 Spanish patients with Pea allergy, allergicreactions to ingestion of Pea were frequentlyassociated with Lentil allergy. Vicilin andconvicilin were shown to be potential majorallergens from Pea, and these cross-reactedwith the major Lentil allergen Len c 1 (4).Similarly, analysis of the epitopes and vicilinallergens Ara h 1 from Peanut, Len c 1 fromLentil, and Pis s 1 from Pea were shown tobe similar, readily accounting for the IgE-binding cross-reactivity commonly observedamong the vicilin allergens from these ediblelegume seeds (3).

Clinical Experience


Lentil is the most common legumeimplicated in allergic reactions in food-allergic paediatric patients in theMediterranean area and in many Asiancommunities. Approximately 20% ofpatients allergic to these legumes presentwith severe and systemic symptoms,although isolated cutaneous reactions aremost common (5). Lentils are ranked fourthas a cause of hypersensitivity reactions inSpanish children, fifth in India. There areseveral reports in the literature of allergicsymptoms caused by Lentil (8,19-20). In aSpanish study, 10,1% of 355 paediatricpatients with food allergy had a convincinghistory of allergy to Lentils, and urticariaand oral allergy syndrome (OAS) were themost frequent symptoms. The symptomsmay develop after ingestion of cooked Lentiland/or after inhalation of steam from boilingLentil. Symptoms include angioedema,urticaria, asthma and anaphylaxis (1,16).

In a Spanish study, in 20 of 22 subjects whoexperienced allergy symptoms followingexposure to Lentil, the most frequent symptomswere oropharyngeal ones (40%) and acuteurticaria (30%); 3 patients also reportedsymptoms when they were exposed to steamfrom cooked Lentil. Onset of sensitisationoccurred at less than 4 years of age, and 9patients had allergic reactions to other legumes:Chick pea (6 patients), Pea (2 patients), andGreen bean (1 patient) (21). Similar symptoms,

i.e., urticaria, angioedema, abdominalsymptoms, rhinoconjunctivitis and asthma,following ingestion or inhalation of vapoursfrom cooked legumes (Lentil, Bean or Chickpea) have been reported, but Lentil was foundto induce the most severe reactions (22).

In an Indian study based in Delhi, therelevance of serum total and IgE antibodieswas investigated in asthmatics with foodsensitisation. Out of 216 consecutive patients,172 were found to have elevated serum totalIgE. Rice elicited marked positive skin pricktest reactions (SPT) in 24 (11%) asthmapatients, followed by Blackgram with 22(10%), Lentil with 21 (9.7%) and Citrusfruits with 20 (9.2%) (23).

Four episodes of anaphylaxis occurred inan 8-year-old girl, which could be attributedto Lentil. These episodes occurred betweenthe ages of 3 and 7 years. The first 3 involvedingestion of cooked Lentil and each episoderequired smaller amounts to inducesymptoms. The fourth episode occurred withexposure by inhalation to cooking Lentilsoup. Skin reactivity and serum IgEantibodies to Lentil were confirmed (24).Severe reactions may occur in adults. A 20-year-old man experienced episodes ofasthma when exposed to the steam fromcooking either Chick pea or Lentil. Type Ihypersensitivity was demonstrated by meansof serum IgE, skin reactivity, histaminerelease tests, and RAST inhibition. Specificbronchial challenges with the heated (75 °Cfor 30 minutes) extracts of Chick pea andLentil elicited an immediate response (25).

Other reactions

Infantile food protein-induced enterocolitissyndrome (FPIES) is a severe cell-mediatedgastrointestinal food hypersensitivitytypically provoked by Cow's milk or Soy. Astudy reported on other foods causing thissyndrome: 14 infants with FPIES caused bygrains (Rice, Oat, and Barley), vegetables(Sweet potato, Squash, String beans, Pea),or poultry (Chicken and Turkey) wereidentified. Symptoms of typical FPIES aredelayed (median: 2 hours) and includevomiting, diarrhoea, and lethargy/dehydration. Eleven infants (78%) reactedto >1 food protein, including 7 (50%) who

95

reacted to >1 grain. Nine (64%) of allpatients with solid food FPIES also hadCow's milk and/or Soy FPIES. Initialpresentation was severe in 79% of thepatients, prompting sepsis evaluations(57%) and hospitalisation (64%) fordehydration or shock. None of the patientsdeveloped FPIES to maternally ingestedfoods while breastfeeding unless the causalfood was fed directly to the infant. (26)Similarly, 6 patients (4 males, 2 females, aged3-12 months) were diagnosed with FPIEStriggered by foods other than Cow's milkand Soy: Chicken in 4, Turkey in 2, Pea in1, and Lentils in 1. (Five patients reacted tomore than 1 food type.) All reactionsdeveloped within 2 hours of ingestion of theallergenic food (27).

If Lentils are to be eaten whole, they mustbe boiled an extra 15 minutes to destroyharmful toxins found in the skins.

Aspiration of leguminous vegetables cancause a granulomatous pneumonitis, knowas Lentil aspiration pneumonia, thatmanifests on radiological studies with small,poorly defined nodular opacities (28).

The Lentil pest Bruchus lentis was reportedto have resulted in occupational asthma in anagronomist (29). In a more recent study of 16patients with asthma and anaphylaxis as aresult of inhalation of Lentil particles oringestion of Lentils, SPT was positive toinfested Lentils and B. lentis in all patients andnegative to noninfested Lentil extracts. Fiveasthmatic patients were positive on bronchialchallenge tests for Bruchus extract. Oralchallenges performed with boiled infestedLentils were positive in 6 of 7 patients. Thesepatients had no IgE antibodies to Lentil-specific proteins. The Lentil pest B. lentis cantherefore be a cause of IgE-mediatedrhinoconjunctivitis and asthma in patientseating or inhaling infested Lentil particles (30).

References1. Sanchez-Monge R, Pascual CY, Diaz-Perales A,

Fernandez-Crespo J, Martin-Esteban M,Salcedo G. Isolation and characterization ofrelevant allergens from boiled lentils.J Allergy Clin Immunol 2000;106(5):955-61


3. Barre A, Borges JP, Rougé P. Molecularmodelling of the major peanut allergen Ara h 1and other homotrimeric allergens of thecupin superfamily: a structural basis for theirIgE-binding cross-reactivity.Biochimie 2005;87(6):499-506

4. Sanchez-Monge R, Lopez-Torrejon G,Pascual CY, Varela J, Martin-Esteban M,Salcedo G. Vicilin and convicilin are potentialmajor allergens from pea.Clin Exp Allergy 2004;34(11):1747-53

5. Lopez-Torrejon G, Salcedo G, Martin-Esteban M,Diaz-Perales A, Pascual CY, Sanchez-MongeR. Len c 1, a major allergen and vicilin fromlentil seeds: protein isolation and cDNAcloning. J Allergy Clin Immunol2003;112(6):1208-15


7. Ibanez Sandin D, Martinez San Ireneo M,Maranon Lizana F, Fernandez-Caldas E,Alonso Lebrero E, Laso Borrego T. SpecificIgE determinations to crude and boiled lentil(Lens culinaris) extracts in lentil-sensitivechildren and controls.Allergy 1999;54(11):1209-14

8. Martinez San Ireneo M, Ibanez Sandin MD,Fernandez-Caldas E, Maranon F, MunozMartinez MC, Laso Borrego MT. Thediagnostic value of crude or boiled extracts toidentify tolerant versus nontolerant lentil-sensitive children. Ann Allergy AsthmaImmunol 2001;86(6):686-90

9. Finkina EI, Balandin SV, Serebryakova MV,Potapenko NA, Tagaev AA, Ovchinnikova TV.Purification and primary structure of novellipid transfer proteins from germinated lentil(Lens culinaris) seeds.Biochemistry (Mosc) 2007;72(4):430-8




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16. Pascual CY, Fernandez-Crespo J, SanchezPastor S, Ayuso R, Garcia Sanchez G, Martin-Esteban M. Allergy to lentils in Spain.Pediatr Pulmonol 2001;Suppl 23:41-3


18. Kumari D, Kumar R, Sridhara S, Arora N,Gaur SN, Singh BP. Sensitization toblackgram in patients with bronchial asthmaand rhinitis: clinical evaluation andcharacterization of allergens.Allergy 2006;61(1):1-110

19. Sainza T, Zapatero L, Martinez MI, Lozano M,Zubeldia JM, Baera ML. Hypersensitivity toLathyrus sativus. [Abstract] Allergy1995;50S:230

20. Moroz LA, Yang WH. Kunitz soybean trypsininhibitor: a specific allergen in foodanaphylaxis. N Engl J Med1980;302(20):1126-8

21. Pascual CY, Fernandez-Crespo J, Sanchez-Pastor S, Padial MA, Diaz-Pena JM, Martin-Munoz F, Martin-Esteban M. Allergy to lentilsin Mediterranean pediatric patients. J AllergyClin Immunol 1999;103(1 Pt 1):154-8

22. Carrillo Diaz T, Cuevas Agustin M, et al.In vitro immunologic diagnosis ofhypersensitivity to vegetables [Spanish].Allergol Immunopathol 1986;14(2):139-46

23. Kumar R, Singh BP, Srivastava P, Sridhara S,Arora N, Gaur SN. Relevance of serum IgEestimation in allergic bronchial asthma withspecial reference to food allergy. Asian Pac JAllergy Immunol 2006;24(4):191-9


25. Martin JA, Compaired JA, de la Hoz B, Quirce S,Alonso MD, Igea JM, Losada E. Bronchialasthma induced by chick pea and lentil.Allergy 1992;47(2 Pt 2):185-7


27. Levy Y, Danon YL. Food protein-inducedenterocolitis syndrome - not only due to cow'smilk and soy. Pediatr Allergy Immunol2003;14(4):325-9

28. Marom EM, McAdams HP, Sporn TA,Goodman PC. Lentil aspiration pneumonia:radiographic and CT findings. J ComputAssist Tomogr 1998;22(4):598-600

29. Armentia A, Lombardero M, Barber D,Castrodeza J, Calderon S, Gil FJ, Callejo AM.Occupational asthma in an agronomistcaused by the lentil pest Bruchus lentis.Allergy 2003;58(11):1200-1

30. Armentia A, Lombardero M, Blanco C,Fernandez S, Fernandez A, Sanchez-Monge R.Allergic hypersensitivity to the lentil pestBruchus lentis. Allergy 2006;61(9):1112-6

f235 Lentil

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Phaseolus lunatusFamily: Fabaceae (Leguminosae)Commonnames: Lima bean, Butter bean,

Sugar bean, Haba bean,Pallar bean, Burma bean,Guffin bean, Hibbertbean, Sieva bean,Rangoon bean,Madagascar bean,Paiga, Paigya,Butterpea, Prolific bean,Civet bean

Sourcematerial: Dried beansFor continuous updates:www.immunocapinvitrosight.com

f182 Lima bean

Allergen Exposure


Lima bean is a legume (1). Its seed is eatenas a vegetable. It is of Andean andMesoamerican origin. The genus Phaseolusincludes Lima, garden, snap, string, navyand pinto beans.

Lima plants produce pods that are up to15 cm long and contain seeds that atmaturity are 1 to 3 cm long and oval- tokidney-shaped. The seeds are usually quiteflat but in some varieties are more sphericalin shape. Immature seeds are uniformlygreen. At maturity, the most common varietyproduces white seeds, although black,orange, red and mottled seeds are seen.

“Butter bean” is the widespread term fora large, flat, white variety of Lima bean (P.lunatus var. macrocarpus, or P. limensis). Inthe southern United States, the smaller Sievatype are traditionally called Butter beans (orthe Dixie or Henderson type). In that area,Lima beans and Butter beans are seen as 2distinct types. In the United Kingdom, a“Butter bean” is a dried bean that can bere-hydrated, or a canned bean ready to use.In culinary terms, Lima beans and Butterbeans are distinct, the former being smalland green, the latter large and yellow (2).

Lima bean contains a number of anti-nutrients. Raw Lima beans contain cyanide,trypsin inhibitor, lectin, phytin and tannin.Soaking, autoclaving and toasting completelyeliminated trypsin inhibitor and lectin, whileit significantly reduced the levels of phytin,tannin and cyanide. Except for tannin,autoclaving for 20 minutes was found toeliminate all the other anti-nutrients in Limabean (1). Lectin-related polypeptides are aclass of defence proteins found in seeds ofPhaseolus species, including in Lima bean (3).Lectins react indistinctly with erythrocytes ofthe ABO blood system; however, the lectinof Lima bean is specific to the blood grouptype A (4).

Lima beans contain linamarin, acyanogenic glucoside, although the beans arerendered safe when cooked, and low-linamarin varieties are typically used forculinary purposes. Cyanogenic glycosidesare present in green plant tissue as well asin seeds such as Almonds, flax seed, and wildLima beans (5).

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Allergens

Early studies demonstrated that Lima beancontains at least 23 proteins that may haveallergenic potential (6).

In a survey of food allergy among asthmaand rhinitis patients in Delhi, India,evaluation of sera of patients with evidenceof Lima bean skin reactivity demonstrated12 IgE binding proteins of 18-96 kDa inLima bean (7-8).

More recently, a study examining the invitro cross-reactivity of Mesquite pollen andLima bean demonstrated the presence of 20,26, 35, 66 and 72 kDa proteins as sharedIgE binding components between the 2extracts (8).

Other proteins of unknown allergenicpotential have previously been isolated; theyhave been shown to have allergenic potentialin other plants. These include a 20 kDacysteine proteinase inhibitor with an N-terminal sequence homologous to othermembers of the cystatins. The protein wasrelatively heat-labile, which suggested it couldbe inactivated with normal cooking (9). Atrypsin inhibitor was isolated (10) and shownto be very thermostable, retaining activityeven after boiling for 10 minutes (11).


There are reports suggesting, based on SPT,that Lima bean cross-reacts with otherallergenic legumes, such as Soya, Peanut, andblack gram (6,12-13).

However, previous studies havedemonstrated that, although the degree ofbiochemical cross-reactivity amongmembers of the legume family is high, theclinical significance of this is low, so thatbeing allergic to one legume does notnecessarily require excluding other legumesfrom the diet. Results of skin prick testsalone should not be used for prescribingprolonged food restriction diets (12).

This is also suggested by a study reportingthat only 2 of 41 legume-allergic patients(diagnosed by double-blind, placebo-controlled oral food challenge or“convincing history” of anaphylaxis) had anIgE-mediated hypersensitivity reaction to

more than a single member of the legumefamily, even though extensive immunologiccross-reactivity was demonstrated amonglegume antigens in in vitro and in vivoassessments of 6 legumes (Peanut, Soybean,Lima bean, Pea, garbanzo bean and Greenbeans) (6).

The particular allergen within a legumewill probably determine the extent anddegree of cross-reactivity. This is illustratedby a report of a patient who suffered adversereactions when eating Peas, Lentils, Peanuts,Kidney, Lima and navy beans; heexperienced the most severe episodesfollowing ingestion of Soybean products. AIgE antibody response to the Kunitz Soybeantrypsin inhibitor polypeptide wasdemonstrated (14).

IgE-mediated food allergy often developsas a consequence of allergic sensitisation topollen proteins. Recently, cross-reactivitywas demonstrated between Mesquite treepollen (Prosopis juliflora) and Lima bean asa food, both members of the familyLeguminosae (Fabaceae).

In a study of 110 patients with asthmaand/or rhinitis, of whom 20 showed markedpositive reactions with Prosopis pollenextract, 12 patients showed elevated IgEantibody level to Prosopis pollen extractalone and 4 to both Phaseolus and pollenextract. P. lunatus extract could inhibit IgEbinding to P. juliflora in a dose-dependentmanner. The presence of 20, 26, 35, 66 and72 kDa proteins as shared IgE bindingcomponents between the 2 extracts wasdemonstrated (8).

A study reported on a 33-year-old womanwho developed tongue swelling and burningand mouth itching within minutes of eatingbaked beans. Similar symptoms occurredfollowing ingestion of other legumeproducts, including Peas, a bean burrito, andKidney and pinto beans. SPT was positiveto Red kidney and White beans but not toPea, string or Lima beans, confirming thatcross-reactivity between the legumes is notabsolute (15).

f182 Lima bean

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Clinical Experience


Lima bean may induce symptoms of foodallergy in sensitised individuals, althoughthis is uncommon (12-13).

However, a number of studies havedemonstrated sensitisation to Lima bean. Ina survey of food allergy among asthma andrhinitis patients in Delhi, India, when allergyto Lima bean was claimed on history,sensitisation to Lima bean using SPT wasdemonstrated in approximate 3-4% (16) of470 cases. Immunoblot analysis with allergicpatients' sera confirmed and demonstratedthe presence of IgE binding proteins in Limabean (7).

In a study that investigated the in vitrocross-reactivity of Mesquite pollen and Limabean, of 110 patients with asthma, rhinitisor both, 20 were shown to have IgEantibodies to Mesquite pollen extract; andof these, 12 patients showed elevated IgEantibody level to Mesquite pollen extractalone, and 4 to both Lima bean and pollenextract (8).

References1. Adeparusi EO. Effect of processing on the

nutrients and anti-nutrients of lima bean(Phaseolus lunatus L.) flour.Nahrung 2001;45(2):94-6

2. Wikipedia. Phaseolus lunatus. http://en.wikipedia.org/wiki/Lima_bean.Accessed May 2008

3. Sparvoli F, Lanave C, Santucci A, Bollini R,Lioi L. Lectin and lectin-related proteins inlima bean (Phaseolus lunatus L.) seeds:biochemical and evolutionary studies.Plant Mol Biol 2001;45(5):587-97

4. Feria M, Pérez-Santiago A, Cuevas D,Martínez M, Córdoba F. Purification andpartial characterization of a new anti-A1lectin of Phaseolus coccineus collected inOaxaca, Mexico.Prep Biochem Biotechnol 1996;26(1):31-46

5. Frehner M, Scalet M, Conn EE. Pattern of theCyanide-Potential in Developing Fruits :Implications for Plants AccumulatingCyanogenic Monoglucosides (Phaseoluslunatus) or Cyanogenic Diglucosides in TheirSeeds (Linum usitatissimum, Prunusamygdalus). Plant Physiol 1990;94(1):28-34

6. Bernhisel Broadbent J, Taylor S, Sampson HA.Cross-allergenicity in the legume botanicalfamily in children with food hypersensitivity.II. Laboratory correlates. J Allergy ClinImmunol 1989;84(5 Pt 1):701-9

7. Indian Council of Medical Research Studieson foods as sensitizing and inducing factorsof allergy disorders with special reference tobronchial asthma. Project report: New Delhi:Indian Council of Medical Research IndianCouncil of Medical Research 2006:1-34


9. Lawrence JC, Nielsen SS. Partial isolationand characterization of a cysteine proteinaseinhibitor from Lima bean (Phaseolus lunatus).J Agric Food Chem 2001;49(2):1020-5

10. Birk Y. Lima bean trypsin inhibitors.Methods Enzymol 1976;45:707-9

11. Samudzi C, Schroeder S, Griffith S, Chen X,Quinn TP. Crystallization and preliminarystudies of lima bean trypsin inhibitor.Proteins 1997;27(2):311-4


13. Kumar R, Singh BP, Srivastava P, Sridhara S,Arora N, Gaur SN. Relevance of serum IgEestimation in allergic bronchial asthma withspecial reference to food allergy. Asian Pac JAllergy Immunol 2006;24(4):191-9

14. Moroz LA, Yang WH. Kunitz soybean trypsininhibitor: a specific allergen in foodanaphylaxis.N Engl J Med 1980;302(20):1126-8

15. Zacharisen MC, Kurup V. Anaphylaxis tobeans. J Allergy Clin Immunol 1998;101(4Pt 1):556-7

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Linum usitatissimumFamily: LinaceaeCommonnames: Linseed, FlaxseedSourcematerial: Dried seedsFor continuous updates:www.immunocapinvitrosight.com

f333 Linseed

Allergen Exposure


Flax has been cultivated and has grownsemi-wild wild in various temperate andtropical regions for so many centuries thatit is not even clear which hemisphere theplant originated from. Egyptians, Hebrews,Greeks, Romans and New Worldcivilisations used the seeds as food and thefibres (flax) for textiles.

Flax is an annual, 0.3-1 m high, wiry,more or less branching plant with small,unstalked, dark or grayish-green leaves. Theflowers are borne on the ends of the stalks.Each flower produces a round capsule inwhich 1 to 10 seeds develop. There aredifferent cultivars for the production ofLinseed oil and flax. Linseed plants areshorter, and their flowers are commonlybright blue, less commonly pale blue orwhite, while most flax cultivars bear whiteflowers.

Environment

Linseed is a common food in North Europe.It is often used in cereals and breads,including the German Leinsamenbrot. It canbe sprouted and served in salads. It is alsoan ingredient in cattle feeds. Linseed mealmay be what is left over from the oilextraction process, or it may be part of the“oil cake” because the hull is highlynutritious.

The seed contains 30 - 40% oil, whichcomprises mainly linoleic and linolenic acids.It is used mainly in the preparation ofvarnish, paint, linoleum, and soap. Linseedoil has recently been used as a laxative.

Flaxseed has experienced millennia ofmedicinal usage, mainly as a laxative,expectorant and demulcent. Recently, it hasbeen noted that Linseed containsphytoestrogens, compounds with weakestrogenic or antiestrogenic activity, whichhave purported health benefits such asmitigation of hormone-dependent breast andprostate cancers, osteoporosis, cognitivedysfunction, cardiovascular disease, immunesystem dysfunction, inflammation, andinfertility (1).

Flaxseed has recently gained particularattention in the area of cardiovasculardisease. It not only contains lignans, aphytoestrogen. It is also the richest knownsource of alpha-linolenic acid (ALA), theparent compound of the omega-3 fatty acids.(In comparison, fish contain only traceamounts of ALA, and fish oil can adverselyaffect the taste and odour of food products.)It is, furthermore, rich in soluble fibre (2).

Unexpected exposure

Linseed may be “hidden” in cereals, milkfrom cows fed flax, laxatives (Flaxolyn, etc.),shampoo, hair tonic, infusions, depilatories,cattle feed, dog food, patent leather,insulating materials, carpets, cloth, coughremedies, breads, health shop muffins, andother “health food” products (3-5).

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f333 LinseedAllergens

Linseed contains potent allergens (6), but noallergens from this plant have yet beencharacterised.

Five allergens with molecular weights of38, 35, 30, 22, and 20 kDa have beendetected (5). However, in another study,allergens with a higher molecular weight(150-175 kDa), intensely bound with IgE,were found, as were other more discretebindings with lower molecular weightallergens (90-100 kDa). Under reducingconditions, the high-molecular-weight bandsdisappeared and discrete bands of lowermolecular weight (25-100 kDa) weredetected (7).

In a study, the major allergen of Linseedwas implicated in the case of a 39-year-oldwoman who developed anaphylaxis toLinseed grains; this allergen was shown tobe a dimmer, consisting of a pair of 28 kDamonomers bound by SH2 groups. Theauthors suggest that the candidate may bemalate dehydrogenase MDH-1, found inflax seeds (8).


An extensive cross-reactivity among thedifferent individual species of the genuscould be expected but has not been clinicallyrecorded (9).

Clinical Experience


Linseed may uncommonly induce symptomsof food allergy in sensitised individuals; butcases could increase in number and varietybecause of the increased use of Linseed inbread and laxatives, and in a range ofproducts from health food shops (3).

Anaphylaxis induced by Linseed ingestionwas described in a 39-year-old woman whodeveloped symptoms immediately after theingestion of the first spoonful of Linseedgrains prescribed as a laxative. Skinreactivity and IgE antibodies to Linseed wasdemonstrated (3).

A 40-year-old man had had, over a 6-yearperiod, 5 or 6 episodes of intestinal/abdominal pain, vomiting, diarrhoea,generalised urticaria, acute dyspnoeawithout bronchospasm, hydrorrhoea,successive sneezing, nasal obstruction,pruritis, and intense general malaise whichrequired emergency treatement, all occurringwithin 2-3 minutes after ingestion ofmultigrain bread. SPT and IgE antibodydetermination were positive (7).

Anaphylaxis in a 40-year-old woman wasreported to be caused by the ingestion ofLinseed oil used as a laxative. Ten minutesafter the intake of the first spoonful, sheexperienced ocular pruritus and weeping,followed by strong palmar pruritus andgeneralised urticaria, nausea, and vomiting.SPT and IgE antibody determination werepositive (5).

In 102 patients initially diagnosed withidiopathic anaphylaxis and then evaluatedwith a battery of 79 food-antigen skin pricktests, 10 different antigens provokedanaphylaxis, including Linseed. The studyconcluded that around 7% of the patientsin question who were suspected of“idiopathic” anaphylaxis on the basis ofhistory were not truly idiopathic (10).

Occupational dermatitis caused bySunflower seeds and Linseed has beenreported (11).

Other reactions

Flax is an important cause of respiratorydisease. Non-IgE-mediated byssinosis,caused by inhalation of dust in theprocessing of flax, has been described in flaxworkers (12), as well as IgE-mediatedoccupational asthma from the processing ofLinseed oil (13). (Byssinosis, a respiratorydisease also caused by dust of cotton andsoft hemp, is classically characterised asshortness of breath, cough, and chesttightness on Mondays or the first day ofreturn to work after other time off (14)).Flaxseed hypersensitivity was described by2 different authors in the 1930s, 1 describingFlaxseed sensitisation in 6 individuals (4,15).

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f333 LinseedLinseed may be a source of cyanide

exposure. Linseeds are cyanogenic, but toxiceffects are unknown from normal conditionsof manufacture, which involve high-temperature treatment or from traditionaland moderate use by humans. Also, safercultivars have been developed. (However,unprocessed whole seeds and Linseed cakesprocessed under low temperature can betoxic to animals.) The potential cyanide yieldcan vary from 4 to 12 mmol/kg. Linseedcontains the same cyanogenic glucosides asCassava. Authors have suggested that excessintake (via laxatives) may be dangerous (16).

The oil in the seed contains 4% L-glutamic acid, or MSG, and therefore mightcause MSG-type reactions.

The seed is hard to digest and provokesflatulence.

References1. Dixon RA. Phytoestrogens.

Annu Rev Plant Biol. 2004;55:225-612. Bloedon LT, Szapary PO. Flaxseed and

cardiovascular risk.Nutr Rev 2004;62(1):18-27

3. Leon F, Rodriguez M, Cuevas M. Anaphylaxisto Linum. Allergol Immunopathol (Madr)2003;31(1):47-9

4. Black WC. Flax hypersensitiveness.JAMA 1930;94:1064

5. Alonso L, Marcos ML, Blanco JG, Navarro JA,Juste S, del Mar Garces M, Perez R,Carretero PJ. Anaphylaxis caused by linseed(flaxseed) intake. J Allergy Clin Immunol1996;98(2):469-70

6. William R, Kenneth P. Aerobiology andinhalant allergens. In: Middleton E Jr, Reed CE,Ellis EF, Adkinson NF Jr, Yunginger JW,editors. Allergy: principles and practice. 3rded CV Mosby Company 1988:312-72

7. Lezaun A, Fraj J, Colas C, Duce F,Dominguez MA, Cuevas M, Eiras P.Anaphylaxis from linseed.Allergy 1998;53(1):105-6

8. Leon F, Rodriguez M, Cuevas M. The majorallergen of linseed. Allergy 2002;57(10):968


10. Stricker WE, Anorve-Lopez E, Reed CE. Foodskin testing in patients with idiopathicanaphylaxis. J Allergy Clin Immunol1986;77(3):516-9

11. Rajka E. Occupational dermatitis caused bysunflower seeds and linseeds. [UndeterminedLanguage] Int Arch Allergy Appl Immunol1950;1(2):161-70

12. Nowier M, El-Sadik Y, El-Dakhakhny A,Osmar H. Dust exposure in manual flaxprocessing in Egypt.Br J Ind Med 1975;32:147-52

13. Bernstein D, Bernstein I. Occupationalasthma. In: Middleton E Jr, Reed CE, Ellis EF,Adkinson NF Jr, Yunginger JW, editors.Allergy: principles and practice. 3rd edition.St Louis: CV Mosby Company, 1988:1197-218

14. Salvaggio JE, O'Neil CE, Butcher BT.Immunologic responses to inhaled cottondust.Environ Health Perspect 1986;66:17-23

15. Grant LR. A report of six cases of flaseedsensitization with review of the literature.J Allergy 1931;3:469-77

16. Rosling H. Cyanide exposure from linseed.Lancet 1993;341(8838):177

103

Lupinus albusFamily: Fabaceae (Leguminosae)Commonnames: Lupin, Lupine, Blue

lupin, White lupin,Yellow lupin, Sweetlupin

Sourcematerial: Dried seedsSynonyms: L. sativus, L. termisSee also: Lupin w207For continuous updates:www.immunocapinvitrosight.com

Allergen Exposure


The Lupin is a member of the Legume familyand the genus Lupinus, which includes 450species. Four species are of agricultural interest:the White lupin (Lupinus albus), the Blue lupin(Lupinus angustifolius), the Yellow lupin(Lupinus luteus), and Lupinus mutabilis. Asulfur-rich transgenic variety is available foranimal feed. Lupin flour is an excellent sourceof proteins, having a higher content of albumin(55.6%) than globulins (31.5%).

Lupin is cultivated globally, primarily foruse as animal feed, but also to be ploughedunder as a soil enhancer (1).

The Lupin is an annual growing to 1.2 mby 0.25 m, with conspicuous colourfulflowers. It can grow wild, but has beencultivated for at least 2,000 years, probablystarting in Egypt. It is a useful spring-sowngreen manure crop, especially on light soils.

It is important as a stock food. Up to the1920s, when “Sweet lupin” crops weredeveloped, the seeds required soaking beforeconsumption to remove toxic alkaloids, butthe new types are safe to eat without anyprocessing.

f335 Lupin seed

Environment

The edible seeds (from cultivated varietiesof the plant) are employed as a protein-richvegetable or savoury dish in all of the waysthat cooked beans are used. They can alsobe roasted or ground into a powder andmixed with cereal flours. They have alsoused as a thickener of food products. Edibleoil is obtained from the seed and the roastedseed is used as a coffee substitute. The seedis high in protein. Dried Lupin (usually called“lupini”), prepared by boiling Lupin seed,is a traditional snack (like Peanuts) in someMediterranean countries.

Certain countries, e.g., France, allowLupin flour to be added to ordinary foodsuch as bread (2).

If the seed is bitter, this is due to thepresence of toxic alkaloids, and the seedshould be thoroughly leached by soaking itand then discarding the soak water.

The seeds, taken internally, are diuretic,emmenagogue, hypoglycaemic andvermifuge. When bruised and soaked inwater, they are used as a poultice on ulcers,etc.

Unexpected exposure

Lupin flour and bran are increasingly beingused in food manufacturing, where theycontribute protein, bulk, fibre, and sometextural properties. Lupin may be regarded

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f335 Lupin seedas a “hidden” allergen. Inclusion of Lupinin Wheat flour was first permitted in theUnited Kingdom in 1996, and in France atthe end of 1997 (1). Since then, Lupin flourand bran have been widely used in Europeancountries such as France, the Netherlands,Italy, Spain and Germany, in bread, biscuitsand other baked products, pasta,confectionery, Soya substitutes, and dietaryand health foods. Bakery goods may containup to 10% Lupin flour (3).

Lupin oil is used in making soap. A fibreobtained from the stems is used for makingcloth and other products. See also underEnvironment.

Allergens

In an individual with allergy to Lupin,important allergenic proteins of 71, 59 and34 kDa in size, along with less important24 and 17 kDa proteins, were isolated (4).In another study of 2 individuals with Lupinallergy, strong differences in proteins inextracts of fresh and cooked seeds weredemonstrated. Sensitisation to low-molecular-weight bands was demonstrated;a doublet of 9 and 10 kDa was found inraw and cooked seeds and was more clearlyrepresented in skin than in pulp (5). A studyreported the isolation of allergens thatseemed to be in the 35 kDa to 55 kDa rangeand heat-stable, with a 21 kDa proteinappearing to be a major protein (6). Anotherstudy reported a reduction in allergenicityafter autoclaving at 138 °C for 20 minutes.In the case of IgE antibodies from 2individual sera that had recognised allergenicprotein bands at 23 and 29 kDa in samplesautoclaved at 138 °C for 20 minutes, auto-claving for 30 min abolished the IgE bindingto these 2 components. A previouslyundetected band at 70 kDa was recognisedby an individual serum. The authorsconcluded that prolonged autoclaving mighthave an important effect on the allergenicityof Lupin for the majority of patients (7).

In a study that sought to identify allergensassociated with Lupin allergy, 6 patients witha history of allergic reactions to Lupin flourwere evaluated. Two patients allergic toLupin but not to Peanut displayed IgEbinding predominantly to proteins of

approximately 66 kDa, and weak bindingto 14 and 24 kDa proteins, whereas patientswith both Peanut allergy and Lupin allergyshowed weak binding to Lupin proteins ofabout 14 to 21 or 66 kDa (1). Similarly, in astudy of 2 patients with oral allergicsyndrome following Lupin ingestion, and nosymptoms associated with Peanut or otherlegumes, sera IgE from both patientsrecognised proteins of approximately 34 kDaand in the 40-65 kDa range. The secondpatient's serum also recognised 7-15, 38, 77,162 and 195 kDa proteins (8).


Lup a 11S Globulin (1,9-11).

Lup a gamma Conglutin (9-14).

Lup a beta Conglutin (1,9,11,13-14).

Lup a Vicilin (1,11).

Lup a LTP, a lipid transfer protein (15).

A 2S albumin has been isolated (10,16).The 2S albumin fraction appears to consistof a number of isoforms ranging from 4 to11 kDa (16-17). However, the 2S albumin,unlike 2S albumins from other seeds, maybe non-allergenic (10).

Plant stress was shown to activate a class-III chitinase, designated IF3. The protein wasdetected in the seed, leaves and roots. Inhealthy, nonstressed tissues of the plant athaumatin-like protein was also detected, thepresence of which researchers could notexplain. Whether these proteins also occurin the pollen is unknown (18-19). Proteinsthat show similarity to PR-10 proteins havealso been detected in the leaves (20).Although chitinase and thaumatin proteinshave allergenic potential, their clinicalsignificance in this plant has not beenelucidated as yet.

A common feature of most legumeallergens is their natural resistance tothermal, chemical, and in some waysproteolytic denaturation (21).

In an investigation of “hidden” Lupinseed in biscuits, chicken bouillon and adehydrated chicken soup, a Lupin allergenwith a molecular weight close to 14 kDa wasdetected (22).

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f335 Lupin seedPotential cross-reactivity

An extensive cross-reactivity among thedifferent individual species of the Fabaceae(legume family) could be expected but in factdoes not occur frequently (23-24). In an invitro study, the IgE binding to proteinextracts of 11 food legumes was examinedby IgE antibody determination and RASTinhibition. Cross-allergenicity wasdemonstrated to be most marked among theextracts of Peanut, Garden pea, Chick pea,and Soybean (25). However, clinical studieshave found little cross-reactivity amongmembers of the legume family, with thepossible exception of cross-reactivitybetween Lupin seed and Peanut (26-27).

In a study of 6 Lupin-allergic individuals,3 were co-sensitised to Peanut and Lupin (1).But in a study of 2 patients with oral allergicsyndrome following Lupin ingestion,investigations supported the conclusion thatLupin is capable of inducing allergicsensitisation without cross-reactivity withPeanut (8). Significantly, individuals may havesubstantial levels of Peanut-specific IgEwithout being clinically allergic to Peanut (28).

A study of the legumes Peanut, Soybean,Green bean, Pea, and Lima beandemonstrated that clinical hypersensitivityto one legume does not warrant dietaryelimination of all legumes. The authorspointed out that results of SPT should notbecome the basis of prolonged foodrestriction diets (26). However, legumesensitisation may be a dynamic process, asdescribed in a patient whose symptomsstarted with reactions to only a single legume(Chick pea) and who then progressivelydeveloped sensitisation to Lentil, Whitebean, Lupin, and Pea (24).

Cross-allergic clinical reactions to othermembers of the legume family such asSoybean and Lentils occur in about 5% ofPeanut-allergic patients, but cross-allergicreactions were found to be 68% betweenPeanut and Lupin (26). Among 24 Peanut-allergic patients, SPT to Lupin flour werepositive in 11 (44%). Oral challenges withLupin flour were positive in 7 of 8 subjectswith the same dose as of Peanut. The majorLupin flour allergen, a 43 kDa protein, was

found to be present in Peanuts. RASTinhibition and immunoblot tests showedcross-reactivity of Peanut with Lupin flourand pollen. The authors felt that the risk ofcross-reactive Peanut-Lupin allergy is high,contrary to the risk with other legumes (29).Similar results have been reported by otherresearchers; one study reported that 68%of a group of Peanut-allergic patientsshowed positive reactions to Lupin flourwhen tested (6,30-31). Subjects with positiveSPT to Lupin also reported a history ofreactions to Green pea (6).

In a study of severe anaphylaxis toAlmond, a 45 and a 30 kDa protein isolatedfrom Almond showed a 60% homology tothe conglutin gamma protein from Lupinseed and to the 7S globulin from Soybeanrespectively. Immunoblot inhibitionexperiments were performed, and IgEbinding to Almond 2S albumin andconglutin gamma was detected in thepresence of cross-reacting Walnut or Hazelnut antigens (32). The clinical relevance ofthis finding was not established. There weresimilar findings in other connections, with2S albumin from Sunflower seeds beingreported to be homologous with albuminfrom Lupin seeds (conglutin delta) (17). Thefull clinical significance of these cross-reactions will require further elucidation.However, the 2S albumin, unlike 2Salbumins from other seeds, may be non-allergenic (10).

A study using computer-aided amino acidsequence comparison and 3-dimensionalmodelling of the suspected cross-reactiveproteins to compare their molecular surfacesreported highly significant sequencehomology and molecular similarity betweenallergen Ara h 8 of Peanut and pathogenesis-related protein PR-10 of White lupin.Another protein of Lupin, the beta-conglutinprecursor, was found to be significantlyhomologous to the Ara h 1 allergen ofPeanut. The molecular surfaces of Ara h 8and PR-10 were remarkably similar (13).The full clinical significance of this was notelucidated.

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f335 Lupin seed

Clinical Experience


Lupin flour may commonly inducesymptoms of food allergy, allergic rhinitisand asthma in sensitised individuals afteringestion of the food or inhalation of theflour (2,7,22,24,33-40). Lupin flour in foodhas also been reported to produce urticariaand anaphylaxis (24,36,41). Case reports ofindividuals experiencing oral allergysyndrome to Lupin have been made (1,8,42).Contact urticaria elicited by Lupin has beenreported (43-44).

The eliciting dose of Lupin flour may bevery small. In a study of 6 Lupin-allergicpatients, the eliciting dose for subjectivesymptoms (oral allergy symptoms) was 3 mgor less, and 300 mg or more for objectivesymptoms (1).

Lupin allergy may arise either by primarysensitisation, or by clinical cross-reactivityin Peanut-allergic persons (8,28,45). Theprevalence of allergic reactions to Lupinflour or seed appears to be increasing alongwith the practice of adding protein-rich flourto bread. Because Lupin flour has gainedfavour mainly in Europe, Lupin flour allergyhas been reported mainly in Europeanpatients. These are known to commonly beallergic to other legumes, particularlyPeanut, Soya and Pea (37). The prevalenceof Lupin allergy has increased markedly insome countries, especially France, where theaddition of Lupin flour to Wheat flour wasfirst permitted in 1997 (2). The first reportof Lupin anaphylaxis there was in 1999 (3).In 2002, Lupin was the fourth most frequentcause of severe food-associated anaphylaxisreported to the French Allergy VigilanceNetwork. Two instances of anaphylaxisresulted from a chocolate drink containingLupin flour. Both children were also allergicto Peanuts, and the authors attributed thesereactions to cross-reactivity mechanisms(36). In a recent Portuguese study aimed atdetermining the prevalence of Lupinsensitisation in 1,160 subjects and utilising,among other tests, SPT to Lupin, asensitisation rate of 4.1% was found. A 75%co-sensitisation rate was found betweenLupin and legumes, 82.1% co-sensitisation

between Lupin and pollen, and 28.5% co-sensitisation between Lupin and Latex (46).

Lupin allergy may also occur in youngchildren (47). A 5-year-old girl with Peanutallergy experienced urticaria andangioedema after ingesting spaghetti-likepasta fortified with Lupin flour (6). In a childwho had experienced anaphylaxis to Lupinflour, SPT was positive and in vitro cross-reactivity with other legumes wasdemonstrated, but this was shown to not beclinically relevant in this instance (24).

An 8-year-old asthmatic child, withallergy to Peanut, suffered an asthma attackwhile playing with his brother, who had beeneating Lupin seed as a snack. SPT waspositive to Lupin extract, Peanut, Garbanzobean, Navy bean, Pea, Green bean, Lentil,Soybean, and a number of pollens. The prick-by-prick tests both from dried seeds and thosepreserved in salt and water were stronglypositive. Serum IgE antibody level to Lupinewas 1.43 kUA/l, Peanut 4.32 kUA/l, Soy2.15 kUA/l, Lentil 3.12 kUA/l and Garbanzo0.7 kUA/l. A challenge with Lupin seedsresulted in asthma symptoms within 5minutes of contact (35).

The first reported instance of ananaphylactic reaction caused by theingestion of Lupin flour was that of apaediatric patient without a known Peanutallergy, an 8-year-old boy who developednose and eye discharge followed by oedemaof the face and difficulty breathing 30minutes after eating a waffle containingLupin flour. SPT was positive to Peanut, anda prick to prick test using Lupin flour wasstrongly positive. The IgE antibody level wasraised for Lupin seed (20.8 kUA/l) andPeanuts (> 100 kUA/l) (28).

An interesting report was made of a 30-year-old technician who experiencedrepeated episodes of rhinitis, conjunctivitisand palpebral angiodema related to herhandling of Lupin flour used for skin pricktests and oral challenges. She toleratedPeanuts (4).

Anaphylaxis was described in a 25-year-old Peanut-allergic woman after she ate arestaurant meal. During the meal, shedeveloped pruritus of her mouth and lips,

107

and her tongue started to swell. Fifteenminutes later she had difficulty in breathingand her throat had “narrowed”. Lupin wasidentified as the cause and had been presentin the onion ring batter she had consumed.She had not previously had allergic reactionsto Lupin. SPT and IgE antibodies to Lupinwere positive (37).

A description of 3 individuals whoexperienced adverse reactions to Lupinhighlights potential consequences of Lupinallergy. The first, a 42-year-old woman,developed acute urticaria and angioedema,with throat tightness and cough, after a mealthat included a bread roll. A more severeanaphylactic reaction, including markedbreathlessness requiring oxygen andadrenaline, had occurred on another occasionfollowing ingestion of the same type of breadroll. Lupin bran was a constituent of theserolls. SPT with saline extracts of the rawLupin bran and of the baked bread roll werestrongly positive, but negative for Soybeanand Peanut. A mild generalised reactionfollowed ingestion of a specialty bread thatwas later found to contain Lupin bran. Asecond patient, a 42-year-old woman, wasdescribed who had developed acuteabdominal discomfort, urticaria, facialoedema, cough and shortness of breath 10-15 minutes after eating a bread roll thatcontained Lupin bran. SPT was positive toan extract of Lupin bran. The third patient,a 26-year-old woman who had often eatenlupini (boiled and dried Lupin in the form ofa snack food), on one occasion, after eatingcommercially prepared lupini from a jar,developed urticaria, angioedema andrespiratory difficulty, requiringhospitalisation. Subsequently, a similar butless severe reaction occurred after she ingesteda small portion of home-prepared, boiled andsalted lupini. She had also experiencedurticaria and angioedema after eating gingerbiscuits, which were subsequently found tocontain Lupin flour. SPT was strongly positiveto a Lupin bran extract, and her IgE antibodylevel was 12.9 kUA/l (38).

A 24-year-old woman with Peanut allergyexperienced acute swelling of the lips,urticaria and rhinoconjunctivitis on 4separate occasions when eating a certain

brand of hot dog bread containing Lupinflour (48).

A male patient reported several episodesof generalised angioedema after ingestion ofsnacks that included Lupin seeds. SPT waspositive for a number of tree nuts as well asSunflower seed. Skin reactivity was foundagainst Lupin seed (both the skin and thepulp), and IgE antibodies was found toLupin. The same report also described afemale patient who had reportedangioedema of the lip and generalisedurticaria following ingestion of several Lupinseeds. She had previously eaten this snackon a number of occasions with no adverseeffects. Skin reactivity was present for Maizeflour, Hazel nut, Peanut, Walnut, Sunflowerseed, Chestnut, Green bean, Tomato, Lettuceand Mustard. Skin reactivity was also foundfor Lupin seed (skin and pulp) and the LupinIgE antibody level was raised (5).

A 52-year-old woman developed facial andmucosal oedema, followed by dizziness andshortness of breath, a few minutes afteringestion of a nut croissant containing Lupinflour; she required emergency care. The IgEantibody level for Lupin seed was 42.9 kUA/l.SPT using Lupin flour was strongly positive.No evidence of cross-reactivity with Peanutcould be detected through in vitro or in vivotests (49).

Further evidence for the close relationshipbetween Peanut allergy and Lupin allergywas demonstrated in a study of 24 Peanut-allergic patients, in whom SPT for Lupinflour was positive in 11 (44%). Oralchallenges using the same dose as used withPeanut were positive in 7 of 8 subjects (29).A study reported acute asthma in a patientwith allergy to Peanuts. SPT to raw andcooked Lupin flour was positive. The levelof allergen-specific IgE to Lupin flour washigh. An oral challenge test induced acuteasthma at a dose of 965 mg of Lupin flour,an amount that may be found in 100g ofbread (31). Researchers have stated thatcases of isolated allergy to Lupin flour,without pre-existence of Peanut allergy aswell as workplace asthma by inhalation, arerarely seen (30).

f335 Lupin seed

108

Occupational allergy may occur to Lupin,particularly in mill workers. A study reportson 3 workers who showed allergic symptomsto Lupin flour following inhalation. Skinreactivity to Lupin seed flour extract waspresent in all 3 patients, and Lupin-specificIgE antibodies were detected in 2 (50).

Other reactions

The seeds of many Lupin species containbitter-tasting toxic quinolizidine alkaloids,though there are often sweet varieties withinthe same species that are completelywholesome. The alkaloid profiles are ratherconstant (51). Taste is a very clear indicator.Lupin seed alkaloids appear to be toxicmainly to animals and non-toxic to humans,although not all researchers are in agreementabout this (52). Anticholinergic toxicityassociated with the ingestion of lupini beanswas reported in a 46-year-old female ofItalian descent, who presented with blurryvision, dry mouth, facial flushing, andconfusion. Symptoms had begun quitesuddenly over the course of about 30minutes, 3 to 4 hours after ingesting lupinibeans. Lupini beans derive their bitterflavour from the high levels of quinolizidinealkaloids they contain and must undergo ade-bittering process of washing with water,a process that normally takes 4 days. (Someauthors state that these toxic alkaloids canbe leeched out by soaking overnight anddiscarding the soak water. It may also benecessary to change the water once duringcooking.) The patient had soaked her lupinibeans for only 36 hours before she ateseveral handfuls of them (53).

The number, type, and level of alkaloidsare highly variable among species. InSouthern Europe and the Middle East, high-alkaloid Lupines or “Bitter lupins” aregrown. The primary crop cultivated in

Australia is low-alkaloid Lupin or “Sweetlupin”. The level of alkaloids remaining inEuropean lupins after the de-bitteringprocess is approximately 500 mg/kg,whereas the level of alkaloids in Sweet lupinsis about 130 to 150 mg/kg (53).

Fungal toxins also readily invade thecrushed seed and can cause chronic illness,usually in animals. Lupinosis is amycotoxicosis caused by the ingestion oftoxins produced by the fungus Phomopsisleptostromiformis, which grows on Lupineplants. Outbreaks of natural lupinosis mayoccur in lambs.

Ungerminated legume seeds (broad bean,Chick pea and Lupin) may contain biogenicamines. Tryptamine was the main biogenicamine detected, and its concentrationincreased considerably during germination.Beta-phenylethylamine was detected in smallamounts, and its concentration slowlyincreased during germination. Theconcentration of tyramine showed afluctuation pattern during germination in alltested legumes. Heat treatment seems tohave little effect on the concentration ofbiogenic amines in legume sprouts (54).

A 7-year-old boy was operated on forintestinal obstruction due to a phytobezoar.He had eaten an exceptionally large amountof Lupin seeds a few hours before the onsetof pain (55).

f335 Lupin seed

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f335 Lupin seedReferences

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8. Quaresma RR, Viseu R, Martins LM, Tomaz E,Inacio F. Allergic primary sensitization tolupine seed. Allergy 2007;62(12):1473-4

9. Dooper MM, Holden L, Faeste CK,Thompson KM, Egaas E. MonoclonalAntibodies against the Candidate LupinAllergens alpha-Conglutin and beta-Conglutin. Int Arch Allergy Immunol2006;143(1):49-58

10. Magni C, Herndl A, Sironi E, Scarafoni A,Ballabio C, Restani P, Bernardini R,Novembre E, Vierucci A, Duranti M. One- andtwo-dimensional electrophoreticidentification of IgE-binding polypeptides ofLupinus albus and other legume seeds.J Agric Food Chem 2005;53(11):4567-71

11. Magni C, Scarafoni A, Herndl A, Sessa F,Prinsi B, Espen L, Duranti M. Combined 2Delectrophoretic approaches for the study ofwhite lupin mature seed storage proteome.Phytochemistry 2007;68(7):997-1007

12. Foss N, Duranti M, Magni C, Frokiaer H.Assessment of lupin allergenicity in thecholera toxin model: induction of IgEresponse depends on the intrinsic propertiesof the conglutins and matrix effects. Int ArchAllergy Immunol 2006;141(2):141-50

13. Guarneri F, Guarneri C, Benvenga S.Identification of potentially cross-reactivepeanut-lupine proteins by computer-assistedsearch for amino acid sequence homology.Int Arch Allergy Immunol 2005;138(4):273-7

14. Wait R, Gianazza E, Brambilla D, Eberini I,Morandi S, Arnoldi A, Sirtori CR. Analysis ofLupinus albus storage proteins by two-dimensional electrophoresis and massspectrometry. J Agric Food Chem2005;53(11):4599-606


16. Salmanowicz BP. Capillary electrophoresis ofseed 2S albumins from Lupinus species.J Chromatogr A 2000;894(1-2):297-310

17. Egorov TA, Odintsova TI, Musolyamov AKh,Fido R, Tatham AS, Shewry PR. Disulphidestructure of a sunflower seed albumin:conserved and variant disulphide bonds inthe cereal prolamin superfamily.FEBS Lett 1996;396(2-3):285-8

18. Regalado AP, Ricardo CP. Study of theintercellular fluid of healthy Lupinus albusorgans. Presence of a chitinase and athaumatin-like protein.Plant Physiol 1996;110(1):227-32

19. Regalado AP, Pinheiro C, Vidal S, Chaves I,Ricardo CP, Rodrigues-Pousada C. TheLupinus albus class-III chitinase gene, IF3,is constitutively expressed in vegetativeorgans and developing seeds.Planta 2000;210(4):543-50

20. Pinto MP, Ricardo CP. Lupinus albus L.pathogenesis-related proteins that showsimilarity to PR-10 proteins.Plant Physiol 1995;109(4):1345-51


22. Rojas-Hijazo B, Garces MM, Caballero ML,Alloza P, Moneo I. Unsuspected lupinallergens hidden in food. Int Arch AllergyImmunol 2006;141(1):47-50


24. Matheu V, de Barrio M, Sierra Z, Gracia-Bara MT, Tornero P, Baeza ML. Lupine-induced anaphylaxis. Ann Allergy AsthmaImmunol 1999;83(5):406-8




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f335 Lupin seed28. Wassenberg J, Hofer M. Lupine-induced

anaphylaxis in a child without known foodallergy. Ann Allergy Asthma Immunol2007;98(6):589-90

29. Moneret-Vautrin DA, Guerin L, Kanny G,Flabbee J, Fremont S, Morisset M. Cross-allergenicity of peanut and lupine: the risk oflupine allergy in patients allergic to peanuts.J Allergy Clin Immunol 1999;104(4 Pt1):883-8

30. Leduc V, Moneret-Vautrin DA, Guerin L.Allergenicity of lupin flour. [French] AllergImmunol (Paris) 2002;34(6):213-7

31. Kanny G, Guerin L, Moneret-Vautrin DA. Riskof serious acute asthma due to lupine flourassociated with peanut allergy. [French] RevMed Interne 2000;21(2):191-4

32. Poltronieri P, Cappello MS, Dohmae N, Conti A,Fortunato D, Pastorello EA, et al.Identification and Characterisation of the IgE-Binding Proteins 2S Albumin and Conglutingamma in Almond (Prunus dulcis) Seeds. IntArch Allergy Immunol 2002;128(2):97-104

33. Rance F. Current childhood food allergies.[French] Allerg Immunol (Paris)2000;32(10):366-76

34. Romano C, Ferrara A, Falagiani P. A case ofallergy to globe artichoke and other clinicalcases of rare food allergy. J Investig AllergolClin Immunol 2000;10(2):102-4

35. Moreno-Ancillo A, Gil-Adrados AC,Dominguez-Noche C, Cosmes PM. Lupineinhalation induced asthma in a child.Pediatr Allergy Immunol 2005;16(6):6-544

36. Moneret-Vautrin DA, Kanny G, Morisset M,Rance F, Fardeau MF, Beaudouin E. Severefood anaphylaxis: 107 cases registered in2002 by the Allergy Vigilance Network.Allerg Immunol (Paris) 2004;36(2):46-51

37. Radcliffe M, Scadding G, Brown HM.Lupin flour anaphylaxis.Lancet 2005;365(9467):1360

38. Smith WB, Gillis D, Kette FE. Lupin: a newhidden food allergen.Med J Aust 2004;181(4):219-20

39. Lovik M. Lupine – a “sneaking” foodallergen? [Norwegian] Tidsskr Nor Laegeforen2003;123(15):2076-7

40. Kanny G. Acute asthma due to lupine, anallergen at very high hazard. Abstract.AAAAI 56th Annual Meeting 2000

41. Sampson, HA, Mendelson, L, Rosen, JP.Fatal and near-fatal anaphylactic reactions tofood in children and adolescents.N Engl J Med 1992;347:380-4

42. Romano C, Ferrara A, Tarallo S. Allergicreaction to lupine seed (Lupinus albus).[Abstract] Allergy 1997;52(37):113-4

43. Martinez R, Gutierrez D, Garcia Cubillana A,et al. Contact Urticaria from Lupine (Lupinusalbus). [Abstract] Allergy 1997;52(37):114

44. Gutierrez D, Conde A, Duran S, Delgado J,Guardia P, Martinez R, Garcia-Cubillana A,Gonzalez J, Conde J. Contact urticaria fromlupin. Contact Dermatitis 1997;36(6):311

45. Holden L, Faeste CK, Egaas E. QuantitativeSandwich ELISA for the Determination ofLupine (Lupinus spp.) in Foods.J Agric Food Chem 2005;53(15):5866-71

46. Reis AM, Fernandes NP, Marques SL, Paes MJ,Sousa S, Carvalho F, Conde T, Trindade M.Lupine sensitisation in a population of 1,160subjects. Allergol Immunopathol (Madr)2007;35(4):162-3

47. Novembre E, Moriondo M, Bernardini R,Azzari C, Rossi ME, Vierucci A. Lupin allergyin a child. J Allergy Clin Immunol1999;103(6):1214-6

48. Faeste CK, Lovik M, Wiker HG, Egaas E. Acase of peanut cross-allergy to lupine flour ina hot dog bread. Int Arch Allergy Immunol2004;135(1):36-9

49. Brennecke S, Becker WM, Lepp U, Jappe U.Anaphylactic reaction to lupine flour.J Dtsch Dermatol Ges 2007;5(9):774-6

50. Crespo JF, Rodriguez J, Vives R, James JM,Reano M, Daroca P. et al. Occupational IgE-mediated allergy after exposure to lupineseed flour. J Allergy Clin Immunol2001;108(2 Pt 1):295-7

51. Torres KB, Quintos NR, Necha LL, Wink M.Alkaloid profile of leaves and seeds ofLupinus hintonii C. P. Smith.Z Naturforsch [C] 2002;57(3-4):243-7

52. Smith RA. Potential edible lupine poisoningsin humans.Vet Hum Toxicol 1987;29(6):444-5

53. Litkey J, Dailey MW. Anticholinergic toxicityassociated with the ingestion of lupini beans.Am J Emerg Med 2007;25(2):215-7

54. Shalaby AR. Changes in biogenic amines inmature and germinating legume seeds andtheir behavior during cooking.Nahrung 2000;44(1):23-7

55. Tsin G, Hadary A. Intestinal obstruction dueto lupin phytobezoar in a child. [Hebrew]Harefuah 1994;127(7-8):227-8

111

Macadamia spp.Family: ProteaceaeCommonnames: Macadamia nut,

Queensland nut,Australian nut

Sourcematerial: Shelled nutsFor continuous updates:www.immunocapinvitrosight.com

f345 Macadamia nut

Allergen Exposure


Macadamia nuts are the fruit of anAustralian tropical evergreen tree, and arealso known as Queensland or Australiannut. The tree was exported to Hawaii in the1890's as a source of shade but subsequentlybecame a crop. It is also grown in warmMediterranean areas, in the southern USAand in South Africa. The seed grows on 2species of trees (M. tetraphylla and M.intergrifolia). The commercial Macadamiatree (M. intergrifolia) grows more than 12m tall and has creamy-white flowers.

The “nut” is not truly a nut but a seed(1). The round, whitish kernel is enclosed inan extremely hard, brown shell, about 2.5cm in diameter and 2 to 3 mm thick. Theshell is in turn contained in a fibrous greenhusk.

Australia is the world's largest producerof the nut. For 7 months of the year the nutsfall on their own and are harvested from theground by hand and taken to the factory forprocessing. Workers (“nut sorters”) standbeside the “shell” conveyer and pick out byhand salvageable nut kernels that haveescaped the mechanical separators. Theimportance of this process for allergyconsists in both the intense occupationalexposure and the relative rarity andcostliness of the nuts. The kernels are thendry- or oil-roasted (2).

The nuts are richly flavoured and high inprotein. Their oil content (70%) is higherthan that of other nuts.

Environment

Macadamias can be consumed fresh orroasted and are added to a variety of foods,including snack bars, cereals, and nut mixes.Ground Macadamia meal is becoming anincreasingly popular ingredient in bakedgoods, as is cold pressed Macadamia oil (3).

Allergens


A 17.4 kDa protein appears to be themajor allergen and is present in raw androasted extracts (4).

A vicillin with anti-bacterial propertieshas been isolated, but its allergenicity wasnot determined (5).


Macadamia nut belongs to the Proteaceaefamily, which are classified separately frommost other tree nuts and from Peanuts.

Partial cross-reactivity has been reportedbetween Hazel nut and Macadamia nut (4).In a study of Almond, antibodies developedto Almond were shown to be specific forAlmond; however, some cross-reactivity wasobserved with extracts of some tree nuts and

112

f345 Macadamia nutof Sesame seeds. Sodium dodecylsulfate-polyacrylamide gel electrophoresis andWestern immunoblotting indicated that anti-Almond antibodies recognised proteinsextracted from Black walnuts, Brazil nuts,Cashews, Hazel nuts, Macadamia nuts,Pistachios, and Sesame seeds, in addition tothose from Almond (6).

Clinical Experience


Macadamia nut, although not as common afood as many other tree nuts, mayoccasionally cause serious allergic reactionsin sensitised individuals. Cases are perhapsbecoming more frequent because of theincreasing use of Macadamia nuts, alone andin other products (7-8). In particular,Macadamia nut is becoming more frequentlyavailable in nut mixes and is being sold incountries which did not previously import it.

In an American study of 115 patientsaged 4-19.5 years, moderately severereactions to Macadamia were reported in 3(13%) individuals, and severe reactions in2 (4%) (9). In a telephonic survey, of 118subjects reporting an allergy to Peanut ortree nut, 2 self-reported allergy toMacadamia nut (10).

Macadamia nut-induced uvularangioedema, angioedema of the posteriorpart of the tongue, dysphagia, chesttightness, chest pain, and chest pruritis weredescribed in a 36-year-old man. Symptomsoccurred 5 minutes after eating a singlechocolate-covered Macadamia nut. A prickto prick test with fresh Macadamia nut waspositive (11).

A study reported on 2 patients withallergy to Macadamia nut. A 48-year-oldwoman reported oral allergy symptomsoccurring within 10 minutes of ingestion of6-8 Macadamia nuts, followed bypalpitations, dyspnoea, dizziness, flushingand severe itch. Skin reactivity was detected.A 34-year-old man presented with tongueswelling, itchy, hot palms, swollen hands andthroat tightness, which developed withinminutes after eating a single Macadamia nut.SPT was positive (3).

Reactions may be severe and result inanaphylaxis (8,12). An 18-year-old womanhad immediate oral itching when eatingflourless orange cake made with Macadamiameal. Within 5 minutes, this reaction hadprogressed to anaphylaxis (4). Anaphylaxisfollowing contact with Macadamia nut hasbeen reported in an infant (13).

A 42-year-old man developed generalisedpruritus, itching of the throat, rhinitis,dyspnoea and dizziness 5 minutes aftereating a few roasted Macadamia nuts. Skinprick tests were positive to Hazel nut androasted Macadamia nut but negative toPeanut, Almond, Brazil nut and Walnut. A34-year-old man repeatedly developed severeoral burning, itching and swelling aftereating Hazel nut, Walnut, Brazil nut,Almond and Macadamia nut, but toleratingPeanut and Cashew nut. SPT was positiveto Peanut, Almond, Hazel nut, Brazil nutand Walnut but negative to Cashew nut. Aprick-to-prick IgE determination waspositive for Macadamia nut (14).

A 23-year-old female with a history ofatopic dermatitis, allergic rhinitis, andallergic conjunctivitis reported that in herfourth year of primary school, she ateMacadamia nuts and developed oraldiscomfort and generalised urticaria. In hersecond year of junior high school, she ateMacadamia nuts and developed oral andpharyngeal discomfort, followed bygeneralised urticaria and dyspnoea. At theage of 20 years, she also developed oraldiscomfort after eating vegetables in aChinese dish containing Macadamia nuts.SPT using Macadamia oil extract waspositive. Although she developed oral allergysyndrome after eating Macadamia nuts, shewas negative for Bet v 1 and Bet v 2 asallergens (15).

Nut oils may pose a threat to patientswith allergy, depending on the method ofprocessing. IgE reactivity to proteins inMacadamia oil has been reported, based intesting of sera from patients withMacadamia allergy (16).

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f345 Macadamia nutOther reactions

Occupational dermatitis from Macadamianut shells was described in 15 nut sorters ata Macadamia nut processing plant. Thenature of the allergen was not found but wasthought to be confined to the shell, asopposed to the plant leaf or kernal (2).

References1. Hartung ME, Storey WB. The development of

the fruit of Macadamia ternifolia.J Agric Res 1939;59:397-406

2. Knight TE, Hausen BM. Dermatitis in anutshell: occupational exposure toMacadamia integrifolia.J Am Acad Dermatol 1996;35(3 Pt 1):482-4

3. Falk M, Katelaris CH, Fulcher DA.Macadamia allergy.ACI International 2000;12(5):240-2

4. Sutherland MF, O'Hehir RE, Czamy D,Suphioglu C. Macadamia nut anaphylaxis:demonstration of specific IgE reactivity andpartial cross-reactivity with hazelnut.J Allergy Clin Immunol 1999;104:889-90

5. Marcus JP, Green JL, Goulter KC, Manners JM.A family of antimicrobial peptides isproduced by processing of a 7S globulinprotein in Macadamia integrifolia kernels.Plant J 1999;19(6):699-710

6. Hlywka JJ, Hefle SL, Taylor SL. A sandwichenzyme-linked immunosorbent assay for thedetection of almonds in foods.J Food Prot 2000;63(2):252-7


8. Yunginger, JW, Sweeney, KG, Stumer, W,Giannandrea, LA, et al. Fatal food-inducedanaphylaxis. JAMA 1988;260:1450-1452


10. Sicherer SH, Munoz-Furlong A, Sampson HA.Prevalence of peanut and tree nut allergy inthe United States determined by means of arandom digit dial telephone survey: a 5-yearfollow-up study. J Allergy Clin Immunol2003;112(6):1203-7

11. Pallares DE. Allergy to macadamia nut. AnnAllergy Asthma Immunol 2000;85(5):385-6

12. Harris RM, Johnson M Macadamia nutinduced anaphylaxis: a case report.AAAAI56th Annual Meeting 2000;March 3-8

13. Yamada H, Shimizu A, Tsuchiya T, Yoshihara S.Case of infant with anaphylaxis due tomacadamia nuts. [Japanese] Arerugi2007;56(10):1306

14. Lerch M, Egger C, Bircher AJ. Allergicreactions to macadamia nut.Allergy 2005;60(1):130-1

15. Inaba Y, Yagami A, Suzuki K, Matsunaga K.Allergy to macadamia nut. [Japanese] Arerugi2007;56(7):699-702


114

Zea maysFamily: Poaceae (Gramineae)Commonnames: Maize, Corn, Sweet

Corn, Indian Corn,Field Corn

Sourcematerial: Untreated planting seedsSee also: Maize, Corn g202Cultivars within the genus may bedivided into 6 general types: Popcorn(everta), Flint corn (indurata), Dentcorn (indenta), Flour corn (amylacea),Sweet corn (saccharata) and Pod corn(tunicata).There are, however, only 2 basic types:“Sweet corn” is distinguished from“Field corn” by the high sugar contentof the kernels at the early “dough”stage and by wrinkled, translucentkernels when dryFor continuous updates:www.immunocapinvitrosight.com

f8 Maize/Corn

Allergen Exposure


Maize kernels grow on long “ears” at theleaf axils of this unusual plant. The originalhabitat was probably South America orMexico, where Maize was the staple diet ofthe American Indian. Maize is now grownalmost anywhere summers are reasonablywarm, although approximately 50% of theworld's Maize is produced in the USA. It isa staple cereal of the human diet in Centraland South America and in many parts ofAfrica. It is extremely important in livestockrearing, food processing and othercommercial activities in developed countries.Few plants are grown more extensively orput to more diversified uses than Maize.

Environment

In the US and Europe, Maize is used almostentirely for animal feeding, as grain orfodder. But it is important as a vegetable,and as the snack popcorn. Kernels may beeaten straight from the cooked cob or cutoff and used in succotash, custards, fritters,soups and chowders. Kernels are also usedin mixed pickles and vegetable relishes. Cornmeal, grits, and hominy are prepared forms

of Maize kernels. Maize is also convertedinto various substances that have a widerange of usage, such as starch, syrup,dextrin, oil, and zein. Maize serves in themaking of whiskey and other alcoholicproducts, and condensed milk. The roastedseed is a coffee substitute. Riboflavin andnicotinamide are added to fortified Maize.

The various parts of the plant have beenused in the treatment of a variety of ailments.

Unexpected exposure


Allergens

Various allergens have been characterised:

Zea m 14, a 9 kDa lipid transfer protein (1-9).

Zea m 25, a thioredoxin (1,8,10-11).

Zea m 27kD Zein, a 27 kDa protein, aglutenin (12-13).

Zea m 50kD Zein, a 50 kDa protein, aglutenin (12).

115

f8 Maize/CornThe following allergens have been

characterised in Maize pollen: Zea m 1, Zeam 2, Zea m 3, Zea m 4, Zea m 5, Zea m 12,Zea m 13, Zea m CBP, and Zea m Zm13m.See Maize pollen g202.

Zea m 14, a lipid transfer protein, has alsobeen isolated from Maize flour. Skin reactivityand IgE antibodies to this allergen weredetected in 19 of 22 patients (86%) withsystemic symptoms following the ingestionof Maize, confirming this as the Maize majorallergen (1). Maize lipid transfer protein ishighly heat-stable, and even heat treatmentat 100 °C for 160 minutes, though it almosttotally eliminated the IgE-binding activity ofthe higher-molecular-weight bands seen inMaize, did not affect that of the lipid transferprotein (9).

Zea m 27kD Zein, a Maize zein, has beenidentified in an extensively hydrolyzed caseinformula, Nutramigen. These proteins arewater-insoluble and presumably originatedfrom the Maize starch in Nutramigen.Although rabbits immunised with thisformula developed antibodies against zeinsbut not against Cow's milk proteins, theclinical relevance of these proteins inNutramigen remains to be established (13).

A 16 kDa allergen, recognised by 36%of Maize-allergic patients, was also isolatedand shown to be the Maize inhibitor oftrypsin (1).

A 22 kDa protein from Maize seed, witha 52% homology with the protein thaumatinand a 99% homology with the 22 kDatrypsin/alpha-amylase inhibitor, has beenisolated (14). The allergenicity of this proteinwas not evaluated.

A 50 kDa allergen, belonging to the reducedsoluble protein (RSP) fraction, has beenisolated and shown to be stable to heat anddigestion. In a study of 16 patients with specificIgE to Maize, only 6 patients weresymptomatic. These 6 patients were DBPCFC-positive on challenges, and SPT with thepurified RSP fraction was positive for all ofthe 6 DBPCFC-positive patients (15).

A protein similar to an isoflavonereductase (IFR) and/or an isoflavonereductase-like (IRL) protein has beenisolated. (16) The allergenic potential of thisprotein was not determined.

In an individual with Maize dust-inducedIgE-mediated occupational asthma andrhinitis, 10 IgE-binding components withsizes of 9 to 140 kDa were detected withinthe Maize dust extracts (17).

A chitinase has been isolated from Zeamays seeds (18). The allergenicity of thischitinase was not evaluated.

Maize seed contains the panallergenprofilin, but at much lower levels than thosefound in Maize pollen (Zea m 12) and infoods such as Celery and Tomato (19). Thisprofilin may be of low clinical significance,as heat processing destroys the protein.Nonetheless, the presence of profilin inMaize seed may play a role in occupationalasthma where inhalation of Maize flour ordust is possible.

Normal Maize contains about 7-13%protein, which can be fractionated intovarious solubility classes. The salt-extractable fraction (albumins andglobulins) mainly comprises proteins withmetabolic functions. Extraction withaqueous alcohol isolates the prolaminfraction that contains the storage proteinsof the seed. These constitute around 60-70%of the Maize endosperm proteins and arecalled zeins. These are various polypeptides,classified as alpha, beta, delta and gammazeins. The reduced soluble proteins arealcohol-extractable and soluble in water.Also present is an alcohol-insoluble glutelinfraction (15).


An extensive cross-reactivity among thedifferent individual species of the genuscould be expected (20). In vitro cross-reactivity among the IgE binding proteinsof Maize, Rice, Soybean and Peanut wasdemonstrated. The high degree of cross-reactivity between Rice and Maize wasthought to be due to the fact that they bothbelong to the same botanical family. But theauthors were not able to clarify the clinicalsignificance of these cross-reactivities andsuggested further clinical studies to put thesefindings into perspective (21). An earlierstudy reported that, by using RASTinhibition tests, cross-antigenicity could be

116

f8 Maize/Corndemonstrated among different cereal grains,the degree of cross-reactivity closelyparalleling their taxonomic relationship inthe following order of decreasing closeness:Wheat, Triticale, Rye, Barley, Oat, Rice andMaize (22).

The major Maize allergen is a lipidtransfer protein (7,23). A high degree ofcross-reactivity has been demonstratedamong the LTPs of Peach, Apple, Walnut,Hazel nut, Peanut, Maize, Rice, Sunflowerseed, French bean and Apricot (1,24-26).Not all LTPs from plants are closely related.Mature Cherry LTP shows a great deal ofidentity with LTPs from Peach (88%) andApricot (86%), but less with Maize (59%)(27). Similarly, Maize LTP was shown tocross-react completely with Rice and PeachLTP but not with Wheat or Barley LTP (1).Lipid transfer protein from Cowpea has ahigh homology of similarity to lipid transferproteins of Maize (72%) (28). Rice non-specific lipid transfer protein has also beenreported to closely resemble the structuresof Wheat, Barley and Maize ns-LTPs (29).

A sensitisation rate of 47% among bakerswith occupational asthma and of 35% amongpatients with grass pollen allergy, but withouta clinical history of cereal allergy, wasdemonstrated to Tri a 25, a thioredoxin.Maize thioredoxin (Zea m 25) shares a 74%identity with Tri a 25, and exhibits distinctIgE cross-reactivity with its Wheathomologue. The study concluded thatthioredoxins are cross-reactive allergens thatmight contribute to the symptoms of baker'sasthma and might in addition be related tograss pollen allergy, and that therefore similareffects may be postulated for Zea m 25 (10).A more recent publication questionedwhether this protein in Wheat is a trueallergen, since it had been found thatthioredoxin alleviates the allergic responseand that there was no evidence thatthioredoxin acted as an allergen (11).

A 16 kDa allergen, isolated and shownto be a Maize inhibitor of trypsin, was shownto cross-react completely with Grass, Wheat,Barley, and Rice trypsin inhibitors (1).

A Birch pollen protein with a mass of35 kDa was isolated and shown to cross-

react with 34 and 35 kDa proteins in Apple,Pear, Carrot, Banana and other exotic fruits.A high degree of sequence identity toisoflavone reductases (IFRs) and isoflavonereductase-like (IRL) proteins from severalplants that also had a similar size wasdemonstrated, ranging from 56% for IFRfrom Pea and Chick pea and an IRL fromMaize, to 80% for a Tobacco IRL. Theauthors postulated that this allergen may beresponsible for less common pollen-relatedfood allergies in patients allergic to Birchpollen (16).

The primary structure of the Japanesecypress (Chamaecyparis obtusa) allergen,Cha o 2, shows significant identity with thepolygalacturonases of Avocado, Tomato,and Maize (30). The clinical implications ofthis finding have not been clarified yet.

In a study assessing the possibleassociation of Oral allergy syndrome (OAS)with allergy to London plane tree (Platanusacerifolia), out of 720 patients evaluated, 61(8.48%) were sensitised to P. acerifoliapollen. Food allergy was observed in 32(52.45%) of the 61 patients, the allergensmost frequently implicated being Hazel nut,Peach, Apple, Peanut, Maize, Chickpea andLettuce. This study concluded that OAS inthese patients may have been caused byprimary respiratory sensitisation to Planetree pollen. The authors suggest that profilinmay be the responsible allergen (31).

Cross-allergenicity among 5 cereal grains,Rice, Wheat, Maize, Japanese millet(Echinochloa crus-galli) and Italian millet(Setaria italica), was examined byradioallergosorbent test and RAST inhibitionassay. Significant close correlations betweenevery combination of IgE antibody value forthe 5 cereal grain extracts were found. A Riceprotein of 16 kDa was shown to be one ofthe major allergens in Rice grain extracts (32).

Importantly, individuals with allergy toMaize pollen may also demonstrate allergyto Maize seed. In a group of 56 children withhay fever as a result of Maize pollen, morethan half were sensitised to Maize seedallergens (33).

117

f8 Maize/Corn

Clinical Experience


Maize may moderately often sensitise orinduce symptoms of food allergy in sensitisedindividuals (7,15,31,34-37). Allergicsymptoms reported have includedabdominal pain, nausea, vomiting, rhinitis,asthma, angioedema, atopic dermatitis, andanaphylaxis.

Latent sensitisation has often beendescribed as a feature of Maize allergy. In34 children with atopic dermatitis, 33 wereSPT positive to Wheat and 18 to Oats. IgEantibodies to Wheat and Oats could bedetected in 32 and 30 patients respectively.SPT to Rice, Maize, Millet or Buckwheatwas positive in 16/34 patients (38-39). In16 subjects with skin reactivity and thepresence of IgE antibodies to Maize flour,only 6 complained of urticaria and/or otherallergic symptoms following the ingestion ofMaize-based foods. These patientsdeveloped symptoms following oralchallenge with cooked Maize flour (polenta).The authors concluded that the presence ofpositive in vivo and in vitro tests to Maizeflour had no clinical significance for mostof the patients studied, and that food allergyto Maize has to be proven by DBPCFCstudies. In these patients, a 50 kDa proteinisolated was shown to be stable to cookingand digestion (15).

In a cross-sectional, descriptive,questionnaire-based survey conducted inToulouse schools in France to determine theprevalence of food allergies amongschoolchildren, of 192 questionnairesreporting a food allergy, of which 10 wereexcluded, the main foods reported as causingadverse reactions were Cow's milk (n=29),Egg (n=23), Kiwi (n=22), Peanut (n=20), Fish(n=19), Tree nuts (n=19), and Shrimp(n=13). Two individuals reported allergy toMaize (40).

Anaphylaxis to Maize protein has beenreported (1,41). Anaphylaxis has evenoccurred during double-blind, placebo-controlled Maize challenges. (42) The Maizelipid transfer protein (Zea m 14) is reportedto be responsible for this severe form ofallergic reaction (5). Food-dependant

exercise-induced anaphylaxis to Maize hasalso been described (43). In a study reportingon 7 cases of food-dependant exercise-induced anaphylaxis, responsible foods wereWheat (2 cases), Maize, Barley, Shrimp,Apple, Paprika and Mustard (44).

An unusual report was made of a 34-year-old carpenter who had previously beendiagnosed with occupational asthma due toRye flour added to wood boards. Hedeveloped severe anaphylaxis after testinga spoonful of baby cereal food – a non-Gluten, Rice and Corn formula. Skinreactivity and IgE antibodies weredemonstrated for Wheat, Barley, Rye flour,Peanut and Mustard. A DBPCFC waspositive for 0.1 g of the cereal. A 37 kDaprotein band was demonstrated in the babyfood, flours and Mustard. In addition, a welldefined 23 kDa band was found in the Maizeflour (45). The patient was specificallychallenged with Maize alone.

Allergic reactions, including dermatitis,have been described with the Maize by-products Corn syrup, Corn dextrimaltose,Corn invert sugar, Corn isomerised dextroseand Corn D-psicose (46-48). Intravenousadministration of a Maize-derived dextrosesolution in a 23-year-old pregnant femalepatient at term gestation resulted inanaphylaxis. Symptoms included orofacialswelling, difficulty in breathing,hypotension, cardiac arrhythmia, voicehoarseness, total body warmth and flushing.These occurred within 8 minutes of initiationof a 5% dextrose Lactated Ringer's solution.Although the reaction elicited in this patientwas unusual, clinicians should be aware ofthe possibility of Maize allergy due to theadministration of IV fluids containingMaize-derived dextrose (49).

Patients allergic to Maize seed may alsobe allergic to Maize pollen, as Zea m 13 andhomologous proteins are conserved plantallergens (4).

Occupational exposure to Maize, Maizeflour, or Maize dust may result inoccupational asthma or rhinitis, in particularin bakery workers, mill workers and thoseworking in the animal feed industry (50).Whether atopy plays a dominant role or atmost a minor role in the development of

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f8 Maize/Corngrain dust-induced airway disease has notbeen fully evaluated yet. Occupationalasthma to grain dust resulting inbronchoconstriction induced by an IgE-mediated reaction has been reported (17).Antigen-specific IgE, IgG and IgG4antibodies to Maize dust in exposed workershave also been described (51). In a group of35 men working in an animal foodprocessing plant, the most frequent positiveskin prick reactions occurred to thefollowing occupational allergens: Fish flour(82.9%), Carotene (77.1%), Maize (65.7%),four-leaf clover (62.9%), Sunflower(54.3%), Chicken meat (31.4%), Soy(28.6%), and Yeast (22.7%) (52).

In 42 employees working in the animalfeed industry, 15/42 (34.9%) had work-related respiratory dysfunction with orwithout nasal symptoms (53). In 32 Swinefarmers, 37% were reported to be allergicto Maize flour (54).

Allergic reactions have also been reportedto cornstarch powder used as a glovelubricant. Symptoms included urticaria,intermittent episodes of dyspnoea,oculorhinitis, angioedema, and asthma (55).Anaphylaxis to cornstarch glove powder hasbeen described in 2 nurses. Both exhibitedskin reactivity to cornstarch powder inwater, with resultant anaphylaxis in 1. Bothhad negative in vitro and in vivo tests toMaize. Analysis of the cornstarch powderrevealed only glucose and inorganic salts.The authors tentatively suspected thatcornstarch, and not residual Maize proteins,was the responsible allergen (56).

Similarly, a 33-year-old nurse presentedwith persistent hand dermatitis. The IgEantibody levels were moderately raised forLatex, Avocado and Banana. Despiteavoidance of latex gloves, she failed toimprove. Repeated investigation demon-strated no skin reactivity for Latex, but astrong reaction to Maize, which was thepowder (cornstarch) being used on thegloves (57). Furthermore, if Corn oil is notpurified it may contain Maize protein.

Other reactions

Maize has been implicated as one of thecausative foods of eosinophilic esophagitis,a disorder with symptoms suggestive ofgastroesophageal reflux disease butunresponsive to conventional refluxtherapies (58).

Contact urticaria and an anaphylactoidreaction from cornstarch surgical glovepowder have also been described (59-60).

The dust of stored Maize has beenreported as a cause of respiratory symptoms.During the storage process, Maize dust canbe contaminated by moulds andthermophilic actinomycetes, which have notbeen described until now as causativeantigens of these symptoms. Mould as acontaminant of Maize seed should beconsidered as a possible cause ofhypersensitivity reactions to Maize (61). Astudy described occupational hyper-sensitivity pneumonitis in an agriculturalworker who planted and stored Maize.Clinical findings, precipitating antibodies,and his improvement after avoidance of hiswork environment confirmed the diagnosis.Aspergillus species contaminating the Maizedust were probably the antigens that causedthe disease (62).

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f8 Maize/CornReferences


2. Pastorello EA, Farioli L, Pravettoni V, Ispano M,Scibola E, Trambaioli C, Giuffrida MG,Ansaloni R, Godovac-Zimmermann J, Conti A,Fortunato D, Ortolani C. The maize majorallergen, which is responsible for food-induced allergic reactions, is a lipid transferprotein. J Allergy Clin Immunol2000;106(4):744-51

3. Pastorello EA, Pompei C, Pravettoni V,Brenna O, Farioli L, Trambaioli C, Conti A.Lipid transfer proteins and 2S albumins asallergens. Allergy 2001;56 Suppl 67:45-7

4. Heiss S, Flicker S, Hamilton DA, Kraft D,Mascarenhas JP, Valenta R. Expression ofZm13, a pollen specific maize protein, inEscherichia coli reveals IgE-binding capacityand allergenic potential.FEBS Lett 1996;381(3):217-21

5. Midoro-Horiuti T, Brooks EG, Goldblum RM.Pathogenesis-related proteins of plants asallergens. Ann Allergy Asthma Immunol2001;87(4):261-71

6. Pantoja-Uceda D, Bruix M, Santoro J, Rico M,Monsalve R, Villalba M. Solution structure ofallergenic 2 S albumins.Biochem Soc Trans 2001;30(6):919-24


8. Weichel M, Vergoossen NJ, Bonomi S,Scibilia J, Ortolani C, Ballmer-Weber BK,Pastorello EA, Crameri R. Screening theallergenic repertoires of wheat and maizewith sera from double-blind, placebo-controlled food challenge positive patients.Allergy 2006;61(1):1-135

9. Pastorello EA, Pompei C, Pravettoni V, Farioli L,Calamari AM, Scibilia J, Robino AM, Conti A,Iametti S, Fortunato D, Bonomi S, Ortolani C.Lipid-transfer protein is the major maizeallergen maintaining IgE-binding activityafter cooking at 100 degrees C, asdemonstrated in anaphylactic patients andpatients with positive double-blind, placebo-controlled food challenge results.J Allergy Clin Immunol 2003;112(4):775-83

10. Weichel M, Glaser AG, Ballmer-Weber BK,Schmid-Grendelmeier P, Crameri R. Wheatand maize thioredoxins: a novel cross-reactive cereal allergen family related tobaker's asthma. J Allergy Clin Immunol2006;117(3):676-81

11. Buchanan BB, Frick OL. Thioredoxin andfood allergy. J Allergy Clin Immunol 2007Feb;119(2):513-4; author reply 514-5

12. Lee SH, Benmoussa M, Sathe SK, Roux KH,Teuber SS, Hamaker BR. A 50 kDa maizegamma-Zein has marked cross-reactivity withthe almond major protein.J Agric Food Chem. 2005; 53(20):7965-70

13. Frisner H, Rosendal A, Barkholt V.Identification of immunogenic maize proteinsin a casein hydrolysate formula. PediatrAllergy Immunol 2000; 11(2):106-10

14. Huynh QK, Borgmeyer JR, Zobel JF. Isolationand characterization of a 22 kDa protein withantifungal properties from maize seeds.Biochem Biophys Res Commun1992;182(1):1-5

15. Pasini G, Simonato B, Curioni A, Vincenzi S,Cristaudo A, Santucci B, Peruffo AD,Giannattasio M. IgE-mediated allergy to corn:a 50 kDa protein, belonging to the ReducedSoluble Proteins, is a major allergen.Allergy 2002;57(2):98-106

16. Vieths S, Frank E, Scheurer S, Meyer HE,Hrazdina G, Haustein D. Characterization of anew IgE-binding 35-kDa protein from birchpollen with cross-reacting homologues invarious plant foods.Scand J Immunol 1998;47(3):263-72

17. Park HS, Nahm DH. Identification of IgE-binding components in occupational asthmacaused by corn dust. Ann Allergy AsthmaImmunol 1997;79(1):75-9

18. Verburg JG, Smith CE, Lisek CA, Huynh QK.Identification of an essential tyrosine residuein the catalytic site of a chitinase isolatedfrom Zea mays that is selectively modifiedduring inactivation with 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide.J Biol Chem 1992;267(6):3886-93

19. van Ree R, Voitenko V, van Leeuwen WA,Aalberse RC. Profilin is a cross-reactiveallergen in pollen and vegetable foods. IntArch Allergy Immunol 1992;98(2):97-104


21. Lehrer SB, Reese G, Malo JL, Lahoud C,Leong-Kee S, Goldberg B, Carle T, Ebisawa M.Corn allergens: IgE antibody reactivity andcross-reactivity with rice, soy, and peanut. IntArch Allergy Immunol 1999;118(2-4):298-9




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25. Conti A, Fortunato D, Ortolani C, Giuffrida MG,Pravettoni V, Napolitano L, Farioli L, PeronoGaroffo L, Trambaioli C, Pastorello EA.Determination of the primary structure of twolipid transfer proteins from apricot (Prunusarmeniaca). J Chromatogr B Biomed Sci Appl2001;756(1-2):123-9

26. Pastorello EA, Ortolani C, Baroglio C,Pravettoni V, Ispano M, Giuffrida MG,Fortunato D, Farioli L, Monza M, et al.Complete amino acid sequencedetermination of the major allergen of peach(Prunus persica) Pru p 1.Biol Chem 1999;380:1315-20

27. Scheurer S, Pastorello EA, Wangorsch A,Kastner M, Haustein D, Vieths S.Recombinant allergens Pru av 1 and Pru av 4and a newly identified lipid transfer proteinin the in vitro diagnosis of cherry allergy.J Allergy Clin Immunol 2001;107(4):724-31

28. Carvalho AO, Souza-Filho GA, Ferreira BS,Branco AT, Araújo IS, Fernandes KV,Retamal CA, Gomes VM. Cloning andcharacterization of a cowpea seed lipidtransfer protein cDNA: expression analysisduring seed development and under fungaland cold stresses in seedlings' tissues. PlantPhysiol Biochem 2006;44(11-12):732-42

29. Poznanski J, Sodano P, Suh SW, Lee JY, Ptak M,Vovelle F. Solution structure of a lipidtransfer protein extracted from rice seeds.Comparison with homologous proteins.Eur J Biochem 1999;259(3):692-708

30. Mori T, Yokoyama M, Komiyama N, Okano M,Kino K. Purification, identification, andcDNA cloning of Cha o 2, the second majorallergen of Japanese cypress pollen. BiochemBiophys Res Commun 1999;263(1):166-71

31. Enrique E, Cistero-Bahima A, Bartolome B,Alonso R, San Miguel-Moncin MM, Bartra J,Martinez A. Platanus acerifolia pollinosis andfood allergy. Allergy 2002;57(4):351-6

32. Urisu A, Yamada K, Masuda S, Komada H,Wada E, Kondo Y, Horiba F, Tsuruta M, Yasaki T,Yamada M, et al. 16-kilodalton rice protein isone of the major allergens in rice grainextract and responsible for cross-allergenicitybetween cereal grains in the Poaceae family.Int Arch Allergy Appl Immunol1991;96(3):244-52

33. Buczylko K, Kowalczyk J, Zeman K, Kardas-Sobantka D, Fiszer A. Allergy to food inchildren with pollinosis. Rocz Akad MedBialymst 1995;40(3):568-72

34. Hofman T. Analysis of food allergy incidencein children up to 5 years of age in theWielikopolska region. [Polish] Pol MerkuriuszLek 1998;5(30):341-5

35. Aruin LI, Balabolkin II, Gershman GB,Subbotina OA, Shcherbakov PL, Sofonov AB.Mucous membrane of the jejunum in allergyto cereal protein. [Russian] Arkh Patol1992;54(6):20-5

36. Dockhorn RJ. Clinical studies of food allergyin infants and children.Ann Allergy 1987;59(5 Pt 2):137-40

37. Speer F. Food allergy: the 10 commonoffenders.Am Fam Physician 1976;13(2):106-12


39. Vidal C, Gonzalez-Quintela A. Food-inducedand occupational asthma due to barley flour.Ann Allergy Asthma Immunol1995;75(2):121-4

40. Rance F, Grandmottet X, Grandjean H.Prevalence and main characteristics ofschoolchildren diagnosed with food allergiesin France.Clin Exp Allergy 2005;35(2):167-72

41. David TJ. Anaphylactic shock duringelimination diets for severe atopic eczema.Arch Dis Child 1984;59(10):983-6

42. Tanaka LG, El-Dahr JM, Lehrer SB. Double-blind, placebo-controlled corn challengeresulting in anaphylaxis. [Letter] J AllergyClin Immunol 2001;107(4):744

43. Pauls JD, Cross D. Food-dependent exercise-induced anaphylaxis to corn. J Allergy ClinImmunol 1998;101(6 Pt 1):853-4


45. Asensio T, Armentia A, Lombardero M,Callejo A, Martin G, Castrodeza J. Cereal-induced anaphylaxis in an adult after eatinga baby cereal formula. Allergol Immunopathol(Madr) 2004;32(5):310-1

46. Howard W.A, Todd RH, Dalton GL. Studies onthe allergenicity of corn products.J Allergy 1959;30:381-6

47. Nishioka K, Katayama I, Sano S, Numata T,Yamamoto S. Monosaccharides in highfructose corn syrup as an etiologic factor ofurticaria. J Derm 1984;11:391-396

48. Nishioka K, Katayama I, Sano S. Urticariainduced by D-psicose.Lancet 1983;2:1417-8

49. Guharoy SR, Barajas M. Probableanaphylactic reaction to corn-deriveddextrose solution.Vet Hum Toxicol 1991;33(6):609-10

50. Quirce s, Sastre J. Occupational asthma[Review]. Allergy 1998;53:633-41

51. Park HS, Nahm DH, Kim HY, Suh CH, Kim KS.Role of specific IgE, IgG and IgG4 antibodiesto corn dust in exposed workers.Korean J Intern Med 1998;13(2):88-94

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52. Zuskin E, Kanceljak B, Schachter EN, Witek TJ,Maayani S, Goswami S, Marom Z, Rienzi N.Immunological and respiratory changes inanimal food processing workers.Am J Ind Med 1992;21(2):177-91

53. Park HS, Nahm DH, Suh CH, Kwon OY, Kim KS,Lee SW, Chung HK. Occupational asthma andIgE sensitization to grain dust.J Korean Med Sci 1998;13(3):275-80

54. Zuskin E, Kanceljak B, Schachter EN,Mustajbegovic J, Goswami S, Maayani S,Marom Z, Rienzi N. Immunological andrespiratory findings in swine farmers.Environ Res 1991;56(2):120-30

55. Crippa M, Pasolini G. Allergic reactions dueto glove-lubricant-powder in health-careworkers. Int Arch Occup Environ Health1997;70(6):399-402

56. Seggev JS, Mawhinney TP, Yunginger JW,Braun SR. Anaphylaxis due to cornstarchsurgical glove powder.Ann Allergy 1990;65(2):152-5

57. Liu W, Nixon RL.Corn contact urticaria in a nurse.Australas J Dermatol 2007;48(2):130-1

58. Spergel JM, Andrews T, Brown-Whitehorn TF,Beausoleil JL, Liacouras CA. Treatment ofeosinophilic esophagitis with specific foodelimination diet directed by a combination ofskin prick and patch tests. Ann AllergyAsthma Immunol 2005 Oct;95(4):4-343

59. Fisher AA. Contact urticaria andanaphylactoid reaction due to corn starchsurgical glove powder.Contact Dermatitis 1987;16(4):224-5

60. Assalve D, Cicioni C, Perno P, Lisi P. Contacturticaria and anaphylactoid reaction fromcornstarch surgical glove powder.Contact Dermatitis 1988;19(1):61

61. Poulsen KB, Nielsen HW. Health problemsamong persons exposed to grain dust.[Danish] Ugeskr Laeger1991;153(28):1986-90

62. Moreno-Ancillol A, Dominguez-Noche C, Gil-Adrados AC, Cosmes PM. Hypersensitivitypneumonitis due to occupational inhalationof fungi-contaminated corn dust. J InvestigAllergol Clin Immunol 2004;14(2):165-7

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Avena sativaFamily: Poaceae (Gramineae)Commonnames: Oats, Oat, Oatmeal,

Oat groatsSourcematerial: Untreated planting seedsSee also: Cultivated oat g14For continuous updates:www.immunocapinvitrosight.com

f7 Oat

Allergen Exposure


Oats, from an erect, tufted annual grassgrowing to 1.2 m, are of uncertain origin,but probably arose in Europe from 2 species,Wild oats (A. fatua L.) and Wild red oats(A. sterilis L.). Oats are now cultivatedthroughout the temperate zones of theworld. The major growing areas are theUSA, southern Canada, the USSR andEurope, particularly near the Mediterranean.Oats serve as food for humans, animalfodder and bedding, and - especially in theform of extracts - in a variety of industrialuses. There are many named varieties, withnew forms being developed each year.

Environment

Oats are available as whole Oat grains whenonly the husks are removed; Oatmeal fromcut or ground Oats; and rolled Oats whengrains are cut in slices and then steamed androlled. Oats are by far the most nutritious ofthe cereal grasses. They are high in vitaminB-1 and contain vitamins B-2 and E. Eatenas a cereal, they are probably best knownas the breakfast cereal “porridge” or

“oatmeal”, but can also be used in manyother ways. The seed can be sprouted andserved in salads. The grain can be groundinto flour and used in making biscuits,sourdough, etc. Oats are fairly low in glutenand so not suitable for making bread. Oatflour inhibits rancidity and, as an additive,increases the length of shelf-stability of fattyfoods such as vegetable oils. Oats are alsoone of the basic ingredients of whisky. Theroasted seed is a coffee substitute. Edible oilis obtained from the seed and used in themanufacture of breakfast cereals. Oats areoften a major ingredient in cosmetics, creamsand skin cleansers.

Oats are widely thought to havemedicinal actions. Oat straw and the grainare prescribed to treat general debility anda wide range of nervous conditions.

Unexpected exposure


Allergens

No allergens from this food have yet beencharacterised.

Allergens of 46 and 66 kDa have beenisolated from Oats and have been classifiedas major IgE binding proteins in childrenwith atopic dermatitis (1). The 66 kDaprotein was found to bind to IgE antibodiesin serum of 28 of 33 (84%) adult patientswith atopic dermatitis. Non-specific bindingto a region of this protein occurred, whichthe authors suggest may also representlectin-like binding (2).

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f7 OatOats has been shown to contain the

panallergen profilin, but at very low levelscompared to other foods, e.g., a profilin IgEantibody level of 0.9 vs. 27.3 kUA/l forCelery (3).

Three proteins of 25, 27 and 32 kDa havebeen identified, by immunoblotting usingsera from patients with coeliac disease, asthe major coeliac serum IgA-bindingcomponents of Oat endosperm. Thesecorresponded to alpha 2, gamma 4, andgamma 3 avenins, respectively (4). Thesegluten-like allergens are in very lowconcentration in Oats, and recent studieshave reported no adverse effect in patientswith coeliac disease, even after long-termconsumption of Oats.


An extensive cross-reactivity among thedifferent individual species of the genusPoaceae could be expected (5). By RASTinhibition tests, cross-antigenicity was shownto exist among the cereal grains Rye, Wheat,Triticale, Barley, Oat, Maize and Rice. Thedegree of cross-reactivity closely paralleledtaxonomic relationship and appeared to bein the following order of decreasing closeness:Wheat, Triticale, Rye, Barley, Oat, Rice andMaize. The allergenic activity in the Rye andWheat extracts was found to be distributedamong various fractions of differentmolecular weights (6). These results weresupported by other studies reporting that insubjects sensitised to Wheat and Rye flour,there is significant cross-reactivity among theseed extracts of 12 cereals: Wheat, DurumWheat, Triticale, Cereal rye, Barley, Rye grass,Oats, Canary grass, Rice, Maize, Sorghumand Johnson grass. Results of the studysuggested that the bran layers of cereal grainsare at least as allergenic as the flour (7).Sixteen proteins have been reported to becommon among Wheat, Rye and Barleyextracts, suggesting cross-reactivity amongthese cereals (2). However, in a study withchallenges to the common cereals, 80%reacted to only 1 grain (8).

Wheat gliadin and the correspondingproteins of Rye, Barley and Oats were foundto be the allergens in cereal-dependentexercise-induced anaphylaxis (9). Barleycontains less gliadin than the other cereals.

A 51-year-old woman developedanaphylaxis following Millet ingestion;cross-reactivity to cereals could bedemonstrated by positive SPT and/or IgEantibody measurements. However, thesewere not clinically relevant (10).

Cross-reactivity among Wheat, Rye,Barley, Oats, Maize, Rice, and thecorresponding grass pollens has beenreported (11).

Clinical Experience


Oats may uncommonly induce symptoms offood allergy in sensitised individuals (12).Symptoms may include angioedema,urticaria, atopic dermatitis, asthma, rhinitis,and gastrointestinal symptoms such asnausea, vomiting and abdominal pain.Although IgE antibodies may be detected inpatients, this may indicate only latentsensitisation (13-14).

On oral provocation studies in a groupof children with cereal allergy, 18 exhibiteda positive response to Wheat, 3 to Rye, 1 toBarley, and 1 to Oats. Symptoms involvedthe skin and the gastrointestinal andoropharyngeal regions. Onset wasimmediate in 8 children, delayed in 14, andboth immediate and delayed in 1 (9).

Wheat gliadin and the correspondingethanol-soluble proteins of taxonomicallyclosely related cereals, including Oats, werefound to be the allergens in cereal-dependentexercise-induced anaphylaxis. Five patientswith positive SPT to a Wheat suspension hadIgE antibodies to Wheat, Rye, Barley andOats. The IgE antibodies were in particulardirected against the ethanol-soluble proteinfractions. The patients had been unawareof any cereal allergy, since anaphylaxisoccurred only in association with exercisepostprandially.

Oats may be a more relevant allergen inchildren with atopic dermatitis. In a studyof 34 children with this condition, 33 wereSPT positive to Wheat and 18 to Oats. IgEantibodies to Wheat was found in 32children and in 30 to Oats (1). In a studyevaluating topical treatments of atopic

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f7 Oatdermatitis and the role of percutaneoussensitisation to Oats, it was concluded thatOat sensitisation in children with atopicdermatitis seen for allergy testing is higherthan expected, and may have resulted fromrepeated applications of cosmetics with Oatson a predisposed impaired epidermal barrier(15). In a study evaluating the frequency ofatopic dermatitis in an unselected Germanpopulation and the role of food allergy inthis condition, 27 selected patients werefurther evaluated, of whom 19 were shownto have skin reactivity to pollen and/or foodallergens. Four were shown to have positiveSPT to Oats (16).

Allergy to Oats may also result fromoccupational exposure, in particular inanimal, bakery and mill workers. Baker'sasthma has been reported (5).

Cough, wheezing, shortness of breath,fever, stuffy nose, and skin itching/rash onexposure to grain dust have beendocumented. The condition “grain fever”may also occur (17). Whether thesesymptoms result from antibody response orphysical irritation has not been fullyelucidated.

Other reactions

Allergic contact dermatitis to an Avenaextract has been reported (18).

Infantile food protein-inducedenterocolitis syndrome (FPIES) is a severe,cell-mediated gastrointestinal foodhypersensitivity typically provoked byCow's milk or Soy; it may also be provokedby Oats. Symptoms of typical FPIES aredelayed and include vomiting, diarrhoea,lethargy and dehydration. Initialpresentation may be severe, resulting in asuspicion of sepsis (19-20).

Oats were previously implicated as acereal affecting individuals with coeliacdisease. Recent studies have shown that theregular consumption of moderate amountsof Oats is safe and well tolerated by adultswith coeliac disease and dermatitisherpetiformis (21). However, there areconcerns that even if Oats themselves aresafe, they nonetheless may be contaminatedwith Wheat, Rye, or Barley (22). Recentevidence suggests that oats that are pure anduncontaminated with other gluten-containing grains, if taken in limitedquantities, are safe for most individuals withcoeliac disease (23).

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References1. Varjonen E, Vainio E, Kalimo K, Juntunen-

Backman K, Savolainen J. Skin-prick testand RAST responses to cereals in childrenwith atopic dermatitis. Characterization ofIgE-binding components in wheat and oats byan immunoblotting method.Clin Exp Allergy 1995;25(11):1100-7



4. Rocher A, Colilla F, Ortiz ML, Mendez E.Identification of the three major coeliacimmunoreactive proteins and one alpha-amylase inhibitor from oat endosperm.FEBS Lett 1992;310(1):37-40



7. Baldo BA, Krillis S, Wrigley CW.Hypersensitivity to inhaled flour allergens.Comparison between cereals.Allergy 1980;35:45-56

8. Jones SM, Magnolfi CF, Cooke SK,Sampson HA. Immunologic cross-reactivityamong cereal grains and grasses in childrenwith food hypersensitivity.J Allergy Clin Immunol 1995;96:341-51


10. Stuck BA, Blum A, Klimek L, Hormann K.Millet, a potentially life-threatening allergen.Allergy 2001;56(4):350




14. De Paz Arranz S, Perez Montero A, Remon LZ,Molero MI. Allergic contact urticaria tooatmeal. Allergy 2002;57(12):1215

15. Boussault P, Leaute-Labreze C, Saubusse E,Maurice-Tison S, Perromat M, Roul S, Sarrat A,Taieb A, Boralevi F. Oat sensitization inchildren with atopic dermatitis: prevalence,risks and associated factors.Allergy 2007 Nov;62(11):1251-6

16. Goujon-Henry C, Hennino A, Nicolas JF.Do we have to recommend not using oat-containing emollients in children with atopicdermatitis? Allergy 2008 Jun;63(6):781-2

17. Manfreda J, Holford-Strevens V, Cheang M,Warren CP Acute symptoms followingexposure to grain dust in farming.Environ Health Perspect 1986;66:73-80

18. Pazzaglia M, Jorizzo M, Parente G, Tosti A.Allergic contact dermatitis due to avenaextract. Contact Dermatitis 2000;42(6):364


20. Sicherer SH. Food protein-inducedenterocolitis syndrome: case presentationsand management lessons.J Allergy Clin Immunol 2005;115(1):149-56

21. Hallert C, Olsson M, Storsrud S, Lenner RA,Kilander A, Stenhammar L. Oats can beincluded in gluten-free diet. [Swedish]Lakartidningen 1999;96(30-31):3339-40

22. Thompson T. Oats and the gluten-free diet.J Am Diet Assoc 2003;103(3):376-9

23. Rashid M, Butzner D, Burrows V, Zarkadas M,Case S, Molloy M, Warren R, Pulido O,Switzer C. Consumption of pure oats byindividuals with celiac disease: a positionstatement by the Canadian CeliacAssociation. Can J Gastroenterol 2007Oct;21(10):649-51

f7 Oat

126

Pisum sativumFamily: Fabaceae (Leguminosae)Commonnames: Pea, Common pea,

Garden pea, Greenpea,Green pea, Dry pea.Snow pea, Sugar snappea

Sourcematerial: Dried peasSynonym: P. humileFor continuous updates:www.immunocapinvitrosight.com

f12 Pea

Allergen Exposure


Pea probably originated in south-westernAsia, but it spread nearly throughout theworld. Green peas are the number-oneprocessed vegetable in the UK and the USA.The plant is an annual, dwarf or climbing,growing as high as 2 m. The Pea is a small,round, smooth or wrinkled seed, growingin pods.

There are many varieties of Pea, somegrown to be eaten fresh, others to be useddried. (Dried Peas were the staple food ofEurope during the Middle Ages.) Pod Peasare those that are eaten pod and all, namelythe Snow pea and Sugar snap pea. Dried Peasare high in carbohydrate and fibre and lowin fat, and an economical source of protein.

Environment

Green peas are marketed fresh, canned, orfrozen. They can be cooked alone as avegetable or added to other dishes. They canalso be sprouted and added to salads, soups,etc. The mature seed may be dried and usedwhole or split (in which form it is oftenserved as dhal), or ground into a powderand then used to enrich the protein contentof flour. Roasted Peas can be a coffeesubstitute. The leaves and young shoots arecooked as a potherb. Peas, either whole orground and extruded, are increasinglypopular snack items.

Peas are reported to be contraceptive,fungistatic and spermacidal, and are said tohave several other medicinal properties. Thedried and powdered seed, for example, hasbeen used as a poultice for skin complaints,including acne.

Allergens

Pea contains a number of allergens, of whicha few have been characterised. In a study of8 patients with adverse reactions afteringestion of foods from the legume family,IgE binding to a Pea 30-33 KDa proteinregion occurred in 7, and in 4 patients thesewere the major bands (1).

The following allergens from this planthave been characterised:

Pis s 1, a 44 kDa protein, a 7S vicilin-likeglobulin (2-5).

Pis s 2, a 63 kDa protein, a convicilin (4).

Pis s IFR, an isoflavone reductase (6-8).

Pis s profilin (9-10).

Two isoforms of Pis s 1, Pis s 1.0101 andPis s 1.0102, have been characterised, andone of Pis s 2, Pis s 2.0101.

Immature Peas have low allergenicitycompared to ripe Peas, as there are fewstorage albumin proteins at this stage.Allergens are expected to be found in thestorage proteins. However, all levels ofmaturation of Green pea seeds showallergenicity and IgE-binding capacity, as doimmature seeds, but total IgE-bindingcapacity rises with the progress of maturation.

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f12 PeaThe highest allergenic potency is caused bythe albumin fraction, but globulin andglutelin fractions also contribute to theallergenicity of Green pea (11).

The globulin storage protein accounts for75-80% of the total seed protein, andalbumin the remainder. The amount dependson the cultivar. Skin reactivity has not beendetected to globulin extracts, whereasalbumin retained its allergenicity even whenheated at 60 °C for 30 minutes or boiled at100 °C for 5 minutes. Autoclaving at 120 °Cfor 15 minutes significantly reducedallergenic activity (12-13). Although somestudies have shown no skin reactivity to theglobulin protein, a protein belonging to thevicilin (7S globulin) family has been isolatedand may yet be shown to have allergenicpotential, as a vicilin from English walnutkernel (Jug r 2) has been shown to be a majorallergen (14). Indeed, in a study of 3 patientswith a history of anaphylaxis to Pea whosubsequently had symptoms after ingestionof Peanut, immunoblotting studiesdemonstrated strong IgE binding, mainly tovicilin in Pea extract and exclusively to Arah 1 in crude Peanut extract. IgE binding toPeanut could be inhibited by Pea but not oronly partially the other way around (5).

A common feature of most legumeallergens is their natural resistance tothermal, chemical, and, in some respects,proteolytic denaturation (15).


An extensive cross-reactivity among thedifferent individual species of the genus couldbe expected but in fact is not seen frequently(16). In an in vitro study, the IgE antibodybinding to protein extracts of 11 food legumeswas examined by IgE antibody determinationand RAST inhibition. Cross-allergenicity wasdemonstrated to be most marked among theextracts of Peanut, Garden pea, Chick pea,and Soybean (17-18), and between Pea andSoybean (19). However, clinical studies havefound that there is little cross-reactivity amongmembers of the legume family (20-22).

Substantial clinical allergenic cross-reactivity exists among Lentil, Chick pea andPea in the Mediterranean area, where theselegumes are widely consumed, in contrastwith the low clinical significance of legumecross-reactions (mainly between Peanut andSoybean) reported in the USA. Allergicreactions to Pea ingestion are frequentlyassociated with Lentil allergy in the Spanishpopulation. Vicilin and convicilin arepotential major allergens from Pea seeds,and all of these proteins cross-react with themajor Lentil allergen Len c 1, a vicillin (4).

In a study of Spanish children, evaluationof allergen-specific IgE demonstrated thatmost of the children were sensitised to morethan 1 legume species. That a high degreeof cross-reactivity existed among Lentil,Chick pea, Pea and Peanut was shown byinhibition studies. Thirty-nine patients werechallenged with 2 or more legumes, and 32(82%) reacted to 2 or more legumes: 43,5%to 3, 25,6% to 2, and 13% to 4 legumes.Seventy-three per cent of the patientschallenged with Lentil and Pea had positivechallenge to both, 69,4% to Lentil andChick pea, 60% to Chick pea, and 64,3%to Lentil, Chick pea and Pea simultaneously.Peanut allergy was associated with allergyto Lentil, Chick pea and Pea, but lessfrequently. In this study, 82% of the childrenallergic to legumes were sensitised to pollen.Pea and Bean were the legumes with morein vitro cross-reactivity with Loliumperenne, Olea europea and Betula alba,probably as a result of common antigenicdeterminants or the coexistence of pollenand legume allergy. Panallergens as the causeseem to be less probable (23).

It is important to differentiate patientsallergic to a legume from those onlysensitised. This is demonstrated by a studyof 8 patients with adverse reactions afteringestion of foods from the legume family.The majority had experienced symptomswith more than 1 legume (median 3legumes), but sensitisation to other legumeswithout clinical symptoms also occurred(medium 5 legumes). Sensitisation andsymptoms to 1 legume were observed onlyin 1 patient. IgE binding to a Pea 30-33 KDaprotein region occurred in 7 out of 8 patients,

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f12 Peaand in 4 patients these were the major bands.Serum IgE to Pea was <0.35 kUA/l in 4patients. For the Pea sensitised patients,immunoblotting assays with Chick pea andBean detected numerous IgE binding proteinsbands, but no predominant IgE bindingpattern could be seen. This study thusdemonstrated by in vivo and in vitro tests thatmost of the patients were sensitised to morethan 1 food of the legume family (1).

In a Spanish study aimed at determiningthe prevalence of Lupin sensitisation in 1,160subjects, using SPT evaluation, a 4,1%sensitisation rate (28 patients) was found,with a 75% co-sensitisation between Lupinand other legumes. Of the 28 patients, 7 wereSPT positive to at least 1 legume: 9 to Favabean, 8 to Soy, 13 to Chick pea, 8 to Pea, 12to Peanut, 13 to Bean, 7 to Lentil (but 18were not tested), 23 to at least 1 Pollen, 14to grasses, 11 to Birch pollen, 15 to Mugwort,10 to Olive and 8 to Latex (24).

An early study reported that the Ara h 1from Peanut has significant homology of 60%to 65% with the vicilin seed storage proteinfound in Pea, and that there is homology ofvicillin in most higher plants (25). In a morerecent study of 3 patients with a history ofanaphylaxis to Pea who subsequently hadsymptoms after ingestion of Peanut,immunoblotting revealed strong IgE binding,mainly to vicilin in Pea extract and exclusivelyto Ara h 1 in crude Peanut extract.Immunoblot and ELISA inhibition studieswith crude extracts, as well as with purifiedproteins, showed that IgE binding to Peanutcould be inhibited by Pea but not or onlypartially the other way around. Clinicallyrelevant cross-reactivity between Pea andPeanut did not occur. Vicilin homologues inPea and Peanut (Ara h 1) were thought to bethe molecular basis for this cross-reactivity.(5) Tri f 1 from Fenugreek is a vicilin-likeglobulin and has been shown to be similar tovicilins from Soy, Pea, Bean, Lentil, Chick pea,and Lupin, which all cross-reactedserologically with the IgE antibodies fromPeanut allergic patients (26).

Ana o 1 from Cashew has a 52-62%similarity to proteins found in African oilpalm, Macadamia nut, Pea, Soybean andEnglish walnut. These proteins have beenvariously described as vicilin-like proteinpre-cursors, sucrose-binding proteins andprecursors, and 7S globulins (27).

The Soybean glycinin G1 acidic chainshares IgE epitopes with Peanut Ara h 3. Theglycinins in Ara h 3, Soybean, and Pea havea sequence similarity of 62% to 72% (28).

The isoflavone reductase allergendetected in Pea has a 56-80% sequenceidentity with IFR homologue proteins fromvarious plants, e.g., Birch, Apple, Pear,Orange, Mango, Litchi, Carrot, Banana, andChick pea (7-8).

An association between grass pollinosisand sensitisation to Tomato, Potato, Pea,Peanut, Watermelon, Melon, Apple, Orangeand Kiwi has been reported. A considerablyhigh frequency of positive reactions to Tomato(39.2%), Peanut (22,5%), Pea (13.7%), andWheat (11.7%) was observed in children withallergy to grass pollen (29-30).

Clinical Experience


Legumes are among the most common foodscausing allergic reactions in children andadults. Pea, a legume, may commonly inducesymptoms of food allergy in sensitisedindividuals, and IgE antibodies to Pea havebeen detected in sensitised individuals(4,11,21, 31-34). Symptoms reportedinclude atopic dermatitis, asthma, rhinitis,angioedema, dermatitis, oral pruritis,nausea, vomiting, and diarrhoea (1).

In a study of 8 Spanish patients withadverse reactions after ingestion of foodsfrom the legume family, the majorityexperienced symptoms with more than 1legume (median 3 legumes), but sensitisationto other legumes without clinical symptomsalso occurred (medium 5 legumes).Sensitisation and symptoms to 1 legumewere observed only in 1 patient. Thesymptoms were urticaria (4); oral allergysyndrome (2); anaphylaxis (1); angioedema(2) and asthma (1). Significantly, although

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IgE binding to a Pea protein occurred in 7out of 8 patients, and in 4 patients these werethe major bands. Serum IgE antibodies toPea were <0.35 KUA/l in 4 patients. Thisstudy concluded that, according to in vivoand in vitro tests, most of these patients weresensitised to more than 1 food of the legumefamily (1). It is important, however, todifferentiate patients allergic to a legumefrom those who are only sensitised. In theMediterranean, where legume ingestion ishigh, clinical allergy is more common thanin other Western countries such as the USA,where sensitisation may occur alone (4).

In this study in Delhi, the relevance of serumtotal and Pea-specific IgE were investigated in216 asthmatics with food sensitisation. SPTwas positive to Pea in 13 (35).

Food-induced anaphylaxis to Pea hasbeen reported (36). Anaphylaxis to Pea hasbeen reported in 3 patients who sub-sequently had symptoms after ingestion ofPeanut. Although these patients were alsoaffected by Peanut, clinically relevant cross-reactivity between Pea and Peanut did occur(5). Similarly, 5 patients with Peanutsensitivity had a history of adverse reactionsto Pea (37).

A study reported on a 33-year-old womanwho developed tongue swelling and burningand mouth itching minutes after eating bakedbeans. Similar symptoms occurred a day afteringesting Pea soup, and on another occasionwithin 15 minutes after eating a Bean burrito,and again 20 minutes after eating chillicontaining Kidney and Pinto beans. SPT waspositive to Red kidney and White bean butnegative to Pea, Green and Lima beans.However, IgE antibodies were found to Pea,Red kidney, White and Pinto bean, and toChick pea and Black-eyed pea (38).

In a study of 99 children with atopicdermatitis, Egg was the most common foodallergen in children under 1 year of age. Afterthat age, Apple, Carrot, Pea, and Soybeanelicited positive reactions as often as Egg (39).

Pea has resulted in asthma followingexposure to the cooking vapours (40).Occupational asthma has also been reportedfollowing exposure to Pea flour (41).

Other reactions

Infantile food protein-induced enterocolitissyndrome (FPIES) is a severe cell-mediatedgastrointestinal food hypersensitivitytypically provoked by Cow's milk and Soy.A study reported on other foods causing thissyndrome: 14 infants with FPIES caused bygrains (Rice, Oat, and Barley), vegetables(Sweet potato, Squash, String beans, Pea),or poultry (Chicken and Turkey) wereidentified. Typical symptoms of FPIES aredelayed (median: 2 hours) and includevomiting, diarrhoea, and lethargy/dehydration. Eleven infants (78%) reactedto >1 food protein, including 7 (50%) whoreacted to >1 grain. Nine (64%) of allpatients with solid food FPIES also hadCow's milk and/or Soy FPIES. Initialpresentation was severe in 79% of thepatients, prompting sepsis evaluations(57%) and hospitalisation (64%) fordehydration or shock. None of the patientsdeveloped FPIES to maternally ingestedfoods while breastfeeding, unless the causalfood was fed directly to the infant. (42)Similarly, 6 patients (4 males, 2 females, aged3-12 months) were diagnosed with FPIEStriggered by foods other than Cow's milkand Soy: Chicken in 4, Turkey in 2, Pea in1, and Lentils in 1. (Five patients reacted tomore than 1 food type.) All reactionsdeveloped within 2 hours of ingestion of theallergenic food (43).

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References1. Geraldes L, Carrapatoso I, Santos A, Bom AT,

Chieira C. Sensitisation patterns inleguminous allergy. (Poster) 2nd Int SympMolecular Allergol, Rome, Italy 2007;April22-24

2. Barre A, Borges JP, Rougé P. Molecularmodelling of the major peanut allergen Ara h 1and other homotrimeric allergens of thecupin superfamily: a structural basis for theirIgE-binding cross-reactivity.Biochimie 2005 Jun;87(6):499-506


4. Sanchez-Monge R, Lopez-Torrejon G,Pascual CY, Varela J, Martin-Esteban M,Salcedo G. Vicilin and convicilin are potentialmajor allergens from pea.Clin Exp Allergy 2004;34(11):1747-53

5. Wensing M, Knulst AC, Piersma S, O'kane F,Knol EF, Koppelman SJ. Patients withanaphylaxis to pea can have peanut allergycaused by cross-reactive IgE to vicilin (Ara h 1).J Allergy Clin Immunol 2003;111(2):420-4


7. Karamloo F, Schmitz, N, Scheurer S, et al.Molecular cloning and characterization of abirch pollen minor allergen, Bet v 5,belonging to a family of isoflavone reductase-related proteins.J Allergy Clin Immunol 1999;104:991-9

8. Vieths S, Frank E, Scheurer S, Meyer HE,Hrazdina G, Haustein D. Characterization of anew IgE-binding 35-kDa protein from birchpollen with cross-reacting homologues invarious plant foods.Scand J Immunol 1998;47(3):263-72


10. Barkholt V, Jørgensen PB, Sørensen D,Bahrenscheer J, Haikara A, Lemola E, Laitila A,Frøkiaer H. Protein modification byfermentation: effect of fermentation on thepotential allergenicity of pea.Allergy 1998;53(46 Suppl):106-8

11. Sell M, Steinhart H, Paschke A. Influence ofMaturation on the Alteration of Allergenicityof Green Pea (Pisum sativum L.).J Agric Food Chem 2005;53(5):1717-22

12. Malley A, Baecher L, Mackler B, Perlman F.Isolation of allergens from the green pea.J Allergy Clin Immunol 1975;56:282-90

13. Malley, A, Baecher, L, Mackler, B, Perlman, F.Further characterization of a low-molecularweight allergen fragment isolated from thegreen pea.Clin Exp Allergy 1976;25:159-64

14. Teuber SS, Jarvis KC, Dandekar AM,Peterson WR, Ansari AA. Identification andcloning of a complementary DNA encoding avicilin-like proprotein, jug r 2, from englishwalnut kernel (Juglans regia), a major foodallergen. J Allergy Clin Immunol 1999Dec;104(6):1311-20




18. Bardare M, Magnolfi C, Zani G. Soysensitivity: personal observation on 71children with food intolerance.Allerg Immunol (Paris) 1988;20(2):63-6

19. Bush RK, Schroeckenstein D, Meier-Davis S,Balmes J, Rempel D. Soybean flour asthma:detection of allergens by immunoblotting.J Allergy Clin Immunol 1988;82(2):251-5





24. Reis AM, Fernandes NP, Marques SL, Paes MJ,Sousa S, Carvalho F, Conde T, Trindade M.Lupin sensitisation in a population of 1,160subjects. Allergol Immunopathol (Madr )2007 Jul 1;35(4):162-3

25. Burks AW, Cockrell G, Stanley JS, Helm RM,Bannon GA. Recombinant peanut allergenAra h I expression and IgE binding inpatients with peanut hypersensitivity.J Clin Invest 1995;96(4):1715-21

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26. Christiane K. Faeste, Ellen Namork.Fenugreek proteins are potential foodallergens. (Poster) 2nd Int Symp MolecularAllergol, Rome, Italy 2007;April 22-24


28. Beardslee TA, Zeece MG, Sarath G, Markwell JP.Soybean glycinin G1 acidic chain shares IgEepitopes with peanut allergen Ara h 3. IntArch Allergy Immunol 2000;123(4):299-307

29. Caballero T, Martin-Esteban M. Associationbetween pollen hypersensitivity and ediblevegetable allergy: a review. J Investig AllergolClin Immunol 1998;8(1):6-16

30. de Martino M, Novembre E, Cozza G,de Marco A, Bonazza P, Vierucci A.Sensitivity to tomato and peanut allergens inchildren monosensitized to grass pollen.Allergy 1988 Apr;43(3):206-13

31. Matheu V, de Barrio M, Sierra Z, Gracia-Bara MT, Tornero P, Baeza ML. Lupine-induced anaphylaxis. Ann Allergy AsthmaImmunol 1999;83(5):406-8


33. Ortolani C, Ispano M, Pastorello EA, Ansaloni R,Magri GC. Comparison of results of skin pricktests (with fresh foods and commercial foodextracts) and RAST in 100 patients with oralallergy syndrome.J Allergy Clin Immunol 1989;83(3):683-90


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35. Kumar R, Singh BP, Srivastava P, Sridhara S,Arora N, Gaur SN. Relevance of serum IgEestimation in allergic bronchial asthma withspecial reference to food allergy. Asian Pac JAllergy Immunol 2006 Dec;24(4):191-9

36. Moneret-Vautrin DA, Kanny G. Food-inducedanaphylaxis. A new French multicenter studyBull Acad Natl Med 1995;179(1):161-72,178-84

37. Hefle SL, Lemanske RF Jr, Bush RK. Adversereaction to lupine-fortified pasta. J AllergyClin Immunol 1994;94(2 Pt 1):167-72


39. Hannuksela M. Diagnosis of dermatologicfood allergy.Ann Allergy 1987 Nov;59(5 Pt 2):153-6

40. Garcia Ortiz JC, Lopez Asunsolo A, Cosmes P,Duran AM. Bronchial asthma induced byhypersensitivity to legumes. Allergologia etImmunopathologia 1995;23(1):38-40

41. Bhagat R, Swystun VA, Cockcroft DW.Occupational asthma caused by pea flour.[Letter] Chest 1995;107(6):1772


43. Levy Y, Danon YL. Food protein-inducedenterocolitis syndrome – not only due tocow's milk and soy. Pediatr Allergy Immunol2003;14(4):325-9

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Arachis hypogaeaFamily: Fabaceae (Leguminosae)Commonnames: Peanut, Groundnut,

MonkeynutSourcematerial: Shelled nutsFor continuous updates:www.immunocapinvitrosight.com

f13 Peanut

Allergen Exposure


Peanuts were first cultivated in SouthAmerica, as early as 3000 BC. Portugueseexplorers transplanted Peanut plants toAfrica, and from there they were carried byexplorers to the rest of the world.

Peanuts are the seeds of an annuallegume, which grows close to the ground andproduces its fruit below the soil surface. Thisis in contrast to tree nuts like Walnuts andAlmonds. Peanut is a member of theFabaceae or legume family, whereas tree nutsare not. The Peanut plant is oval-leafed andabout 45 cm tall. Delicate yellow flowersdevelop around the lower portion. Theflowers pollinate themselves and then losetheir petals as the fertilised ovary begins toenlarge. The budding ovary or “peg” growsdown toward the soil. The Peanut embryoburrows into the soil surface and begins tomature, taking the form of the Peanut.

Multiple Peanut varieties are grown in theUSA, with more than 40% of the AmericanPeanut crop consumed as Peanut butter (1).Runners have become the dominant Peanuttype grown in the U.S. due to the spectacularincrease in yield that they allow; they are avery important source of Peanut butter.Virginias have the largest kernels andaccount for most of the Peanuts roasted andsold in their shells. Spanish peanuts havesmaller kernels covered with a reddish-brown skin. They are used predominantlyin Peanut candy, but with significantquantities also used for salted nuts andPeanut butter. They have higher oil contentthan the other types of Peanuts, which isadvantageous for oil extraction. Valenciasare small, very sweet Peanuts usually roastedand sold in the shell, or boiled, but seldomused in processed foods.

Environment

Peanuts are consumed mainly as Peanutbutter, as snacks (roasted, salted, plain ordry roasted), in candy and in baked goods.Peanuts also yield widely used cooking oils(both refined and crude, aromatic and non-aromatic). In China, Peanut is second onlyto Soy as a source of fat and oil. Peanut flouris an important ingredient in a variety ofprocessed foods. The American GeorgeWashington Carver developed more than300 uses for Peanuts, some of themindustrial rather than culinary.

Peanut oil is the refined fixed oil obtainedfrom the seed kernels. Hydrogenated Peanutoil, Peanut acid, and Peanut glycerides are

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f13 Peanutall derived from Peanut oil. The oils andglycerides are skin-conditioning agents incosmetics. The acid functions as a surfactantor cleansing agent, and the flour is anabrasive, bulking agent and/or viscosity-increasing agent. Peanut oil, if not highlypurified (and cold-pressed or extruded oils tendnot to be), may contain Peanut allergen (2-4).Some Peanut-allergic patients react to crudePeanut oil but not refined Peanut oil (5). Thequality of Peanut oil in chocolate, forexample, may be crucial in determiningwhether or not allergic reactions occur.Peanut oil has been used to manufactureinfant food, resulting in sensitisation in somechildren as a result of the presence of Peanutallergens (6-7). Creams and ointmentscontaining Peanut oil may lead tosensitisation; oily solution vitaminpreparations are an example (8-9).

Peanut flour is made from raw Peanutsthat have been cleaned, blanched, roastedand processed to produce a lower-fat Peanutflour with a strong roasted Peanut flavour.Peanut flour is used in confectionery,seasoning blends, bakery mixes, frostings,fillings, and health-food bars (10).

Peanuts have been deflavoured,reflavoured and sold as Walnuts, Almonds,and Pecan nuts (11).

Unexpected exposure


Allergens

Peanut contains up to 32 different proteins,of which at least 18 have been identified asbeing capable of binding specific IgE (12-13).Varieties of Peanuts from different parts ofthe world contain similar proteins, includingAra h I and Ara h 2, and the IgE-bindingproperties have also been reported to besimilar to a great extent (14).

The major Peanut allergens are homologousto the seed storage proteins of the conglutin,vicilin, and glycinin families (15).

Peanut proteins were originally classifiedas albumins (water-soluble) or globulins(saline-soluble); the globulins were in turn

subdivided into arachin and conarachinfractions (the major storage proteins). Thereare 2 polymorphic forms of arachin, A and B.Conarachin can be separated by ultra-centrifugation into 7.8 S and 12.6 Scomponents. The latter component isdesignated as conarachin II or alphaconarachin. Other components of thealbumin fraction of Peanuts are agglutinins,lectin-reactive glycoproteins, proteaseinhibitors, alpha-amylase inhibitors andphospholipases (16).

The major storage proteins of legumes areglobulins, subdivided into legumins andvicillins. The 2 major Peanut allergens, Ara h 1and Ara h 2, are heat-stable vicillinproteins (17).

A number of allergens have beencharacterised to date:

Ara h 1, a 63.5 kDa - 65 kDa protein, aheat-stable major allergen, and a vicilin seedstorage protein (17-37). Ara h 1 alsocontains a carbohydrate moiety (38).

Ara h 2, a 17.5 kDa protein, a major allergen,a conglutin seed storage protein and a trypsininhibitor (18,21,24,26,28, 34,37,39,40-52).The isoforms Ara h 2.0101 and Ara h 2.0201have been isolated (53-54).

Ara h 3, a 60 kDa protein, a major allergen,and an 11S globulin (glycinin-like) seed storageprotein (21,26,33,37,55-62). Ara h 3 may alsofunction as a trypsin inhibitor (63-64).

Ara h 4, a glycinin seed storage protein(24,28,33). Ara h 4 and Ara h 3 areconsidered to be the same allergen (57).

Ara h 5, a 15 kDa protein, and a profilin(24,65-66).

Ara h 6, a 2S albumin, a heat- and digestion-stable protein (24,26,28,48,51-52,67-68).

Ara h 7, a 2S albumin (24,28).

Ara h 8, a 16.9 kDa protein, a Bet v 1-homologous allergen (28,69-71).

Ara h 9, a lipid transfer protein (37,72-73).

Ara h Oleosin, a 18 kDa protein (74).

Ara h Agglutinin (75-76).

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f13 PeanutRecombinant proteins include:

rAra h 1 (77-78).

rAra h 2 (79).

Ara h 3 (57).

Ara h 4 (80).

Ara h 5 (66).

rAra h 6 (67).

rAra h 8 (70).

Ara h 1 comprises 12% to 16% of thetotal protein in Peanut. It has a stabletrimeric structure that protects IgE bindingepitopes from degradation (21,81). In astudy where native Ara h 1 from Peanutswas purified using only size exclusionchromatography, the allergen appeared toexist in an oligomeric structure rather thana trimeric structure. As structuralcharacteristics are important for a protein'sallergenicity, this may imply a differentallergenicity for Ara h 1 than previouslydescribed (29).

At least 23 different linear IgE-bindingepitopes, located throughout the length of theAra h 1 protein, have been identified (18).Ara h 1 and Ara h 2 are recognised by 70-90% of patients with Peanut allergy (82-83).However, some subjects fail to bind to eitherAra h 1 or Ara h 2 (84). But this may varyamong populations: in population studies,Ara h 1 was recognised by over 95% ofpatients from a North American population(17), whereas the same allergen wasrecognised by only 35% (19), 65% (24) and70% (82) of patients of 3 Europeanpopulations. These differences in recognitionwere not found for Ara h 2 (14). In somepopulation groups, Ara h 2 may be the moreprevalent allergen, and previouslyunidentified Peanut proteins with molecularweights somewhat lower than 15 kDa maybe important allergens as well (85).

Although the major allergens are heat-stable and resist gastric acid fluiddegradation, and Ara h 2 subjected toroasting has been shown to protect Ara h 1from proteolytic digestion when co-incubated (39), the allergenicity of Peanutallergens has been clearly shown to be

dependant on the degree of heat thesubstance is exposed to, and it is evident thatroasting increases the allergenicity ofPeanuts (90,86-88). For example, theprevalence of Peanut allergy in China ismuch lower than in the West. The methodsof frying or boiling Peanuts practiced inChina were shown to result in lessallergenicity, compared with the method ofdry roasting practiced widely in the UnitedStates. Roasting uses higher temperatures(150-170 °C) than boiling (100 °C) or frying(120 °C). This may help explain thedifference in prevalence of Peanut allergyobserved in the 2 countries. Compared withthe amount in roasted Peanuts, the amountof Ara h 1 was reduced in the fried andboiled preparations, resulting in a significantreduction of IgE-binding intensity. There wassignificantly less IgE binding to Ara h 2 andAra h 3 in fried and boiled Peanuts,compared with that in roasted Peanuts, eventhough the protein amounts were similar inall 3 preparations (89). The decrease inallergenicity of boiled compared to roastedPeanut may result mainly from a transfer oflow-molecular-weight allergens into thewater during cooking (32).

Although native Ara h 1 undergoes asignificant heat-induced denaturation on amolecular level, the allergenicity of Ara h 1is unaffected by heating, indicating that therecognition of conformational epitopes ofAra h 1 by IgE either is not a dominantmechanism or is restricted to parts of theprotein that are not sensitive to heatdenaturation (23). Other studies havereported that the protein modifications madeby the Maillard reaction contribute to thiseffect (90- 91).

Furthermore, mature roasted Peanuts havebeen shown to exhibit a higher IgE bindingand advanced glycation end adducts levelthan immature roasted Peanuts (91-92).

Other factors may also be involved: forexample, the protein concentration is higherin raw Peanuts (approx 16.6 g per 100 g)than in roasted Peanuts (approx 2.6 g per100 g), and the increased histamine contentmay have some influence (93). Ara h 1 levelsare up to 22-fold higher in oven-roasted thanin raw Peanuts (820 vs. 37 µg/ml) (31).

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f13 PeanutSaliva has been shown to contain up to 1,110mg/ml Ara h 1, and therefore, as calculatedthrough extrapolation, a single kiss couldtransfer up to 88.8 mg of Peanut proteins insaliva (94).

In the case of Ara h 2, a protein thatfunctions as a trypsin inhibitor, it was shownthat roasting caused a 3.6-fold increase intrypsin inhibitory activity. Functional andstructural comparison of the Ara h 2 purifiedfrom roasted Peanuts to native and reducedAra h 2 from raw Peanuts revealed that theroasted Ara h 2 mimics the behaviour of nativeAra h 2 in a partially reduced manner (39).

Ara h 2 consists of 2 isoforms, namelyAra h 2.0101 and Ara h 2.0201.Ara h 2.0201 has similar but higher IgEbinding than the originally sequencedAra h 2.0101 isoform (81% vs. 77%) andcontains other IgE specificities (53). Of the2 Ara h 2 isoforms, Ara h 2.02 might be themore potent allergen (54). Ara h 2 wasfound to be a much more potent allergenthan Ara h 1 (95). The 2S albumin Ara h 2is homologous with the minor allergenAra h 6. Native Ara h 2 and Ara h 6 havevirtually identical allergenic potency. Theextreme immunological stability of the corestructures of Ara h 2 and Ara h 6 provides anexplanation for the persistence of the allergenicpotency even after food processing (48).

Children with Peanut allergy recognisemainly Ara h2 and Ara h6, and thisrecognition remains stable over time. InPeanut-allergic adults, IgE is mainly directedto Ara h1 and Ara h2 (51).

Ara h 1, Ara h 2, and Ara h 3 areconsidered to represent >30% of the totalprotein content of Peanut (96).

Ara h 3 was in the first instance identifiedas a 14 kDa protein, but cloning of its generevealed a protein of approximately 60 kDa(55,57,64). Ara h 3 is recognised by serumIgE antibodies from 45% - 50% of patientswith Peanut sensitivity (64,97). Ara h 3consists of a series of polypeptides rangingfrom approximately 14 to 45 kDa that canbe classified as acidic and basic subunits; thisis similar to the subunit organisation of Soyglycinin (57). Various levels of the 3 majorPeanut allergen genes, Ara h 1, Ara h 2 and

Ara h 3, and of their corresponding proteins,have been found in all Peanut cultivars.However, Ara h 3 expression patternsamong cultivars are more variable thanpatterns of Ara h 1 and Ara h 2. Transcriptswere tissue-specific, observed in seeds butnot in leaves, flowers, or roots, and wereundetectable during seed germination (98).In a study, 60 accessions in the U.S. Peanutcore collection were analysed, along with 88Florida Peanut breeding program lines. Anaccession from India had the lowest level ofAra h 1 (7.0%). An accession from Nigeriahad the highest level of Ara h 1 (18.5%),but the lowest level of Ara h 2 (6.2%). Anaccession from Zambia had the highest levelof Ara h 2 (13.2%), but the lowest level ofAra h 3 (21.8%). Two accessions, 20 lines,and 2 Peanut cultivars (Florunner andGeorgia Red) contained little or no trace ofa 36 kDa Ara h 3 isoform, Ara h 3-im (99).

Although Ara h 3 is regarded as a minorallergen, in a study of a group of Peanut-allergic Italian children, it was found thatthey were specifically sensitised to the basicsubunit of Ara h 3 (62).

Ara h 5 shows up to 80% amino acidsequence identity with the panallergenprofilin, but Ara h 5 is present only in lowamounts in Peanut extracts (66); 13% to16% of Peanut-allergic individuals aresensitised to Peanut profilin (65-66).

Ara h 6, which has structural similaritiesto Ara h 2, also has equal in vitro and invivo potency (95). Ara h 6 has been reportedto be a minor allergen. However, in a studyof 29 Peanut-allergic patients, Ara h 6 wasrecognised by 20. Ara h 6 has homology toAra h 2, especially in the middle part and atthe C-terminal part of the protein; andalmost complete inhibition of IgE-Ara h 6by Ara h 2 demonstrates that at least partof the epitopes of Ara h 6 are cross-reactivewith epitopes on Ara h 2; furthermore,Peanut-allergic patients recognise Ara h 6 bothin vitro and in vivo to a similar extent as inthe case of Ara h 2. Researchers have thereforeconcluded that Ara h 6 should be considereda major Peanut allergen as well (52).

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f13 PeanutCompared with Ara h 6, Ara h 2 appears

to be the more potent allergen, even thoughthe 2 Peanut allergens share substantial cross-reactivity. Both allergens contain cores thatare highly resistant to proteolytic digestionand to temperatures of up to 100 °C. Thereduction in IgE antibody-binding capacitydoes not necessarily translate into reducedallergenic potency, and native Ara h 2 andAra h 6 have virtually identical allergenicpotency, compared with the allergens thatwere treated with digestive enzymes. Thefolds of the allergenic cores are virtuallyidentical with each other and with the foldsof the corresponding regions in the undigestedproteins. The extreme immunologicalstability of the core structures of Ara h 2 andAra h 6 provides an explanation for thepersistence of the allergenic potency evenafter food processing (48).

In a study of recombinant Ara h 6, thepresence of allergen-specific IgE to Ara h 6was strongly associated with patients havingsymptoms of anaphylaxis and urticaria, butnot with patients having isolated oral allergysyndrome. This may be an indication thatAra h 6 is a candidate for association withsevere clinical reactions (100).

As mentioned above, children with Peanutallergy recognise predominantly Ara h2 andAra h6, which remains stable over time. InPeanut-allergic adults, IgE antibodies aremainly directed to Ara h 1 and Ara h 2. Arole for Ara h 6 in diagnosis has beenproposed. In contrast to adults, IgE inchildren can fluctuate over time, indicatingthat children may have a more dynamicreactivity to Peanut. In a study thatexamined the IgE reactivity to major Peanutallergens in Peanut-allergic children at 2points in time, 20 Dutch children (3-15 yearsold) with Peanut allergy DBPCFC wereevaluated. Before DBPCFC, all Peanut-allergic children showed IgE reactivity torecombinant Ara h 2; Ara h 6 was recognisedby 16 children, and Ara h 1 and Ara h 3 by10 children. After 20 months, Peanut-specificIgE levels (median 23 kUA/l) and theindividual recognition of major allergens werecomparable with the levels and recognitionbefore challenge (median 28.2 kUA/l). SPTwith Ara h 2 and Ara h 6 was positive inmost children, whereas SPT for Ara h 1 and

Ara h 3 was positive in approximately halfof the children. Ara h 6 induced the largestwheals. Therefore, Ara h 2 and Ara h 6 werethe most frequently recognised major Peanutallergens in children (101).

Ara h 8 has a low stability to roastingand no stability to gastric digestion. rAra h8 inhibited IgE binding to Peanut in 4 of 7tested patient sera (70).

In a study of sera from 12 patients withatopic dermatitis and a positive DBPCFC toPeanut, Peanut agglutinin bound IgE in only50% of the sera (75). Although Peanutagglutinin is considered in the literature tobe a minor allergen, a study reported thatthe majority of sera from Peanut-sensitivepatients showed a high level of IgE bindingto the lectin even after heat treatment; andthat, contrary to published data, non-enzymatic browning reactions seemed todeteriorate the IgE affinity of the lectin (102).

Nonetheless, individuals are sensitised toa number of allergens in a heterogeneous way,rather than stereotypically to only 1 or 2. Forexample, in an examination of sera of 40Peanut-allergic patients, 14 individualrecognition patterns and the followingfrequency of allergen-specific IgE bindingemerged: Ara h 1 was recognised by 65%,Ara h 2 by 85%, Ara h 4 by 53%, Ara h 5by 13%, Ara h 6 by 38% and Ara h 7 by43% of the sera (24).

Similarly, in a study of 30 Peanut-allergicindividuals, the majority of patients with apositive SPT were sensitised to Ara h 2 (25/30, 83%) and Ara h 6 (26/30, 87%). Sixteenpatients (53%) were sensitised to Ara h 1and 15 patients (50%) to Ara h 3. Allpatients with a positive SPT to Ara h 1 and/or Ara h 3 were also sensitised to Ara h 2and/or Ara h 6. The eliciting dose forsubjective reactions varied from 0.1 mg upto 300 mg Peanut, and from 10 to 3,000 mgfor objective symptoms (95).

Furthermore, a number of uncharacterisedallergens have been detected in Peanut. APeanut agglutinin has been isolated, andbound IgE in 50% of the Peanut challenge-positive patients (75). An oleosin, a memberof a family of proteins involved in theformation of oil bodies, has been isolated

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f13 Peanutand found to bind with 3 of 14 sera ofPeanut-allergic patients (74). Hybridisationmay have no effect on the allergenicity ofPeanut: high-oleic Peanuts, known as theSunOleic type, show no difference inallergenicity (88). Similarly, no difference inthe allergic components of either raw orroasted extracts of Korean or AmericanPeanuts could be demonstrated (103).

Two different genes encoding class IIchitinases have been isolated from Peanut,suggesting that stress to the plant can resultin the formation of a chitinase protein (104).The clinical relevance of either gene has notbeen determined. Similarly, during Peanutmaturation and curing, a new class ofproteins, namely stress proteins or dehydrin-like proteins, is produced (105).

Peanut allergens have been shown tocross into breast milk and may sensitiseinfants. In a study of 23 lactating womengiven 50 g of Peanut to eat, Peanut proteinwas detected in the breast milk of 11. It wasdetected in 10 subjects within 2 hours ofingestion and in 1 subject within 6 hours.The median peak Peanut proteinconcentration in breast milk was 200 ng/ml(range, 120-430 ng/ml). Both major Peanutallergens, Ara h 1 and Ara h 2, were detected(106). Indeed, Peanut proteins can be foundin breast milk for several hours after amother has eaten Peanuts (107).

Although sensitisation to Ara h 1 andAra h 2 occurs in the great majority ofPeanut-allergic individuals, the wide range ofallergens present in whole Peanut proteinextract appears to be most appropriate toconsider when testing for Peanut allergy (84).

However, appreciating the involvementof individual Peanut allergens may enablebetter diagnosis and better assessment ofseverity and prognosis, and may aidimmunotherapy.

For example, a Dutch study investigatedwhether sensitisation to the individual allergensAra h 1, Ara h 2, Ara h 3 and Ara h 6 correlatedwith clinical severity. The reactivity ofpurified Peanut allergens was measured bySPT and by IgE immunoblot in 30 patients.The majority of patients recognised Ara h 2and Ara h 6. Patients with severe symptoms

had a higher skin reactivity to Ara h 2 andAra h 6 at low concentrations and to Ara h 1and Ara h 3 at higher concentrations,compared with patients who had mildsymptoms. Patients with severe symptomsalso recognised a greater number of allergensand showed a higher cumulative SPTresponse, compared with patients with mildsymptoms. No significant differences wereobserved between patients with a low ED andpatients with a high ED. Therefore, Ara h 2and Ara h 6 appeared to be more potent thanAra h 1 and Ara h 3. Skin reactivity both tolow concentrations of Ara h 2 and Ara h 6,and to higher concentrations of Ara h 1 andAra h 3, was shown to be indicative of severesymptoms (95). However, in a similar studyconducted in the UK to evaluate whether thepattern of IgE binding to specific Peanutallergens is associated with the severity ofclinical symptoms, the results demonstratedthat the promiscuity of IgE binding appearedmore important than the recognition ofindividual proteins (36).


An extensive cross-reactivity among thedifferent individual species of the Fabaceae(Leguminosae) could be expected but in factdoes not occur frequently (108). Moreover,the taxonomic classification of Peanut andtree nuts does not appear to predictallergenic cross-reactivity (109).

Although Peanut shares homologousproteins with other beans and legumes, andalthough several studies have demonstratedthat individuals with clinical reactions to asingle legume often (38 to 79%) show thepresence of IgE sensitisation in SPT andallergen-specific IgE tests to a variety oflegumes, the majority do not show clinicalreactions to the other legumes (110-112).Further evidence indicates that although onewould expect Peanut-allergic individuals tohave a high risk of cross- or co-reactivity toSoya bean, a family member, blinded foodchallenges have shown a low rate (109).

Similarly, in a study reporting onreactivity of the sera of Peanut-allergicsubjects to 11 different legumes, as shownby in vitro tests, cross-allergenicity wasdemonstrated to be most marked among the

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f13 Peanutextracts of Peanut, Garden pea, Chick pea,and Soybean; yet clinical studies found littlecross-reactivity among members of thelegume family (109). In a study of 60children with Peanut allergy who wereevaluated for allergy to Soy and otherlegumes (Pea, String bean, Lima bean) byblinded food challenges, 6.5% of those withsevere Peanut allergy had reactions to Soy.Overall, only 2 of 41 (5%) with any 1positive challenge reacted to more than 1legume. Up to 15% of Peanut-allergicpatients may react to other members of thelegume family (113). Furthermore, otherlegumes rarely provoke severe anaphylacticreactions or result in a lifelong allergy (114).

However, patients with Soya bean allergymainly mediated by cross-reactivity to Birchpollen allergens have been recentlydescribed; a majority of whom were reportedto have Peanut allergy. Of 9 Swiss and 11Dutch patients with Peanut and Birch pollenallergy and a positive double-blind, placebo-controlled food challenge result to Peanut,all experienced symptoms in the oral cavity,progressing to more severe symptoms in 40%of patients. Recombinant Ara h 8-specific IgEwas demonstrated in 85%, and IgE bindingto Ara h 8 was inhibited by Bet v 1 ininhibition studies. In EAST inhibition,recombinant Ara h 8 inhibited IgE bindingto Peanut in 4 of 7 tested patient sera. Thestudy concludes that Peanut allergy mightbe mediated in a subgroup of the patientsby means of cross-reaction of Bet v 1 withthe homologous Peanut allergen Ara h 8.The study also demonstrated a low stabilityof Ara h 8 to roasting and no stability togastric digestion. Basophil histamine releasewith rAra h 8 was demonstrated in 5 of 7tested sera (70).

Lupin, which is not a common food insome parts of the world (e.g. USA), is alegume that appears to have a high degreeof cross-reactivity with Peanut. In a Frenchstudy, 11 of 24 Peanut-allergic individualswere shown to have skin reactivity to Lupinflour. Double blind oral challenges withPeanut and Lupin flour performed in 8 ofthe 24 patients were positive in 7 when thesame dose of both was used. The majorLupin flour allergen (a 43 kDa protein) ispresent in Peanuts. The risk of cross Peanut-

Lupin allergy was reported to be high, incontrast to the risk with other legumes. Theauthors suggested that the inclusion of 10%Lupin flour in Wheat flour withoutmandatory labelling makes Lupin a hiddenallergen, presenting a major risk of cross-reaction in subjects already allergic to Peanutproducts (115). Further confirmation of thehigh risk of cross-reactivity between Lupinand Peanut is documented by a case ofPeanut cross-allergy to Lupin flour in hotdog bread (116); there is also reported to bean increased risk of serious acute asthma dueto Lupin flour, a risk associated with Peanutallergy (117).

Reactivity to tree nuts is a seriousproblem for Peanut-allergic people. Peanutand tree nut allergic reactions coexist in 25-50% of Peanut-allergic patients, and allergicreaction to tree nuts such as Walnuts,Cashews, Pecans and Pistachios can developeven though tree nuts are from a differentbotanical family (118-120). Reactionsfrequently occur on first known exposureand may be life-threatening. It is unclearwhether this is due to genuine cross-reactivity or to the coexistence of separateallergies in broadly atopic individuals.Patterns of reported co-sensitisation varyamong studies. In 60 adult Peanut-allergicindividuals, 40 (66%) reported allergy totree nuts, but 50 (83%) had a positive SPTto 1 or more tree nuts (5). The relativefrequency of allergy to individual tree nutsconcomitant with Peanut allergies isreported to reflect the consumption ofvarious types of nuts by the generalpopulation: Almond, Hazel and Brazil nutsare implicated far more commonly thanPecan, Cashew and Pistachio (164).

Of course, cross-reactivity can becalculated from the other direction. Forexample, 5 of 12 Brazil nut-allergicindividuals were also allergic to Peanut (121).

Ara h 1 has a high sequence similaritywith other plant vicilins, members of thecupin superfamily (122). However, althoughthere are significant areas of homologybetween Ara h 1 and Soy vicillins, these areasdo not appear to be significantly involvedin the binding of IgE antibodies, which mayaccount for the low frequency of co-existent

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f13 PeanutPeanut and Soy allergy, despite the frequencyof positive SPT to Soy (55,78). Similarly,even though Jug r 2, the allergen fromWalnut, exhibited significant homology to thevicilin group of seed proteins, including thosein Cocoa bean (Theobroma cacao) andCottonseed (Gossypium hirsutum), there isminimal or no cross-reactivity between Jug r 2and Pea vicilin, Peanut proteins, or Cacaoproteins (123). Nonetheless, this may not becompletely clear-cut, as demonstrated by areport on 3 patients with a history ofanaphylaxis to Pea who subsequently hadsymptoms after ingestion of Peanut. Peanut-related symptoms consisted of oralsymptoms in all patients, with additionalurticaria and dyspnoea or angioedema in 2patients. All patients had a positive skinprick test response and an increased IgEantibody level to Pea and Peanut.Immunoblotting revealed strong IgEbinding, mainly to vicilin in Pea extract andexclusively to Ara h 1 in crude Peanutextract. IgE binding to Peanut could beinhibited by Pea but not, or only partially,the other way around. Clinically relevantcross-reactivity between Pea and Peanutdoes occur and is attributable to vicilinhomologues (124).

The major Peanut allergen Ara h 2 sharesIgE-binding epitopes with Almond andBrazil nut allergens, which may contributeto the high incidence of tree nut sensitisationin Peanut-allergic individuals (125).However, an earlier study reported thatconformational analysis of the linear IgE-binding epitopes mapped on the molecularsurface of Ara h 2 showed no structuralhomology with the corresponding regionsof Walnut Jug r 1, Pecan Car i 1 or Brazilnut Ber e 1; it was inferred that the absenceof epitopic community does not confirm theallergenic cross-reactivity observed betweenPeanut and Walnut or Brazil nut, whichpresumably depends on other ubiquitousseed storage protein allergens, namely thevicilins. However, the major IgE-bindingepitope identified on the molecular surfaceof the Walnut Jug r 1 allergen shared apronounced structural homology with thecorresponding region of the Pecan nut Car i 1allergen. With the exception of Peanut, 2S

albumins could thus account for the IgE-binding cross-reactivity observed among someother nuts, e.g., Walnut and Pecan nut (49).

Ara h 3, an 11S globulin seed storageprotein family member, may result in cross-reactivity between Peanut other foodscontaining other such family members,including Hazel nut and Soya bean.Homology among these 3 proteins rangesfrom 45% to 50%. One IgE binding epitopeof Ara h 3 has a 67% homology of aminoacid residues with the corresponding areaof Cor a 9 of Hazel nut (56).

Ara h 5 shows up to 80% amino acidsequence identity with the panallergenprofilin, but this allergen is present only inlow amounts in Peanut extracts.Immunoblot analysis of 50 sera fromindividuals sensitised to Peanut showed that16% had mounted a detectable IgE responseto the newly identified Peanut profilin,which indicates some risk for cross-reactivitywith other profilin-containing foods andplants (66).

Ara h 8 also has cross-reactive potential.Examination of the sera of 5 patients inrelation to 4 recombinant allergens led tothe conclusion that IgE cross-reactivityexisted between Bet v 1 and its homologuesGly m 4 from Soybean, Ara h 8, and Pru av 1from Cherry. On all 4 proteins, 1 IgE-bindingsurface area that was recognised by allpatients, and 2 that were recognised by 3patients, were identified (126). Lupin is anemerging cause of food allergy because ofrecent large-scale introduction intoprocessed foods and frequent cross-reactionswith other members of the legume family.Sequence comparison and modellingdemonstrated highly significant sequencehomology and molecular similarity betweenthe allergen Ara h 8 of Peanut and thepathogenesis-related protein PR-10 of Whitelupin. (Another protein of Lupine the beta-conglutin precursor, was found to besignificantly homologous to the Ara h 1allergen of Peanut) (127).

In a study, approximately a third ofpatients sensitised to grass pollen werefound, in IgEantibody investigations, to havesignificant serum levels of anti-Peanut IgE,

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f13 Peanutwithout positive Peanut skin reactivity andwithout Peanut-related allergic symptoms.This was attributed to the presence of cross-reactive carbohydrate determinants (CCD)of glycoproteins. In a study investigating thebiologic activity of IgE directed to CCD,cross-reactive IgE directed to carbohydratedeterminants of glycoproteins, as found ingrass pollen-sensitised patients, was shownto have poor biologic activity, thereforecausing positive IgE antibody results withoutapparent clinical significance (38).

Clinical Experience


Peanuts are a significant cause of seriousfood allergy in both adults and children.Unlike other food allergies, Peanut allergyusually begins in childhood and persiststhroughout the affected individual's lifetime.Only approximately 20% of young childrenwill develop tolerance (111,128). Moreprecisely, Peanut allergy persists in about80% of young children reacting to Peanutin the first 2 years of life, and virtually allindividuals reacting to Peanut beyond theage of 5 years (129). Approximately 75%of children experience a reaction with theirfirst known Peanut exposure suggesting,early sensitisation (119,130-131). Peanutallergic reactions are more likely to be severeor even fatal than reactions to other foodallergens (13).

Atopic dermatitis, angioedema, asthma,diarrhoea, nausea and vomiting, andanaphylaxis have been reported. Urticariamay be a prominent symptom (132).Angioedema of the lips and tongue followingingestion of Peanut butter, and localisedurticarial reactions following direct skincontact, were described (133). A patient witha history of a burning tongue, together withdiscomfort of the labial and buccal mucosae,improved after Peanut was removed fromher diet (134). Severe reactions may beassociated with abdominal pain at the onsetof the response (17,43). In one study, thecommonest symptom was facialangioedema, and the major featureaccounting for life-threatening reactions waslaryngeal oedema (118). Food-dependant

exercise-induced anaphylaxis has beendescribed (135-137). A study reported a highfrequency (50%) of food hypersensitivity inpatients with allergic rhinoconjunctivitis;Peanut was one of the most frequent foodallergens encountered (138). A significantassociation was reported to exist betweenrecurrent serous otitis media and foodallergy in 81 of 104 patients. An eliminationdiet resulted in a significant amelioration ofthe disease in 86% of the patients, and achallenge diet provoked recurrence ofsymptoms in 94%. The most prevalentallergens involved were Cow's milk, Wheat,Hen's egg, Peanut, Soy and Corn (139).

Although not reported frequently, asthmamay be a significant feature in Peanut allergy.In a French study evaluating 163 asthmaticchildren with food allergy, and exploringfood-induced asthma via double-blindplacebo controlled food challenges, the mostfrequent offending foods were found to be(sometimes in association) Peanut (30.6%),Hen's egg (23.1%), Cow's milk (9.3%),Mustard (6.9%), Codfish (6%), Shrimp(4.5%), Kiwi fruit (3.6%), Hazel nut (2.7%),Cashew nut (2.1%), Almond (1.5%), andGarlic (1.2%) (140). Asthma caused byPeanuts in a 3-year-old child was establishedby chance, and strict avoidance of Peanut ledto complete remission of symptoms and rapidtermination of inhalation therapy. Theauthors suggested that as severe Peanutallergy in asthmatic infants carries a risk ofanaphylaxis, it is useful to look for Peanutallergy in all infants with severe asthma (141).

Food allergy affects 6-8% of children< 4 years of age in the USA, and 2% of thepopulation >10 years of age. It is the leadingcause of anaphylaxis treated in hospitalcasualty departments (113). Food allergyaccounts for about 30,000 anaphylacticreactions, 2,000 hospitalisations and 200deaths each year in the USA (142). Allergyto Peanuts and tree nuts accounts for themajority of fatal and near-fatal anaphylacticreactions (143-144). About a third ofPeanut-sensitive patients have severereactions to Peanuts. As little as 100micrograms of Peanut protein provokesymptoms in some subjects with Peanutallergy. Asthmatics with Peanut sensitivityappear more likely to develop fatal reactions,

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f13 Peanutand this is thought to be because of theexquisite sensitivity that asthmatics have tothe chemical mediators of anaphylaxis.Severe reactions may occur within a fewminutes of ingestion. Peanut may inparticular affect children with chronic severeasthma. In a double-blind food challenge of38 children, Peanut resulted in adversereactions, which were chiefly gastro-intestinal, even though asthma was thecommon presenting complaint (145).

In the USA, a national survey indicatedthat about 0.8% of children reported allergyto Peanut (146). Other studies concur,showing that almost 1 in 150 children has aPeanut and/or tree nut allergy (147). In oneregistry of patients with Peanut allergy, morethan 70% had had their first allergic reactionafter their first apparent contact withPeanuts. Since reactions require previousexposure for sensitisation, and since IgEantibodies do not cross the placenta, thesefindings suggest that Peanut protein wasencountered in in soe other way in utero, orthrough breast milk (105,148). In a Frenchstudy of 54 infants who were less than 11days old and 71 who were 17 days to 4months old, 8% had a positive skin-pricktest for Peanut (149). Approximately a thirdof American children with moderate tosevere atopic dermatitis and foodhypersensitivity are allergic to Peanuts (150).

Peanut allergy is self-reported by 1 in 200of the British population (151). Accordingto a population-based study of 3- to 4-year-olds in the United Kingdom, the prevalenceof sensitisation to Peanuts increased 3-foldfrom 1.1% to 3.3% from 1994 to 1996. Of41 sensitised children in a study, 10 reporteda convincing clinical reaction to Peanut, and8 had positive oral challenge results, givingan overall estimate of Peanut allergy of 1.5%(18/1246) (152). Serological evidence ofsensitivity to Peanuts from data gatheredfrom 1988 to 1994 indicated that about 6%of Americans had IgE antibodies to Peanut(although the majority would not have anallergic reaction when eating Peanuts) (153).

The prevalence of Peanut allergy in astudy of 7768 primary school children inMontreal, Canada, was 1.50%. Whenmultiple imputations were used to

incorporate data on those responding to thequestionnaire but withdrawing beforetesting, the estimated prevalence increasedto 1.76%. When data regarding the Peanutallergy status of non-responders were alsoincorporated, the estimated prevalence was1.34% (154).

In a group of 580 patients in France withreactions to food, 60 presenting with severe,near-fatal reactions, 37% were sensitised toPeanut (155). A second French study of foodallergy in 544 children aged 0 to 15 years,who were evaluated with oral foodchallenges, found that 24% had Peanutallergy and 4% had a tree nut allergy.Clinical symptoms attributed to Peanutallergy included atopic dermatitis (46%),urticaria/angioedema (32%), asthma (15%),generalised anaphylaxis (5%), andgastrointestinal symptoms (3%) (156).

There is good evidence that Peanut allergyis on the increase (145,151,157). When andhow does sensitisation occur, and why is itincreasing? Several possibilities have beeninvestigated. A factor postulated to havecontributed to Peanut allergy in the UK isthe cutaneous exposure to ultra-low dosesof Peanut antigens in Peanut oil found indiaper rash emollients, which are applied tothe skin of infants with eczema or diaperrash (146,158). Differences in the wayPeanuts are prepared may contribute to thevariations in prevalence. For example, theper capita consumption of Peanuts in Chinais similar to that of the United States; yetPeanut allergy is very rare in China (113).

First sensitisation has been attributed tothe presence of Peanut allergen in breastmilk. In a report on 8 infants with immediatehypersensitivity reactions to foods, includingPeanut, occurring at the first-knownexposure, the most likely route ofsensitisation was thought to be breast milk,and reactions were thought to be dose-dependent. Symptoms experienced includedirritability, erythematous rash, urticaria,angioedema, vomiting, rhinorrhoea, andcough (159).

Peanut allergy has also been reported to betransferred through liver, kidney (160-161),and bone marrow transplantation (162).

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f13 PeanutHighly processed oils (acid-extracted,

heat-distilled) do not contain Peanut protein(5). However, cold-pressed or extrudedPeanut oils contain Peanut protein. This mayresult in adverse reactions, such as fromPeanut oil-based vitamin preparations (8)and infant milk formulae (6). In a study ofadverse reactions to crude Peanut oil, 10%of Peanut-allergic subjects reported allergicreactions. Refined Peanut oil did not pose arisk to any of the subjects (5).

Peanut may be a hidden allergen, with veryserious consequences. For example, fatalanaphylaxis to ingestion of undeclared Peanutflour was reported (163). The problem isespecially severe in that Peanut can result insevere reactions to even minute amounts, andeven through skin contact (129,164). Infantshave reacted adversely even to breast feedsafter maternal consumption of Peanut (165).However, the risk of adverse reactions may beproduct-specific: casual exposure to Peanutbutter is unlikely to elicit significant allergicreactions. The authors, however, warn that theresults cannot be generalised to largerexposures or to contact with Peanut in otherforms (flour and roasted Peanuts) (166).

But extreme cases should be kept in mind.A 9-month-old male developed localisedurticaria when his mother kissed him aftershe had eaten cereal with milk, andgeneralised urticaria manifested after hisbrother ate a Peanut butter sandwich andbarely touched his bare leg. His first dose ofEgg white as half a teaspoon of meringuecaused generalised urticaria andconjunctivitis. Approximately an eighth ofa slice of bread caused a similar reaction.Similarly, a 5-year-old developed wheezingwhen entering a classroom of a teacher whohad just eaten Peanuts (167). Peanutallergens may be transferred on playingcards (168). As the fat content of a challengevehicle has been shown to have a profoundeffect on the reaction experienced afterallergen ingestion, fat content may need tobe considered in assessing the risk of certainfoods to food-allergic individuals (169).

Reactivity to tree nuts is a seriousproblem for Peanut-allergic people. Peanutand tree nut allergic reactions coexist in 25-50% of Peanut-allergic patients (117-119).

In a study of 62 patients with nut allergy(adults and children), Peanuts were thecommonest cause of allergy (47), followedby Brazil nuts (18), Almonds (14), and Hazelnuts (13) (118). Similarly, in a study of 122children attending a food allergy clinic, 68experienced acute reactions to Peanut alone,20 to tree nuts but not Peanut, and 34 toboth Peanut and at least 1 tree nut. Of thetotal of 54 children with reactions to treenuts, 34 had reactions to 1 kind of tree nut,and 20 had reactions to 2 or more differenttree nuts, the most common being Walnut,Almond, and Pecan. First reactions usuallyoccurred at home, and at a median age of24 months for Peanut and 62 months fortree nuts. The skin was the most commonorgan affected (89% of reactions, 39% asthe only system involved), but therespiratory (52%) and gastrointestinal tract(32%) were also affected (117).

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156.Rance F, Kanny G, Dutau G, Moneret-Vautrin DA. Food hypersensitivity in children:clinical aspects and distribution of allergensPediatr Allergy Immunol 1999;10(1):33-8

157.Tariq SM, Stevens M, Matthews S, Ridout S,Twiselton R, Hide DW. Cohort study of peanutand tree nut sensitisation by age of 4 years.BMJ 1996;313(7056):514-7

158.Lack G, Fox D, Northstone K, Golding J; AvonLongitudinal Study of Parents and ChildrenStudy Team. Factors associated with thedevelopment of peanut allergy in childhood.N Engl J Med 2003;348(11):977-85

159.van Asperen PP, Kemp AS, Mellis CM.Immediate food hypersensitivity reactions onthe first known exposure to the food.Arch Dis Child 1983;58(4):253-6

160.Legendre C, Caillat Zucman S, et al. Transferof symptomatic peanut allergy to therecipient of a combined liver-and-kidneytransplant.N Engl J Med 1997;337(12):822-4

161.Phan TG, Strasser SI, Koorey D,McCaughan GW, Rimmer J, Dunckley H,Goddard L, Adelstein S. Passive transfer ofnut allergy after liver transplantation.Arch Intern Med 2003;163(2):237-9

162.Bellou A, Kanny G, Fremont S, Moneret-Vautrin DA Transfer of atopy following bonemarrow transplantation. Ann Allergy AsthmaImmunol 1997;78(5):513-6

163.McKenna C, Klontz KC. Systemic allergicreaction following ingestion of undeclaredpeanut flour in a peanut-sensitive woman.Ann Allergy Asthma Immunol1997;79(3):234-6

164.Steinman HA. Hidden Allergens in Foods.J Allergy Clin Immunol 1996;98(2):241-50

165.Hourihane JO Peanut allergy – current statusand future challenges.Clin Exp Allergy 1997;27(11):1240-6

166.Simonte SJ, Ma S, Mofidi S, Sicherer SH.Relevance of casual contact with peanutbutter in children with peanut allergy.J Allergy Clin Immunol 2003;112(1):180-2

167.Tan BM, Sher MR, Good RA, Bahna SL.Severe food allergies by skin contact. AnnAllergy Asthma Immunol 2001;86(5):583-6

168.Lepp U, Zabel P, Schocker F. Playing cardsas a carrier for peanut allergens.Allergy 2002;57(9):864

169. Grimshaw KE, King RM, Nordlee JA, Hefle SL,Warner JO, Hourihane JO. Presentation ofallergen in different food preparations affectsthe nature of the allergic reaction – a caseseries.Clin Exp Allergy 2003;33(11):1581-5

f13 Peanut

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Carya illinoensis/Carya illinoinensisFamily: JuglandaceaeCommonnames: Pecan nut, Hickory nutSourcematerial: Shelled & heated nutsFor continuous updates:www.immunocapinvitrosight.com

f201 Pecan nut

Allergen Exposure


The large Pecan tree, native to and verycommon in southern and especially south-eastern North America, is important for itstimber and edible nuts. The Pecan nut wasa major food source for the AmericanIndians for thousands of years.

The US South yields 250 million poundsof the nuts in an average year, Texas beingthe largest producer. The tree is planted farbeyond this range, however, covering severalof the world's warmer temperate zones andsubtropical areas.

The Pecan tree bears sweet edible nuts,deep brown in color, that range from 2.5 to5 cm in length. The nuts have smooth shellsand a mild, Walnut-type flavor. Pecan nutsare not produced until trees are 5 or 6 yearsold. The nuts ripen from mid-Septemberuntil December in the Northern Hemisphere.They are harvested after they fall to theground. Pecans can last up to 6 months intheir shells if refrigerated.

Environment

Over 100 varieties are commerciallyavailable, e.g., Shagbark hickory nuts andMockernut hickory nuts. They are usedwhole or crushed. Oil from the nuts is aningredient in processed foods, is used in themanufacture of cosmetics and soap, and isa drying agent in paints.

Allergens

Only 1 Pecan allergen has beencharacterised to date:

Car i 1, a 2S Albumin commonly callednapin (1-2).

The allergen profile may change as thePecan matures, is stored or heated. One studydemonstrated that IgE antibodies to allergenspresent in aged or heated Pecan nuts couldbe detected, but no IgE to any in fresh Pecans.These neoallergenic determinants werelocated on protein(s) with a molecular weightof approximately 15 kDa (3). Maillard-typereactions may be responsible for the changein allergenicity of the protein (4). Pecan nutallergens in small quantities may result insevere reactions.

Furthermore, analysis of the native andheat-denatured proteins that were previouslysubjected to in vitro simulated gastric fluiddigestions indicates that stable antigenicpeptides are produced (5).

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f201 Pecan nutPotential cross-reactivity

Pecan appears to be highly cross-reactivewith Walnut at even the lowestconcentrations used, and this correlates withclinical reports of cross-reactivity in thepatients in question (6-7). Some degree ofcross-reactivity between Peanut and Pecanhas been observed (8).

Conformational analysis of the linear IgE-binding epitopes mapped on the molecularsurface of Ara h 2 showed no structuralhomology with the corresponding regionsof the Walnut Jug r 1, the Pecan nut Car i 1or the Brazil nut Ber e 1 allergens. Theabsence of epitopic community does notsupport the allergenic cross-reactivityobserved between Peanut and Walnut orBrazil nut, which presumably depends onother ubiquitous seed storage proteinallergens, namely the vicilins. However, themajor IgE-binding epitope identified on themolecular surface of the Walnut Jug r 1allergen shared a pronounced structuralhomology with the corresponding region ofthe Pecan nut Car i 1 allergen. With theexception of Peanut, 2S albumins couldtherefore account for the IgE-binding cross-reactivity observed among some otherdietary nuts, e.g. Walnut and Pecan nut (1).

Clinical Experience


IgE-mediated allergy to foods containing Pecannuts is common. Pecan nut allergy frequentlyhas an onset in the first few years of life andgenerally persists, accounting for severe andpotentially fatal allergic reactions (9-12).

The Food Allergy and AnaphylaxisNetwork (FAAN) Peanut and Tree NutAllergy Registry in the USA, covering 5149patients (mainly children), reports Walnutas the first cause of allergic reactions to treenuts in 34%, followed by Cashew (20%) andAlmond (15%). Nine percent of self-reporting tree nut-allergic patients list Pecanas an allergen (13).

Pecan nut allergens may be absent in freshPecan nuts, which become allergenic as thePecan nut protein matures during aging (2-3).

Neoallergens may result from the heatingprocess for roasting Pecan nuts, and havebeen identified as the cause in anaphylaxis ina child who experienced this condition aftereating cookies containing these nuts (2).

In a group of 122 children who hadexperienced acute reactions to nuts, 68reacted to Peanut alone, 20 only to tree nuts,and 34 to both. Of those reacting to treenuts, 34 had reactions to 1 type, 12 to 2,and 8 to 3 or more, the most common beingWalnut, Almond, and Pecan. Initial reactionsusually occurred at home and were thoughtto result from a first exposure in 72% ofcases. Eighty-nine percent of the reactionsinvolved the skin (urticaria, angioedema),52% the respiratory tract (wheezing, throattightness, repetitive coughing, dyspnoea),and 32% the gastrointestinal tract(vomiting, diarrhoea). Two organ systemswere affected in 31% of initial reactions, andall 3 in 21% of reactions (14).

IgE antibodies would appear to be mostuseful in confirming the diagnosis of nuthypersensitivity in children or in particularlyhighly allergic patients for whom skin testingposes a risk of anaphylaxis (5).

Other reactions

Commercial products may contain Peanutsthat have been deflavoured and reflavouredand coloured to resemble Walnuts, Pecans,or Almonds. This may result in anaphylaxisin Peanut-sensitive individuals (15).

Protein contact dermatitis from Pecan nuthas been reported (16).

A patient is described who experiencedan acute vesicular cutaneous reaction afterprolonged contact with pecans (17).

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f201 Pecan nutReferences

1. Barre A, Borges JP, Culerrier R, Rouge P.Homology modelling of the major peanutallergen Ara h 2 and surface mapping of IgE-binding epitopes.Immunol Lett 2005; 100(2):153-8


3. Malanin K, Lundberg M, Johansson SG.Anaphylactic reaction caused by neoallergensin heated Pecan nut.Allergy 1995;50(12):988-91

4. Berrens L. Neoallergens in heated Pecan nut:products of Maillard-type degradation?Allergy 1996;51(4):277-8

5. Venkatachalam M, Teuber SS, Peterson WR,Roux KH, Sathe SK. Antigenic stability ofpecan [Carya illinoinensis (Wangenh.) K.Koch] proteins: effects of thermal treatmentsand in vitro digestion. J Agric Food Chem2006;54(4):1449-58.

6. Teuber SS, Sathe SK, Roux HK, PetersonWR. Cross-reactivity of Walnut and Other TreeNuts by IgE Immunoblot Inhibition. AAAAI56th Annual Meeting 2000, March

7. Goetz DW, Whisman BA, Goetz AD. Cross-reactivity among edible nuts: doubleimmunodiffusion, crossedimmunoelectrophoresis, and human specificigE serologic surveys. Ann Allergy AsthmaImmunol 2005;95(1):1-52


9. Sicherer SH, Sampson HA. Peanut and treenut allergy.Curr Opin Pediatr 2000;12(6):567-73

10. Boyd GK. Fatal nut anaphylaxis in a 16-year-old male: case report.Allergy Proc 1989;10(4):255-7

11. Yunginger JW, Sweeney KG, Sturner WQ,Giannandrea LA, Teigland JD, Bray M,Benson PA, York JA, Biedrzycki L, Squillace DL,et al. Fatal food-induced anaphylaxis.JAMA 1988;260(10):1450-2

12. Fleischer DM, Conover-Walker MK, Matsui EC,Wood RA. The natural history of tree nutallergy.J Allergy Clin Immunol 2005;116(5):5-1093



15. Yunginger JW, Squillace DL, Jones RT,Helm RM. Fatal anaphylactic reactionsinduced by peanuts.Allergy Proc 1989;10(4):249-53

16. Guin JD, France G. Protein contact dermatitisfrom Pecan.Contact Dermatitis 2000;43(5):309-10

17. Joyce KM, Boyd J, Viernes JL. Contactdermatitis following sustained exposure topecans (Carya illinoensis): a case report.Cutis 2006;77(4):209-12

153

Pinus edulisFamily: PinaceaeCommonnames: Pine nut, Pignoles,

Pinon nut, Pignola,Pinyon nut, Pine kernals

Sourcematerial: Shelled nutsSynonyms: Pinus pinea, P. cembra,

P. cembroidesSee also: Pine t213 and

White pine t16For continuous updates:www.immunocapinvitrosight.com

f253 Pine nut

Allergen Exposure


Pine nuts, coming from several varieties ofPine trees, are abundant in south-westernNorth America, but also in similar climateselsewhere, most notably the Mediterranean.They were an important food source forNative Americans. The high-fat, high-protein, ivory-coloured nuts are actuallyinside the Pine cone, which generally mustbe heated to facilitate their removal. Thenuts, though tiny (about 1.5 cm in length),must be taken out of their thin, soft shellsas well. This long process is what makes thenuts so expensive.

The Pine nut has in many varieties,including the Italian or Mediterranean andthe Chinese.

EnvironmentPine nuts are often sold as a health product.They are used raw and intact, ground up,and for oil. They are popular as a snack, insalads, and in sweet and savoury ethnicdishes, especially the classic Italian pesto andas a seasoning in the cuisine of theMediterranean area of Spain.

Allergens


In previous studies, 30 protein bands havebeen demonstrated in Pine nut, 3 of which(66 to 68 kDa in size) bound IgE in a Pinenut-allergic patient's serum in immunoblotstudies (1). A 17 kDa protein has also beendetected and found to be sensitive toreducing agents, losing its IgE-bindingproperties through reduction (2). A 17 kDaprotein was isolated by serum from 2 youngchildren who experienced anaphylaxis tothis nut (3). Pine nut protein bands of 30and 44 kDa, which disappear in theinhibition of immunoblotting with Peanut,have been isolated (4). An importantallergenic band of 50 kDa, whichdisappeared after blotting inhibition with anAlmond extract, has also been reported (5).


An extensive cross-reactivity among thedifferent individual species of the genuscould be expected (6). Cross-reactivitybetween the botanically related seeds ofPinus pinea and P. cembra has beendemonstrated by RAST inhibition (7). It waspostulated, based on the cross-reactivitybetween Pine nut and Pine pollen extracts,that co-sensitisation to these allergens couldbe the reason for a case of Pine nut allergydescribed in a single patient with Pine pollen

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f253 Pine nutallergy (8). However, the allergens were notstudied in this case, and among individualswho had experienced anaphylactic reactionsto Pine nut, none were Pine tree pollen-allergic (3,9).

Studies have also reported the existenceof common antigenic proteins between Pinenut and Peanuts (4), and cross-reactivitybetween Pine nut and Almond (5); however,many individuals with allergy to Pine nuthave no IgE antibodies to these nuts and donot experience allergic reactions followingingestion.

Clinical Experience


Pine nut may commonly induce symptomsof food allergy in sensitised individuals(5,10-14).

A study reports on 4 paediatric patientswith allergy reactions on ingestion of Pinenuts. Ages ranged from 12 months to 6years. All patients had a history of atopy.Severe systemic reactions occurred in 3 cases.Two of the children had allergic reactionsto other nuts. In all cases, both the skin testand the serum IgE antibody test werepositive (11).

Reactions may be severe. Anaphylaxisafter Pine nut ingestion has been oftenreported (2,9-10,15-18). Anaphylaxis aftereating Pine nut was reported in a 10-year-old boy, who had been previously diagnosedwith seasonal rhinoconjunctivitis withsensitisation to grass and Olive pollen (4).A 21-year-old white male developed life-threatening systemic anaphylaxis withinseconds of ingesting a small amount of acookie containing Pine nut. SPT, ELISA, andbasophil histamine release studiesdemonstrated Pine nut-specific IgEantibodies (1). A patient with Bird-EggSyndrome who experienced an anaphylacticreaction after eating some of her Parrot'sfood (containing Pine nut) has beenreported. Allergen-specific IgE against Pinuspinea (Stone pine) was demonstrated by IgEantibody testing (7).

Two young girls who experiencedanaphylaxis caused by small amounts of Pinenuts were described. Allergy to Pine nut wasconfirmed by skin reactivity and IgEantibodies, but negative tests for other nutsand for Pine pollen. The patients had IgEantibodies directed against a Pine nut proteinband of approximately 17 kDa that couldbe considered the main allergen. The 17 kDaprotein could be correlated with the severeclinical symptoms. Both girls weremonosensitised to Pine nut (3).

A 22-year-old man, without a history ofatopy or drug allergy, presented withdifficulty in breathing and swallowing,profuse sweating, abdominal pain, andvisual disturbances 15 minutes after eatingseveral Pine nuts (2).

Acute anaphylaxis after skin testing forPine nut was reported in a 20-year-oldwoman. Her initial complaints were that shehad developed generalised urticaria, swellingof the face and dyspnoea after eating a saladcontaining Pine nuts. Similar symptoms wereexperienced after the skin test, including astrong local skin reaction (19).

Anaphylaxis to Pine nuts was describedin a 53-year-old man, who experiencedangioedema, acute dyspnoea and circulatorycollapse for the first time after a meal ofspaghetti and pesto sauce (olive oil, herbs,Pine nuts and sardines). Skin reactivity wasdemonstrated for Pine nut but not for theother ingredients. Ten minutes after an oralchallenge of a teaspoonful of Pine nuts, hedeveloped marked conjunctivalinflammation and periorbital itching andreddening. The IgE antibody level for Pinenut was Class 4 (17).

Anaphylaxis to Walnuts and Pine nutsinduced by ACE inhibitor has beendocumented (20).

A number of collections of case reportshave further extended the understanding ofthe implications of Pine nut allergy.

In a study of Pine nut allergy, three casereports are given:

A 43-year-old female suddenlyexperienced anaphylaxis while eating in aPolynesian-style restaurant. SPT forcommon Oriental food ingredients were all

155

negative. The chef disclosed that crushedPine nuts were used in the salad. SPT with aPine nut extract was positive within 3minutes, and a 18 x 24 mm wheal, whichfeatured pseudopodia and intense pruritus,had formed at 10 minutes. Contact withother sources of Pine, such as natural Pineresins, bark and needles, was not associatedwith any immediate or delayed respiratory,skin or other reactions in this patient (10).

The second case was of recurrent urticariain a 28-year-old woman. She noted aspreading urticaria about an hour aftereating a dish containing Pine nut. She wasinitially unable to identify the cause of thisskin reaction, but about 5 months later, shehad a recurrent and more severe urticarialepisode, which she attributed to Pine nut.She was reluctant to be tested, but when awhole Pine nut was rubbed on her forearm,she developed erythema and a wheal,followed by a slightly scaly, rough,eczematoid eruption that lasted 3 or 4 days.Notable, she had consumed “2 or 3 glasses”of a resin-flavoured wine (Greek retsina, awhite or rosé wine flavoured with Pine resin)without any reaction suggestive of allergy.External contact with Pine and otherevergreen products did not appearassociated with any clinical hypersensitivityin her case either (10).

The third case was of a 17-year-old malestudent with a history of multiple foodsensitivity, including dermal, respiratory andgastrointestinal reactions to a variety of“nuts”. Almond had caused “stomachupsets”; Peanut (and other legumes) wereblamed for asthma-like symptoms, andPistachio had reportedly caused stomatitisand epigastric pain. Skin reactivity for Pinenut was present, but an oral challenge “didnot appear then - or subsequently - to be ofany practical benefit to this multiply atopicindividual”. The authors neverthelessadvised him to avoid Pine nut (10).

Severe anaphylaxis to Pine nut wasdescribed in 3 patients. A 28-year-old chefpresented with generalised urticaria, swellingof the face, acute dyspnoea, and pulmonarycollapse a few minutes after eating a saladdressing containing Pine nut. SPT for sometree nuts and Peanut, among other substances,were negative, but positive for Pine nut. Pine

nut-specific IgE was 11 kUA/l. A secondpatient, a 35-year-old man who hadpresented with 2 episodes of anaphylaxisfollowing ingestion of Pine nuts, reportedthat within minutes after ingestion, he haddeveloped generalised urticaria, facialswelling, acute dyspnoea, and pulmonarycollapse. He also reported generalisedurticaria after eating Brazil nut. SPT wasnegative to a number of allergens, includingHazel nut, Almond and Peanut, and positiveto Brazil nut, Chestnut, Walnut and Pine nut,among other allergens. Pine nut-specific IgEwas 6.25 kUA/l and raised for Brazil nut andChestnut. The third patient, a 19-year-oldman, developed facial angioedema, acuterhinoconjunctivitis, and asthma rapidly aftereating pesto sauce. He had previouslyexperienced generalised urticaria afterhandling Pine nut. SPT was negative for Peanutand some tree nuts, except for Pine nut. TheIgEantibody level was 79.9 kUA/l. None of thepatients was Pine pollen-allergic (9).

Two further cases are also illustrative. A23-month-old girl had during 3 monthsexperienced moderate respiratory difficultyfollowing ingestion of a small amount ofPine nut; she then experienced 2 episodes ofangioedema of the eyelids, lips, face and feet.She had a third episode immediately aftersucking Pine nuts: angioedema, wheezingand acute dyspnoea requiring emergencytreatment. The patient tolerated normal foodin her diet, including Almond, Walnut, Hazelnut and other nuts (3). A second patient, a15-year-old girl, had at the age of 4 sufferedsevere urticaria, angioedema of the lips andeyelids, laryngeal oedema, hoarseness anddizziness after ingestion of a single Pine nut.At the age of 14, she had an episode ofanaphylaxis, with vomiting, itching of themouth, oedema of the tongue and larynx,general urticaria, severe respiratorydifficulty, cyanosis and thoracic pain aftereating a sausage that the authors suggestmay have contained Pine nut. She toleratedPeanut, tree nuts and Sunflower seed. In bothpatients, SPT was negative to tree nuts andPine tree pollen, but positive for Pine nut.Allergen-specific IgE for tree nut and Peanutwere negative, and respectively 7 and1.7 kUA/l, for Pine nut. Both girls weremonosensitised (3).

f253 Pine nut

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Allergy to Pine nut has been described ina patient who showed no clinical symptomsto Pine pollen despite the presence in herserum of Pine tree pollen-specific IgE. SPTwith fresh Pine nut and IgE antibodyevaluation with Pine nut and Pine pollenextracts showed high levels of IgE againstboth. Immunoblotting experiments showedthe presence in serum of IgE antibodiesagainst several components of Pine nuts andpollen. Immunoblotting inhibitionexperiments demonstrated the presence ofsome cross-reacting components. This dataconfirmed the existence of food allergyinduced by Pine nuts, but there were nosymptoms of Pine pollen allergy. The authorssuggest that the development of pollinosismay require a longer period of exposure toallergens but that, because of the cross-reactivity between Pine nut and Pine pollenextracts, co-sensitisation to these allergenscould be possible (8). Similarly, a studyreported on 3 individuals with Pine nutallergy and Pine pollen sensitisation (21).

References1. Koepke JW, Williams PB, Osa SR, Dolen WK,

Selner JC. Anaphylaxis to pinon nuts.Ann Allergy 1990;65(6):473-6

2. Garcia-Menaya JM, Gonzalo-Garijo MA,Moneo I, Fernandez B, Garcia-Gonzalez F,Moreno F. A 17-kDa allergen detected in pinenuts. Allergy 2000;55(3):291-3

3. Ibanez MD, Lombardero M, San Ireneo MM,Munoz MC. Anaphylaxis induced by pine nutsin two young girls.Pediatr Allergy Immunol 2003;14(4):317-9

4. A MA, Maselli JP, Sanz Mf ML, Fernandez-Benitez M. Allergy to pine nut. AllergolImmunopathol (Madr) 2002;30(2):104-8

5. de las Marinas D, Vila L, Sanz ML. Allergy topine nuts. Allergy 1998;53(2):220-2


7. Jansen A, Vermeulen A, Dieges PH,van Toorenenbergen AW. Allergy to pine nutsin a bird fancier. Allergy 1996;51(10):741-4

8. Senna G, Roncarolo D, Dama A, Mistrello G.Anaphylaxis to pine nuts and immunologicalcross-reactivity with pine pollen proteins.J Investig Allergol Clin Immunol2000;10(1):44-6

9. Roux N, Hogendijk S, Hauser C.Severe anaphylaxis to pine nuts.Allergy 1998;53(2):213-4

10. Falliers CJ. Pine nut allergy in perspective.Ann Allergy 1989;62(3):186-9

11. Rubira N, Botey J, Eseverri JL, Marin A.Allergy to pine nuts in children.Allerg Immunol (Paris) 1998;30(7):212-6

12. Fine AJ. Hypersensitivity reaction to pinenuts (pinon nuts--pignolia).Ann Allergy 1987;59(3):183-4



15. Falliers CJ. Anaphylaxis to pinon nuts.[Letter] Ann Allergy 1991;66(4):355

16. Beyer AV, Gall H, Peter RU. Anaphylaxis topine nuts. Allergy 1998;53(12):1227-8

17. Nielsen NH. Systemic allergic reaction afteringestion of pine nuts, Pinus pinea. [Danish]Ugeskr Laeger 1990;152(48):3619-20

18. Nielsen, NH. Systemic allergic reaction topine nuts. Ann Allergy 1990;64:132-133

19. van de Scheur MR, Bruynzeel DP. Acuteanaphylaxis after pine nut skin testing.[Letter] Ann Allergy Asthma Immunol2004;92(1):93

20. Moneret-Vautrin DA, Blain H, Kanny G, Bloch Y.Anaphylaxis to walnuts and pine nutsinduced by ACE.Allergy 1998;53(12):1233-4

21. Armentia A, Quintero A, Fernandez-Garcia A,Salvador J, Martin-Santos JM. Allergy to pinepollen and pinon nuts: a review of threecases. Ann Allergy 1990;64(1):49-53

f253 Pine nut

157

Pistacia veraFamily: AnacardiaceaeCommonnames: Pistachio, Pistachio nutSourcematerial: Shelled nutsFor continuous updates:www.immunocapinvitrosight.com

f203 Pistachio

Allergen Exposure


Pistachio is a green, edible seed obtainedfrom the Pistachio tree, which belongs to theAnacardiaceae (Sumac) family, along withMango and Cashew nut. The Pistachio treegrows up to 10 m high and has deciduouspinnate leaves up to 20 cm long. It is nativeto the mountainous regions of central andsouth-western Asia. Pistachio is nowcultivated in other parts of the world,particularly in California and Australia.

The plants are dioecious, with separatemale and female trees. The flowers have nopetals and are borne in panicles. Pistachioharvests are heavier in alternate years. Thefruit is a drupe (in culinary but not botanicalterms a nut), containing an elongated seedwith a hard, whitish shell around 2 cm longand a striking light green kernel. It has avery characteristic flavour. When the fruitripens, the shell splits partway open with anaudible pop, but the nut remains enclosedand is usually marketed in this state as asnack. The shell of the Pistachio is naturallya beige colour, but it is sometimes dyed redfor commercial sale.

Pistachio is often confused with some ofthe other 9 species in the genus Pistacia, suchas P. terebithus and P. lentiscus. These specieshave a different distribution, in theMediterranean and south-west Asia, andhave much smaller nuts, lacking the hardshell of P. vera.

Environment

Pistachio nuts are widely used in the cateringindustry in ice creams, cakes and otherconfectionary, mortadella (a sausage) andoriental dishes. They are also eaten roastedas a popular snack.

Oil is processed from the seed and maypose a threat to patients with allergy,depending on the method of manufactureand processing (1).

Pistachio nuts are reported to be highlyflammable when stored in large quantities,and are prone to self-heating andspontaneous combustion.

Allergens

A number of allergens have been isolated,and some characterised (2).

In 3 adults with anaphylaxis to Pistachio,allergenic proteins of 34, 41, 52 and 60 kDawere found (3). In a similar study of 3patients who had experienced anaphylaxisto Cashew nuts and were sensitised to theclose family member Pistachio, both nutswere shown to have several IgE bindingprotein bands, the strongest of these bandshaving similar molecular weights of 15, 30and 60 kDa (4). In an investigation of 2children who had experienced anaphylaxisto Pistachio, IgE binding was found to bestrongest in 3 bands between 30 and 41 kDa,the strongest at the 34 kDa band (5).

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f203 PistachioThe following allergens have beencharacterised:

Pis v 1, a 2S albumin (2,4).

Pis v 2, an 11S globulin (6).

Pis v 3, a vicilin-like protein (6).

Pis v 4, a magnesium superoxide dismutase (6).

A lipid transfer protein (LTP) may bepresent, as suggested by a study of lipidtransfer proteins in Rosaceae memberswhich found that the Rosaceae LTP reactedto a broad range of foods, includingPistachio (7).

Preliminary evidence for the presence ofa 2S albumin has been reported (4).


The close relationships among theAnacardiaceae suggest cross-reactivity, andthis is supported by studies demonstratingcross-reactivity between Cashew andPistachio (8). In a study of 42 children withCashew allergy, 7 had an associated foodallergy to Pistachio (9).

By means of serum from 2 children withPistachio nut allergy, both were shown tobe reacting to several Pistachio and Cashewallergens with common antigenicdeterminants. Cross-reactivity was alsofound between Pistachio nut and Mangoseed, but not Mango pulp (5).

In a study of 3 individuals whoexperienced anaphylaxis to Cashew nut, alldemonstrated IgE antibodies to Cashew andPistachio. Evaluation of the allergen foundthat the strongest IgE-binding bands hadsimilar molecular weights and that a 15 kDaprotein band may have been a 2S albuminpanallergen (4). Whether further cross-reactivity occurs as a result of other foodscontaining the 2S albumin has not beenevaluated, but cross-reactivity has beendemonstrated between Pistachio, Peanut,Walnut and Sunflower seed (3), all knownto contain the albumin; and similarly, cross-reactivity has been reported to occur amongallergens in Sesame seed and allergens inother foods, including Hazel nut, Rye, Kiwi,Poppy seed, Black walnut, Cashew,Macadamia, Pistachio, and Peanuts (10).

Cross-reactivity among Pistachio, Mango(14) and Artemisia (11) has been suggested.Sensitisation to Pistachio is common inParietaria allergy (12). Cross-reactivity may alsooccur between Pellitory and Pistachio (13).

Cross-reactivity with other lipid transferprotein-containing foods is possible (6).

As Pistachio contains an 11S globulin(Pis v 2) and a vicilin-like protein (Pis v 3),cross-reactivity with other foods containingthese allergens is possible, but it has not beenelucidated as yet.

Cashew nut, and possibly Pistachio nut,allergy may be associated with pectin allergy,and the possibility of pectin allergy shouldbe considered in Cashew- or Pistachio-allergic patients who have unexplainedallergic reactions. A study describes a 3 1/2-year-old boy who developed anaphylaxisafter eating Cashew nut and later after eatinga pectin-containing fruit “smoothie”. Thechild had skin reactivity to pectin and a highIgE antibody level to Cashew nut andPistachio nut, as well as a low levels toGrapefruit, to which he had previously alsoreacted. The pectin in the smoothie wasconfirmed to be of citrus origin (14).

Clinical Experience


Pistachio may uncommonly cause symptomsof food allergy in sensitised individuals.Adverse reactions are similar to those seen withother tree nuts and include symptoms of oralallergy and food allergy, cutaneousmanifestations, angioedema and severeanaphylaxis (3,5,15-16). Most of these reportshave concerned small children. The IgE-mediated mechanisms have been confirmedwith SPT and IgE antibody testing (5). Asmore exotic foods are introduced into morecountries, more reactions are likely to beseen (17).

Two children were described as havingallergy to Pistachio nut. Skin reactivity forPistachio and Cashew were detected in both,and for Mango seed in one. IgE antibodiesfor Pistachio and Cashew nut were found inboth (5).

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f203 PistachioTwo uncommon cases of oral allergy

syndrome after eating Pistachio nuts werereported, involving a 54-year-old man anda 3-year-old girl. Both were shown to haveskin reactivity for Parietaria and Pistachionut. A double-blind, placebo-controlled foodchallenge was performed on the adult patientand was negative, but a positive intraoralreaction was noted when the oral mucosawas slightly scratched. It was suggested thatbreaking the shells with his teeth had slightlyinjured the oral mucosa, which hadenhanced the local response and resulted insymptoms (14).

Anaphylaxis to Pistachio has beendescribed in 3 individuals who were allergicto both Mango and Pistachio nut. Theindividual history of each is informative.One, a 3-year-old boy, developed facialoedema and inspiratory stridor withinminutes after eating Pistachio ice-cream.After eating a single Pistachio nut on asubsequent occasion, he developedgeneralised itching, hives and facialangioedema. A 28-year-old womandeveloped generalised urticarial eruptions on2 separate occasions after ingesting Paprika,Curry and Celery. Three months later, shecomplained of a burning sensation in hermouth, swelling of the lips, face and tongue,and nausea and abdominal crampsimmediately after eating a Mango. A 28-year-old man experienced episodes ofgeneralised itching and hives, profusesweating, abdominal pain, nausea andvomiting immediately after eating Peanut,Peach, Paprika, Hazel nut or Mango, ondifferent occasions. Two of these patientswere found to have skin reactivity toPistachio. All were found to have skinreactivity to fresh Mango but not to Mangoextracts of peel or pulp (15).

Anaphylaxis has also been reported in 3other adults (3).

Food-dependent exercise-inducedanaphylaxis to Pistachio has been describedin a 16-year-old boy; it occurred 30 minutesafter he began to play football after havingingested Pistachio nuts. SPT evaluation usingroasted Pistachios was negative. No allergen-specific IgE antibodies were detected toPistachio, Cashew Nuts or Mango. An open

oral challenge test with Pistachio in restingconditions was negative. A specific foodexercise challenge using a treadmillergonometric stress test was positive 60minutes after the patient had ingested 50 gof Pistachio nuts, with the onset of milddiffuse erythema and small wheals on hisface and thorax (18).

In a study of 42 French children withCashew allergy, 7 were found to have anassociated food allergy to Pistachio. Theauthors stated that the increase in Cashewallergy was of concern because it affectsyoung children who may have a reactionwithout ever having been exposed toCashews. One could surmise that this maybe valid for the close family memberPistachio as well (8). Indeed, it has beenrecommended that Pistachio be included inthe list of foods to be tested in theinvestigation of anaphylactic reactions ofunknown origin in small children (5).

160

References1. Teuber SS, Brown RL, Haapanen LA.

Allergenicity of gourmet nut oils processed bydifferent methods.J Allergy Clin Immunol 1997;99(4):502-7


3. Parra FM, Cuevas M, Lezaun A, et al.Pistachio nut hypersensitivity: identificationof pistachio nut allergens.Clin Exp Allergy 1993;23:996-1001

4. Garcia F, Moneo I, Fernandez B, Garcia-Menaya JM, Blanco J, Juste S, Gonzalo.Allergy to Anacardiaceae: description ofcashew and pistachio nut allergens.J Investig Allergol Clin Immunol2000;10(3):173-7.

5. Fernandez C, Fiandor A, Martinez Garate A,Martinez Quesada J. Allergy to pistachio:crossreactivity between pistachio nut andother Anacardiaceae.Clin Exp Allergy 1995;25(12):1254-9



8. Goetz DW, Whisman BA, Goetz AD. Cross-reactivity among edible nuts: doubleimmunodiffusion, crossedimmunoelectrophoresis, and human specificigE serologic surveys. Ann Allergy AsthmaImmunol 2005;95(1):1-52

9. Rance F, Bidat E, Bourrier T, Sabouraud D.Cashew allergy: observations of 42 childrenwithout associated peanut allergy.Allergy 2003;58(12):1311-4

10. Gangur V, Kelly C, Navuluri L. Sesameallergy: a growing food allergy of globalproportions? Ann Allergy Asthma Immunol2005;95(1):1-11

11. Garcia Ortiz JC, Cosmes PM, Lopez-Asunsolo A.Allergy to foods in patients monosensitized toArtemisia pollen.Allergy 1996;51(12):927-31

12. Liccardi G, Russo M, Mistrello G, Falagiani P,D'Amato M, D'Amato G. Sensitization topistachio is common in Parietaria allergy.Allergy 1999;54(6):643-5

13. Egger M, Mutschlechner S, Wopfner N,Gadermaier G, Briza P, Ferreira F. Pollen-foodsyndromes associated with weed pollinosis:an update from the molecular point of view.Allergy 2006;61(4):461-476

14. Ferdman RM, Ong PY, Church JA. Pectinanaphylaxis and possible association withcashew allergy. Ann Allergy Asthma Immunol2006;97(6):759-60

15. Liccardi G, Mistrello G, Noschese P,Falagiani P, D'Amato M, D'Amato Oral allergysyndrome (OAS) in pollinosis patients aftereating pistachio nuts: two cases with twodifferent patterns of onset.Allergy 1996;51(12):919-22

16. Jansen A, de Lijster de Raadt J,van Toorenenbergen AW, van Wijk RG. Allergyto pistachio nuts.Allergy Proc 1992;13:255-8


18. Porcel S, Sanchez AB, Rodriguez E, Fletes C,Alvarado M, Jimenez S, Hernandez J. Food-dependent exercise-induced anaphylaxis topistachio. J Investig Allergol Clin Immunol2006;16(1):71-3

f203 Pistachio

161

Papaver somniferumFamily: PapaveraceaeCommonnames: Poppy, Opium poppy,

Blue bread seed poppy,White poppy

Sourcematerial: White & blue seedsImportant other varieties are:Papaver rhoeus L., known as Corn orField poppy, and native to Europe andAsia; the alkaloids rhoeadine,morphine, and papaverine have beenreported in this species.Papaver orientale L., formerly Papaverbracteatum Lindl., a morphine-freealkaloid source, used medicinally.Mexican or Prickly poppy, Argemonemexicana L., reported to havetoxicological propertiesFor continuous updates:www.immunocapinvitrosight.com

f224 Poppy seed

Allergen Exposure


Poppy is an annual herb native to south-eastern Europe and western Asia. There arewild and cultivated varieties. The species iscultivated extensively in many countries,especially in Asia and Central and SouthAmerica.

The plant can reach a height of 1.2 m. Itcan have white, pink, red, or purple flowersand is an important ornamental. Seeds rangein colour from white to blue-black. The seedsare rather small, but there are large numbersof them contained in capsules 3 cm or morein diameter, and so they are easy to harvestand utilise. They are often eaten asflavouring but can also be processed asdrugs, including the illicit drugs opium andheroin.

Environment

Poppy seeds are employed raw or cooked.They are used as flavouring in cakes, bread,fruit salads, etc. The crushed and sweetenedseeds are a filling in certain crêpes, strudels,and other pastries. The seeds are perfectlysafe to eat, containing very little if any ofthe narcotic principles; however, they havebeen reported to cause false positives ondrug tests. The seeds are highly nutritious.A high-quality edible drying oil, also notnarcotic, is obtained from the seed andmakes a good substitute for olive oil. Theyoung leaves, raw or cooked, are edible andprobably do not contain narcotic principles,but caution is advised.

The latex from the unripe green seedcontains a wide range of alkaloids (includingmorphine, opium, codeine, noscapine,papaverine, thebaine and narcotine) andyields valuable medicines, especially usefulin bringing relief from pain. But thissubstance (and especially the opium andmorphine it contains) can cause addictionand so should be treated with extremecaution and used only under the supervisionof a qualified practitioner.

Unexpected exposure

Seeds of the plant are not always apparentor noticed when used in bakery products.Poppy seed is sometimes used as a colouringin cough syrups and other products.

162

f224 Poppy seedPoppy seed is sometimes used for its oil,

which can also be a “hidden allergen”. ThePoppy seeds and the fixed oil that can beexpressed from them are not narcotic,because the seeds develop after the capsulehas lost its opium-yielding potential.However, the narcotic principles are stillpresent and may be detected in urinesampling.

Poppy oil is used for lighting, and in themanufacture of paints, varnishes, and soaps.Poppy latex features in a number ofmedicinal products.

Allergens

The following allergens from this planthave been isolated:

Pap s 17kD, a Group 1 Fagales-relatedprotein, a Bet v 1 homologue (1).

Pap s 34kD (1).

Pap s Profilin (1).

In a study of sera of 11 Poppy seed-allergicpatients, specific IgE from the sera of 10 boundto a 45 kDa, 4 to a 34 kDa, 5 to a 17 kDa,5 to a 14 kDa, and 3 to a 5 kDa protein.Individual IgE binding to proteins of 20, 25,30 and 40 kDa was also seen. The 40 and45 kDa allergens were glycoproteins andcontained IgE binding carbohydrate moieties.Cross-reacting homologues of pollenallergens, including Bet v 1 and profilin, weredetected in Poppy seed extract (1).

In individuals with occupational asthmafrom working with shells of P. somniferum,a major protein band with an estimated sizeof 52 kDa was detected (2).


An extensive cross-reactivity among thevarious individual species of the genus andfamily, including the Californian poppy(Eschscholzia californica), the Mexicanpoppy (Argemone mexicana) and celandine(Chelidonium majus), could be expected (3).

Poppy seed contains homologues of Bet v 1and profilin, which indicates the possibility ofcross-reactivity with other plants containingthese panallergens. Nine of 11 patients in a

study of allergenicity to Poppy seed showedconcomitant IgE binding to allergens of Birch,Mugwort or grass pollen in laboratory tests.They reported characteristic seasonalsymptoms (1).

Allergy to Kiwi, Poppy seeds, and/orSesame seeds has been reported to occuroften in patients with a simultaneoussensitisation to nuts and flour. In a studyinvestigating this association, the degree ofcross-reactivity among Kiwi, Sesame seeds,Poppy seeds, Hazel nuts, and Rye grain wasfound to be very high in the patients studied.The existence of both cross-reacting andunique allergens was observed; however, thecross-reacting and unique allergens couldhave been different for different patients (4).

A study describes 3 patients with severeimmediate-type allergic reactions to Poppyseed, all of whom had serum showing IgEantibody binding specific for Sesame seed.The authors considered that this might be dueto a cross-reactivity to similar allergens (5).

In a report of a 17-year-old female withan apparent allergic reaction from ingestionof a Poppy seed cake, a novel allergencausing cross-sensitisation to Buckwheatwas described (6).

Clinical Experience


Poppy seed commonly induces symptoms offood allergy in sensitised individuals, whichmay be confirmed by SPT and IgE antibodydetermination. It has been suggested that theprevalence of Poppy seed allergy isincreasing as a result of the increased numberof vegetarian and ethnic dishes.

Immediate-type allergic reactions rangefrom mild local symptoms to severeanaphylactic reactions, and may involve thegastrointestinal, respiratory or skin systems(1,7-10). A patient who experienced animmediate-type hypersensitivity reactionagainst Poppy seed described symptoms ofswelling of the oral mucosa, vomiting,respiratory distress, and urticaria. Poppyseed-specific IgE was demonstrated (5).

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f224 Poppy seedOther studies have described similar

severe immediate-type reactions to Poppyseed; these studies include a report of 3patients in whom SPT and IgE antibody testwere positive (5). Immediate-type allergycaused by Poppy seed in a 52-year-old manwas described. Symptoms includedepigastric pain, angioedoema, andrespiratory distress a few minutes aftereating Poppy seed cake. SPT and IgEantibody test were positive (7). A 17-year-old female had an apparent food-allergicreaction after ingestion of a Poppy seed cake.Laboratory investigation led to theidentification of a novel cross-sensitisationwith Buckwheat (6).

Anaphylaxis and food-dependant exercise-induced anaphylaxis have been reported (11-12). Food-dependant exercise-inducedanaphylaxis was described in a 46-year-oldman who had experienced 4 episodes ofgeneralised urticaria, all occurring within 1hour after ingestion of a Poppy seed cake.These episodes occurred only in combinationwith exercise, although he had been eatingthis cake every Friday for about a year. SPTfor Poppy seed was positive and allergen-specific IgE was 13.4 kUA/l. Oral challengeswithout exercise were negative. On followup, the patient reported that he had continuedto eat Poppy seed cake every Friday, but thatonly in combination with gardening hadgeneralised urticaria occurred (13).

A study described immune and non-immune hypersensitivity reactions to Poppyseed in a 21-year-old woman and a 32-year-old man, in both of whom life-threateningsymptoms and signs of anaphylaxisdeveloped after consumption of Poppy seedsin various situations, e.g., after consumptionof a roll with Poppy seeds on it, and of acake prepared on a moulding board onwhich Poppy seed paste had previously beensqueezed. The female patient was reportedto have a history of atopy, and in her caseskin reactivity was detected to a range ofpollen allergens and to Hazel nuts, whereasSPT for various allergens was negative forthe male. In the female, the IgE antibodylevels were raised for Celery and nut mixturebut negative for Poppy seed, whereas in themale the IgE antibody levels for Poppy and

nut mixture were both raised (Class 2). Inthe male patient, among SPT with topicalanesthetics and narcotic analgesics derivedfrom Poppy, tests were positive for xylocaineand codeine. The authors concluded thathypersensitivity to Poppy seed may occurthrough IgE-dependent or non-immunemechanisms, and that a history of atopy isnot completely determinant (13).

Inhalation of Poppy seed resulting inerythema, angioedema, conjunctivitis, anddyspnoea in a 16-year-old boy wasdescribed. Skin reactivity was present forPoppy seed, Hazel nut, and Chickpea. IgElevels for Poppy seed, Hazel nut, and Peanutwere 3.36 kUA/l, 1.5 kUA/l, and 6.17 kUA/l,respectively. This is the first report oninhalant allergy to Poppy seed (14).

Allergic contact dermatitis and contacturticaria have been reported to closely relatedfamily members, Papaver rhoeas and Papavernudicaule (Icelandic poppy) (15-16).

Other reactions

IgE reactions have also been reported toPoppy shells, which contain the seeds. Sixof 28 workers in a pharmaceutical factoryproducing morphine and extracting otheralkaloids from shells of Papaver somniferumwere found to have clinical symptoms ofsensitisation to Poppy. Skin reactivity wasdemonstrated. A bronchial provocation testwas found to be positive for 4 workers, andin all of these cases IgE antibodies weredemonstrated to an aqueous extract of P.somniferum. Histamine release tests usingthe same antigen were also positive in the 4samples from sensitised patients. A majorprotein of around 52 kDa was isolated.These findings suggest that P. somniferumallergy is mediated by an IgE mechanism andnot by a pharmacological or toxic effect ofthe alkaloids or polyphenols (2).

This plant contains a number of verytoxic compounds, many of which areextracted and used as pain killers, etc. Theyare also used to make various narcotic drugs,which do not all fit the stereotypes of highlyrefined “street drugs”. Danish Poppycapsules contain 3-5 mg morphine percapsule, and the content of morphine in

164

opium exuded from the capsules mayamount to 24%. This has resulted in misuse,as both fresh and dried Poppy capsules canyield “opium tea”. During the period 1982-1985, 7 casualties occurred among drugaddicts in Denmark that were solely orpartly caused by these Opium capsules (17).A patient presenting with dependence onOpium poppy tea has also been reported.But Poppy tea drinking, although previouslydescribed in certain parts of the UK, rarelypresents as a dependence syndrome (18).

Because Poppy seed may be an ingredientin ordinary confections, caution is warrantedin environments with drug testing. In a studyin which 9 volunteers ingested cake containingPoppy seed, several urine specimens containedmorphine with concentrations higher than 1microg/ml, and the peak values wereapproximately 10.0 µg/ml. Because theInternational Olympic Committee has set acut-off for morphine at 1 µg/ml, athletes couldfall foul of testing after consumption ofproducts containing Poppy seeds (19).

References1. Jensen-Jarolim E, Gerstmayer G, Kraft D,

Scheiner O, Ebner H, Ebner C. Serologicalcharacterization of allergens in poppy seeds.Clin Exp Allergy 1999;29(8):1075-9

2. Moneo I, Alday E, Ramos C, Curiel G.Occupational asthma caused by Papaversomniferum. Allergol Immunopathol (Madr)1993;21(4):145-8



5. Gloor M, Kagi M, Wuthrich B. Poppyseedanaphylaxis. [German] Schweiz MedWochenschr 1995;125(30):1434-7

6. Oppel T, Thomas P, Wollenberg A. Cross-Sensitization between Poppy Seed andBuckwheat in a Food-Allergic Patient withPoppy Seed Anaphylaxis. Int Arch AllergyImmunol 2006 Apr 5;140(2):170-3

7. Frantzen B, Brocker EB, Trautmann A.Immediate-type allergy caused by poppyseed. Allergy 2000;55(1):97-8

8. Crivellaro M, Bonadonna P, Dama A, SennaGE, Mezzelani P, Mistrello G, Passalacqua G.Severe systemic reactions caused by poppyseed. J Investig Allergol Clin Immunol1999;9(1):58-9

9. Kalyoncu AF, Stalenheim G. Allergy to poppyseed. Allergy 1993;48(4):295

10. Haupt H. Toxic and less toxic plants.Papaver. [German] Kinderkrankenschwester1999;18(1):33

11. Richter J, Susicky P. Latex allergy. [Czech]Cesk Slov Oftalmol 2000;56(2):129-31

12. Kutting B, Brehler R. Exercise-inducedanaphylaxis. Allergy 2000;55(6):585-6

13. Bant A, Kruszewski J, Droszcz W, Stepien K.Hypersensitivity to poppy seeds. [Polish]Wiad Lek 2005;58(7-8):447-50

14. Keskin O, Sekerel BE. Poppy seed allergy: acase report and review of the literature.Allergy Asthma Proc 2006;27(4):396-8

15. Jury CS, Lever R. Allergic contact dermatitisdue to Icelandic poppy (Papaver nudicaule).Contact Dermatitis 2000;42(5):300-1

16. Gamboa PM, Jauregui I, Urrutia I, Gonzalez G,Barturen P, Antepara I. Allergic contacturticaria from poppy flowers (Papaverrhoeas).Contact Dermatitis 1997;37(3):140-1

17. Steentoft A, Kaa E, Worm K. Fatalintoxications in Denmark following intake ofmorphine from opium poppies.Z Rechtsmed 1988;101(3):197-204

18. Unnithan S, Strang J. Poppy tea dependence.Br J Psychiatry 1993;163:813-4

19. Thevis M, Opfermann G, Schanzer W. Urinaryconcentrations of morphine and codeine afterconsumption of poppy seeds.J Anal Toxicol 2003;27(1):53-6

f224 Poppy seed

165

Cucurbita pepoFamily: CucurbitaceaeCommonnames: Pumpkin, Field

pumpkin, Naked-seededpumpkin, Pimpkin

Sourcematerial: Peeled seedsSynonyms: C. moschata, C.

maxima, C. mixta,Cucumis pepo

See also: Pumpkin f225For continuous updates:www.immunocapinvitrosight.com

f226 Pumpkin seed

Allergen Exposure


The Pumpkin is thought to have originatedin Central America, possibly Mexico, but itis now grown widely in both temperate andtropical zones. It is an annual climber,typically with a large, round, ribbed, edibleorange fruit. But Pumpkin comes in severalother forms, such as the finer-textured,straw-colored Cheese pumpkin, the Gemsquash and the Winter squash. All of thesehave a hard, smooth rind, sometimes lightlyribbed, covering edible flesh and the centralseed cavity. Varieties within and betweenspecies can cross-pollinate to producehybrids: hence the great number of shapesand sizes. Pumpkins, however, can bedifferentiated from other squashes by theirfruit stalk: it is angular and polygonal inPumpkins but thick, soft and round in othersquashes.

Pumpkin seeds are consumed as a snackin many cultures throughout the world andare especially popular in Central Americancountries, where strains have been selectedprimarily for edible seed use. Worldproduction of the seed for food, on the otherhand, is meagre.

Environment

The seeds, with their hulls intact, can beroasted or deep-fried and eaten as a saltedsnack, like nuts. Pumpkin seeds are a sourceof vegetable oil, but it is difficult to obtainbecause the seed is small and the fibrous hullmust be removed. Flour may also beproduced, and mixed with other cereals formaking bread, etc. Fish bait is made fromthe seeds as well. The seeds can be sproutedand used in salads, etc. Pumpkin seeds arerich in protein.

The seeds are often used for medicinalpurposes. (They are especially popular fortapeworm removal in pregnant women andsmall children, for whom harsher remediesare unsuitable.)

Unexpected exposure

The oil of the seed is sometimes used forlighting, but if pure, should contain noallergens.

Allergens

No allergens from this substance have yetbeen characterised.

166

f226 Pumpkin seedIn 3 Pumpkin seed-allergic individuals,

immunoblot technique was used to isolateallergens of 13, 14, 36, 48, 77, and 87 kDa.The 14 kDa allergen appears to be aprofilin (1).

Whether similar allergens are present inthe seed and pulp has not yet beendetermined. Pumpkin pulp contains anascorbate oxidase and a profilin (2).


An extensive cross-reactivity among thedifferent individual species of the genuscould be expected, as well as to a certaindegree among members of the familyCucurbitaceae (3). Clinical cross-reactivityhas been demonstrated among Pumpkin,Pumpkin seed, Muskmelon, Watermelon,Cucumber and Zucchini (4).

A cDNA clone encoding a Soybeanallergen, Gly m Bd 28K, has been isolated,which exhibits high homology with theproteins in Pumpkin seeds and with a Carrotglobulin-like protein. The clinicalsignificance of this has not yet beendetermined (5).

Clinical Experience


Pumpkin can induce symptoms of foodallergy in sensitised individuals (4).Dermatitis, asthma, rhinoconjuctivitis,itching of the mouth, angioedema of the faceand lips, generalised itching and milddyspnoea after eating Pumpkin soup orvermicelli made with Pumpkin have beenreported in a patient (4). Similar symptomshave been reported in 3 individuals afteringestion of roasted Pumpkin seed. All thepatients fished for sport and used pressedPumpkin seed flour as bait. IgE antibodieswere detected to proteins from Pumpkin seedextract. Inhalation of Pumpkin seed flourduring fishing was suggested as the route ofsensitisation, leading to food allergy toPumpkin seed (1).

Other reactions

Pumpkin seeds may be aspirated into thetrachea in young children (6).

The sprouting seed produces a toxicsubstance in its embryo.

References1. Fritsch R, Ebner H, Kraft D, Ebner C. Food

allergy to pumpkinseed – characterization ofallergens. Allergy 1997;52(3):335-7

2. Altmann F. Structures of the N-linkedcarbohydrate of ascorbic acid oxidase fromzucchini. Glycoconj J 1998;15(1):79-82


4. Figueredo E, Cuesta-Herranz J, Minguez A,Vidarte L, Pastor C, De Las Heras M, Vivanco F,Lahoz C. Allergy to pumpkin and cross-reactivity to other Cucurbitaceae fruits.J Allergy Clin Immunol 2000;106(2):402-3

5. Tsuji H, Hiemori M, Kimoto M, Yamashita H,Kobatake R, Adachi M, Fukuda T, Bando N,Okita M, Utsumi S. Cloning of cDNAencoding a soybean allergen, Gly m Bd 28K.Biochim Biophys Acta 2001;1518(1-2):178-82

6. Yuksel H, Coskun S, Onag A. Pumpkin seedaspiration into the middle of the trachea in awheezy infant unresponsive to bronchodilators.Pediatr Emerg Care 2001;17(4):312-3

167

Chenopodium quinoaFamily: Amaranthaceae

(Chenopodiaceae)Commonname: QuinoaSourcematerial: Dried seedsSee also: Goosefoot / Lamb's

quarters w10For continuous updates:www.immunocapinvitrosight.com

f347 Quinoa

Allergen Exposure


Quinoa (pronounced “keen-wa”) has beencultivated in the Andean highlands since3,000 BC. Its small, very nutritious seedsresemble millet and are very versatile incooking.

Chenopodium plants have characteristicleaves shaped like a goose foot. (The genusalso includes a common weed, Goosefootor Lamb's quarters.) Quinoa is a small seedthat in size, shape, and colour looks like across between Sesame seed and Millet. It isusually a pale yellow colour, but species varyfrom almost white through pink, orange,red, purple and black. Quinoa is not a truecereal grain but is technically a fruit of theChenopodioideae subfamily.

Environment

Quinoa is a versatile ingredient, and thedishes it features in range from staple foodsto spicy delicacies. Quinoa flour, groundfrom whole seeds, has a delicate, nuttyflavour. A gluten-free product, it is suitablefor anyone afflicted by Wheat allergies.Quinoa seeds are naturally coated with abitter-tasting saponin that protects themfrom birds and insects.

Allergens



An extensive cross-reactivity among thedifferent individual species of the genuscould be expected but has not been describedto date (1). Closely related family membersinclude the weed Goosefoot or Lamb'squarters, which may be of relevance forpollen exposure.

Clinical Experience


Quinoa may rarely induce symptoms of foodallergy in sensitised individuals.

Other reactions

Saponin, a component of the pericarp ofQuinoa seed, is a known toxic glycoside.Saponin can be found in the pericarp ofseveral other species such as Alfalfa, Hops,and Soybean and is easily identified byproduction of a soapy lather when placedin water, and by solubility in pure alcohol.It also gives unwashed Quinoa a bitterflavour and has antinutritional properties.

References1. Yman L. Botanical relations and immuno-

logical cross-reactions in pollen allergy. 2nded. Pharmacia Diagnostics AB. Uppsala.Sweden. 1982: ISBN 91-970475-09

168

Brassica napusFamily: BrassicaceaeCommonnames: Rape seed, Rapeseed,

Canola, Oilseed RapeSourcematerial: Whole seedsSee also: Rape w203Brassica napus is a quite variablespecies, with 3 important subspecies:B. napus napobrassica (rutabagas orswedes)B. napus pabularia (Siberian kale,Hanover salad, etc.)B. napus oleifera (Rape seed)For continuous updates:www.immunocapinvitrosight.com

f316 Rape seed

Allergen Exposure


Rape is an annual plant similar to the turnipand rutabaga. It is thought that Brassicanapus originated from a hybridisationbetween the turnip (B. rapa) and kale (B.oleracea acephala). Rape originated innorthern Europe and was cultivated near theMediterranean Sea, but is now grownthroughout the world. Canola, a selectivelybred variant of Rape, was developed in thelate 1970s in Canada as a more nutritioussource of vegetable oil than Rape seed.

The Rape plant is an annual or biennialgrowing up to 1.2 m, with yellow flowersthat in their season make Rape fields astriking sight. At the same time, the releasedvolatile organic compounds (there are 22altogether (1)) create a distinct smell. Theslick, turnip-like flat leaves are 10 to 30 cmlong. Unlike turnip, Rape has no swollenroot, only a thin taproot. Sickle-shaped podscontaining tiny round seeds are produced.

Environment

This plant has become a very common cropin the UK and elsewhere. Rape is generallygrown in large fields for green livestockfodder, birdseed or Rape seed oil. Canola isa new type of Rape grown commercially forthe seed, which is lower in saturated fats andfatty acids than the original cultivar. Canolaoil is also almost free of erucic acid, a toxiccompound plentiful in older varieties.

Unexpected exposure

Canola oil has become a common ingredientin both homemade and commercial foods.

Allergens

Rape seed contains 2 main storage proteins, ahigh-molecular-mass legumin-like 12 Sglobulin and a low-molecular-mass 2 S protein(also known as napin or nIII) (2-4,6, 9).

The 2 S protein has been characterised asthe following:

Bra n 1, a 2S albumin (napin); the proteinconsists of 2 different chains of 9.5 and4.5 kDa (5-12).

In a study to identify possible majorallergens in Rape seed and Turnip rape usingsera from 72 atopic children with positiveSPT to these proteins, major reactivity was

169

f316 Rape seeddemonstrated to a group of homologous,approximately 9.5 to 14.5 kDa proteins thatwere identified as 2S albumins (napins).Approximately 80% of the patients had IgEantibodies to purified napins from bothplants. In SPT using purified napins, positivereactions were demonstrated in all 6 childrentested (12).

Rape seed is able to generate chitinasewhen wounded, as demonstrated by a studyin which complementary and genomic DNAstrands coding for a Brassica napus chitinasehave been cloned and sequenced (13-14).The allergenic potential of this protein is notknown to date.

Low-molecular-mass trypsin isoinhibitorshave been isolated (but their antigenicity isunknown) (15).

A 2S albumin recombinant protein fromthe seeds of Brassica napus was shown tohave a high thermal stability, and theseresults suggest that rproBnIb, like other 2Salbumins, may be able to reach the gutimmune system intact (11).


An extensive cross-reactivity among thedifferent individual species of the familycould be expected to occur clinically withRape seed (16). A study of children sensitisedto Rape seed reported that the highcorrelation in the skin reactivity betweenRape seed and Turnip rape suggested cross-reactivity, and this is supported by the factthat they both contain homologous 2Salbumins (17).

The 2S albumin storage protein in Rapeseed exhibits extensive sequence similaritywith 2S albumins from other seeds. Cross-reactivity between Mustard and Rape seedflours as a result of this protein has beenreported (6). Similarly, the Mustard allergenSin a 1 was found to be related to other low-molecular-mass albumins, such as thoseisolated from Rape seed, Castor bean andBrazil nut. Structural similarity was alsoreported between the glutamine-rich largechain of Sin a I and a proline-rich zein, agliadin, and trypsin and alpha-amylaseinhibitors isolated from the seeds of severalmonocotyledons (18).

Clinical Experience


Rape seed protein may induce symptoms ofallergy in sensitised individuals,predominantly in occupational settings suchas animal feed factories, grain mills andfarms. Individuals may be sensitised to eitherRape seed as a food or Rape seed pollen asan inhalant. For allergy to the pollen, seeRape w203.

A 48-year-old man who had beenworking in a feed processing plant sufferedepisodes of wheezing with shortness ofbreath after exposure to Rape seed flour.After 5 years of exposure, he noted sneezingand rhinorrhoea whenever the flour wasbeing discharged from the mill and he wasin the vicinity. Symptoms subsided 2 hoursafter the exposure ended. He also developedoedema and pruritis of the lips, oral mucosaand pharynx, and facial urticariaimmediately after ingestion of a smallamount of Mustard sauce. The reactionswere attributed to cross-reactivity with the2S albumin allergen from Rape seed flourand Sin a 1 from Mustard (6).

A 48-year-old man, employed in a grainand animal feed store for 9 years, reportedrhinorrhea, sneezing, nasal obstruction,ocular burning, coughing and wheezing,which had all occurred over the previous 12months and were induced by Rape flour (19).

A 43-year-old male working in the grainindustry experienced cough and chesttightness during working hours. SPT waspositive to Rape extract. A broncho-provocation test was positive. The studyresults confirmed that the inhalation of Rapedust, not pollen, was the cause of his IgE-mediated occupational asthma (20).Similarly, a study demonstrated thatinhalation of Rape flour causedbronchoconstriction, induced aneosinophilic inflammatory bronchialresponse, and increased bronchialhyperresponsiveness in sensitised asthmaticfarmers. Contact with the allergen tookplace through its presence as flour in animalfodder (21).

170

f316 Rape seedIn a Finnish study, skin prick testing for

suspected food allergy in young childrenwith atopic dermatitis frequently foundpositive reactions with Turnip rape and Rapeseed. A subsequent study of 1,887 Finnishchildren, who were screened with SPT forsensitisation to Turnip rape and Rape, foundthat 206 (10.9%) had reactivity for Turniprape and/or Rape seed (9.3% for Turnip rapeand 9.4% for Rape seed). Twenty-five (89%)of 28 children enrolled in the challenge studyshowed a positive challenge reaction toTurnip rape. Seventeen reacted with labialwhealing after labial challenge, and 8 hadfacial urticaria, flare-up of atopic dermatitisor abdominal symptoms after oral challenge.One child developed rhinitis. Four childrenhad immediate symptoms within 3 hours,and 4 experienced delayed reactions.Allergen-specific IgE determination forTurnip was positive in 17 of those positiveto labial challenge. Three challenge-positivechildren showed a flare up of atopicdermatitis when the oral challenge had lastedfor 2-5 days. The high correlation in skinreactivity between Rape seed and Turniprape suggested cross-reactivity, and this issupported by the fact that both substancescontain homologous 2S albumins (17).

In a subsequent study, 64 of thesechildren, with atopic dermatitis and thepresence of skin reactivity IgE to Turnip rapeand/or Oilseed rape, were assessed for anycommon sensitisation pattern to certainfoods or pollens, and were shown to havesignificantly more prevalent skin- andserum-specific sensitisation to various foods(Cow's milk, Egg, Wheat, Mustard) andpollens (Birch, Timothy, Mugwort) than acontrol group (22).

Other reactions

Pure Rape seed oil is reported not to causeallergic reactions (23). However, occupationalallergic contact dermatitis from PEG-4 Rapeseed amide in massage oil has beenreported (24).

In the 1980s, Spanish toxic oil syndromeoccurred as a result of the presence of anilineas a permitted adulterant for importedFrench Rape seed oil; this caused disease in20,000 people and over 2,500 deaths. Thetoxic oil syndrome was a multisystemicdisease brought on by the ingestion of Rapeseed oil denatured with 2% aniline (25-26).

References1. Butcher RD, Macfarlane Smith W,

Robertson GW, Griffiths DW. Theidentification of potential aeroallergen/irritant(s) from oilseed rape (Brassica napusspp. Oleifera): volatile organic compoundsemitted. Clin Exp Allergy 1994;24:1105-14

2. Schwenke KD. Structural studies on nativeand chemically modified storage proteinsfrom rapeseed (Brassica napus L.) andrelated plant proteins.Nahrung 1990;34(3):225-40

3. Inquello V, Raymond J, Azanza JL. Disulfideinterchange reactions in 11S globulinsubunits of Cruciferae seeds. Relationshipsto gene families.Eur J Biochem 1993;217(3):891-5

4. Sjodahl S, Rodin J, Rask L. Characterizationof the 12S globulin complex of Brassicanapus. Evolutionary relationship to other 11-12S storage globulins.Eur J Biochem 1991;196(3):617-21

5. Palomares O, Monsalve RI, Rodriguez R,Villalba M. Recombinant pronapin precursorproduced in Pichia pastoris displaysstructural and immunologic equivalentproperties to its mature product isolated fromrapeseed.Eur J Biochem 2002;269(10):2538-45

6. Monsalve RI, Gonzalez de la Pena MA,Lopez-Otin C, Fiandor A, et al. Detection,isolation and complete amino acid sequenceof an aeroallergenic protein from rapeseedflour. Clin Exp Allergy 1997;27(7):833-41

7. Monsalve RI, Villalba M, Lopez-Otin C,Rodriguez R. Structural analysis of the smallchain of the 2S albumin, napin nIII, fromrapeseed. Chemical and spectroscopicevidence of an intramolecular bondformation. Biochim Biophys Acta1991;1078(2):265-72

171

8. Pantoja-Uceda D, Bruix M, Santoro J, Rico M,Monsalve R, Villalba M. Solution structure ofallergenic 2 S albumins.Biochem Soc Trans 2001;30(6):919-24

9. Monsalve RI, Lopez-Otin C, Villalba M,Rodriguez R. A new distinct group of 2 Salbumins from rapeseed. Amino acidsequence of two low molecular weightnapins. FEBS Lett 1991;295(1-3):207-10

10. Schmidt I, Renard D, Rondeau D, Richomme P,Popineau Y, Axelos MA. Detailedphysicochemical characterization of the 2Sstorage protein from rape (Brassica napus L.).J Agric Food Chem 2004;52(19):5995-6001

11. Pantoja-Uceda D, Palomares O, Bruix M,Villalba M, Rodriguez R, Rico M, Santoro J.Solution structure and stability againstdigestion of rproBnIb, a recombinant 2Salbumin from rapeseed: relationship to itsallergenic properties.Biochemistry 2004;43(51):16036-45

12. Puumalainen TJ, Poikonen S, Kotovuori A,Vaali K, Kalkkinen N, Reunala T, Turjanmaa K,Palosuo T. Napins, 2S albumins, are majorallergens in oilseed rape and turnip rape.J Allergy Clin Immunol 2006;117(2):426-32

13. Hamel F, Bellemare G. Characterization of aclass I chitinase gene and of wound-inducible, root and flower-specific chitinaseexpression in Brassica napus. BiochimBiophys Acta 1995;1263(3):212-20

14. Rasmussen U, Bojsen K, Collinge DB.Cloning and characterization of a pathogen-induced chitinase in Brassica napus.Plant Mol Biol 1992;20(2):277-87

15. Ascenzi P, Ruoppolo M, Amoresano A, Pucci P,Consonni R, Zetta L, Pascarella S, Bortolotti F,Menegatti E. Characterization of low-molecular-mass trypsin isoinhibitors from oil-rape (Brassica napus var. oleifera) seed.Eur J Biochem 1999;261(1):275-84


17. Poikonen S, Puumalainen TJ, Kautiainen H,Burri P, Palosuo T, Reunala T, Turjanmaa K.Turnip rape and oilseed rape are newpotential food allergens in children withatopic dermatitis. Allergy 2006;61(1):124-7

18. Menendez-Arias L, Moneo I, Dominguez J,Rodriguez R. Primary structure of the majorallergen of yellow mustard (Sinapis alba L.)seed, Sin a I.Eur J Biochem 1988;177:159-66

19. Di Giacomo GR, Boschetto P, et al. Asthmaand rhinoconjunctivitis caused by rape flour:description of a clinical case. [Italian] MedLav 1998;89(3):226-31

20. Suh CH, Park HS, Nahm DH, Kim HY.Oilseed rape allergy presented asoccupational asthma in the grain industry.Clin Exp Allergy 1998;28(9):1159-63

21. Alvarez MJ, Estrada JL, Gozalo F, Fernandez-Rojo F, Barber D. Oilseed rape flour: anotherallergen causing occupational asthma amongfarmers. Allergy 2001;56(2):185-8

22. Poikonen S, Puumalainen TJ, Kautiainen H,Palosuo T, Reunala T, Turjanmaa K.Sensitization to turnip rape and oilseed rapein children with atopic dermatitis: a case-control study. Pediatr Allergy Immunol 2008Jan 22; [Epub ahead of print]

23. Gylling H. Rape seed oil does not causeallergic reactions. Allergy 2006;61(7):895

24. Isaksson M. Occupational allergic contactdermatitis from PEG-4 rapeseed amide in amassage oil.Contact Dermatitis 2002;47(3):175-6

25. Diggle GE. The toxic oil syndrome: 20 years on.Int J Clin Pract. 2001;55(6):371-5

26. Martín-Arribas MC, Izquierdo Martínez M,de Andrés Copa P, Ferrari Arroyo MJ,Posada de la Paz M. Characteristics ofdisability and handicap among Toxic OilSyndrome (TOS) cohort patients: a cross-sectional study, 17 years after the originalfood intoxication.Disabil Rehabil 2003;25(20):1158-67

f316 Rape seed

172

Phaseolus vulgarisFamily: Fabaceae (Leguminosae)Commonnames: Red kidney bean,

Kidney bean, BeanSourcematerial: Dried beansSynonyms: P. vulgaris var. humilis,

P. vulgaris var. mexicanusSee also: White bean f15 and

Green bean f315For continuous updates:www.immunocapinvitrosight.com

f287 Red kidney bean

Allergen Exposure


Cultivated in many parts of the world, thisfirm, medium-sized bean has a dark red skinand cream-coloured flesh. Its popularity canbe attributed to its full-bodied flavour. Thereare many named varieties of the plant,ranging from dwarf forms about 30 cm tallto climbing forms up to 3 m tall.

The seeds of older Green bean pods areknown as Red kidney beans, especially whenthey are dark red. White kidney beans, alsoreferred to as Cannellini beans, do not havethe robust flavour of the Red kidney bean.

Environment

Red kidney beans are the main ingredientof chilli con carne, and are also often servedwith rice. The mature seeds can be cannedor dried. They can be boiled, baked, pureed,ground into a powder, or fermented. Theseed can also be sprouted and used in saladsor cooked. The roasted seeds have been usedas a coffee substitute. The green pods maybe used as a vegetable. The young leaves canbe eaten raw or cooked as a potherb.

The green or dried mature pods, or theseeds alone, are reported to have laxative,diuretic, hypoglycaemic and hypotensiveactions. Ground into flour, the seeds are used

externally in the treatment of ulcers. Theseeds or whole plant may be used as ahomeopathic remedy for a variety ofdiseases.

Haemagglutinin, a lectin, occurs naturallyin the Red kidney bean. It is inactivated bythorough cooking of well soaked beans (1).

Unexpected exposure

Red kidney beans are the source of a browndye, of a fluid for treating used woollenfabrics, and of phaseolin, which has afungicidal activity.

Allergens


An alpha-amylase inhibitor has beendetected (2). The allergenicity of this proteinis unknown.


An extensive cross-reactivity among thedifferent individual species of the genuscould be expected but in fact is not seenfrequently (3). In an in vitro study, thespecific IgE binding by protein extracts of11 food legumes was examined by IgEantibody determination and RAST inhibition.Cross-allergenicity was demonstrated to bemost marked among the extracts of Peanut,Garden pea, Chick pea, and Soybean (4-5).

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f287 Red kidney beanHowever, clinical studies have found thatthere is little cross-reactivity among membersof the Fabaceae (Leguminosae) (6-9).

A study investigated the in vitro cross-reactivity of allergens from Mesquite treepollen (Honey locust tree; Prosopis juliflora)and Lima bean (Phaseolus limensis/Phaseolus lunatus). Of 110 patients withasthma, rhinitis or both, found throughintradermal skin determination to beevaluated, 20 were highly positive toMesquite pollen extract. Of these, 12patients showed elevated level of IgEantibodies to Mesquite pollen extract alone,and 4 to both Lima bean and pollen extract.Lima bean extract could inhibit IgE bindingto Mesquite in a dose-dependent manner.Also, humoral and cellular cross-reactivitywas demonstrated (10). Although cross-reactivity was not investigated betweenMesquite and Red kidney bean per se, cross-reactivity may exist between pollen from thistree and other species of Phaseolus.

Clinical Experience


Red kidney bean does not commonly inducesymptoms of food allergy in sensitisedindividuals, but as with other legumes,allergic reactions are possible (11).

A study reports on a 33-year-old womanwho developed tongue swelling and burningand mouth itching minutes after eatingbaked Beans. Similar symptoms occurred aday after ingesting Pea soup, and on anotheroccasion within 15 minutes of eating a Beanburrito, and again 20 minutes after eatingchilli containing Kidney and Pinto beans.SPT was positive to Red kidney and Whitebean but negative to Pea, Green and Limabean. IgE antibodies were detected to Redkidney, White, and Pinto bean, and to Chickpea, Pea and Black-eyed pea (12).

Hand eczema was investigated among 50caterers and found to be a result ofoccupation in 47 and endogenous in 3 cases.Contact dermatitis to Red kidney bean,along with skin reactivity, was found in 1 offormer group (13).

Other reactions

Red kidney beans contain haemag-glutinating lectins, which are toxic (14).Between 1976 and 1989, 50 incidents ofsuspected Red kidney bean poisoning werereported in the UK. Of these patients, 9reported the onset of nausea, vomiting anddiarrhoea within 1-7 hours of ingestion. Thediagnosis was confirmed by the detection ofhaemagglutinin in the Beans. The diagnosiswas made in a further 23 incidents on thebasis of symptoms, incubation time and thepreparation of beans prior to consumption.In many of the outbreaks reported, theimplicated Beans were consumed raw orfollowing an inadequate heating process (1).

The root is dangerously narcotic. Largequantities of the raw mature seed arepoisonous. This Bean is a notorious sourceof flatulence.

Occupational contact dermatitis causedby leaves of the Phaseolus plant wasreported in a 41-year-old male farmer. Skinlesions appeared soon after he started workon the farm. His main activity wascultivation of Sugar beet, Kidney beans,cereals, Potatoes and Rape. Initially, therewere inflamed, scaly patches disseminatedover the body. Several years later, a chronichand eczema appeared. The skin lesions onthe body showed a seasonal pattern, withaggravations starting in spring, reachingmaximum intensity in summer, andgradually fading in the autumn after the endof field work on the farm. Field work andthreshing pods of the Red kidney bean plantin order to recover Kidney beans wereactivities particularly associated with hisskin problems. Approximately 2 to 3 hoursafter the start of these activities, pruritusappeared, and several hours later erythemaof exposed skin appeared, followed byeczema and vesicles. While threshingPhaseolus pods, the patient also experienceddyspnoea. SPT with the leaf was negative,but positive with patch tests (15).

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References1. Rodhouse JC, Haugh CA, Roberts D, Gilbert RJ.

Red kidney bean poisoning in the UK: ananalysis of 50 suspected incidents between1976 and 1989.Epidemiol Infect 1990;105(3):485-91

2. Wilcox ER, Whitaker JR. Some aspects of themechanism of complexation of red kidneybean alpha-amylase inhibitor and alpha-amylase. Biochemistry 1984;23(8):1783-91



5. Bardare M, Magnolfi C, Zani G. Soysensitivity: personal observation on 71children with food intolerance.Allerg Immunol (Paris) 1988;20(2):63-6


7. Bernhisel-Broadbent J, Taylor S, Sampson HA.Cross-allergenicity in the legume botanicalfamily in children with food hypersensitivity.II. Laboratory correlates.J Allergy Clin Immunol 1989;84(5 Pt1):701-9

f287 Red kidney bean


9. Yunginger JW. Classical food allergens.Allergy Proc 1990;II:7-9


11. Gall, H, Forck, G, Karveram, K J, LersnerLenders von, S. Soforttypallergie aufHulsenfruchte (Leguminosen)( Immediatetype allergy to legume food).Allergologie 1990;13:352-5


13. Cronin E. Dermatitis of the hands in caterers.Contact Dermatitis 1987;17(5):265-9

14. Venter FS, Thiel PG. Red kidney beans – toeat or not to eat?S Afr Med J 1995;85(4):250-2

15. Spiewak R, Dutkiewicz J. Occupationalcontact dermatitis to Phaseolus vulgaris in afarmer - a case report.Ann Agric Environ Med 2000;7(1):55-9

175

Oryza sativaFamily: Poaceae (Gramineae)Commonnames: Rice, Jasmine rice,

Wild rice, Basmati rice,popped Rice, Ricesemolina

Sourcematerial: Unpolished riceAll Rice grown in the United States andmost of that cultivated in other countriesis of the species Oryza sativa L. Some20 to 25 species of Oryza are known.The species O. glaberrinia Steud. iscultivated in AfricaFor continuous updates:www.immunocapinvitrosight.com

f9 Rice

Allergen Exposure


Rice is an erect annual grass, up to 1.2 mtall, producing tiny oblong grains (28,000to 44,000 per kg, depending on the variety).The hard, starchy kernel is the part eaten;this is surrounded by a series of bran coats(rich in vitamins and minerals) and a roughouter, inedible hull. Native to the tropics andsubtropics of Southeast Asia (where it wascultivated since at least 5000 B.C.), Rice isnow grown in many localities throughoutthe world with favourable climaticconditions. More than 90% of the worldRice production is in Asia, China and Indiabeing the largest producers.

Rice is a staple for almost half the world'spopulation. The 8,000-plus varieties of Riceare grown in 2 ways. Aquatic Rice (paddy-grown) is cultivated in flooded fields. Thelower-yielding, lower-quality hill-grownRice can be grown on almost any tropicalor subtropical terrain. Rice is also classifiedby size and shape, as long-, medium- orshort-grain, and by colour, as white (withthe husk, bran and germ removed) or brown(with only the inedible husk removed). Manymethods of milling, polishing, parboiling,etc., are employed in different cultures,resulting in many different forms andnutrient values of the final product. Among

these forms are regular milled white Rice,instant/pre-cooked Rice, jasmine, wild,basmati, and popped Rice, and Ricesemolina, aka Rice flour.

Environment

Rice is used in a great variety of dishes, oftenas a base for meat or vegetables. Specialisedethnic dishes include Italian risotto andJapanese sushi.

Rice that is rich in starch is usedextensively as breakfast food - as puffedRice, flakes, or Rice crispies. Starchy typesof Rice are also used in pastries, soups, andstarch pastes; glutinous types, containing asugary material instead of starch, are usedin the Orient in candies and for other specialpurposes. Rice is important in themanufacture of alcoholic beverages. Riceflour is used in various mixes.

Rice is a good source of carbohydrate;brown Rice provides the same energy aswhite, but contains more vitamins andminerals. Rice bran, the grain's outer layer,is high in soluble fibre and is effective inlowering cholesterol. Enriched or convertedRice contains calcium, iron and many B-complex vitamins, with brown Rice beingslightly richer in all the nutrients.

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f9 RiceAll parts of the plant, and even the water

from soaking or cooking Rice, and the lyefrom charred stems, figure in folk medicine,in a great variety of uses. B vitamin-richunpolished Rice is a preventative andtreatment of beriberi.

Unexpected exposure

See under Environment. Rice hulls (bran) areused for animal fodder, fuel, insulation, andin certain manufacturing processes such asthe production of purified alpha celluloseand furfural. Rice straw is used as roofingand packing material, animal feed, fertiliser,fabric, and fuel.

Allergens

In Rice allergy, proteins with molecularmasses of 14-16, 26, 33, and 56 kDa havebeen demonstrated to be potentiallyallergenic. The 33 kDa allergen wasidentified as a novel type of plant glyoxalaseI that is expressed in various plant tissues,including maturing seeds. (1) The majorityof the allergic components are albumins withmolecular weights between 14 and 16 kDa(2). The 16 kDa Rice protein has beenreported to be a major allergen andresponsible for cross-allergenicity betweencereal grains in the Poaceae family (3). A19 kDa globulin protein has also beenisolated (4).

Other allergens partially characterisedhave been designated RAP, RAG 1, RAG 2,RAG 5, RAG 14, and RAG 17. RAG 17 is a16 kDa protein, a member of the alpha-amylase/trypsin inhibitor protein family (5-6). Although raw Rice is more allergenic thancooked, some of the allergens are probablyheat-stable and resist proteolysis (7).

In a more recent study that evaluated Riceallergy in Indian patients, in sera ofindividuals allergic to Rice, 14-16, 33, 56and 60 kDa proteins were shown to be majorIgE-binding components in Rice. Boiled Riceretained 4 IgE-reactive proteins of 16, 23,33 and 53 kDa (8).


Ory s LTP, a 14 kDa lipid transfer protein.(9-13).

Ory s aA/TI, a 16 kDa alpha-amylase/trypsininhibitor. (5-6,14-20).

Ory s Glyoxalase I, a glyoxalase (1,3,12,21).

Ory s 12, a profilin (22-23).

Ory s 1, Ory s 2, Ory s 3, Ory s 7, Ory s 11,Ory s 12 and Ory s 13 have been characterisedin Rice pollen and contribute to asthma,allergic rhinitis and allergic conjunctivitis as aresult from exposure to Rice pollen. Ory s 12,a profilin, has been detected in both Rice seedand Rice pollen (22,24).

Rice also contains a lipid transfer protein(9 10). LPTs are heat-stable proteins andmay play a role in allergy to cooked Rice. Areport was made of 3 individuals whodeveloped rhinoconjunctivitis and asthma asa result of exposure to the lipid transferprotein of raw Rice thrown at weddings, butwho could tolerate cooked Rice. This mayindicate some modification of Rice lipidtransfer protein during cooking (12).

At least 5 alpha-amylase/trypsininhibitors have been isolated from Rice,including Ory s aA/TI. Patients may reactwith all 5 proteins, whereas othersspecifically react with individual proteinsonly (16). This family of allergens is highlyresistant to digestive enzymes (20) and isheat-stable (6). There is a suggestion thatsome epitopes of recombinant versions ofthese proteins are still immunoreactive whenthey are expressed as their fragments (18).

Although Rice seed contains thepanallergen profilin, the levels of this aremuch lower than those in foods commonlyknown to contain profilin, e.g., Celery (22).

A chitinase has been isolated from Rice.The substance accumulates to a high levelin the roots of the plant, but only low levelsare found in stem and leaf tissue (25).Whether the chitinase is found in the seed,and whether this chitinase has allergenicpotential, are questions that have not yetbeen evaluated.

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f9 RicePotential cross-reactivity

An extensive cross-reactivity among pollenof the different individual species and tribesof the Poaceae family could be expected andin fact does occur frequently. (26) Althoughsimilar patterns of cross-reactivity may occuramong the seeds/grains of the family, thishas not been as well determined as in thecase of pollen. In vitro cross-reactivity hasbeen demonstrated among IgE bindingproteins of Corn, Rice, Soybean and Peanut.A high degree of cross-reactivity betweenRice and Corn was thought to be due to thefact that they both belong to the samebotanical family. The authors state that theclinical significance of these cross-reactivitiesis not yet known and that clinical studieswill be required to put these findings intoperspective (27).

Cross-allergenicity among the cereal grainsRice, Wheat, Corn, Japanese Millet and ItalianMillet was examined by RAST inhibitionassay, and significant close correlations inevery combination of IgE antibody values forthe 5 grain extracts were found (3).

Allergens of 14 and 18 kDa have beenisolated from Buckwheat and shown to bemajor proteins. These were found to sharesome homology with Rice proteinsassociated with Rice allergy, and cross-allergenicity with Buckwheat proteins waspostulated (28). However, some Buckwheat-allergic subjects do not develop immediateadverse reactions after ingesting Buckwheat,despite high levels of Buckwheat-specific IgEantibodies. Further investigation has led tothe conclusion that there is IgE antibodycross-reactivity between Buckwheat andRice, and that IgE antibodies fromimmediate hypersensitivity reaction-negativesubjects might recognise the epitopes onBuckwheat antigens that cross-react withRice antigens, whereas IgE antibodies fromimmediate hypersensitivity reaction-positivesubjects might bind to Buckwheat-specificepitopes (29-30). Thus, in spite of cross-allergenicity between Buckwheat and Rice,Rice ingestion only uncommonly inducesimmediate hypersensitivity reactions, evenin subjects with high IgE for Rice; this is notthe case for Buckwheat-induced immediatehypersensitivity reactions (31).

Approximately 86% of Maize-allergicpatients were shown to have allergen-specificIgE to a 9 kDa protein, shown to be a lipidtransfer protein. Immunoblotting inhibitionshowed that this LTP cross-reacts completelywith Rice and Peach LTPs but not withWheat or Barley LTPs. A 16 kDa allergenwas also isolated (recognised by 36% ofpatients) and shown to be the Maizeinhibitor of trypsin. This protein cross-reactscompletely with grass, Wheat, Barley, andRice trypsin inhibitors (2,32). Other studieshave confirmed the high degree of cross-reactivity between Rice and LTPs from otherfoods (10). Cross-reactivity has beendemonstrated between Rice lipid transferprotein and those from Peach and Apple(11). The 3-dimensional structure of Ricelipid transfer protein closely resembles thepublished structures of Wheat, Barley andMaize LTPs (13).

Clinical Experience


Rice may uncommonly induce symptoms offood allergy, asthma, rhinitis, eczema andurticaria in sensitised individuals; however,in communities where Rice is a staple food,e.g., in the Far East, reactions may be morefrequently encountered (33-40). With theincrease of Rice consumption in the West,the prevalence of allergy to Rice mayincrease. Symptoms reported in Rice-allergicindividuals include abdominal cramping andsimilar pain, nausea, vomiting, rhinitis,rhinoconjunctivitis, dyspnoea, asthma,contact urticaria, atopic dermatitis,dermatitis, angioedema and anaphylaxis.Individuals may be sensitised without beingsymptomatic (41-43). A high percentage ofthis sensitisation may be of this kind (9).

In 148 Malaysian adults with symptomsof nasal congestion and rhinorrhoea and 113control subjects without rhinitis symptoms,SPT evaluation of 11 foods common in theMalaysian diet showed that 48% of thepatients with rhinitis had skin reactivity tofood, compared with 4.4% of controlsubjects. The most commonly implicatedfoods were Shrimp (48%) and Rice (30%),both of which are common in the Malaysiandiet (34).

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f9 RiceIn a study that evaluated Rice allergy in

Indian patients, of 1,200 patients screened,165 presented with a history of Rice allergy,and of these, 20 (12.1%) demonstratedmarked skin reactivity and 13 showedsignificantly raised IgE antibodies to Rice.DBPCFC confirmed Rice allergy in 6/10patients. The authors concluded that IgE-mediated Rice allergy affects approximately0.8% of Indians with asthma and rhinitis (8).

Rhinoconjunctivitis, asthma and contacturticaria from handling Rice and othercereals were reported in a housewife. Shetolerated cooked cereals. SPT with a Riceextract and cutaneous challenge with rawRice were positive. Raw Rice producedimmediate and late clinical effects, andobjective lung function tests confirmed thesymptoms of asthma (44). Other studieshave also reported Rice-induced asthma inadults (45-46). The allergen-specific IgE levelmay be raised in these individuals (46). Inaddition, a high frequency of foodhypersensitivity may occur in individualswith allergic rhinoconjunctivitis (47).

A 9-year-old girl seen during a follow-upvisit for asthma (perennial symptoms)reported that she “disliked” foods with Riceand had avoided eating them for the last 3years. Attempts to feed her with Rice hadresulted in immediate nausea, abdominalpain and diarrhoea. On one occasion, shehad suffered urticaria-angioedema in thekitchen while her mother was sorting Rice.She had previously been found allergic tograss pollens through intradermal but notepidermal tests. Skin prick tests and prick-prick tests with various cereals, includingRice, Wheat, Barley, Oat and Lentil,demonstrated a marked wheal and flarereaction only to Rice with both tests. TotalIgE was 165 kU/l, and Rice-specific IgE was13.2 kUA/l. A double-blind, placebo-controlled food challenge resulted in nausea,abdominal pain and diarrhoea within 10minutes of ingestion. She had no problemswhen eating other cereals. She thereforedemonstrated allergy to the ingestion ofcooked Rice and to inhalation of raw Riceproteins (48).

Rice thrown at weddings may result inrhinoconjunctivitis and asthma. Threepatients are described who experiencedasthma or rhinoconjunctivitis to raw Riceby inhalation of Rice dust at these events.All were able to tolerate Rice by ingestion,but were allergic to Peach. IgE antibodiesto Rice and Peach were detected in all 3patients. Recombinant Pru p 3, as well asRice seed lipid transfer protein, bound IgEfrom sera of 2 patients whose sera wereavailable for testing. SPT was positive fornatural Pru p 3. The authors suggest that,as lipid transfer proteins are purported tobe heat-stable, the fact that these patientscould tolerate cooked Rice may indicatesome modification of Rice lipid transferprotein during cooking (12).

Anaphalaxis and anaphalactoid reactionshave also been reported in adults andchildren (49-50). Food-dependant exercise-induced anaphylaxis (FDEIA) may occur(51), as well as FDEIA related to multiplefood intake (52). The observed recurrenceof FDEIA following intervention may be aresult of concomitant ingestion of otherfoods such as Rice and Peanut (53).Anaphylaxis has also been reported to theinhalation of Rice dust (54).

Allergy to Rice dust was also reported in2 children. A 7-year-old girl with asthma wasable to eat cooked Rice, but she was foundto have IgE antibodies to Rice of 38.3 kUA/l.It was thought that her asthma wasexacerbated by Rice powder inhalation, asthe family milled Rice. Her symptomsimproved greatly when she was away fromthe business. The second patient, a 3-yearold boy with atopic dermatitis whose familybrewed sake (made from Rice), was shownto have allergen-specific IgE of 2.21 kUA/lto Rice. The dermatitis improved when Ricewas removed from his diet, but a flareoccurred once when he came near Rice-threshing or milling machinery (55).

Three individuals who experienced severeallergic reactions to Rice, includinganaphylaxis, were reported. The severity ofthe allergic response was related to thepresence of the lipid transfer protein allergenin Rice. A 50-year-old woman with a historyof grass pollen hypersensitivity and oral

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f9 Riceitching following the ingestion of many kindsof fruits and tree nuts experiencedgeneralised urticaria and angioedemaassociated with dyspnoea about 30 minutesafter eating a “risotto” dish (boiled Rice withmushrooms), and about 2 months later sheexperienced oral allergy syndrome followedby generalised urticaria and collapsefollowing the ingestion of a risotto withsaffron. A 25-year-old woman with grasspollen allergy and oral allergy to a numberof fruits and nuts had experiencedgeneralised urticaria and angioedemaassociated with dyspnoea about 1 hour aftereating a risotto dish (boiled Rice withsaffron). A 30-year-old man with a historyof grass pollen allergy, and oral itchingfollowing the ingestion of fruits and nuts,experienced several urticaria reactionsfollowing the ingestion of risotto dishes (Ricewith Chicory) and Onion. In vitro inhibitionstudies using lipid transfer protein purifiedfrom both Rice and Apple, as well as wholePeach extract, demonstrated that the lipidtransfer protein was the relevant allergen inthese patients, and demonstrated cross-reactivity between Rice lipid transfer proteinand those from Peach and Apple (11).

Children may also develop allergy toRice, although anaphylaxis appears to beuncommon. Three admissions of a 6-month-old girl due to the sudden onset ofrespiratory and gastrointestinal symptoms,paleness and a reduced level of consciousnessfollowing ingestion of Rice flour have beenreported. A provocation test resulted in ananaphylactic reaction (56). A similar reportof anaphylaxis to Rice flour in a 6-month-old girl has been documented (57).

The effect of Rice allergy on the skin hasbeen documented by many studies. In 200of 226 patients (90.5%) with atopicdermatitis visiting a Japanese hospital, oralfood challenge tests showed that food allergywas involved, and Rice allergy affected 2.5%(58). In a study of 1006 Japanese patientswith typical and atypical lesions of atopicdermatitis, who were analysed statisticallyby correlating the clinical severity to serumIgE antibody values, the suggestion wassupported that Rice allergy stronglycontributed to the development of theseverity of this condition. Of 25 patients

with severe atopic dermatitis and a IgEantibodies to Rice who were treated by aRice exclusion diet, 9 were remarkablyimproved, 10 were moderately improved,and no effect was seen in 6 (37). The resultsof a study suggested that ocular-type atopicdermatitis belongs to the most severe end ofthe spectrum of atopic dermatitis, and thatRice and Wheat may contribute to thepathogenesis of severe atopic dermatitis,resulting in ocular complications (47,59).

Based on a statistical analysis of thecorrelation between Rice-specific IgE scoreand clinical severity in atopic dermatitispatients, the probable involvement of Riceallergy in many severe cases was postulated(60-61).

Contact urticaria from Rice has also beenreported (62). Similar allergic effects wererecorded in a 17-year-old female presentingwith acute erythema of the hands, oedemaof the eyelids, dyspnoea and cough followingcontact with raw Rice, which occurred fromthrowing raw Rice during a wedding. Shewas able to tolerate cooked Rice byingestion. The authors suggested that theadverse respiratory and skin reactionsresulted from Rice dust (63). Further insightinto this condition comes from a report ona 30-year-old man with atopic dermatitiswho experienced erythema, itching andurticarial erythema of the hands severalminutes after washing Rice in water, thoughhe had always eaten cooked Rice withoutproblems. SPT with water used to washregular Rice was markedly positive, but onlymildly positive with water used to washallergen-reduced Rice. Total serum IgE was4,200 kU/l, and serum Rice-specific IgE wasreported as class 2. Immunoblotting analysisof 3 atopic dermatitis patients with high IgEantibody levels to Rice detected severalpolypeptides, but none for this patient. Theauthors concluded that these findingssuggest that the allergen responsible forcontact urticaria in this patient might bewater-soluble, heat-unstable, and notcontained in allergen-reduced Rice (61).

Occupational contact dermatitis and/orasthma may occur in Rice workers andoccasionally in bakers (64,66).

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f9 RiceOther reactions

Food protein-induced enterocolitissyndrome, a symptom complex of severevomiting and diarrhoea occurring in infantsseveral hours after the ingestion of particularfood proteins, has been reported to becaused by Rice in some instances (67).Although food-sensitive enteropathy is moreoften caused by milk, Rice and ground Ricemay also temporarily damage the smallintestinal mucosa in infancy (68-69).Reactions may be severe. Shock, nausea,vomiting, and diarrhoea have been reportedin 4 infants. Occult blood in stools of theseinfants was positive. All immunologic testswere negative. Nevertheless, the authorsconclude that, based on the clinical findingsin these patients, the adverse effects wereprobably allergic in nature (70).

Red yield rice (Cholestin) is produced fromthe fermentation of Rice with the mouldMonascus purpureus went, a traditionaloriental food commonly known as Hongquin China and as Red yeast rice in the UnitedStates and said to have health-enhancingqualities. A 26-year-old butcher wasinvestigated following a severe anaphylacticepisode, with sneezing, rhinitis, conjunctivitis,and generalised pruritus followed bywidespread urticaria, angioedema anddyspnoea, after preparing sausagescontaining Red yield rice (71). Althoughuncommon, anaphylaxis to Red yield rice hasbeen reported in other studies (72).

A distinct clinical syndrome seems to beassociated with exposure to Rice husk dust.The manifestations of this “Rice millers'syndrome” include acute and chronic irritanteffects on the eyes, skin, and upperrespiratory tract; and allergic-like responsessuch as rhinitis, dyspnoea, bronchospasm,and eosinophilia. Radiological opacities inthe chest, probably representing earlysilicosis or extrinsic allergic alveolitis, havebeen reported (73). Similarly, findingssuggesting increased asthma prevalenceamong California Rice farmers and workershave been reported. Radiologic findingswere consistent with dust or fibre exposure,although no association with specificfarming activities was identified (74).

Individuals working with Rice may in factbe allergic to Rice pollen and not Rice perse (75). Among 260 Costa Rican patientswith asthma and 100 non-atopic subjectsstudied with skin prick tests for all Poaceaetribes, 51.2% were positive to at least 1 tribe.The pollen of the Oryzeae tribe (Rice)showed the highest positivity among asthmapatients of the province producing most ofthe country's grains (76-77).

Contact dermatitis from Rice leaf hasbeen reported (78).

Talc-coated Rice (clearly labelled as such)is available only in a few markets, usuallythose specialising in South American foods.It must be thoroughly rinsed before cooking,as the talc can be contaminated withasbestos.

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18. Alvarez AM, Fukuhara E, Nakase M, Adachi T,Aoki N, Nakamura R, Matsuda T. Four riceseed cDNA clones belonging to the alpha-amylase/trypsin inhibitor gene family encodepotential rice allergens. Biosci BiotechnolBiochem 1995;59(7):1304-8


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27. Lehrer SB, Reese G, Malo JL, Lahoud C,Leong-Kee S, Goldberg B, Carle T, Ebisawa M.Corn allergens: IgE antibody reactivity andcross-reactivity with rice, soy, and peanut. IntArch Allergy Immunol 1999;118(2-4):298-9

28. Yoshimasu MA, Zhang JW, Hayakawa S, Mine Y.Electrophoretic and immunochemicalcharacterization of allergenic proteins inbuckwheat. Int Arch Allergy Immunol2000;123(2):130-6

29. Yamada K, Urisu A, Kondou Y, Wada E,Komada H, Inagaki Y, Yamada M, Torii S.Cross-allergenicity between rice andbuckwheat antigens and immediatehypersensitive reactions induced bybuckwheat ingestion. [Japanese] Arerugi1993;42(10):1600-9

30. Yamada K, Urisu A, Morita Y, Kondo Y, Wada E,Komada H, Yamada M, Inagaki Y, Torii S.Immediate hypersensitive reactions tobuckwheat ingestion and cross allergenicitybetween buckwheat and rice antigens insubjects with high levels of IgE antibodies tobuckwheat. Ann Allergy Asthma Immunol1995;75(1):56-61

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31. Wada E, Urisu A, Kondo Y, Horiba F, Tsuruta M,Yasaki T, Masuda S, Yamada K, Kozawa T,Hida Y, et al. Relationship betweenimmediate hypersensitive reactions bybuckwheat ingestion and specific IgE for ricein subject with positive IgE-RAST forbuckwheat. [Japanese] Arerugi1991;40(12):1493-9

32. Pastorello EA, Farioli L, Pravettoni V, Ispano M,Scibola E, Trambaioli C, Giuffrida MG,Ansaloni R, Godovac-Zimmermann J, Conti A,Fortunato D, Ortolani C. The maize majorallergen, which is responsible for food-induced allergic reactions, is a lipid transferprotein. J Allergy Clin Immunol2000;106(4):744-51

33. Wuthrich B, Scheitlin T, Ballmer-Weber B.Isolated allergy to rice.Allergy 2002;57(3):263-4

34. Gendeh BS, Murad S, Razi AM, Abdullah N,Mohamed AS, Kadir KA. Skin prick testreactivity to foods in adult Malaysians withrhinitis. Otolaryngol Head Neck Surg2000;122(5):758-62

35. Andre F, Andre C, Colin L, Cacaraci F,Cavagna S. Role of new allergens and ofallergens consumption in the increasedincidence of food sensitizations in France.Toxicology 1994;93(1):77-83

36. Granel C, Olive A, Randazzo L, Tapias G,Martinez A, Valencia M. Hypersensitivityreaction to rice. A case report. AllergolImmunopathol (Madr) 1992;20(4):171-2

37. Ikezawa Z, Miyakawa K, Komatsu H, Suga C,Miyakawa J, Sugiyama A, Sasaki T, Nakajima H,Hirai Y, Suzuki Y. A probable involvement ofrice allergy in severe type of atopic dermatitisin Japan. Acta Derm Venereol Suppl (Stockh)1992;176:103-7

38. Komatsu H, Suga C, Miyakawa K, Miyakawa J,Sugiyama A, Ikezawa Z, Nakajima H. 25atopic dermatitis patients with positive RASTfor rice were treated with a rice eliminationdiet (the mean duration of elimination: 5.2months). The clinical effects and the changein RAST for rice and wheat, serum IgE valuesand the number of eosinophils wereexamined. [Japanese] Arerugi1990;39(4):402-9

39. Miyakawa K, Hirai Y, Miyakawa J, Sugiyama T,Komatsu T, Suga S, Ikezawa Y, Nakajima H.Statistical analyses of the diagnostic criteria,clinical severity, IgE-RAST score, and serumIgE value in patients with atopic dermatitis(AD) – probable involvement of foodantigens, especially rice, in severe cases.[Japanese] Arerugi 1988;37(11):1101-10

40. van den Hoogenband HM, van Ketel WG.Allergy to rice.Contact Dermatitis 1983;9(6):527-8

41. Noma T, Yoshizawa I, Ogawa N, Ito M, Aoki K,Kawano Y. Fatal buckwheat dependentexercised-induced anaphylaxis. Asian Pac JAllergy Immunol 2001;19(4):283-6



44. Lezaun A, Igea JM, Quirce S, Cuevas M,Parra F, Alonso MD, Martin JA, Cano MS.Asthma and contact urticaria caused by ricein a housewife. Allergy 1994;49(2):92-5

45. Owan I, Shimoji K, Miyazato A, Yara S,Kakazu T, Kaneshima H, Saito A. An adultcase of rice-induced asthma with aspirinidiosyncrasy. [Japanese] Arerugi1995;44(7):708-10

46. Arai T, Takaya T, Ito Y, Hayakawa K, Toshima S,Shibuya C, Nomura M, Yoshimi N,Shibayama M, Yasuda Y. Bronchial asthmainduced by rice.Intern Med 1998;37(1):98-101

47. Ortega Cisneros M, Vidales Diaz MA, del RioNavarro BE, Sienra Monge JJ. Cutaneousreactivity to foods among patients withallergic rhinoconjunctivitis. [Spanish] RevAlerg Mex 1997;44(6):153-7

48. Orhan F, Sekerel BE. A case of isolated riceallergy. Allergy 2003;58(5):456-7

49. Borchers SD, Li BU, Friedman RA, McClung HJ.Rice-induced anaphylactoid reaction. JPediatr Gastroenterol Nutr 1992;15(3):321-4

50. Golbert, T, Patterson, R, Pruzansky, JJ.Systemic allergic reactions to ingestedantigens. J Allergy 1969;44:96-107

51. Hanakawa Y, Tohyama M, Shirakata Y,Murakami S, Hashimoto K. Food-dependentexercise-induced anaphylaxis: a case relatedto the amount of food allergen ingested.Br J Dermatol 1998;138(5):898-900


53. Guinnepain MT, Eloit C, Raffard M, Brunet-Moret MJ, Rassemont R, Laurent J. Exercise-induced anaphylaxis: useful screening of foodsensitization. Ann Allergy Asthma Immunol1996;77(6):491-6

54. Fiocchi A, Bouygue GR, Restani P, Gaiaschi A,Terracciano L, Martelli A. Anaphylaxis to riceby inhalation.J Allergy Clin Immunol 2003;111(1):193-5

55. Nambu M, Shintaku N, Ohta S. Rice allergy.Pediatrics 2006;117(6):2331-2

56. Klein SK, Kremers EM, Vreede WB. Six-month old girl with an anaphylactic reactionto rice flour, a rare food allergy. [Dutch] NedTijdschr Geneeskd 2001;145(30):1471-3

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57. Rondeel JM. Six-month old girl with ananaphylactic reaction to rice flour, a rare foodallergy. [Dutch] Ned Tijdschr Geneeskd2001;145(39):1912

58. Ogura Y, Ogura H, Zusi N. The incidence offood allergy in atopic dermatitis. [Japanese]Arerugi 2001;50(7):621-8

59. Uchio E, Miyakawa K, Ikezawa Z, Ohno S.Systemic and local immunological features ofatopic dermatitis patients with ocularcomplications.Br J Ophthalmol 1998;82(1):82-7

60. Ikezawa Z, Ikebe T, Ogura H, Odajima H,Furosaka F, Komatau H. Mass trial ofhypoallergenic rice (HRS-1) produced byenzymatic digestion in atopic dermatitis withsuspected rice allergy. Acta Dermato-venereologica 1992;(Suppl 176):108-112

61. Yamakawa Y, Ohsuna H, Aihara M, Tsubaki K,Ikezawa Z. Contact urticaria from rice.Contact Dermatitis 2001;44(2):91-3

62. Sasai S, Takahashi K, Takahashi K, Tagami H.Contact urticaria to rice.Br J Dermatol 1995;132(5):836-7

63. di Lernia V, Albertini G, Bisighini G.Immunologic contact urticaria syndrome fromraw rice. Contact Dermatitis 1992;27(3):196

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65. Racz I, Lengyel B. The professionaldermatitis of the rice field workers. [German]Berufsdermatosen 1967;15(6):335-45

66. Yang KL, Tchou TK, T'ang CC, Ho TK, Luo HC.A study on dermatitis in rice farmers. ChinMed J 1965;84(3):143-59

67. Sicherer SH, Eigenmann PA, Sampson HA.Clinical features of food protein-inducedenterocolitis syndrome.J Pediatr 1998;133(2):214-9

68. Walker-Smith J. Food sensitive enteropathy:overview and update.Acta Paediatr Jpn 1994;36(5):545-9

69. Vitoria JC, Camarero C, Sojo A, Ruiz A,Rodriguez-Soriano J. Enteropathy related tofish, rice, and chicken.Arch Dis Child 1982;57(1):44-8

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74. McCurdy SA, Ferguson TJ, et al. Respiratoryhealth of California rice farmers. Am J RespirCrit Care Med 1996;153(5):1553-9

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76. Riggioni O, Montiel M, Fonseca J, Jaramillo O,Carvajal E, Rosencwaig P, Colmenares A.Type I hypersensitivity to gramineae pollen(by tribe), in bronchial asthma patients.[Spanish] Rev Biol Trop 1994;42 Suppl1:65-70, 19

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78. Nakamura T. Contact dermatitis to oryza.Contact Dermatitis 1983;9(1):80

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Secale cerealeFamily: Poaceae (Gramineae)Commonnames: Rye, RoggeSourcematerial: Untreated planting seedsSee also: Cultivated rye g12There is a need to differentiatebetween Rye the foodstuff (Secalecereale), Cultivated Rye grass pollen(Secale cereale) g12, Rye grass pollen(Lolium perenne) g5, and Wild Ryegrass pollen (Elymus tricoides) g70.This distantly related genus, Elymus,contains species known as Wild Ryes,which are used as cover and for forage.A Wheat hybrid is known as Giant RyeFor continuous updates:www.immunocapinvitrosight.com

f5 Rye

Allergen Exposure


Rye, a hardy, tufted annual grass 1-1.5 mtall, was probably native to south-westernAsia but is now widely cultivated in thetemperate regions of the world (often whereconditions are unfavourable for Wheat),where it is used mostly as a bread grain andas a livestock feed. It is grown especiallyextensively in northern Europe and Asia. Itapparently co-evolved with Wheat andBarley for over 2,000 years until its valuefor food was recognised. But it has manyother uses. Rye is taller but similar in habitto Wheat, reaching 0.5 to 1.2 m, with anodding, longer, more slender, somewhatterminal spike.

Less than 50% of the Rye grown in theU.S. is harvested for grain, with theremainder used as pasture, hay, silage or asa cover crop. About half of the amountharvested for grain is used for livestock feedor exported, and the remainder is used foralcoholic beverages, food, and seed.

Environment

Rye is used in bread making, alcoholicfermentation, and as feed for livestock. Thestraw may be useful for thatching.

The grain is used to make flour, theimportance of which is second only to Wheatflour. Although Rye flour does not developtrue gluten, it has proteins that give it thecapacity for making leavened bread; whichis, however, denser and usually darker thanWheat bread. Rye is usually mixed with 25to 50% Wheat flour for bread making. Ryebread is especially popular in northernEurope. Rye can also be used to make cakes,etc. The seed can be sprouted and added tosalads. The roasted grains are a substitutefor coffee.

Malt, a sweet substance produced bygerminating the seed, is extracted from theroasted germinated seed and used as asweetening agent and in making beer, etc.Canadian and United States whiskies aremade mainly from Rye.

The grains are used in folk remedies fortumours and other cancers. They arereported to be laxative.

Unexpected exposure

See under Environment. The straw is usedas a fuel; for thatching, paper-making,weaving hats, mats, etc.; as a packingmaterial for nursery stock, bricks and tiles;

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f5 Ryefor bedding, paper manufacture, archerytargets, and mushroom compost. Rye flouris frequently used in the wood industry toincrease the viscosity of the glue employedto manufacture boards (1).

Allergens

The following allergens have been isolated:

Sec c 12, a profilin (2).

Sec c 20, a secalin (3-7).

Sec c a A TI, a 13.5 kDa alpha-amylases/trypsin inhibitor (8-10).

Sec c 1, Sec c 2, Sec c 4, Sec c 5, Sec c 12and Sec c 13 have been characterised inCultivated rye grass pollen and contributeto asthma, allergic rhinitis and allergicconjunctivitis from exposure to this pollen.Sec c 12, a profilin, has been detected in bothRye seed and Cultivated rye pollen (1). SeeCultivated rye grass g12.

Rye seed contains the panallergenprofilin, but at much lower levels than foundin Rye pollen and in other foods such asCelery or Tomato (1), and may be of lowclinical significance, as heat processing willdestroy the protein. Nonetheless, profilin inRye seed may play a role in occupationalasthma, caused by bakers inhaling Rye flouror dust.

Various other allergenic proteins havebeen detected but not characterised.

Using IgE-immunoblotting analysis andserum samples from 40 adult patients withallergy to cereals (35 patients with atopicdermatitis, 1 with rhinitis and 4 withurticaria), polyspecific binding patterns weredemonstrated with each cereal; Ryeexhibited 35 bands. The most commonprotein binding to patients' sera (16/35,46%) was a 40 kDa protein. There were 16similar proteins detected in Wheat, Rye andBarley extracts, suggesting cross-reactivityamong these cereals (11). Rye flour proteinsof 21 and 12 kDa have been identified asmajor allergens in serum from Wheat-hypersensitive individuals (12).

The major Wheat allergen associated withexercise-induced anaphylaxis is an omega-5 gliadin. Similar allergens have been

detected in Rye. Through SPT with theseallergens in Rye, gamma-70 secalin wasdetected in 10/15 (67%) of patients, togamma-35 secalin in 3/15 (20%) patients,and to gamma-3 hordein in 7/15 (47%)patients (3).

The salt-soluble proteins of Wheat andRye flour dust are considered the mostrelevant allergens in Baker's asthma (9,13).Members of the cereal alpha-amylase/trypsininhibitor family are main allergens involvedin allergic reactions to cereal flours.However, different allergenic behaviourswere found among homologous allergensfrom Rye, Barley, and Wheat (7-8). ThreeRye proteins, namely Sec c 1, RDAI-1 andRDAI-3, were shown to provoke positiveSPT in more than 50% of Rye-allergicpatients, although the serum IgE antibodylevels were lower (7-8). Franken et al.isolated 2 allergens with molecular weightsof 35 and 14 kDa in water-soluble Rye flourextracts using immunoblotting techniques onsera from 100 bakers (14). Garcia-Casado etal. isolated a protein of about 13.5 kDa fromRye flour. This allergen may be the same asthe 14 kDa allergen isolated by Franken etal. This protein provoked positive skin-specific IgE responses in 15/21 (71%)patients with Baker's asthma (9).

In 2 bakery workers with baker's asthmacaused mainly by exposure to Rye flour, Ryeflour immunoblotting showed IgE-bindingbands of around 12-15 kDa that correspondto Rye flour enzymatic inhibitors and thatwere not present in the Wheat flourimmunoblot (15).

In a report describing occupationalallergy to Rye flour in 9 wood workers whowere exposed to wood dust and experiencedasthma and/or rhinoconjuncitivis, implicatedallergens were 3 purified Rye allergensbelonging to the cereal alpha-amylaseinhibitor family, and in particular Sec c 1(8/9 patients) (1). These inhibitors, as wellas their Wheat and Barley homologues, havebeen identified as prominent allergensassociated with baker's asthma (10).

Six distinct gamma- and omega-typesecalins, together with 2 low-molecular-massglycoproteins, have been identified as themajor coeliac immunoreactive proteins from

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f5 RyeRye endosperm. A group of secalins has beenisolated: an omega-type secalin of 40 kDa(omega 1-40); 3 gamma-type secalins, a 70 kDa(gamma-70), 2 35 kDa (gamma-35) proteins,and 2 low-molecular-mass glycoproteins of15 and 18 kDa. These proteins are alsoinvolved in non-IgE mediated coeliac disease(4). It appears that the presence of IgA andIgG antibodies to different cereal antigens isa result of natural exposure and in atopicdermatitis displays little diagnosticsignificance, in contrast to antigliadinantibody response in dermatitis herpetiformisand coeliac disease (16).

Class I and class II chitinases have beenisolated from Rye seed. The chitinaseaccumulates in the seed during the later stageof development. The allergenic potential wasnot evaluated (17-18).

Antifreeze proteins, which are proteinsthat have the ability to retard ice crystalgrowth, have been identified as the mostabundant apoplastic proteins in cold-acclimated winter Rye leaves. All testsindicated that these antifreeze proteins aresimilar to members of 3 classes ofpathogenesis-related proteins, namely,endochitinases, endo-beta-1,3-glucanases,and thaumatin-like proteins (19).


An extensive cross-reactivity among thedifferent individual species of the genuscould be expected (20). By using RASTinhibition tests, cross-antigenicity wasshown to exist between different cerealgrains: Rye, Wheat, Triticale, Barley, Oat,Maize and Rice. The degree of cross-reactivity closely paralleled their taxonomicrelationship and appeared to be in thefollowing order of decreasing closeness:Wheat, Triticale, Rye, Barley, Oat, Rice andMaize. The allergenic activity in the Rye andWheat extracts was found to be distributedamong various fractions of differentmolecular weights (21). Other studies havedocumented cross-reactivity between Ryeand Wheat (22), and Rice may cross-reactwith Rye, Maize, Wheat and Rye pollen (23).Cross-reactivity between Rye and Rye pollenhas been shown, as they both contain theSec c 1 (b) allergen (7-8). Cross-reactivity has

also been demonstrated among grain extractsof Wheat, Rye, Barley and Oats. The resultsof the study suggested that the bran layers ofcereal grains are at least as allergenic as theflour derived from the grain (24).

A number of Wheat and Barley flourproteins that belong to the cereal alpha-amylase/trypsin inhibitor family have beenidentified as major allergens associated withbaker's asthma. Members of the Rye alpha-amylase inhibitor family are main allergensinvolved in allergic reactions to cereal flours.In a study comparing the allergenic potentialamong the homologous allergens from Rye,Barley, and Wheat, different degrees ofallergenicity were shown among thecomponents in Rye, as compared with theWheat and Barley homologues (7-8). IgEantibody studies have also shown a strongassociation between the levels of allergen-specific IgE to Wheat flour and those to Ryeand Barley flour, and cross-reacting proteinscould be demonstrated using competitiveRAST inhibition studies (11). The existenceof cross-reacting proteins between Barley,Rye and Wheat flour extracts, as well asamong the pollens of cereals and cerealflours, has been reported (25).

The major Wheat allergen associated withexercise-induced anaphylaxis is an omega-5gliadin, and similar allergens have beendetected in Rye. The gamma-70 and gamma-35 secalins in Rye and the gamma-3 hordeinin Barley were shown to cross-react withomega-5 gliadin, a major allergen in Wheat-dependent, exercise-induced anaphylaxis,suggesting that Rye and Barley may also elicitsymptoms in patients with Wheat-dependent,exercise-induced anaphylaxis (3).

Allergy to Kiwi, Poppy seed, and/orSesame seed often occurs in patients with asimultaneous sensitisation to nuts and flour.In a study characterising these cross-reactivities, the degree of cross-reactivityamong Kiwi, Sesame seeds, Poppy seeds,Hazel nuts, and Rye grain was found to bevery high in these patients. The existence ofboth cross-reacting and unique componentswas observed; however, the authors reportthat the cross-reacting and uniquecomponents could be different for differentpatients (26).

187

f5 RyePapain has been reported to cross-react

with Bromelain, Wheat flour, Rye flour,Grass pollen and Birch pollen (27).

In a Polish study investigating therelationship between hypersensitivity in 944children to grass pollens and to Wheat, Ryeand Soya, a very high correlation betweenhypersensitivity to grass and the presence ofIgE antibodies to Wheat, Rye and Soya wasfound (28).

Clinical Experience


Rye and Rye flour may commonly inducesymptoms of food allergy in sensitisedindividuals, in particular in bakers.Symptoms may include asthma, rhinitis,sneezing and wheezing. Food allergy withgastrointestinal symptoms, includingnausea, vomiting, gastric irritation,abdominal pain and diarrhoea, has beenreported. Cutaneous symptoms may includepruritis, urticaria, dermatitis, atopicdermatitis and angioedema. Anaphylaxis orvascular collapse with exercise has beendocumented (29-33).

In a Polish study utilising SPT for foodallergens in 270 pollen-allergic patients, themost prevalent allergens were found to beto nuts, Celery, Rye flour, Carrot,Strawberry, Pork and beans (28). Oralprovocation tests have also shown therelevance of Rye as a food allergen. Allergen-specific IgE and histamine-release tests wereemployed to evaluate patients withimmediate hypersensitivity. Patients withdelayed hypersensitivity underwent patch orlymphocyte-proliferation tests (32). In anevaluation of sensitisation to cereal in 40children, the most important allergen wasWheat, followed by Barley and Rye (34).

Anaphylaxis with exercise following theingestion of Rye has been reported (31), aswell as exercise-triggered recurrentanaphylaxis or urticaria as a result of allergyto gliadin (found in Wheat, Rye, Barley andOats) (35). A study has suggested that Ryeand Barley may also elicit symptoms inpatients with Wheat-dependent, exercise-induced anaphylaxis (3).

Eosinophilic esophagitis (EE) is oftenassociated with concomitant atopic diseases;in children with EE, for whom food allergenshave been identified as causative factors,elemental and elimination diets result in animprovement or resolution of symptoms.However, among adults, most patients aresensitised to aeroallergens (most commonlyto grass pollen and cereals), which maycross-react with plant-derived foodallergens. Six adults with permanently activeeosinophilic esophagitis, who were sensitisedto grass pollen and the cereals Wheat andRye, underwent a double-blind placebo-controlled food challenge and were kept onan elimination diet, avoiding Wheat and Ryefor 6 weeks. However, the challenge testswith Wheat and Rye did not provoke anysymptoms of eosinophilic esophagitis in any,and the elimination diet failed in reducingdisease activity. One patient noted animprovement of symptoms, but endoscopicand histopathologic findings wereunchanged (36).

Occupational allergy to Rye exposuremay occur in animal feed and husbandryworkers, bakers and other employees inbakeries, other food industry workers, andwood workers.

Baker's asthma is the most frequentoccupational lung disease in Switzerland andWest Germany. Cereal flours, and morerarely flour parasites, are implicated as theresponsible allergens. In a study of 31patients with Baker's asthma, approximately74% and 61% were found to have IgEantibodies to Wheat and to Rye flourrespectively (37). Other studies havereported similar findings: bakers withworkplace-related respiratory symptomsshowed sensitisation to Wheat flour (64%),Rye flour (52%), Soya bean flour (25%),and alpha-amylase (21%) (38). Asthma hasbeen reported following exposure to cerealflour contained in animal formula feeds (39).

Rye and Rye flour may also causeoccupational rhinitis and dermatitis, asreported in studies conducted on bakers andpastry cooks (40-42). Allergy to Rye flourhas been reported in bakers (43-44).Occupational protein contact dermatitismay result from contact with Rye (45).

188

f5 RyeTwo bakery workers with baker's asthma

and rhinoconjunctivitis, caused mainly byexposure to Rye flour, were described.Specific inhalation challenge with Wheatflour did not elicit an asthmatic reaction;however, both patients showed an earlyasthmatic reaction to a Rye flour challenge(14). Similarly, a baker with asthma reporteda workplace response to Rye flour but noneto Wheat flour, despite co-reactivity to bothWheat and Rye antigens. SPT, IgE antibodydetermination and basophil stimulation testswere positive for both Wheat and Ryeantigen, but quantitatively greater for Ryethan for Wheat. Bronchial challenge eliciteda much greater response to the Rye-Wheatflour mix used in the bakery than to 100%Wheat flour. The authors concluded that thegreater clinical response to Rye than toWheat may be immunologically mediated,but could have also been due to the physicalcharacteristics of Rye flour, such as the largerdose of inhaled airborne particles or anirritative effect (46).

In a South African study of 517supermarket bakery workers, a quarter(27%) of bakers had skin reactivity to cerealflours or additives, with the most commonsensitisers being cereal flours such as Wheatand Rye (16%) and the least common beingAlpha-amylase (3%). A higher proportionhad elevated IgE antibody levels to Wheat(26%), Rye (24%) and Alpha-amylase (4%)(47). In individuals with baker's asthma,immediate asthmatic reactions may occur,or there may be dual reactions consisting ofan immediate reaction followed by latereactions after some hours (48).

In a Korean study evaluating the IgEsensitisation rate and cross-reactivity in anagricultural setting, of 5,340 patientscomplaining of various allergic diseases andvisiting a Korean allergy clinic, thesensitisation rate to Rye grain was 9.5%.Buckwheat and Soybean were the mostprevalent allergens (49).

Cereal flours are used in the woodindustry to improve the quality of the gluesnecessary to produce veneer panels. Threeindividuals were found to be allergic tocereal alpha-amylase inhibitors, which areimportant occupational allergens

responsible for baker's asthma, and whichare members of the alpha-amylase inhibitorfamily, allergenic proteins found in Rye,Barley and Wheat (50).

Occupational allergy to Rye flour wasreported in 9 wood workers who wereexposed to wood dust and experiencedasthma and/or rhinoconjuncitivis. Theyworked as carpenters or sawmill operators.The adverse reactions appeared to be causedby the Rye flour used in the manufacture ofagglomerate boards. SPT for a range ofwood dust extracts was negative in 7 of the9. One individual was shown to havepositive SPT to Western red cedar and ramin,and another to Western red cedar and iroko.In contrast, all subjects were shown to haveskin reactivity to Rye. (A commercial Ryeflour extract was used both in the skin andin the conjunctival tests.) Five were positiveon bronchial challenge tests (1).

Other reactions

Rye contains a gluten-complex proteinwhich may result in coeliac disease (coeliacenteropathy) in genetically susceptibleindividuals. (51) Although the prevalence ofcoeliac disease is high in northern Europe,differences among countries exist. Among771 children (381 Swedish and 390 Danish)investigated for suspected coeliac disease(CD), only 24 CD patients were foundamong the Danish children, compared with155 in the Swedish group, despite the closelyrelated ethnic, geographical, and culturalbackground of the two populations. Thedifference was attributed to a difference inthe amount of gluten-containing Rye floureaten. The Danish infant diet differedsignificantly from the Swedish one incontaining a larger amount of the lower-gluten Rye flour (52).

Vasospasm related to ergot intoxicationhas been recognised since the Middle Ages,when it occurred due to ingestion of Ryecontaminated with the mould Clavicepspurpurea. Today ergotism is a rare cause ofperipheral ischaemia, most often associatedwith ergotamine tartrate therapy formigraine headaches (53). Nevertheless, anawareness of this condition is important, ascases of ergotism may still occur. A 42-year-

189

f5 Ryeold farmer afflicted for 6 months withincreasing pain in both feet and calves wasreported. Angiography demonstratedprogressive narrowing of all lower-legarteries. There were no palpable pulses inthe right foot, and those in the left foot weremarkedly reduced. The patient had beenexposed by inhalation to ergotamine-containing milling dust in the preparationof Rye flour. A high plasma ergotamine levelwas documented. Chronic ergotamineinhalation can cause ergotism affectingperipheral arteries (54).

References1. Armentia A, Garcia Casado G, Vega J,

Sanchez-Monge R, Mendez J, Salcedo G.Occupational allergy to rye flour incarpenters. Allergy 1997;52(11):1151-2




5. Rocher A, Calero M, Soriano F, Mendez E.Identification of major rye secalins as coeliacimmunoreactive proteins.Biochim Biophys Acta 1996;1295(1):13-22

6. Stankovic I, Miletic I, Djordjevic B.Determination of anti-secalin antibodies insera from coeliac patients by ELISA-basedassay.J Pharm Biomed Anal 1998;18(1-2):255-60

7. Snégaroff J, Bouchez-Mahiout I, Pecquet C,Branlard G, Laurière M. Study of IgEantigenic relationships in hypersensitivity tohydrolyzed wheat proteins and wheat-dependent exercise-induced anaphylaxis.Int Arch Allergy Immunol 2006;139(3):201-8

8. Garcia-Casado G, Sanchez-Monge R, Lopez-Otin C, Salcedo G. Rye inhibitors of animalalpha-amylases show different specificities,aggregative properties and IgE-bindingcapacities than their homologues from wheatand barley.Eur J Biochem 1994;224(2):525-31

9. Garcia-Casado G, Armentia A, Sanchez-Monge R, Malpica JM, Salcedo G. Rye flourallergens associated with baker's asthma.Correlation between in vivo and in vitroactivities and comparison with their wheatand barley homologues.Clin Exp Allergy 1996;26(4):428-35

10. Garcia-Casado G, Armentia A, Sanchez-Monge R, et al. A major baker's asthmaallergen from rye flour is considerably moreactive than its barley counterpart.FEBS Lett 1995;364(1):36-40


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14. Franken J, Stephan U, Neuber K,Bujanowski-Weber J, Ulmer WT, Konig W.Characterization of allergenic components ofrye and wheat flour (Secale, Triticumvulgaris) by western blot with sera of bakers:their effects on CD23 expression. Int ArchAllergy Appl Immunol 1991;96(1):76-83

15. Letrán A, Palacín A, Barranco P, Salcedo G,Pascual C, Quirce S. Rye flour allergens: Anemerging role in baker's asthma.Am J Ind Med 2008;51(5):324-8

16. Varjonen E, Kalimo K, et al. IgA and IgGbinding components of wheat, rye, barley andoats. Int Arch Allergy Immunol1996;111(1):55-63

17. Taira T, Ohnuma T, Yamagami T, Aso Y,Ishiguro M, Ishihara M. Antifungal activity ofrye (Secale cereale) seed chitinases: thedifferent binding manner of class I and classII chitinases to the fungal cell walls. BiosciBiotechnol Biochem 2002;66(5):970-7

18. Yamagami T, Funatsu G. Purification andsome properties of three chitinases from theseeds of rye (Secale cereale). BiosciBiotechnol Biochem 1993;57(4):643-7

19. Hon WC, Griffith M, Mlynarz A, Kwok YC,Yang DS. Antifreeze proteins in winter rye aresimilar to pathogenesis-related proteins.Plant Physiol 1995;109(3):879-89



22. Bjorksten F, Backman A, Jarvinen KAJ, et al.Immunoglobulin E specific to wheat and ryeflour proteins. Clin Allergy 1977;7:473-83

23. Lezaun A, Igea J, Davila I, Martin JA, et al.Occupational asthma and contact urticaria torice in a housewife.Annual meeting EAACI 1991;26-29

24. Baldo BA, Krillis S, Wrigley CW.Hypersensitivity to inhaled flour allergens.Comparison between cereals.Allergy 1980;35:45-56



27. Baur X. Studies on the specificity of humanIgE-antibodies to the plant proteases papainand bromelain. Clin Allergy 1979;9:451-7

28. Borysewicz G, Wawrzyniak M, Bulawa E,Szamotulska K, Siwinska-Golebiowska H.Relation between specific IgE antibodies tograss pollens and to wheat, rye, soya inchildren with allergic disease. [Polish] MedWieku Rozwoj 2001;5(4):359-66

29. Hofman T, Buczylko K, Brewczynski P.Typical food allergens for pollinosis inselected regions of Poland. Multiagentstudies. [Polish] Pol Merkuriusz Lek1998;4(20):69-71

30. Bengtsson U, Nilsson-Balknas U, Hanson LA,Ahlstedt S. Double blind, placebo controlledfood reactions do not correlate to IgE allergyin the diagnosis of staple food relatedgastrointestinal symptoms.Gut 1996;39(1):130-5

31. Jones SM, Magnolfi CF, Cooke SK,Sampson HA. Immunologic cross-reactivityamong cereal grains and grasses in childrenwith food hypersensitivity.J Allergy Clin Immunol 1995;96:341-51

32. Armentia A, Martin Santos JM, Blanco M, et al.Exercise-induced anaphylactic reaction tograin flours. Ann Allergy 1990;65:149-51




36. Simon D, Straumann A, Wenk A, Spichtin H,Simon HU, Braathen LR. Eosinophilicesophagitis in adults – no clinical relevanceof wheat and rye sensitizations.Allergy 2006;61(12):1480-3

37. Wuthrich B, Baur X. Baking ingredients,especially alpha-amylase, as occupationalinhalation allergens in the baking industry.[German] Schweiz Med Wochenschr1990;120(13):446-50

38. Baur X, Degens PO, Sander I. Baker'sasthma: still among the most frequentoccupational respiratory disorders. J AllergyClin Immunol 1998;102(6 Pt 1):984-97

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39. Valdivieso R, Pola J, Zapata C, Puyana J,Cuesta J, Martin C, Losada E. Farm animalfeeders: another group affected by cerealflour asthma. Allergy 1988;43(6):406-10

40. Savolainen H. Flour protein antigens inoccupational flour hypersensitivity. OccupMed (Lond) 1997;47(6):341-3

41. Bataille A, Anton M, Mollat F, Bobe M,Bonneau C, Caramaniam MN, Geraut C,Dupas D. Respiratory allergies amongsymptomatic bakers and pastry cooks: initialresults of a prevalence study. [French] AllergImmunol (Paris) 1995;27(1):7-10

42. Schonenberger P, Savolainen H. Proteinantigens in case of asthma, rhinitis anddermatitis in patients occupationally exposedto flour. [German] Schweiz Med Wochenschr1995;125(21):1046-51

43. Baur X, Pau M, Czuppon A, Fruhmann G.Characterization of soybean allergens causingsensitization of occupationally exposedbakers. Allergy 1996;51(5):326-30

44. Popp W, Wagner C, Kiss D, Zwick H, Sertl K.Prediction of sensitization to flour allergens.Allergy 1994;49(5):376-9

45. Iliev D, Wuthrich B. Occupational proteincontact dermatitis with type I allergy todifferent kinds of meat and vegetables.Int Arch Occup Environ Health1998;71(4):289-92

46. Ehrlich R, Prescott R. Baker's asthma with apredominant clinical response to rye flour.Am J Ind Med 2005;48(2):153-5

47. Baatjies R, Jeebhay MF, Lopata AL, Sander I,Raulf-Heimsoth M, Bateman E, Robins TG,Meijster T, Heederik D. Predictors of work-related symptoms, allergic sensitisation andoccupational asthma among supermarketbakery workers. [Abst] Current Allergy andClinical Immunology 2007;20(1):38

f5 Rye48. Quirce S, Fernández-Nieto M, Escudero C,

Cuesta J, de Las Heras M, Sastre J. Bronchialresponsiveness to bakery-derived allergens isstrongly dependent on specific skinsensitivity. Allergy 2006;61(10):1202-8

49. Yoon SH, Kang YM, Ye YM, Kim SH, Suh CH,Nahm DH, Park HS. The sensitization rateand cross-reactivity to homemade agriculturalproducts in adult allergy patients. J AsthmaAllergy Clin Immunol 2005;25(4):269-75

50. Lopez-Rico R, Moneo I, Rico A, Curiel G,Sanchez-Monge R, Salcedo G. Cereal alpha-amylase inhibitors cause occupationalsensitization in the wood industry.Clin Exp Allergy 1998;28(10):1286-91

51. Wieser H. The precipitating factor in coeliacdisease. Baillieres Clin Gastroenterol1995;9(2):191-207

52. Weile B, Cavell B, Nivenius K, KrasilnikoffPA. Striking differences in the incidence ofchildhood celiac disease between Denmarkand Sweden: a plausible explanation.J Pediatr Gastroenterol Nutr 1995;21(1):64-8

53. Fischbach R, Gross-Fengels W, Schmidt R.Ergotism: an occasional unrecognized causeof acute ischemia of the extremities.[German] Rontgenblatter 1990;43(5):213-9

54. Stange K, Pohlmeier H, Lubbesmeyer A,Gumbinger G, Schmitz W, Baumgart P.Vascular ergotism through inhalation of graindust. [German] Dtsch Med Wochenschr1998;123(51-52):1547-50

192

Sesamum indicumFamily: PedaliaceaeCommonnames: Sesame seed, Sesame,

Benne seedSourcematerial: Unpolished seedsOther species of Sesame includeS. indicum, S. radiatum, S. schum,and S. thoronFor continuous updates:www.immunocapinvitrosight.com

f10 Sesame seed

Allergen Exposure


The Pedaliaceae family contains 18 or morespecies, most of them indigenous to Africaand Asia. Sesamum indicum, originally fromIndia, is now grown very widely: in India,the Middle East, the United States, LatinAmerica, China, and elsewhere. It is aperennial herbaceous plant that grows upto 1 metre high. Its flowers are pink or lightblue (1).

Sesame may be the first seasoning everused. The Chinese burned Sesame oil for lightand to make soot for their ink blocks. Africanslaves brought Sesame seeds to America. TheJapanese use Sesame seed as a health foodand lead the world in Sesame seed imports,followed by Europe and the US.

The fruit is a small capsule containingmany seeds, which are black, white, yellowor red. They are used in food eitherunprocessed or after hulling. Sesame seedsare used crushed, for their oil, and as cakes(the solid residue left after processing of theoil). About 70% of the world's Sesame seedis processed into oil and meal.

Environment

The seed is available packaged insupermarkets and can be found in bulk inMiddle Eastern markets and health foodstores. Sesame seeds often feature in candiesand baked goods, and are a commoningredient in savoury dishes of ethniccuisines. A special process produces a clearwhite seed that is common on hamburgerbuns.

The seed can also be ground and used asflour, or as butter, known as “tahini”. It canalso be fermented into “tempeh”, or groundinto a powder and mixed with a sweetenerto make “halva”. The seeds can also besprouted and used in salads. Edible oil isobtained from the seed. It is used forcooking, in margarines, and so on.

Sesame seed is rich in unsaturated fattyacids, calcium, protein, and vitamins A, Band E.

Sesame has bactericidal activities, and italso acts as an antioxidant that can inhibitthe production and absorption ofcholesterol. It is believed to help prevent and/or combat cancer and heart disease and tohave anti-diabetic, anti-ulcer and laxativeproperties. The lecithin in Sesame is atreatment for dermatitis and dry skin. Otheruses include the treatment of blurred vision,dizziness, headaches, and nasal mucosadryness. In addition, Sesame features in ahuge variety of folk remedies, with purposesranging from burn treatment to increasingmilk production in nursing mothers.

193

f10 Sesame seedUnexpected exposure

Sesame is used in the production ofperfumes, cosmetics, toiletries (especiallyUV-barrier creams), lubricants, insecticidesand fungicides. The oil is sometimes burnedfor lighting. Sesame oil is a solvent forintramuscular injections and has been usedin plasters, liniments, ointments, capsules,and emulsions, and in the formulation ofmedicinal suspensions and ophthalmicpreparations. Liniment that contains Sesameoil has been used in the treatment of eczemaand leg ulcers (2).

Sesame oil is often a “hidden allergen”in food. For example, pastries containingSesame that are not sold may be “recycled”and thereby become a hidden allergen (3).Sesame meal is a feed for poultry andlivestock.

Allergens

A wide range of IgE-binding proteins ofSesame seed has been identified: 78, 52, 45,34, 32, 29, 25, 20, 9, and 7 kDa proteins(4). The proteins of white, brown and blackSesame extracts have been shown to havemajor quantitative differences (e.g., whiteseeds have more protein than black seeds,182 vs. 28 mg/g). The white extractcontained 15 proteins of 12-79 kDa in size.Ten of the 15 proteins (12-57.5 kDa) boundto serum-specific IgE from Sesame seed-allergic individuals. The 12-13 kDa and 22-33 kDa proteins were thought to constitutethe main allergens. Similar studies havereported that 2 proteins in this size rangeappear to be major allergens (5).

Similarly, in a study of the allergens ofSesame seed, serum of 12 Sesame-sensitisedpatients (7 with food allergy, 5 with foodsensitisation) were utilised. Sesame proteinextracts were prepared from black, white andbrown Sesame seeds. Analysis showed similarprotein patterns in the 3 extracts, and 19protein bands were isolated. Two proteins,of 14 kDa and 25 kDa, were identified andshown to be the major allergens involved inSesame IgE-dependent hypersensitivity, the25 kDa band displaying several characteristicsof a major allergen (6).

Insoluble 11S globulin and soluble 2Salbumin, conventionally termed alpha-globulin and beta-globulin, are the 2 majorstorage proteins and constitute 60-70 and15-25% of total Sesame proteins,respectively (7-9).

The following allergens have beencharacterised in Sesame seed:

Ses i 1, a 9 kDa protein, a 2S albumin(7,10-12).

Ses i 2, a 7 kDa protein, a 2S albumin(4,7,10).

Ses i 3, a 45 kDa, 7S vicilin-type globulin(4,10,13).

Ses i 4, a 17 kDa protein, an oleosin (10,14).

Ses i 5, a 15 kDa protein, an oleosin (10,14).

Ses i 6, a 11S globulin (7,10,15-16).

Ses i 7, a 11S globulin (7-8,10,15).

Ses i Profilin (17).

Ses i 1, a major protein and a 2S albumin,has been shown to be thermo-stable up to90 °C and also highly resistant to digestion.After 2 hours of gastric digestion, theallergen remained completely intact, andonly the small subunit was cloven during 2hours of subsequent duodenal digestion,leaving a major IgE epitope region of thisprotein intact (12). Ses i 1 has been shownto be a potent allergen. Researchers havequestioned whether the 9 kDa proteincorresponds to a 2S albumin or a lipidtransfer protein (18).

The 45 kDa protein, Ses i 3, a 7S vicilin-type globulin, a seed storage protein, bindsto allergen-specific IgE in 75% of sera ofSesame-allergic patients. Ses i 2, a 7 kDaprotein, is a 2S albumin, another seedstorage protein of Sesame (4).

In some cases of severe allergy to Sesameseed, skin and serum tests do not produceany evidence of IgE reactivity. A study wasdone of the serum of 10 patients out of 32who had displayed severe immediatesymptoms and whose Sesame allergy wasdiagnosed by double-blind placebo-controlled food challenge or convincingclinical history, and in whom no specific skin

194

f10 Sesame seedreactivity or serum IgE antibodies could bedetected. In reducing conditions, 2 proteinbands (15-17 kDa) could be separated from2S albumin proteins and shown to beoleosins, which are present in oil bodyfractions. These proteins were recognised byIgE from all 10 patients' sera. The authorssuggest that oleosins are major allergens ofSesame seed and may in particular berelevant to severe anaphylaxis. Falselynegative prick tests could be due to the lackof oleosins in presently available extracts,or to the epitopes being buried in the innermolecule. The oleosins were named Ses i 4and Ses i 5 (14).

The 11S globulins, Ses i 6 and Ses i 7,have only 36% identity. In 24 patients withSesame seed allergy, 13 showed strong IgEbinding to recombinant Ses i 6, whereas 10of the patients show clear binding torecombinant Ses i 7 (15).

Sesame seed has recently been shown tocontain a lipid transfer protein. This proteinappears to be most abundantly expressed indeveloping seeds but is also detected inflower tissues. The abundant LTPs indeveloping Sesame seed are involved in lipidtransfer into the extracellular matrix (19).The allergenic potential of this LTP was notevaluated.


Cross-reactivity between allergens in Sesameand allergens in other foods, including Hazelnut, Rye, Kiwi, Poppy seed, Black walnut,Cashew, Macadamia, Pistachio, andPeanuts, has been reported (2,20-21). Oneauthor attributed these cross-reactions to 2broad causes: the first being multipleallergens, Sesame proteins or glycoproteins,present in Sesame seed and linked mainly toimmediate hypersensitivity reactionsmediated by IgE antibodies; and the secondbeing lignin-like molecules in Sesame oil(sesamol, sesamin, and sesamolin, which areall reported to be unsaponifiable fractionsof Sesame oil) (2).

Allergy to Kiwi, Poppy seeds, and/orSesame seeds has been reported to oftenoccur in patients with a simultaneoussensitisation to nuts and flour. These cross-

reactions were verified by RAST inhibitionstudies reporting that the degree of cross-reactivity among Kiwi, Sesame seeds, Poppyseeds, Hazel nuts, and Rye was found to bevery high in the patients studied. Theexistence of both cross-reacting and uniquecomponents was seen, but the authorsreported that the cross-reacting and uniquecomponents could be different for differentpatients (20).

A study described 3 patients with severeimmediate-type allergic reactions to Poppyseed, all of whom showed serologicpositivity to Sesame seed. The authorssuggested that this may have been due tocross-reactivity to similar allergens (22). Theclinical relevance was not investigatedfurther.

A known IgE-binding epitope of thePeanut allergen Ara h 1 has been shown tohave an 80% homology with thecorresponding area of the Ses i 3 allergen ofSesame seed. (But the amino acids concernedhad been previously shown not to be criticalfor IgE binding in Ara h 1 of Peanut) (4).Furthermore, tree nut and Sesame allergyhave been reported to occur more often inpatients with Peanut allergy. Although thismay be a coincidence, simply due to apredisposition to food allergy in theseindividuals, cross-reactivity has beendemonstrated between Peanut and Sesameseed. A study described 3 patients, previouslysensitised to but now tolerant of Peanut, whowere diagnosed as having either tree nut orSesame allergy. The study concluded thatdemonstration of tolerance to Peanut maygive false assurance that patients no longerneed to avoid tree nuts or Sesame; on thecontrary, tree nut and Sesame allergy canexist or develop in patients despite thedevelopment of tolerance to Peanut (23).

The 19 kDa protein of Buckwheat has weakhomology with the vicilin-like allergen ofCashew (Ana o 1), English walnut (Jug r 2)and 7 S globulin from Sesamum indicum (24).

The clinical relevance of Sesame profilinand its cross-reactivity have not beeninvestigated (17).

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f10 Sesame seed

Clinical Experience


Sesame seed has become a significant andcommon inducer of food allergy symptomsin sensitised individuals; earlier reports ofthis allergy were quite infrequent (2,25-27).The prevalence of Sesame seedhypersensitivity is increasing due to theincreasing popularity of vegetarian dishes,to Sesame's use in international fast-foodand bakery products, and to the spread ofMiddle Eastern and Asian cuisines. Sesameseed is regarded as an “emerging” foodallergen (9,28-33).

In an evaluation of the results of 4.5million allergen-specific IgE antibody testsperformed on Japanese individuals, Applewas found to have the highest number ofpositive tests, followed by Sesame seed (34).Similarly, Sesame was reported to be a majorcause of IgE-mediated food allergy in Israel,and second only to Cow's milk as a cause ofanaphylaxis. In 9,070 children, the foodallergy prevalence was found to be 1.7%,with Sesame the third most common foodcausing sensitisation (0.18%), followingHen's egg (0.5%) and Cow's milk (0.3%),and exceeding Peanut sensitisation (0.04%).Sesame was second only to Cow's milk as acause of anaphylaxis (35). In a French study,the prevalence of Sesame seed allergy wasreported to be 2.14% in children and 5.81%in adults (36). A prevalence study ofimmediate hypersensitivity to foods amongAustralian children found that Sesame wasin fourth place (0.42%), following Hen's egg(3.2%), Milk (2%), and Peanut (1.9%).Sensitivity to Sesame was more commonthan sensitivity to any single tree nut studied(32). In the report of a government researchproject in the United Kingdom in 1996, theestimated overall prevalence of severeallergic reactions to Sesame in the generalpopulation was 1 in 2,000 (0.05%) (37).

An early report describes 2 individualswho experienced severe allergic reactionswith pruritus, generalised erythema,angioedema of the uvula, clinical shock andwheezing. The author suggested that Sesameseed should be considered an extremelypotent allergen (38). Since then, numeroustypes of allergic reaction have been reported,

including nausea, vomiting, diarrhoea,angioedema, angioedema of the tongue,burning of the mouth and lips, itching ofthe pharynx, symptoms of Oral AllergySyndrome, wheezing, respiratory distressasthma, contact dermatitis and urticaria.

In a study of 14 children recruited from3 allergy clinics in France, all of whom hada diagnosis of Sesame seed allergy based ona convincing clinical history and positiveSPT or allergen-specific IgE, the median agefor the onset of Sesame seed allergy wasfound to be 5 years (the range being from 5months to 16 years). All patients reactedimmediately after Sesame seed consumption,and they presented the following as a firstmanifestation: oedema (9 cases, 48%), andurticaria (5 cases, 27%), and 1 case of eachof the following symptoms: vomiting,rhinitis, conjunctivitis, asthma andanaphylactic shock. One patient hadrecurrent anaphylactic shocks, and anotheran anaphylactic shock after a further Sesameseed exposure; these 2 patients wereasthmatic. SPT with a commercial Sesameseed extract was less sensitive than with thenative seed. The median of Sesame seed-specific IgE was 5.58 kUA/l (range 0.35 to100 kUA/l). Three patients outgrew theirfood allergy. The authors reported that aspontaneous outgrowing of Sesame seedallergy can occur, but that predictive criteriacould not be established (39).

In an Israeli study of 32 children withSesame seed allergy, 3 subgroups wereidentified. Group I (n = 23) manifested IgE-mediated Sesame allergy. The mean age ofthe first allergic reaction was 11.7 months.The main clinical manifestation wasurticaria/angioedema in 14 (60%), butanaphylaxis was the presenting symptom in7 (30%) patients; all of these were youngerthan 1 year. Sixteen (70%) were found tobe allergic to other foods, and other atopicdiseases were identified in 18 (78%). Threepatients “outgrew” their allergy within 1-2years. In Group II (n = 2), Sesame allergywas ruled out based on the lack of positiveSPT and a negative open oral challenge.Group III (n = 7) consisted of patients whowere found to have skin reactivity forSesame as part of a screening for other foodallergies (40).

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A study evaluating Ses i 6 and Ses i 7described 24 patients with Sesame seedallergy. Clinical reactions involved the skinin 19 patients, and these reactions weremainly urticaria and angioedema; reactionsinvolved the gastrointestinal tract in 11patients, and the respiratory system in 6patients. One patient had a decrease in bloodpressure. Twelve patients had more than oneorgan system involved. Sesame seed-specificIgE levels ranged from 0.73 to greater than100 kUA/l (15).

Severe food-induced anaphylaxis has alsobeen reported by many authors (6,10,41-43). Anaphylaxis to Sesame in a vegetableburger has been described (1,44). Sesameseeds were responsible for 3% of life-threatening allergic reactions to foods inFrance in 2002 (45). In Israel, Sesame wassecond only to Cow's milk as a cause ofanaphylaxis (35,41). This may result fromthe high levels of exposure to Sesame in theIsraeli diet, but although the use of Sesamein food is common in India, no publishedreports exist of Sesame allergy from thiscountry (2). In a British study of Sesameallergy, 17% of respondents claimed to havesuffered potentially life-threatening allergicsymptoms, with 65% of severe reactionshappening on first known exposure (46). A6-year-old child who developed ananaphylactic reaction after eating bread andSesame paste has been described (47).Significantly, not all Sesame-allergicindividuals will have IgE antibodies directedat Sesame seed (9).

Sesame seeds are often present in gluten-free foods in therapeutic diets of coeliacpatients; an instance of anaphylaxis in acoeliac patient following Sesame ingestionhas been reported (48-49). Sesame seed canbe regarded as a “hidden” allergen.Significantly, cases of severe allergy toSesame seed may lack corroborationthrough SPT and IgE antibodydeterminations. The reasons for this areunknown. In a study of 32 patients who haddisplayed immediate symptoms such asanaphylactic shock, asthma, urticaria, andangioedema, Sesame allergy was diagnosedby double-blind placebo-controlled foodchallenge or a convincing clinical history.

Ten patients had negative SPT and in vitro testsfor Sesame. The authors were able todemonstrate that the allergens involved wereoleosins (named Ses i 4 and Ses i 5), whichappear to be major allergens of Sesame seedsand may be relevant to severe anaphylaxis (14).

Anaphylaxis has been described both toSesame seed and Sesame oil (50-51). A studyreports on 9 cases of IgE-dependent allergyto Sesame seed and/or Sesame seed oil.Commercial SPT were not very sensitive,whereas the sensitivity of SPT with a freshlyprepared Sesame seed flour extract wasgreater. The diagnosis of this allergy wasestablished by double-blind oral provocationtests, with doses of Sesame seed flourranging from 100 mg to 10 g. Allergy toSesame seed oil was also demonstrated insome of these cases (52). A previous reportdescribed generalised urticaria as a result ofSesame seed, but this could not be confirmedusing SPT or allergen-specific IgE; instead,oral challenges confirmed it (53).

Immediate hypersensitivity reactions toSesame in cosmetics have been reported (54).

An anaphylactic reaction to Cashew nutoccurred in a non-atopic 60-year-old man25 days after receiving a liver allograft froma 15-year-old atopic boy who died ofanaphylaxis after Peanut ingestion. The liverrecipient had no history of nut allergy. Post-transplantation skin prick test results werepositive for Peanut, Cashew nut, and Sesameseed, and the donor had allergen-specific IgEantibodies to the same 3 allergens. Thisillustrates that transfer of IgE-mediatedhypersensitivity can occur after livertransplantation and have seriousconsequences (55).

Occupational exposure to Sesame seedcan occur though animal husbandry, bakery,mill and other work. Occupational asthma,rhinitis and urticaria due to Sesame seedcontact have been reported (56-58). Systemicurticaria, facial erythema, dizziness and lossof consciousness were reported in a 36-year-old baker following exposure to Sesame.Commercial SPT and IgE antibody tests werenegative, but SPT to crushed Sesame seedsin sodium chloride solution was detected (3).

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197

Other reactions

Non-IgE-mediated reactions have beenreported. A 45-year-old woman experiencedfacial erythema, flushing, generalisedpruritus, and conjunctivitis after she hadeaten crackers. Similar symptoms occurredseveral times after ingestion of Sesame oilin various preparations. Within minutes afteringestion of Sesame-dressed chicken, she hadflushing, generalised itching, nausea,vomiting, and dizziness. Skin tests, includingintra-cutaneous testing, were negative forcommon allergens. Skin testing using prickand scratch methods with native Sesame oil(cold-pressed and heat-extracted) and raw,peeled, crushed, and unpeeled Sesame seedswas negative. No IgE antibodies for Sesameseed or for common allergens was detected.In an oral challenge, 10 minutes after 2 bitesof bread masking 10 g crushed Sesame seedand 10 g Sesame oil, the patient developedgeneralised flushing, itching, andconjunctival symptoms. Serum tryptaseremained normal but urinary histamineincreased (59).

If the extraction process for Sesame oil isnot of a high standard, Sesame protein maybe present in the oil, which can result inallergic reactions, including anaphylaxis, insensitised individuals (60-62). Sesame seedoil may be used in cosmetics andpharmaceuticals, resulting in contactdermatitis, as described in 13 patients. Thecontact allergens sesamol, sesamin andsesamolin were identified in crude andpurified (pharmaceutical) Sesame oil. Patchtests showed 8 of 13 patients to be positiveto sesamol and 12 to sesamolin and sesamin(63). Cheilitis due to Sesame oil in a lipstickhas been reported in a female patient. Shereacted to sesamolin and sesamin, but notto sesamol. In this instance, sesamolin andsesamin were detected in the Sesame seedoil, but sesamol was not (52). Contactsensitivity to an ointment composed of 60%Sesame oil, used for the treatment of a burnon the forearm, has also been described.Contact dermatitis developed 10 days afterapplication (64).

Salmonella outbreaks have been reportedas a result of contaminated Sesame seedproducts, including halvah and tahini. Aninternational outbreak of multiresistantSalmonella typhimurium that was correlatedto the consumption of halvah resulted in aninvestigation of Sesame seed products. Outof 117 ready-to-eat food items containingSesame, salmonella was isolated from 11(9.4%). The products included Sesame paste(tahini) and Sesame seed sold for rawconsumption in cereals (65). Similarly, in areport of 3 outbreaks of Salmonellamontevideo infection in Australia and NewZealand, imported tahini was identified asthe source of infection. Of a total of 66 casesof S. montevideo infections, 54 (82%)reportedly involved consumption of Sesameseed-based foods (66).

References1. Kagi MK, Wuthrich B. Falafel burger

anaphylaxis due to sesame seed allergy.Ann Allergy 1993;71(2):127-9


3. Woltsche-Kahr I, Aberer W. Recurrentanaphylactic reactions following hiddeningestion of sesame seed. [Abstract] 8thInternational Symposium on Problems ofFood Allergy. 2001, March 11-13, Venice

4. Beyer K, Bardina L, Grishina G, Sampson HA.Identification of sesame seed allergens by 2-dimensional proteomics and Edmansequencing: seed storage proteins ascommon food allergens. J Allergy ClinImmunol 2002;110(1):154-9

5. Fremont S, Zitouni N, Kanny G, Veneri V,Metche M, Moneret-Vautrin DA, Nicolas JP.Allergenicity of some isoforms of whitesesame proteins.Clin Exp Allergy 2002;32(8):1211-5

6. Kolopp Sarda MN, Moneret Vautrin DA,Gobert B, Kanny G, et al. Specific humoralimmune responses in 12 cases of foodsensitization to sesame seed.Clin Exp Allergy 1997;27(11):1285-91

7. Tai SS, Wu LS, Chen EC, Tzen JT. Molecularcloning of 11S globulin and 2S albumin, thetwo major seed storage proteins in sesame.J Agric Food Chem 1999;47(12):4932-8

8. Hsiao ES, Lin LJ, Li FY, Wang MM, Liao MY,Tzen JT. Gene families encoding isoforms oftwo major sesame seed storage proteins, 11Sglobulin and 2S albumin.J Agric Food Chem 2006;54(25):9544-50

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f10 Sesame seed9. Wolff N, Cogan U, Admon A, Dalal I, Katz Y,

Hodos N, Karin N, Yannai S. Allergy tosesame in humans is associated primarilywith IgE antibody to a 14 kDa 2S albuminprecursor.Food Chem Toxicol 2003;41(8):1165-74


11. Pastorello EA, Varin E, Farioli L, Pravettoni V,Ortolani C, Trambaioli C, Fortunato D,Giuffrida MG, Rivolta F, Robino A, Calamari AM,Lacava L, Conti A. The major allergen ofsesame seeds (Sesamum indicum) is a 2Salbumin. J Chromatogr B Biomed Sci Appl2001;756(1-2):85-93

12. Moreno FJ, Maldonado BM, Wellner N, Mills EN.Thermostability and in vitro digestibility of apurified major allergen 2S albumin (Ses i 1)from white sesame seeds (Sesamum indicumL.). Biochim Biophys Acta2005;1752(2):142-53

13. Navuluri L, Parvataneni S, Hassan H,Birmingham NP, Kelly C, Gangur V. Allergicand Anaphylactic Response to Sesame Seedsin Mice: Identification of Ses i 3 and BasicSubunit of 11s Globulins as Allergens. IntArch Allergy Immunol 2006;140(3):270-6

14. Leduc V, Moneret-Vautrin DA, Tzen JT,Morisset M, Guerin L, Kanny G. Identificationof oleosins as major allergens in sesame seedallergic patients. Allergy 2006;61(3):349-56

15. Beyer K, Grishina G, Bardina L, Sampson HA.Identification of 2 new sesame seedallergens: Ses i 6 and Ses i 7.J Allergy Clin Immunol 2007;119(6):1554-6

16. Wallowitz ML, Chen RJ, Tzen JT, Teuber SS.Ses i 6, the sesame 11S globulin, canactivate basophils and shows cross-reactivitywith walnut in vitro.Clin Exp Allergy 2007;37(6):929-38


18. Reifen R, Dhal I, Clare Mills EN, Alcocer M.Sesame allergy - the 'peanut' of the middleeast? [Poster] 8th International Symposiumon Problems of Food Allergy. 2001, March11-13, Venice

19. Choi AM, Lee SB, Cho SH, Hwang I, Hur CG,Suh MC. Isolation and characterization ofmultiple abundant lipid transfer proteinisoforms in developing sesame (Sesamumindicum L.) seeds. Plant Physiol Biochem2007 Oct 7 [Epub ahead of print]


21. Hlywka JJ, Hefle SL, Taylor SL. A sandwichenzyme-linked immunosorbent assay for thedetection of almonds in foods.J Food Prot 2000;63(2):252-7

22. Gloor M, Kagi M, Wuthrich B. Poppyseedanaphylaxis. [German] Schweiz MedWochenschr 1995;125(30):1434-7

23. Beausoleil JL, Spergel JM. Late diagnosis oftree nut and sesame allergy in patientspreviously sensitized but tolerant to peanut.Ann Allergy Asthma Immunol2006;97(4):443-5

24. Choi SY, Sohn JH, Lee YW, Lee EK, Hong CS,Park JW. Characterization of Buckwheat 19-kD Allergen and Its Application forDiagnosing Clinical Reactivity. Int ArchAllergy Immunol 2007;144(4):267-74

25. Torsney PJ. Hypersensitivity to sesame seed.J Allergy Clin Immunol 1964;35:514 -9

26. Uvitsky IH. Sensitivity to sesame seed.J Allergy 1951;22(4):377-8

27. Rubenstein L. Sensitivity to sesame seed andsesame oil.N Y State J Med 1950;50(3):343

28. Levy Y, Danon YL. Allergy to sesame seed ininfants. Allergy 2001;56(2):193-4

29. Rance F. Current childhood food allergies.[French] Allerg Immunol (Paris)2000;32(10):366-76

30. Senti G, Ballmer-Weber BK, Wuthrich B.Nuts, seeds and grains from an allergist'spoint of view. [German] Schweiz MedWochenschr 2000;130(47):1795-804

31. Dutau G, Rittie JL, Rance F, Juchet A,Bremont F. New food allergies. [French]Presse Med 1999;28(28):1553-9

32. Sporik R, Hill D. Allergy to peanut, nuts, andsesame seed in Australian children. [Letter]BMJ 1996;313(7070):1477-8

33. Perkins MS. Peanut and nut allergy. Sesameallergy is also a problem.BMJ 1996;313(7052):300

34. Kimura S. Positive ratio of allergen specificIgE antibodies in serum, from a large scalestudy. [Japanese] Rinsho Byori2001;49(4):376-80

35. Dalal I, Binson I, Reifen R, Amitai Z, Shohat T,Rahmani S, Levine A, Ballin A, Somekh E.Food allergy is a matter of geography afterall: sesame as a major cause of severe IgE-mediated food allergic reactions amonginfants and young children in Israel.Allergy 2002;57(4):362-5

36. Lemerdy P, Moneret-Vautrin DA, Rance F,Kanny G, Parisot L. Prevalence of foodallergies in pediatric and adult populations.CICBAA Databank Alim'Inter 2003;8:5-7

37. UK Ministry of Agriculture Fisheries andFood. Sesame Seed Allergy Food SafetyInformation Bulletin. UK Ministry ofAgriculture Fisheries and Food, London,England 1996

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[German] Pneumologie 1989;43(12):710-439. Agne PS, Bidat E, Agne PS, Rance F, Paty E.

Sesame seed allergy in children.Allergie et immunologie 2004;36(8):300-5

40. Dalal I, Binson I, Levine A, Somekh E, Ballin A,Reifen R. The pattern of sesame sensitivityamong infants and children. Pediatr AllergyImmunol 2003;14(4):312-6

41. Blamoutier J, Denimal C. Severe allergy tosesame. [French] Rev Infirm 1992;42(9):37-8

42. James C, Williams-Akita A, Rao YA,Chiarmonte LT, Scheider AT. Sesame seedanaphylaxis.N Y State J Med 1991;91(10):457-8

43. Asero R, Mistrello G, Roncarolo D, Antoniotti PL,Falagiani P. A case of sesame seed-inducedanaphylaxis. Allergy 1999;54(5):526-7

44. Kägi M, Wüthrich B. Falafel-burgeranaphylaxis due to sesame seed allergy.Lancet 1991;338(8766):582

45. Moneret-Vautrin DA, Kanny G, Morisset M,Parisot L. The food anaphylaxis vigilancenetwork in France. ACI Int 2003;15:155-9

46. Derby CJ, Gowland MH, Hourihane JO.Sesame allergy in Britain: A questionnairesurvey of members of the AnaphylaxisCampaign.Pediatr Allergy Immunol 2005;16(2):171-5

47. Panizzolo C, Tura M, Barbato A. Anaphylaxisto sesame paste.Allergie et immunologie 2005;37(1):34-5

48. Pajno G B, Vita D, Passalacqua G, Magazzù G,et al. Anaphylaxis to sesame in a patient withceliac disease.AAAAI 56th Annual Meeting 2000

49. Pajno GB, Passalacqua G, Magazzu G,Barberio G, Vita D, Canonica GW. Anaphylaxisto sesame. Allergy 2000;55(2):199-201

50. Chiu JT, Haydik IB. Sesame seed oilanaphylaxis. J Allergy Clin Immunol1991;88(3 Pt 1):414-5

51. Hayakawa R, Matsunaga K, Suzuki M,Hosokawa K, Arima Y, Shin CS, Yoshida M.Is sesamol present in sesame oil?Contact Dermatitis 1987;17(3):133-5

52. Kanny G, De Hauteclocque C, Moneret-Vautrin DA. Sesame seed and sesame seedoil contain masked allergens of growingimportance. Allergy 1996;51(12):952-7

53. Eberlein-Konig B, Rueff F, Przybilla B.Generalized urticaria caused by sesameseeds with negative prick test results andwithout demonstrable specific IgEantibodies.J Allergy Clin Immunol 1995;96(4):560-1

54. Pecquet C, Leynadier F, Saiag P. Immediatehypersensitivity to sesame in foods andcosmetics.Contact Dermatitis 1998;39(6):313

55. Phan TG, Strasser SI, Koorey D,McCaughan GW, Rimmer J, Dunckley H,Goddard L, Adelstein S. Passive transfer ofnut allergy after liver transplantation.Arch Intern Med 2003;163(2):237-9

56. Keskinen H, Ostman P, Vaheri E, Tarvainen K,Grenquist-Norden B, Karppinen O, Nordman H.A case of occupational asthma, rhinitis andurticaria due to sesame seed. [Letter] ClinExp Allergy 1991;21(5):623-4

57. Alday E, Curiel G, Lopez-Gil MJ, Carreno D,Moneo I. Occupational hypersensitivity tosesame seeds. Allergy 1996;51(1):69-70

58. Moneret-Vautrin DA, Kanny G, Lagrange AOccupational asthma caused by organicsubstances (French) Rev Med Interne1994;15 Suppl 2:216s-225s

59. Stern A, Wuthrich B. Non-IgE-mediatedanaphylaxis to sesame.Allergy 1998;53(3):325-6

60. Fremont S, Errahali Y, Bignol M, Metche M,Nicolas JP. Allergenicity of oils. [French]Allerg Immunol (Paris) 2002;34(3):91-4

61. van Dijk E, Dijk E, Neering H, Vitanyi BE.Contact hypersensitivity to sesame oil inpatients with leg ulcers and eczema.Acta Derm Venereol 1973;53(2):133-5

62. van Dijk E, Neering H, Vitanyi BE. Contacthypersensitivity to sesame oil in zinc oxideointment. [Dutch] Ned Tijdschr Geneeskd1972;116(50):2255-9

63. Neering H, Vitanyi BE, Malten KE, vanKetel WG, van Dijk E. Allergens in sesameoil contact dermatitis.Acta Derm Venereol 1975;55(1):31-4

64. Kubo Y, Nonaka S, Yoshida H. Contactsensitivity to unsaponifiable substances insesame oil.Contact Dermatitis 1986;15(4):215-7

65. Brockmann SO, Piechotowski I, Kimmig P.Salmonella in sesame seed products.J Food Prot 2004;67(1):178-80

66. Unicomb LE, Simmons G, Merritt T, Gregory J,Nicol C, Jelfs P, Kirk M, Tan A, Thomson R,Adamopoulos J, Little CL, Currie A, Dalton CB.Sesame seed products contaminated withSalmonella: three outbreaks associated withtahini.Epidemiol Infect 2005;133(6):1065-72

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Glycine max (Soja hispida)Family: Fabaceae (Leguminosae)Commonnames: Soybean, Soya Bean,

Soy, SoyaSourcematerial: Dried beansFor continuous updates:www.immunocapinvitrosight.com

f14 Soybean

Allergen Exposure


Soybean is the world's most importantlegume. Proteins of Soybeans are widely usedin animal and human nutrition.

There are more than 200 varieties ofSoybean. Soya is grown for edible greenpods, half-ripe seeds, and dry seeds. Podsare rough and hairy and contain 3 or 4 seeds;these are smooth and vary in colour, beingblack, brown, green, yellow or white. Theseeds have a higher protein content than doany other edible seeds.

During seed maturation, the membranousinner epidermis of the endocarp detachesfrom the pericarp, or pod wall, to cover theseed, influencing to varying degrees theluster of the seed surface (1). Different seedluster phenotypes have been described,including “shiny”, “intermediate”, “dull”,“bloom”, and “dense bloom” (2).

Soy protein consists of 136phytochemicals (3). Soybean containsgoitrogens, tannins, phytoestrogens, flatus-producing oligosaccharides, phytate, andsaponins (4). Some of Soybean's phyto-chemicals have oestrogenic effects (5).

Environment

The bean can be used fresh, or can beprocessed into Soybean flour, flakes, grits, orSoy milk, or it can be pressed for oil. Soybeansare a primary foodstuff in Asia. Soybean oilis put to many uses. It is included in salad oil,margarine and industrial components, and in

linoleum and glue in the plywood industry,where it is considered an occupationalallergen. Soy sauce, or shoyu, is a fermentedproduct of Soybean and Wheat.

Imitation cheeses may replace 30% ofcasein protein with Soya protein. Soya mince,a good source of protein, may be used as areplacement for meat or fish. Unlike otherpulses, Soya beans have a healthy balance ofamino acids and contain significant amountsof (mostly unsaturated) fat.

Unexpected exposure

Soya protein is found almost ubiquitouslyin processed foods, even in butter andmargarine (6). In recent times, bread,including white bread, may contain Soyflour. In a Spanish study, the most frequentsources of hidden Soy allergens were boiledham, sausages, cheese puffs, precookeddishes, desserts and gravy (7).

Reactions after unexpected food exposure

Soy proteins are frequently found in meatproducts, bread, and a wide range ofindustrially produced food products (8).Examples are Spanish sausage products (9),pizza (10), and candy containing Soylecithin (11).

Soybean lecithin may be used in the bakingindustry, and baker's asthma as a result ofexposure to Soybean lecithin has beendescribed (13). Residual protein in Soylecithin may also be involved in baker'sasthma (12-13). Soybean lecithin allergy hasbeen described in a child (11). Allergicreactions have also been reported to aSoybean protein isolate that comprised 50%of a dietary powder. Of these 20 patients,

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f14 Soybean85% were found to have IgE antibodiesagainst Gly m 4, as well as to the major birchpollen allergen Bet v 1, suggesting anassociation of Birch pollen and Soy foodallergy. Seventeen patients experienced facial,oropharyngeal, and/or systemic allergicsymptoms within 20 minutes after ingestingthe Soy product for the first time (14).

Soya bean oil is extracted from theSoybean and, if not purified, may stillcontain allergens, resulting in allergicreactions (15-16).

In a review of the role of hidden allergensin allergic reactions in Spanish patients, allthe reactions caused by hidden allergens oflegumes occurred in Soy-allergic patients,except for 1 lentil-allergic patient. Thirty-nine percent of the Soy-allergic patients hadsome reaction caused by Soy as a hiddenallergen. The most frequent sources ofhidden Soy allergens were boiled ham,sausages, cheese puffs, precooked dishes,desserts and gravy (7).

Several fatal reactions to Soy recorded inyoung asthmatics with known Peanut allergybut unrecognised sensitivity to Soy (17)reinforce the importance of proper labellingof food and the need for education ofpatients, school staff and healthcarepersonnel. Soybean is more frequently usedas a substitute and constituent in manydifferent foods, and therefore a higherfrequency of adverse reactions to Soybeancan be expected.

Interestingly, the transfer of Egg,Peanut, and Soybean sensit isationfollowing bone marrow transplantationhas been reported (18).

Allergens

Seed proteins in Soybean consist of 2 majorfractions that account for 70% to 80% ofthe total protein: 11S albumins and 7Sglobulins. Approximately 6% of Soybeanproteins are classified as inhibitors of trypsinand chymotrypsin, and approximately 0.5%are sugar-binding lectins. The 2 major classesof inhibitors are the Kunitz trypsin inhibitor,which inhibits trypsin, and the Bowman-Birkinhibitor, which inhibits both trypsin andchymotrypsin. These inhibitors and lectins

can impair the nutritional quality and safetyof Soy-based diets unless removed orinactivated (19-20).

There are at least 21 allergenic proteinsin Soybean, ranging from 14 to78 kDa, thatmay result in IgE binding (21-24). A Kunitztrypsin inhibitor (as indicated above),glycinin, the alpha-subunit of beta-conglycinin, a P34/Gly m Bd 30K protein, athiol protease, and a 50-kDa protein withhomology to chlorophyll A-B bindingprotein have been identified as binding IgEof subjects with Soy allergy (20,25-27). Inanother study, sera of Soybean-allergicatopic dermatitis patients have been shownto recognise about 15 Soybean proteins, ofwhich 3 were identified as major allergens:Gly m Bd 60K, Gly m Bd 30K, andGly m Bd 28K (28).

In a study of 10 Soybean varieties,including those with a “dull” phenotype andthose with a “shiny” phenotype, a 7 kDaband was present in all varieties except inthose with a “shiny” phenotype. In in vitrotests, the varieties with a “shiny” phenotypecontained fewer allergens than the othervarieties studied. However, skin testingfound no response differences among theSoybean varieties (2).

Soybean hulls also contain at least 3unique main allergens; those with sizes of8, 7.5, and 7 kDa have been identified (29).A large quantity of Soybean hydrophobicprotein (HPS), a potentially hazardousallergen that causes asthma in Soybean dust-allergic individuals, is synthesised in theendocarp of the inner ovary wall anddeposited on the seed surface duringdevelopment. Its precise amount variesamong Soybean cultivars and is greater ondull-seeded phenotypes (1).

During the process of harvesting, transportand storage, microbial and moldcontamination can raise the temperature ofSoybeans to 75 °C or higher. In a study usingserum from 68 Soybean asthmatic subjects, itwas demonstrated that the heat during storageand transport of Soybeans could generate 2new allergen determinants or increase epitopeexposure as a result of conformationalchanges. However, the clinical significance ofthis was not assessed (30).

202

f14 SoybeanHydrolysis or fermentation of Soybean

in the manufacture of fermented Soybeanproducts, including miso, tempeh, tofu, andmold-hydrolyzed Soy sauce, has been shownto reduce allergenicity. Depending on theextent of hydrolysis or fermentation, aproportion of Soybean allergens may remainin the processed vegetable proteins (31). Ina study of sera of patients with delayedhypersensitivity to fermented Soybean, 6allergens, including 3 of 38, 28, and 26 kDa,were demonstrated (32). Properly manu-factured Soy sauce is reported to have noresidual allergic activity (33).


Gly m 1, a 7-8 kDa protein, a HPS, Soybeanhydrophobic protein, a major allergen (29-30,34-40).

Gly m 2, an 8 kDa protein, a major allergen(29-30,34,36,41).

Gly m 3, a 12-15 kDa protein, a profilin, amajor allergen (25,34,42-44).

Gly m 4, a Bet v 1 homologue (Group 1Fagales-related protein), a major allergen,previously known as Gly m SAM22(14,25,34,45).

Gly m 2S Albumin, a 2S Albumin (46-48).

Gly m 39kD, a 39 kDa protein, a majorallergen (47,49).

Gly m Bd28K, a 28 kDa protein, a 7S Vicilin-like globulin, a major allergen (50-56).

Gly m Bd30K, a 30-34 kDa protein, a thiolprotease of the papain superfamily, a majorallergen, also known as P34. (21,26,57-66).

Gly m Lectin, lectin, SBA, an agglutinin, amajor allergen (67).

Gly m Bd 60K, a 63-67 kDa protein, a majorallergen (28,43).

Gly m TI, a 20 kDa protein, a trypsininhibitor, a major allergen (27,47,68-70).

Gly m Oleosin, an oleosin (71).

Gly m IFR, an isoflavone reductase (72).

Gly m Glycinin G1, a glycinin, a majorallergen (73).



A class 1 chitinase has been isolated fromSoybean seed coat (74). Its allergenicity wasnot assessed.

Different Soybean allergens are involvedin inhalation and food allergy. Furthermore,the allergens involved in occupationalasthma caused by Soybean flour arepredominantly high-molecular-weightproteins that are present in both the hull andflour of Soybeans; they are different fromthe allergens that cause asthma outbreaksfrom Soybean dust, allergens that are mainlylow-molecular-weight proteins concentratedin the hull, e.g., Gly m 1 (36,75). AirborneSoybean hull proteins are known causes ofasthma epidemics around harbours and Soyprocessing plants, whereas Soy flour dustproteins may cause occupational allergy infood and feed industries (76). Individuals inrural areas where Soybean is grown andharvested may also be exposed to Soybeandust by inhalation (77).

Nonetheless, heterogenous sensitisationto Soybean allergens appears to occur. Anevaluation was done of the main Soybeanhull allergens using the sera of 18 asthmaticpatients affected by the Soybean dust asthmaepidemic in Barcelona. allergen-specific IgEin 15 of the 18 (83.3%) sera wasdemonstrated. In 11 sera, allergens of 8, 7.5and 7 kDa were detected, which are themolecular weights described for Gly m 2,Gly m 1A and Gly m 1B, respectively. In 3sera, an allergen with an estimated size of8.2-8.3 kDa and 4 others of 25-36 kDa weredetected. The study confirmed that Soybeanhulls contain major allergens and additionalhigher-molecular-weight allergens, whichselectively bind specific IgE of the sera thatdo not react with the 3 low-molecular-weight components; there is a dichotomousand non-overlapping pattern (29). The sameauthors demonstrated that in occupationalasthma in Soybean-exposed bakers, IgE-binding occurs mainly to high-molecular-weight allergens: none of the patientsshowed IgE-reactivity against the low-molecular-weight protein Gly m 1, and only

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f14 Soybean1 patient showed IgE-reactivity to theSoybean hull allergen Gly m 2 (36).

Similarly, in a recent study to determinethe clinical characteristics of Soy allergy inEurope, the pattern of IgE reactivity againstproteins with molecular weights of betweenapproximately 10 and 70 kDa was highlyindividual among the patients and did notcorrelate with the severity of symptoms (78).

In Soybean food allergy, the mostimportant allergen is a protein termed P34(Gly m Bd30K), which is abundant in theseeds and other parts of the plant (2).

The low-molecular-weight Soybeanallergens Gly m 1 and Gly m 2 are found inSoybean dust. Gly m 1, although abundantin Soybean dust, occurs in all parts of theSoybean plant at all stages of growth; butthe telae (hulls) and pods are by far therichest source (79). These 2 allergens wereshown to be responsible for epidemic asthmaoutbreaks resulting from Soy dust (36).Gly m 1 occurs in the form of isoallergensnamed Gly m IA (protein S2) and Gly m IB(protein S1), which were recognised by IgEantibodies from 95% of patients whosuffered asthma attacks during these asthmaoutbreaks of 1987 and 1988 in Cartagena,Spain (39).

Gly m 3 is a profilin, a panallergen. In astudy of serum from 13 Soybean-sensitisedsubjects, IgE antibodies to recombinantGly m 3 was detected in 9 (69%) (43).

A study was done of 22 patients allergicto Birch pollen who also had Soy allergy,and among whom 10 experienced symptomslocalised to the oral cavity, while 6 had amore severe reaction following a Soychallenge. Gly m 4-specific IgE was foundin 96% (21/22) of the patients. All patientshad Bet v 1-specific IgE antibodies, and 23%(5/22) had positive Bet v 2 results. Gly m 4is a Bet v 1 homologue. In IgE immuno-blotting, 25% (6/22) of the patientsrecognised Gly m 3 (profilin), and 64% (14/22) recognised other Soy proteins. IgEbinding to Soy was at least 80% inhibited byBirch pollen and 60% inhibited by rGly m 4in 9 of 11 sera tested. Seventy-one percent(67/94) of highly Bet v 1-sensitised patientswith Birch pollen allergy were sensitised to

Gly m 4, and 9 (9.6%) of those patientsreported Soy allergy, confirming that Soybeanis a Birch pollen-related allergenic food. Theauthors concluded that Gly m 4 is the majorSoy allergen for patients allergic to Birchpollen who also have Soy allergy (25).

Similarly, in a study investigating IgE-mediated reactions to a Soy-containing dietfood product in patients allergic to Birchpollen, significant IgE binding wasdemonstrated to the Soy isolate rSAM22(rGly m 4) in 17 of 20 patients. Otherallergenic proteins of 17 kDa (15/20), 22 kDa(1/20), and 35 to 38 kDa (2/20) were alsoisolated from the Soy isolate (14).

Targeting Gly m 4 in diagnosticassessment may facilitate an improvementof diagnostic sensitivity. This substance wasused as a allergen-specific reagent in a studyof 22 individuals with pollen-related allergyto Soybean. While only 10 out of the 22(45%) showed positive in a Soybean extract-based test, all but 1 (96%) showed IgEbinding to rGly m 4 coupled to streptavidin-coupled ImmunoCAP tests (25,80).

Soybean seeds contain a pair of 2Salbumin storage proteins, AL1 and AL3.These 2S albumins were shown to be stableto heat and chemical treatments (46).Soybean 2S albumins have been reported tobe minor allergens in a British patientpopulation assessed (48).

Gly m Bd 28 K is a major Soybeanglycoprotein allergen. It was originallyidentified as a 28 kDa polypeptide inSoybean seed flour. In a study of sera fromSoy-sensitised adults, all sera contained IgEantibodies that recognised the C-terminalregion of this allergen. Gly m Bd 28 Kcontains 2 cupin domains (56).

Gly m Bd 30K is also known as a Soybeanoil-body-associated glycoprotein that ishomologous to Der p (or Der f) 1, a majorallergen of House dust mite, classified underthe Papain superfamily (28). Gly m Bd 30K(P34) is an outlying member of the Papainsuperfamily of cysteine proteases. It isexpressed in developing Soybean seeds andmay be involved in the defence againstPseudomonas infection. P34 was reportedto be the major allergen of Soybean seed and

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f14 Soybeanis present in processed food products thatcontain Soybean protein. In an evaluationof Soybean accessions, all contained similarlevels of P34. Wild relatives of Soybean werealso shown to contain P34. Extracts fromall were shown to bind IgE antibodies frompatients with clinically significant Soybeanallergy (66).

Sensitisation to Gly m TI, a trypsininhibitor, was evaluated in 14 bakerssuffering from workplace-related respiratorysymptoms and sensitised to Soybean. Gly m TIwas found to be a major inhalant Soybeanallergen, recognised by IgE antibodies in seraof 86% of the group. The Soybeanlipoxidase was also found to be a majorallergen in this group (69).

Soybean trypsin inhibitor was alsoevaluated in sera of 5 patients with atopicdermatitis and a positive food challenge toSoybean, and found to bind to IgE antibodiesin only 20% of these patients (27).

Soybean oleosins are a family of smallproteins involved in the formation ofSoybean oil bodies; they are similar toPeanut oleosins. Oil bodies are smallorganelles that hold the reserve oils of seedsand consist mainly of triglycerides,phospholipids, and a few polypeptides (21).In a study of IgE binding with Peanutoleosin, the phenomenon was demonstratedin 3 of 14 sera of patients who had sufferedan allergic reaction to Peanut; the mainreacting bands had a molecular sizeestimated at approximately 34 kDa,approximately 50 kDa and approximately68 kDa, and the size was thought tocorrespond to oleosin oligomers. The sameoccurred with crude Soybean oil fractions,with 2 bands of 16.5 and 24 kDacorresponding to monomers, and 2 bandsof 50 kDa and 76 kDa corresponding todimers and trimers, respectively (71).

Soybean glycinin and beta-conglycininrepresent up to a third of protein in Soybean.Glycinin and beta-conglycinin have beencharacterised as major Soybean allergensinvolved in food hypersensitivity (81). Soyglycinin is resistant to processing (82) andstable to degradation by simulated gastricfluid (83).

The 70 kDa subunit of beta-conglycininwas shown to be recognised by 25% ofSoybean-sensitive patients with atopicdermatitis. Data suggests that at least 1epitope is located within a non-glycosylatedfragment consisting of about 50 amino acidresidues. The beta-conglycinin alpha subunithas been demonstrated to be able to induceanaphylaxis through an IgE mediatedmechanism (73).

The storage protein glycinin accounts forabout 35% of the protein content of theSoybean. It consists of 6 subunits, each ofthem consisting of 2 peptide chains (1 acidicand 1 basic) held together by disulfide bonds(84). The acidic peptides were found to beresponsible for much but not all of the IgEbinding activity of glycinin.


Earlier studies of Soybean demonstratedseveral antigenic components withconsiderable cross-reactivity with otherlegume family members (85). While theclinical usefulness of eliminating legumesfrom the diet of allergic patients is disputed,several reports confirm cross-reactivity. Apatient who suffered adverse reactions wheneating Peas, Lentils, Peanuts, Kidney, Limaand Navy beans experienced the most severeepisodes following ingestion of Soybeanproducts (86). A specific IgE antibodyresponse to the Kunitz Soybean trypsininhibitor polypeptide was demonstrated.

Patients experiencing IgE-mediatedsymptoms after ingestion of Pea, Bean, Lentil,Peanut and Soybean have been reported, butno single patient was allergic to all (87).Similarly, in a study of Soybean sensitive-children, a high correlation of concomitantsensitisation to Pea (38/50) and Peanut (41/50) was reported (88). However, thoughstudies have reported in vitro cross-reactivitybetween Peanut and other legumes, e.g. Pea,Kidney beans, and Lentil, this was notsupported by clinical challenge (89). Similarly,in 22 patients who experienced adversereactions to Lentils, 14 also had experiencedimmediate allergic reactions to Chick pea,and 10 to Peanut; none had experiencedadverse effects to Soy or Soy-derived

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f14 Soybeanproducts. Yet all were shown to have allergy-specific IgE to all 4 legumes (90).

It has been suggested that individualsallergic to both Peanut and Soybean haveIgE antibodies binding preferentially to thelarger proteins, while the antibodies of thosereacting only to Soybean bind strongly toproteins in the lower-molecular-weight range(22,24). Studies on 2 patients both allergicto Peanut and Soy showed extensive cross-reactivity between the 2 legume seeds (91).Several major Peanut allergens have beenshown to share epitopes with Soy storageproteins. (For further information, seePeanut f13.)

An 8 kDa allergen prepared fromSoybean hull shows 71% homology with astorage protein from Cow pea and 64%homology with a protein from Pea. A 17 kDaSoy allergen has also been found to cross-react with a Pea allergen (92).

It is therefore apparent that Soy-allergicindividuals may be sensitised to Soybean anda number of other legumes, but may beclinically unaffected by any or all of theselegumes unless a particular cross-reactiveSoybean panallergen is involved.

Soybean contains a number of cross-reactive panallergens that have beencharacterised and may explain the patternsof co-sensitisation reported previously. Withrecent advances in diagnostics, the precisediagnosis of the specific Soy allergensinvolved may allow the deduction ofpotential sensitisation to other legume familymembers that contain the homologousallergen.

For example, Gly m 3, a profilin, is apanallergen. In a study of serum from 13Soybean-sensitised subjects, IgE antibodies torecombinant Gly m 3 was detected in 9 (69%).The rGly m 3 cross-reacted with Bet v 2, theBirch tree pollen profilin. IgE binding to Bet v2 could be inhibited by rGly m 3 (43).

A study was done of 22 Birch pollen-allergic patients also allergic to Soy. Duringfood challenge, 10 patients experienced oralallergy syndrome, and 6 patients had a moresevere reaction. Gly m 4-specific IgE wasfound in 96% (21/22) of the patients. All

patients had Bet v 1-specific IgE antibodies,and 23% (5/22) had positive Bet v 2 results.In IgE immunoblotting, 25% (6/22) of thepatients recognised Soy profilin (Gly m 3),and 64% (14/22) recognised other Soyproteins. IgE binding to Soy was at least80% inhibited by Birch pollen and 60%inhibited by rGly m 4 in 9 of 11 sera tested.Seventy-one percent (67/94) of highly Bet v 1-sensitised patients with Birch pollen allergywere sensitised to Gly m 4, and 9 (9.6%) ofthose patients reported Soy allergy. Theauthors concluded that these results confirmedthat Soybean is another Birch pollen-relatedallergenic food and that Gly m 4 was themajor allergen for patients allergic to Birchpollen and also Soy (25). In a further study,in which the authors assessed 10 Mungbean-allergic subjects with concomitantrespiratory allergy to Birch tree pollen forsensitisation to Vig r 1, a Bet v 1-homolousallergen, it was reported that 90% weresensitised to Gly m 4 (93). Further evidencefor Bet v 1-homologue cross-reactivity wasdemonstrated between Gly m 4, Ara h 8from Peanut, and Pru av 1 from Cherry (45).

In a report on 3 patients who experiencedanaphylaxis to a Soy drink, cross-reactivityof Soy protein with Birch pollen allergenswas identified as the cause of their severereactions. The authors suggested thatpatients with Birch pollen allergy shouldavoid the intake of Soy protein (94).

Soybean glycinin G1 acidic chain has beenreported to share IgE epitopes with Ara h 3from Peanut, with a sequence similarity of62% between the Soy glycinin and Ara h 3from Peanut (95).

Soybean-specific IgE has also beenreported to be cross-reactive with Potato.SPT evaluation for Soybean and fresh Potatowas performed in 177 children of less than4 years of age who were suspected of havingfood allergy. Further, sera from 17 childrenwith suspected Potato allergy and 12children with suspected Soy allergy wereevaluated for IgE antibodies to naturalSola t 2-4 and Kunitz-type Soybean trypsininhibitor (KSTI). Skin reactivity for Soybeanwas demonstrated in 10/177 (5%) and forPotato in 14 (7%). Of those with positiveSPT for Potato, 70% had IgE antibodies to

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KSTI and 75% to Soybean. However, ofthose suspected of having allergy to Soybean,9 (75%) had IgE antibodies to Sola t 2-4.Cross-inhibition was demonstrated forSola t 2-4 and KSTI. The study concludedthat children with suspected food allergyfrequently have SPT reactivity for Soybeanand Potato; and it may be due to cross-reactive IgE antibodies against structurallyaltered Potato allergens, and vice versa: andthat this should be considered whenexamining children suspected of havingSoybean or Potato allergy (96).

Clinical Experience


Soybean may commonly induce symptomsof food allergy in sensitised individuals. Dustfrom Soybean storage or transport has beenreported to result in exacerbation of asthma,and dust from Soybean flour may precipitateasthma in bakers (36,77).

There are 2 main types of Soy food-allergenic reactions. IgE-mediated reactionsmay result in respiratory, cutaneous, andgastrointestinal symptoms, and anaphylaxis.Delayed non-IgE-mediated reactions,including Soy-induced enterocolitis, may beexperienced (21,97-98).

Soybean is often cited as one of the foodsto which children experience IgE-mediatedreactions (99-100). The prevalence of Soybean sensitisation in a group of 317 Italianchildren (median age 5 months) withsymptoms suggesting food allergy was 22%(101.) In another study, 37/78 (47%) ofAustralian children with Cow's milk allergywere reported to react to Soy at a follow-up5 years later (102).

In an analysis of 580 French patients withreactions to food, of whom 60 presented withsevere, near-fatal reactions, Soybean wasimplicated in 30%, the fifth most commoncause after Wheat (39%), Peanut (37%),Crab (34%), and Celery (30%) (103).

Recent studies have also focussed onthreshold levels that precipitate symptoms.In a recent study to determine the clinicalcharacteristics of Soy allergy in Europe, Soy-allergic patients underwent a titrated,

double-blind, placebo-controlled foodchallenge. All patients but 1 respondedprimarily with subjective symptoms to thechallenge, followed by objective symptomsin 11 subjects, with symptoms ranging fromrhinitis up to a decrease in blood pressure.Cumulative threshold doses for allergicreactions ranged from 10 mg to 50 g forsubjective symptoms and from 454 mg to50 g for objective symptoms. The studyconcluded that in a statistical model, 1% ofpatients with Soy allergy would reactsubjectively with 0.21 mg of Soy protein,and objectively with 37.2 mg of Soy protein,and that both the clinical and immunologicbases of Soy allergy in Europe are highlycomplex. None of the patients with Soyallergy reacted to the starting dose of 2 mgof Soy (1 mg of Soy protein) (78). An earlierstatistical model projected that 0.3 g of Soyflour will elicit an allergic response in 1 outof every 100 Soy-sensitive people (104).

A number of studies concluded thatSoybean, among other foods, may be acommon food allergen in atopic dermatitisin children (105). In 165 American patientsaged 4 months to 22 years and having atopicdermatitis, 7 foods (Milk, Egg, Peanut, Soy,Wheat, Cod/Catfish, Cashew) accounted for89% of the positive challenges (106). In anAmerican study, 28% of 53 Soy-sensitivechildren with atopic dermatitis exhibited anallergic response after ingesting less than 0.5g of Soy flour. This corresponds toapproximately 41 mg of Soy protein (107).

There is evidence that Soy allergens maypass to infants through breast milk, resultingin sensitisation. In a study of a selectedpopulation of 59 predominantly breast-fedyoung Australian infants (mean age 26.5weeks) who had moderate to severegeneralised atopic dermatitis, 53 infants(90%) had demonstrable skin reactivity to 1or more of the 5 common food allergens (Eggwhite, Cow's milk, Peanut, Wheat or Soy),and 80% were positive to Egg white (108).

The fact that Soy reactions are not alwaysobviously immediate may confuse theinterpretation of challenge tests. In a re-challenge of 18 Australian infants who hadstabilised after feeding with a non-allergenicdiet, 12 were found to react to formulas that

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previously had not been tolerated. Theinfants (median age 7 1/2 months) weregiven Neocate formula for 2 months andthen underwent a 7-day double-blindplacebo-controlled challenge with theformula previously best tolerated. In 12 ofthe 18 infants, irritability, vomiting,diarrhoea, and/or eczema flares developedduring the challenge. However, only 2showed immediate symptoms. In theremaining 10, symptoms evolved after 4 to7 days of challenge. Adverse reactionsoccurred to a Soy formula in 6 patients, toWhey hydrolysate in 2, and to Caseinhydrolysate in 4 (109).

Although Soybean is considered a“classical food allergen” (89), it has longbeen regarded as a safe food substitute forchildren showing adverse reactions to Cow'smilk. However, about a fourth of Cow'smilk-sensitive patients may become allergicto Soy protein (110-111). It was found thatSoy formula did not lower the cumulativeincidence of atopic disease, as comparedwith Cow's milk (112). Breast-feeding or lessallergenic formulas should be preferred, butsocioeconomic conditions and other riskfactors should be considered (113-114).

Soybean ingestion may result inanaphylaxis, inducing respiratory, cutaneous,cardiovascular, and gastro-intestinalsymptoms, and even death (115-116).Soybean food-dependant exercise-inducedanaphylaxis has been reported (117). Authorshave cautioned that Soy protein may be anunderestimated cause of food anaphylaxis.In a study of anaphylactic reactions to Soy,the majority of patients had a symptom-freeperiod of 30-90 minutes between the earlymild symptoms and the later severe andrapidly worsening asthma (17).

Anaphylaxis to fermented Soybean hasalso been reported. Researchers havehypothesised that the mechanism of late-onset anaphylaxis to fermented Soybeans isdelayed absorption or release into the bowelrather than an immunologic phenomenon.In a Japanese study of 2 patients withdemonstrable skin reactivity to fermentedSoybean and IgE antibodies to Soybean,challenge with 50 g of fermented Soybeanscaused generalised urticaria and dyspnoea

13 hours later in 1 patient. Plasma histamineand tryptase levels were transiently elevatedduring the anaphylactic event (118).

Anaphylaxis had also been reportedfollowing ingestion of Soy drink in 3 Germanindividuals. The authors concluded that thecause of the severe Soy reactions was cross-reactivity of Soy protein with Birch pollenallergens. The authors suggested thatpatients with Birch pollen allergy shouldavoid the intake of Soy protein (94). Otherauthors have also concluded that Birchpollen and Soybean hypersensitivity mayoccur as a result of cross-reactivity; they holdthat Gly m 4, a Bet v 1-homologue, is theallergen causing Soy-related symptoms.Symptoms caused by different Soy-basedcommercial products ranged from OAS toanaphylaxis (25).

In studies in Japan, IgE antibodies toSoybean were measured by the Pharmacia CAPSystem (119-121). Sensitivity and specificitywere 100% and 87%, respectively (119).

Soy dust asthma and epidemic asthma

The allergens involved in causing asthmaoutbreaks are mainly low-molecular-weightproteins concentrated in the hull, whereasthe allergens involved in occupationalasthma caused by Soybean flour arepredominantly high-molecular-weightproteins that are present both in the hull andflour (36).

Epidemic asthma in areas aroundharbours where Soybeans are unloaded fromships has been reported from Barcelona(122), Cartagena (123), Tarragona (124),Valencia (125), A Coruña (125), Naples(126), New Orleans (127), and NewZealand (128). A large number of fatal cases,probably resulting from anaphylaxis, wererecorded. The major allergens involved werefound in the hull of the bean (although theyare also present in other parts of the bean)(37,41,79,123-124,129). All the asthmaticepidemic patients from Barcelona wereshown to have IgE antibodies for Soybean(129), and the prevalence of Soybeansensitivity in the Cartagena incident wasreported to be 89% (130). Soybean hullantigens were also shown to be involved inhypersensitivity pneumonitis (131), and

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f14 Soybeanirritant effects of Soy dust may contributeto the development of respiratory problemsin Soy mill workers (132).

As this suggests, Soybean hull dust mayalso occur at work (for example, in storageareas) and may result in occupationalasthma without flour-related broncho-constriction (133).

Soy dust allergens have been shown tobe sporadically present in the air in a regionwhere Soybeans are extensively grown, andwere most prevalent during the harvestperiod. The highest level recorded was 73ng/m3 (35).

Rhinitis, conjunctivitis and broncho-spasm following the inhalation of Soybeandust from a “bean bag” toy have beenreported (134).

Baker's asthma

Occupational asthma in bakers, millers andworkers in food processing plants may becaused by Soy flour. The reported prevalenceof Soy sensitisation in bakers withworkplace-related respiratory symptomsranges from 19% (135) to 25% (36,136).

The Soybean allergens causingoccupational asthma in exposed bakers wereinvestigated and compared with thoseinvolved in epidemic asthma. The subjectswere 4 bakers and confectioners with work-related respiratory symptoms who wereexposed to Soybean flour. Sensitisation toSoybean flour was demonstrated by allergen-specific IgE evaluation and was confirmedby positive bronchial challenge tests, whichelicited immediate or dual asthmaticresponses. IgE-binding occurred mainly tohigh-molecular-weight allergens, and no oneshowed IgE-reactivity against thepredominant hull allergen Gly m 1. Only 1patient showed IgE-reactivity to the Soybeanhull allergen Gly m 2. The study concludedthat these bakery workers had developedIgE-mediated occupational asthma toSoybean flour and that the allergens involvedin occupational asthma caused by Soybeanflour are predominantly high-MW proteinsthat are present both in the hull and flour;and that these allergens are different fromthe allergens causing asthma outbreaks,

which are mainly low-MW proteinsconcentrated in the hull (36).

Animal food processing plant workersmay also come into contact with Soybeanflour, resulting in sensitisation. In 35 menworking in an animal food processing plant,the most frequent sensitisation was to fishflour (82.9%), followed by carotene(77.1%), Corn (65.7%), Four-leaf clover(62.9%), Sunflower (54.3%), Chicken meat(31.4%), Soy (28.6%), and Yeast (22.7%).(137) There may be a long delay betweenthe initial contact and subsequentsensitisation, as described in a 43-year-oldwoman who developed asthma 6 years afterbeginning work in a food-processing plantin which Soybean flour was used as a proteinextender. Symptoms of sneezing, coughing,and wheezing would begin within minutesof exposure to Soybean flour and resolve 2hours after exposure ceased (92).

Other reactions

Food protein-induced enterocolitis (FPIES)in infants as a result of Soy ingestion hasbeen reported by a number of authors.Cow's milk is also a prominent cause,although other foods may also be implicated(138-140). FPIES is a severe cell-mediatedgastrointestinal food hypersensitivity and ischaracterised by symptoms occurring severalhours after ingestion of a food or foods.Symptoms typically begin in the first monthof life along with failure to thrive and mayprogress to acidemia and shock. Typicalsymptoms of FPIES are delayed (median 2hours) and include vomiting, diarrhoea,lethargy and dehydration (141). Resolutionof symptoms occurs after removal of thecausal protein from the diet, but symptomsrecur with a characteristic pattern on re-exposure. Approximately 2 hours afterreintroduction of the protein, vomitingensues, followed by an elevation of theperipheral blood polymorphonuclearleukocyte count and diarrhoea. Lethargy andhypotension may also occur. IgE antibodiesto the causal food is generally not present(140,142). An early study on a small groupof children with “Soy intolerance”(suspected enterocholitis) was not conclusivein terms of the role of antibodies, although

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f14 SoybeanIgE antibodies to several fractions werefound. The source and quality of the Soyprotein used in challenge tests was notdeclared (143). It has been proposed thatthe presence of IgE antibodies to the allergeninvolved may be helpful in predicting long-lasting sensitivity (140).

Eosinophilic esophagitis is a disorderidentified in patients with symptomssuggestive of gastroesophageal reflux diseasebut unresponsive to conventional refluxtherapies. In a study of 146 patientsdiagnosed as having eosinophilicesophagitis, as evaluated by skin prick andatopy patch testing, Egg, Cow's Milk, andSoy sensitivity were identified mostfrequently by skin prick testing, whereasCorn, Soy, and Wheat sensitivity wereidentified most frequently with atopy patchtesting. In more than 75% of patients witheosinophilic esophagitis, both outwardsymptoms and esophageal inflammationwere significantly improved with dietaryelimination of foods (144).

Symptoms of allergy to Soy may beatypical. A 39-year-old woman was reportedwho complained of respiratory symptomssuch as dry cough and mild dyspnoeaoccurring after the ingestion of foodcontaining Soya (145). An associationbetween recurrent serous otitis media andfood allergy has been described in 81 of 104patients. An elimination diet resulted in asignificant amelioration of the disease in86% of the patients, and a challenge dietprovoked recurrence of symptoms in 94%.The highest frequency of sensitivity was seenwith Milk, Wheat, Egg, Peanut, Soy andCorn (146).

After measuring Soy-specific IgA and IgGantibodies in children with Soy intoleranceand with coeliac disease, investigatorsconcluded that the observed increase of IgAantibodies correlated to mucosal injury,while the increase of IgG antibodies wasrelated to the increase of antigen entry (147).

Mold contamination of Soybean may occurwith storage and transport and theoreticallymay result in sensitisation, depending on theorganism involved (30). Aflatoxins have beenreported in Soybeans (148).

Various Wheat and Soy protein sources,including the Soy protein isolates used tomake infant formulas, have been said to becausally involved in to juvenile or insulin-dependent diabetes mellitus (IDDM) (149).

Unexpected allergens from otherorganisms may someday occur in Soy.Progress in biotechnology, which allows theintroduction of alien genes for the purposeof improving properties of crops, has openedthe way for new potential allergy risks. Thefact that alien allergens can be and have beenintroduced into Soybean (150) hasstimulated the discussion of potentialchanges of allergenicity in transgenic food(151-152). But it is obvious that the analysisof potential risks for sensitisation is difficultuntil a human population has been exposed.

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Triticum speltaFamily: Poaceae (Gramineae)Commonnames: Spelt, Spelt wheatSourcematerial: Untreated planting seedsSynonym: Triticum aestivum

subsp. speltaFor continuous updates:www.immunocapinvitrosight.com

f124 Spelt wheat

Allergen Exposure


Spelt (Triticum spelta) is a hexaploid speciesof Wheat. Spelt was an important staple inparts of Europe from the Bronze Age tomedieval times; it now survives as a relictcrop in Central Europe and has found a newmarket as a health food. Spelt has a complexhistory. It is sometimes considered asubspecies of the closely related speciesCommon wheat (T. aestivum), in which caseits botanical name is considered to beTriticum aestivum subsp. spelta (1). Fromgenetic evidence, it appears to haveoriginated as a hybrid of domesticatedtetraploid Wheat such as Emmer wheat andthe wild goat-grass Aegilops tauschii (2).

“Wheats”, as defined by US and Codexstandards, can have either 28 chromosomes(e.g., for Durum wheat) or 42 chromosomes(e.g., for Common wheat or Club wheat).Spelt has the same number of chromosomesand the same 3 “genome blocks” asCommon wheat and Club wheat (3).Scientific evidence shows that there is a highpercentage of homology between theproteins of Spelt and those of Commonwheat (4).

Environment

Spelt may be ground into flour for Wheat-like products, e.g., Spelt pasta. Speltproducts are available mostly from specialitystores, although Spelt flour is becomingmore easily available, being recently sold inUK supermarkets.

In Germany, the unripe Spelt grains aredried and eaten as Grünkern, which literallymeans “green grain”.

The Dutch distil Spelt to make a curiositygin, jenever. Beer brewed from Spelt issometimes seen in Bavaria (5).

Spelt matza is baked in Israel for Passoverand is available in some US grocery stores (1).

Unexpected exposure

Spelt has recently been marketed as safe forWheat-allergic or Wheat-intolerantindividuals. This claim is anecdotal and notscientifically supported.

Wheat-allergic patients can react asreadily to Spelt as they do to Commonwheat. Furthermore, Spelt is not suitable forpeople with coeliac disease.

Allergens

The following allergen has beencharacterised:

Tri s LTP, a 9 kDa lipid transfer protein (6).

217


As Spelt and Common wheat are from thesame genus, Triticum, a high percentage ofhomology between the proteins of Spelt andthose of Common wheat is expected. Thisis supported by laboratory data showinghigh specificity of real-time Wheat PCR indetecting Spelt and other Triticum species(7). Furthermore, the National Center forBiotechnology Information Entrez data basecontains 97 sequences for Spelt proteins, andthese sequences are > 95% identical to“Common wheat” protein sequences. Inaddition, the single sequence for a Speltprotein that is known to be a Wheat allergen,alpha-gliadin (accession ABB17533), is 99%identical to a homologous Wheat protein(accession CAB76957). Therefore, cross-reactivity may be similar to that reportedfor Wheat. See Wheat f4.

As Spelt contains a lipid transfer protein,cross-reactivity with other plants containinglipid transfer proteins is possible. This isdemonstrated by a report of occupationalsensitisation to Spelt that was associatedwith symptoms on ingestion of several lipidtransfer protein-containing foods. Inparticular, the individual was unable totolerate the cross-reactive foods Peach andApricot (6).

Clinical Experience


Unexpectedly, allergic reactions to Spelt havenot been commonly reported. This may bea result of Spelt products not beingcommonly available. Reported adversereactions are expected to increase as Speltand Spelt products become increasinglymore accessible. Adverse reactions may besimilar to those reported to Wheat. SeeWheat f4.

A case report describes an individual witha demonstrated allergy to Common Wheatwho had several similar anaphylacticreactions after consuming Spelt (8).

Occupational dermatitis was reported ina 25-year-old woman, following exposureto large amounts of Spelt in her occupational

setting. This was followed by generalisedreactions to other foods. Within few monthsafter avoiding Spelt and changing heroccupation, her food symptoms andsensitisation disappeared, and the patientcould reintroduce into the diet all foods thatshe previously did not tolerate, except forPeach and Apricot. A lipid transfer proteinin Spelt was identified as the dominantallergen and responsible for the cross-reactivity (6,9).

References1. Wikipedia contributors, "Spelt", Wikipedia,

The Free Encyclopedia, http://en.wikipedia.org/w/index.php?title=Spelt&oldid=209778316(accessed May 11, 2008)

2. Blatter RH, Jacomet S, Schlumbaum A.About the origin of European spelt (Triticumspelta L.): allelic differentiation of the HMWGlutenin B1-1 and A1-2 subunit genes.Theor Appl Genet. 2004 Jan;108(2):360-7

3. Slageren, M.W. van (1994) Wild wheats: amonograph of Aegilops L. and Amblyopyrum(Jaub. & Spach) Eig (Poaceae). WageningenAgriculture University Papers 1994-7;82-94

4. Yunginger JW. Food ingredient labeling: howmany ways can wheat be spelt?Allergy Proc 1994;15(4):219-20

5. Dostálek P, Hochel I, Méndez E, Hernando A,Gabrovská D. Immunochemical determinationof gluten in malts and beers.Food Addit Contam 2006;23(11):1074-8

6. Pastorello EA, Farioli L, Robino AM,Trambaioli C, Conti A, Pravettoni V. A lipidtransfer protein involved in occupationalsensitization to spelt. [Letter] J Allergy ClinImmunol 2001;108(1 Pt 1):145-6

7. Sandberg, M, Lundberg, L, Ferm, M, et al.Real Time PCR for the detection anddiscrimination of cereal contamination ingluten free foods.Eur Food Res Technol 2003;217:344-9

8. Friedman HM, Tortolani RE, Glick J, Burtis RT.Spelt is wheat.Allergy Proc 1994;15(4):217-8

9. Robino A., Pravettoni V., Farioli L.,Trambaioli C., Conti A., Pastorello E.A.Occupational sensitisation caused by spelt: acase report [Poster] 8th InternationalSymposium on Problems of Food Allergy,Venice. 2001, March 11-13

f124 Spelt wheat

218

Beta vulgarisFamily: Amaranthaceae

(Chenopodiaceae)Commonnames: Sugar-beet seed, Sugar

beet seedSourcematerial: Dried seedsSee also: Sugar-beet w210For continuous updates:www.immunocapinvitrosight.com

f227 Sugar-beet seed

Allergen Exposure


Beta vulgaris produces sugar from its large,white, conical tap roots. Large-scalecultivation in Europe began during theNapoleonic wars when the British blockadestopped imports of sugar cane from the WestIndies. The Sugar-beet is native to Europeand the Middle East but is now cultivatedworldwide as a commercial sugar crop intemperate climates. About a third of all sugarproduction in the world is derived from thisplant, but this sugar is considered inferiorto cane sugar because it does not crystalliseas well and is absorbed more quickly by thebody

Sugar beet is an annual or biennial plantgrowing to 1.5 m. The leaves are oval inshape and dark green or reddish in colour,frequently forming a rosette from theunderground stem. The flowers are smalland green or red. The Sugar-beet seed is tiny– about half the size of a grain of rice – andrough and bumpy, growing in clusters insidethe dry fruit.

Environment

Beets and their relatives are grownthroughout the world for human and stockfood. The seeds, apart from some isolatedculinary uses (as in India and Pakistan), serveas an animal feed.

Allergens

No allergens from the seed of this plant haveyet been characterised, but a number ofproteins have been isolated from the leaves.

A protein with homology to the chitin-binding (hevein) domain of chitin-bindingproteins, e.g., class I and IV chitinases, hasbeen isolated from the leaf of Sugar-beet (1-2). The allergenicity of these chitinases wasnot assessed, and it may well be present onlyif the plant is stressed.

Two novel, nearly identical antifungalproteins, IWF1 and IWF2, were isolatedfrom Sugar-beet leaves. The proteins wereshown to be related to the family of plantnon-specific lipid transfer proteins (3).


An extensive cross-reactivity among thedifferent individual species of the genuscould be expected but has not been reportedto occur clinically as yet (4).

Clinical Experience


Sugar-beet seed may uncommonly induceallergy symptoms in sensitised individuals,predominantly in occupational settings suchas the animal feed industry and farms.

In a prospective open study over 8months in a group of 10 atopic children withrepeated urticaria, based on oral challengetests along with history, there were 3 casesof allergy to food colourings. Clinicalfeatures were mainly skin symptoms,

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f227 Sugar-beet seedsometimes associated with GI manifestationswhich were non specific. Removal of thecolorants resulted in the disappearance ofthe symptoms in a child (Red cochineal) andregression of symptoms in two others (Redcochineal, Red beet) (5). It was not clearwhether this is beetroot or sugar beet butboth are closely related family members.

Other reactions

The fresh leaf may cause poisoning due tothe 1% oxalic acid content. The leaf mayalso contain dangerous levels of HCN and/or nitrates and nitrites.

References1. Nielsen KK, Nielsen JE, Madrid SM,

Mikkelsen JD. Characterization of a newantifungal chitin-binding peptide from sugarbeet leaves.Plant Physiol 1997;113(1):83-91

2. Berglund L, Brunstedt J, Nielsen KK, Chen Z,Mikkelsen JD, Marcker KA. A proline-richchitinase from Beta vulgaris.Plant Mol Biol 1995;27(1):211-6

3. Nielsen KK, Nielsen JE, Madrid SM,Mikkelsen JD. New antifungal proteins fromsugar beet (Beta vulgaris L.) showinghomology to non-specific lipid transferproteins.Plant Mol Biol 1996;31(3):539-52


5. Zenaidi M, Pauliat S, Chaliier P, Fratta A,Girardet JP. Allergy to food colouring. Aprospective study in ten children. [French]Tunis Med 2005;83(7):414-8

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Castanea sativaFamily: FagaceaeCommonnames: Sweet chestnut,

European chestnut,Spanish chestnut

Sourcematerial: Shelled nutsSee also: Chestnut t206For continuous updates:www.immunocapinvitrosight.com

f299 Sweet chestnut

Allergen Exposure


Sweet Chestnut is a shade-tolerant deciduoustree native to southeastern Europe, AsiaMinor, and North Africa. Several ediblespecies of Chestnut are grown around world,the 4 main species being Sweet chestnut (C.sativa), Chinese chestnut (C. mollissima),Japanese chestnut (C. crenata), andAmerican chestnut (C. dentata). Americanchestnut has been decimated by parasites.China, Korea and Italy are the world'slargest producers of Chestnuts. The principalEuropean producers are Italy, Spain,Portugal, France, and Greece.

The tree can attain a height of 35 m anda trunk diameter of 2 m. The bark is deeplygrooved or fissured in a net-shaped(retiform) pattern, sometimes in a spiral. Theflowers of both sexes are borne in 10-20 cm-long, upright catkins, the male flowers inthe upper part of the tree and the femaleflowers in the lower part. By autumn thefemale flowers, in bunches of 2 or 3 (and upto 7), develop into light-green fruit cupules(husks) covered with sharp spines; eachcupule usually contains 2 dark, shiny, red-brown nuts and, with the nuts ripened, isshed during October. Trees start to bear nutswhen 30-40 years old.

Raw nuts have a bitter taste from tannins,which improves considerably with cooking,developing into a sweet and nutty flavour,with a texture like a firm baked potato -unlike other nuts, which are crunchy.Chestnuts, unlike other nuts, contain verylittle fat or oil (2-3%), compared to over50%; they consist mainly of complexcarbohydrate (50%) and water (40-45%),with small amounts of protein (5-10%).They contain no cholesterol. They have beenpart of the staple diet and a major source ofcomplex carbohydrate in Southern Europe,Turkey and Asia for centuries.

Environment

Edible Chestnuts have been grown forculinary purposes for centuries and can beconsumed fresh, boiled, grilled, or roasted.They can be frozen or pureed for desserts orconfectionery, or used in stuffing or as agarnish. Dried Chestnuts should be soakedin water, cooked, and then treated as fresh.

Traditionally, Chestnuts are roasted overan open fire or in the oven. They can bedried, ground and used as flour in breadsand puddings, or as a thickener in soups.The roasted nut can be a coffee substitute.Some notable specialties include porridge(Italy) and Chestnuts preserved in sugar(marron glacé, a French delicacy). TheCorsican variety of polenta is made withSweet chestnut flour. A variety of Corsicanbeer has Chesnut as one of its ingredients.

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f299 Sweet chestnutAllergens

Chestnut is the third most-prevalent foodallergen among both adult and pediatricallergy patients in Korea. At least 21 IgE-binding components have been isolated, and9 protein bands appear to be major allergens.A heat- and digestion-labile 24 kDa proteinwith homology to a legume protein of Oakacorn was reported to have the highestbinding intensity (1). The 24 kDa componentbound to more than 50% of asymptomaticChestnut-sensitised subjects, with minimalbinding in symptomatic Chestnut-sensitisedsubjects; and a component of 29 kDa boundto more than 50% of symptomatic Chestnut-sensitised subjects, with minimal binding inasymptomatic Chestnut-sensitised subjects.A later study further evaluated these 2components, the 24 and 29 kDa allergens.Simulated gastric digestion decreased IgEbinding of the most significant allergens,except the 24 kDa one, while minimalchanges were noted to occur through SIF(intestinal enzymes). Boiling treatment coulddecrease IgE binding components of themost significant allergens, including the24kDa one (2).


Cas s 5, a chitinase, an approximately 32kDa protein, a major allergen (3-9).

rCas s 5 (3).

Cas s 8, a Lipid Transfer Protein, a 9.7 kDaprotein, a major allergen (10-12).

Cas s 5 belongs to the Class I chitinases,enzymes that contain an N-terminal hevein-like domain homologous to Latex hevein(Hev b 6.02), and a larger catalytic domain.They are the major panallergens in fruitsassociated with Latex-fruit syndrome(3,5,9). Recombinant Cas s 5 is homologousto its natural counterpart (3).

Although Chestnut allergy is stronglyassociated with Latex-fruit syndrome,Chesnut allergy may occur independently ofthis syndrome and has been attributed to thepresence of Cas s 8, a Lipid Transfer Protein.In a study of 12 patients sensitised toChestnut but not to Latex, along with 3control patients with Latex-Chestnut allergy,

a Lipid Transfer Protein was isolated andfound to bind to serum-specific IgE in 91%(as shown by IgE immunoblotting) and 58%(as shown by ELISA) of sera from patientswith Chestnut but not Latex allergy. Sixty-six percent of these patients had positive skinprick test responses to Cas s 8. AllergenicLTPs from Peach fruit and Artemisia vulgarispollen were also reactive. In contrast,Avocado class I chitinase and Latex hevein,allergens associated with Latex-fruitsyndrome, showed no reaction. The authorssuggested that LTPs and class I chitinasescan be used as diagnostic tools in patientswith Chestnut allergy, to predict whether anassociated Latex sensitisation and a risk ofcross-reactivity with other plant foods andpollens exist (7).

Cas s 1 and 2 other allergens, an IPR-protein and a profilin, have been isolatedfrom the pollen of European chestnut treebut have not to date been shown to bepresent in Sweet chestnut (13).


Approximately 30-50% of individuals whoare allergic to Natural rubber latex (NRL)show an associated hypersensitivity to anumber of plant-derived foods, especiallyfreshly consumed fruits (14-17). Someauthors have called this the Latex-fruitsyndrome, and foods associated includeAvocado, Banana, Sweet Chestnut, Kiwi,Peach, Tomato, Potato and Bell pepper (inapproximate decreasing order of relevance).Fig, Pineapple and Peanut have also beenimplicated (18-21). A number of plantprotein families have been shown to beinvolved in Latex-fruit syndrome. Two ofthese are also pathogenesis-related (PR)proteins. Class I chitinases have beenidentified as a major category of IgE-bindingallergens for patients allergic to NRL. Abeta-1,3-glucanase was identified as animportant Latex allergen that shows cross-reactivity with proteins of Bell pepper.Another important NRL allergen, Hev b 7,is a patatin-like protein that shows cross-reactivity with its analogous protein inPotato (19). Furthermore, patients withallergy to plant-derived foods and associatedpollen allergy show a high frequency of IgE

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f299 Sweet chestnutreactivity to the panallergen profilin.However, whether Latex sensitisationprecedes or follows the onset of food allergyhas not been resolved (16).

Allergy to Chestnuts has been widelyreported in connection to Latex-fruitsyndrome. However, few studies addressactual allergy to Chestnuts in patientsreacting primarily to this food. In this study,22 consecutive subjects with proven allergyto Chestnut (according to DBPCFC or aconvincing history of anaphylaxis) werestudied. The age of onset of reactions toChestnut ranged from 5 to 70 years, with 8/22 (36%) patients having experienced severeanaphylactic episodes. SPTs with Chestnutwere positive in 71%, and IgE antibodieswere detected in 54% of patients. Eighty-six percent and 59% of patients also hadpositive responses to pollen and Latexallergens, respectively. Eighteen patients hadactual allergy to other foods, of which thesewere the main ones: Banana, in 45% ofpatients; Avocado, in 40%; and Hazel nut,in 32%. There was a significant associationbetween sensitisation to Latex and clinicalreactivity to Avocado and/or Kiwi (p<0.01);while reactivity to Hazel nut was associatedwith allergy to Peanut (p=0.003) and Walnut(p<0.001) (22).

In a study of 47 Latex-allergic patients,immunological reactivity to foods was foundin 33. Seventeen patients manifested aclinical allergy to at least 1 food, including11 patients with anaphylaxis and 14 withlocal sensitivity reactions. Positive food skintests occurred most frequently with Avocado(53%), Potato (40%), Banana (38%),Tomato (28%), Chestnut (28%), and Kiwi(17%) (19).

Chestnut and Natural rubber latex (NRL)allergy are often associated in Latex-fruitsyndrome. This study's aim was to establishwhether concurrent NRL and Chestnut IgEantibody reactivity are the results of co-sensitisation or cross-reactivity.

Sera from 19 patients with Chestnut- andNRL-specific IgE were selected and testedfor reactivity with recombinant (r) Latexallergens. IgE-antibodies were detected torHev b 6.01 (prohevein) in 58% of the sera,

to rHev b 5 in 32%, to rHev b 12 in 4 of 13sera, to rHev b 7.02 and rHev b 11 in 4,and to rHev b 1 in 2 of 19 sera. rHev b 8-IgE antibodies were found in 9 sera (47%),whereas 6 displayed monosensitisation torHev b 8 with regard to the test panel. Threeof 16 sera showed IgE to cross-reactivecarbohydrate determinants. In most serarecognising rHev b 5 and/or rHev b 6.01 asmajor allergens, the IgE reactivity to NRLremained unaffected by Chestnut extract, andChestnut IgE remained unaffected by NRLextract. Conversely, in sera with rHev b 8 asthe dominant allergen, IgE-binding to NRLwas nearly completely inhibited by Chestnutand vice versa. IgE-binding to rHev b 8 wasabolished by Chestnut extract. The studyconcludes that although patients haveconcomitant IgE antibody reactivity toChestnut and NRL, cross-reactivity could bedemonstrated mainly in those patients withIgE to Hev b 8 (profilin) from NRL (23).

However, the prevalence of combinedNRL and Chestnut allergy may varyaccording to the population in question andmay be very low in some groups. Among137 patients with NRL allergy, food allergyto Chestnut was reported in only 1 patient.(24) In a Taiwanese screening program toidentify Latex-sensitised hospital employees,elevated serum total IgE was found in22(16.9%) of 130 nurses, 3(16.7%) ofwhom had increased Latex-specific IgE,further confirmed by SPT determination. Nocross-reactive fruit allergy (Melon, Banana,Kiwi, Tomato, or Chestnut) was foundamong the Latex-sensitised nurses (25).

Of the plant protein families, a Class Ichitinase containing an N-terminal hevein-like domain homologous to and cross-reacting with hevein (Hev b 6.02) has beenshown to be a major panallergen responsiblefor Latex-fruit syndrome involving cross-reactivity among Chestnut, Banana andAvocado (5-6,9,14-15,26-28). Class Ichitinases have also been detected inCherimoya, Passion fruit, Kiwi, Papaya,Mango, Tomato, and Wheat flour extracts (29).Cross-reactivity is modulated due to chitinasein the Latex plant (Hev b 11), which displays70% identity to the endochitinase fromAvocado and its hevein domain, and 58% to

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f299 Sweet chestnuthevein in Latex (Hev b 6.02). Hev b 11, a classI chitinase, displays a different IgE bindingcapacity than hevein (4).

A review of 28 cases of sensitisation toLatex showed that Banana- and Chestnut-induced allergies were the allergies mostfrequently associated with Latex-inducedallergy (30). In a study of 25 patients withLatex allergy (9 [36%] with anaphylaxis),13 (52%) were found to have concomitantfood allergies to a total of 42 foods, of which23 had caused systemic anaphylaxis. Themost frequent food hypersensitivities wereto Avocado (n=9), Chestnut (n=9), Banana(n=7), Kiwi (n=5) and Papaya (n=3). Cross-reactivity among Latex, Avocado, Chestnut,and Banana was demonstrated (31).

A report was made of 8 patients allergicto Latex and Fruit (Chestnut and Banana),4 of whom had experienced anaphylaxisfollowing ingestion of the fruit. In the 6patients with symptoms after eatingChestnuts, SPT for Chestnut was found in5. Histamine release to Chestnuts waspositive in 3 of the 6. One patient with noskin reactivity to Chestnut, but showing IgEantibodies in serum tests, tolerated the fruit.Other case reports are illustrative ofChestnut allergy. Patient 1, a 32-year-oldhousewife, experienced itching of the mouth,rhinitis, and facial angioedema 30 minutesafter eating a raw Chestnut. Patient 2, a 23-year-old sister of Patient 1, developed itchingof the palate, sneezing, nasal discharge andasthma 10 minutes after eating Chestnuts.Patient 4, a 20-year-old housewife, 10minutes after ingestion of Bananas andChestnuts, developed asthma, rhinitis andurticaria. Patient 6, a 23-year-old womanstudent, experienced anaphylactic episodes(general urticaria, angioedema, and asthma)following the ingestion of Chestnuts andBananas. Patient 7, a 42-year-old housewife,had an anaphylactic reaction after eatingChestnuts. Patient 8, a 17-year-old femalestudent, developed generalised urticaria andangioedema with laryngeal involvementafter eating Chestnuts, and ingestion ofBanana caused itching of the mouth (32).

Similarly, a report describes an 8-year-oldboy, with a number of previous surgicalprocedures, who developed acute episodes ofurticaria following contact with NRL, andthen angioedema and dry cough afteringestion of Chesnuts. SPT for Latex andChestnut was positive. IgE antibodies weredetected to Latex but not to Chestnut. Openoral challenge with Chestnut was positive:15 minutes after ingestion of 0.5 g ofChestnut, he developed bouts of sneezing, drycough, perioral itching and erythema, andisolated facial wheals (20).

However, not all studies indicate thatsensitisation to Chestnut, or cross-reactivitybetween Latex and Chestnut, is clinicallyrelevant. For example, in a Turkish studyinvestigating the prevalence of Latex andLatex-associated food sensitivities amonghospital employees and atopic children – 61hospital employees and 40 atopic children– allergen-specific IgE evaluation confirmedsensitisation to NRL in 30 subjects, but notall were symptomatic. Chestnut sensitisationwas demonstrated in 37, but whether theseindividuals displayed allergic symptoms forChestnut was not investigated; yet theimplication that sensitisation may occurwithout allergic expression is apparent (33).Other authors concur, suggesting thatserologic tests seem to be of low significancefor prediction of food allergy in Latex-allergic patients, and that in many cases,sensitisation occurs with no clinicalexpression (15,34).

Cross-reactivity has also been describedbetween Avocado and Chestnut. In a studyof 17 patients with immediate hyper-sensitivity to Avocado, common antigenicdeterminants were shown to exist amongAvocado, Latex, Chestnut, and Bananaextracts (35). Recent knowledge suggeststhat the panallergen chitinase may have beenresponsible.

Although Chestnut allergy is stronglyassociated with Latex-fruit syndrome,Chesnut allergy may occur independently ofthis syndrome and has been attributed to thepresence of Cas s 8, a Lipid Transfer Protein(7). Cross-reactivity with other foodscontaining LTPs is therefore possible. In a

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f299 Sweet chestnutstudy evaluating, by means of SPT, thereactivity to LTPs from Peach, Apple,Chestnut and Artemisia pollen, Chesnut LTPwas reported to be less cross-reactive thanApple and Peach LTPs. In a group of Peach-allergic individuals, the most frequentpattern of cross-reactivity of LTPs was thecombination Peach-Apple (45%), followedby Peach-Apple-Artemisia-Chestnut (21%).Significant correlations were found betweenPeach and Apple LTPs, and betweenArtemisia and Chestnut LTPs. Positive SPTsto Chestnut LTP were observed only inpatients with positive SPTs to Artemisia LTP.All the patients with positive case historiesto Chestnut reacted to Chestnut LTP. (11)This is in particular relevant in Rosaceaefruit-allergic populations in theMediterranean area, where LTPs have beenidentified as major allergens, especially inApple and Peach. Purified LTPs fromArtemisia pollen and from Chestnut meathave a 43-50% sequence identity with theequivalent allergens of Apple and Peach. Asimilar degree of sequence identity (50%)was found between the Artemisia andChestnut proteins. Therefore, although LTPsfrom Artemisia pollen and Chestnut cross-react with LTPs of Rosaceae fruits,significant differences in specific IgE-bindingcapacities have been noted among membersof the plant LTP family (10).

The study also demonstrated that Latex-allergic patients (23%) recognise a proteinwith sequence homology to the proteinfamily patatin, known to be an importantprotein in Potato. Cross-reactivity betweenLatex and several Potato proteins wasobserved through immunoblot inhibitionanalysis (19).

In 4 patients with an allergy to Ficusbenjamina, 2 patients had a cross-allergy toNRL and the associated cluster of tropical fruit(Banana, Kiwi, Avocado, and Chestnut) (36).

The enzymes Papain and Bromelain mayshare epitopes with Chestnut allergens (14,26).

According to a report of a 4-year-old boywho developed allergic symptomsimmediately after peeling and eating an Oakacorn, partial cross-reactivity wasdemonstrated between Oak acorn andChestnut (37).

Clinical Experience


Allergy to Chestnut on its own is infrequent,considering how common Chestnutconsumption is in certain countries (38); butChestnut allergy is more frequentlyassociated with the complex sensitisation ofNRL-allergic individuals to fruits andvegetables (14-17,24). However, it may bethat allergy to Chestnut is underreported,since the possibility of allergic disease tendsto be insufficiently investigated. In a Koreanstudy evaluating the clinical significance ofChestnut as a food allergen in 1,738 patientswith respiratory allergies, skin reactivity toChestnut was found in 56 (3.2%) (1).

A study investigating the prevalence ofNRL sensitisation and allergy in 74 childrenwith atopic dermatitis reported that 12 ofthe 74 atopic children had IgE antibodies toLatex. Twenty children without provenLatex sensitisation showed increased food-specific IgE, most frequently to Potato,Banana, and Chestnut (39).

Oral allergy syndrome induced byChestnut, followed by rhinoconjunctivitisand asthma, has been described in a 22-year-old woman. She reported that when chewingChestnut, she had felt a burning sensationand itching of the oropharyngeal mucosafollowed by lacrimation, nasal pruritus,violent sneezing salvos, and “moderate”difficulty in breathing, but not severe enoughto require treatment. Symptoms initially hadbeen relatively minor and limited to oralones, but subsequent episodes becameprogressively worse. The challenge withfresh food was positive. Skin prick test witha commercial product and the prick-by-prickmethod with fresh Chestnut were negative.Skin prick testing with a freshly preparedextract of fresh Chestnut, and the passivetransfer reaction, were positive. Serum testswere negative (40).

Four cases of nurses with allergy to NRLfollowed by anaphylaxis to Chestnut werereported. The presence of Chestnut sensitivitywas demonstrated by positive SPT, but IgEantibodies to Chestnut were found in only 2,suggesting that anaphylaxis to Chestnut ispossible even in the absence of serum IgE

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f299 Sweet chestnutantibodies to Chestnut (41). Anaphylaxis toChestnut may be classified as “idiopathic”until investigated further (42).

A 4-year-old boy developed ocular itching,eyelid and lip angioedema, unproductivecough, wheezing and dyspnoea immediatelyafter peeling and eating an Oak acorn.Months later, he experienced similarsymptoms after eating a Chestnut. Hetolerated Latex and Banana. SPT was positiveto Oak acorn peel and Chestnut, and negativeto the pollen. The IgE antibody level wasraised for Chestnut and Oak acorn peel, witha degree of cross-reactivity demonstratedbetween these foods (37).

Chestnut has been reported to causeurticaria-angioedema in a 29-year-old man (43).

Other reactions

Chestnut tree pollen is an aeroallergen (44).

The Horse chestnut, Aesculus hippo-castanum, is an entirely different tree fromthe Sweet chestnut. The Horse chestnut isnot edible; its burs have blunt spikes, whileSweet chestnut burs are very sharp and spiny.

References1. Lee SK, Yoon SH, Kim SH, Choi JH, Park HS.

Chestnut as a food allergen: identification ofmajor allergens.J Korean Med Sci 2005;20(4):573-8

2. Lee S. Chestnut as a food allergen:Identification of the major allergens andeffect of gastric and intestinal fluids.J Allergy Clin Immunol 2004:113:S234

3. Diaz-Perales A, Sanchez-Monge R, Blanco C,Lombardero M, Carillo T, Salcedo G. What isthe role of the hevein-like domain of fruitclass I chitinases in their allergenic capacity?Clin Exp Allergy 2002;32(3):448-54

4. O'Riordain G, Radauer C, Hoffmann-Sommergruber K, Adhami F, et al. Cloningand molecular characterization of the Heveabrasiliensis allergen Hev b 11, a class Ichitinase.Clin Exp Allergy 2002;32(3):455-62

5. Sanchez-Monge R, Blanco C, Diaz-Perales A,Collada C, Carrillo T, Aragoncillo C, Salcedo G.Isolation and characterization of majorbanana allergens: identification as fruit classI chitinases.Clin Exp Allergy 1999;29(5):673-80

6. Diaz-Perales A, Collada C, Blanco C,Sanchez-Monge R, Carrillo T, Aragoncillo C,Salcedo G. Class I chitinases with hevein-likedomain, but not class II enzymes, arerelevant chestnut and avocado allergens.J Allergy Clin Immunol 1998;102(1):127-33

7. Sanchez-Monge R, Blanco C, Lopez-Torrejon G,Cumplido J, Recas M, Figueroa J, Carrillo T,Salcedo G. Differential allergen sensitizationpatterns in chestnut allergy with or withoutassociated latex-fruit syndrome.J Allergy Clin Immunol 2006;118(3):705-10

8. Breiteneder H, Ebner C Molecular andbiochemical classification of plant-derivedfood allergens. J Allergy Clin Immunol2000;106(1 Pt 1):27-36

9. Blanco C, Diaz-Perales A, Collada C,Sanchez-Monge R, Aragoncillo C, Castillo R,Ortega N, Alvarez M, Carrillo T, Salcedo G.Class I chitinases as potential panallergensinvolved in the latex-fruit syndrome. J AllergyClin Immunol 1999;103(3 Pt 1):507-13

10. Diaz-Perales A, Lombardero M, Sanchez-Monge R, Garcia-Selles FJ, Pernas M,Fernandez-Rivas M, Barber D, Salcedo G.Lipid-transfer proteins as potential plantpanallergens: cross-reactivity among proteinsof Artemisia pollen, Castanea nut andRosaceae fruits, with different IgE-bindingcapacities.Clin Exp Allergy 2000;30(10):1403-10

11. Garcia-Selles FJ, Diaz-Perales A, Sanchez-Monge R, Alcantara M, et al. Patterns ofreactivity to lipid transfer proteins of plantfoods and Artemisia pollen: an in vivo study.An in vivo Study. Int Arch Allergy Immunol2002;128(2):115-22


13. Hirschwehr R, Jager S, Horak F, Ferreira F,Valenta R, et al. Allergens from birch pollenand pollen of the European chestnut sharecommon epitopes.Clin Exp Allergy 1993;23(9):755-61

14. Latasa M, Dieguez I, Sanz ML, Parra A,Pajaron MJ, Oehling A. Fruit sensitization inpatients with allergy to latex. J Invest AllergolClin Immunol 1995;5(2):97-102

15. Brehler R, Theissen U, Mohr C, Luger T.“Latex-fruit syndrome”: frequency of cross-reacting IgE antibodies.Allergy 1997;52(4):404-10

16. Wagner S, Breiteneder H. The latex-fruitsyndrome.Biochem Soc Trans 2001;30(6):935-40

17. Bayrou O. Latex allergy. [French] Rev Prat2006;56(3):289-95

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f299 Sweet chestnut18. Ebo DG, Bridts CH, Hagendorens MM, De

Clerck LS, Stevens WJ. The prevalence anddiagnostic value of specific IgE antibodies toinhalant, animal and plant food, and ficusallergens in patients with natural rubber latexallergy. Acta Clin Belg 2003;58(3):183-9

19. Beezhold DH, Sussman GL, Liss GM, Chang NS.Latex allergy can induce clinical reactions tospecific foods.Clin Exp Allergy 1996;26(4):416-22

20. Anibarro B, Garcia-Ara MC, Pascual C.Associated sensitization to latex andchestnut. Allergy 1993;48(2):130-1

21. Rodriguez M, Vega F, Garcia MT, Panizo C, et al.Hypersensitivity to latex, chestnut, andbanana. Ann Allergy 1993;70(1):31-4

22. Rico P, Crespo JF, Feliu A, Rodriguez J.Chestnut allergy: Beyond the latex-fruitsyndrome.J Allergy Clin Immunol 2004:113:S149

23. Raulf-Heimsoth M, Kespohl S, Crespo JF,Rodriguez J, Feliu A, Bruning T, Rihs HP.Natural rubber latex and chestnut allergy:cross-reactivity or co-sensitization?Allergy 2007;62(11):1277-81

24. Kim KT, Hussain H. Prevalence of foodallergy in 137 latex-allergic patients.Allergy Asthma Proc 1999;20(2):95-7

25. Wan KS, Lue HC. Latex allergy in health careworkers in Taiwan: prevalence, clinicalfeatures. Int Arch Occup Environ Health2007;80(5):455-7

26. Serrano L, Pérez Camo I, Durán MA, Madera JF,Cuevas M, Hinojosa M. Allergy to latex andtropical fruits with associated hypersensitivityto enzymes: case report.Allergy 1995;26(50):236-P-0462

27. Velázquez E, González-Pol J, Durán S, Gámez R,Escribano MM, Guardia P, de la Calle A,Conde J. Allergy to latex and fruits.Eur J Allergy and Clin Immunol Suppl1997;37(52):122-375

28. Blanco C. Latex-fruit syndrome.Curr Allergy Asthma Rep 2003;3(1):47-53

29. Diaz-Perales A, Collada C, Blanco C,Sanchez-Monge R, et al. Cross-reactions inthe latex-fruit syndrome: A relevant role ofchitinases but not of complex asparagine-linked glycans. J Allergy Clin Immunol1999;104(3 Pt 1):681-7

30. Moreno Ancillo A, Lopez Serrano MC,Barranco Sanz P, Dominguez Noche C, OrniaFernandez N, Martinez Alzamora F. Latexsensitization in 28 patients. [Spanish]Allergol Immunopathol (Madr)1994;22(6):275-80

31. Blanco C, Carrillo T, Castillo R, Quiralte J,Cuevas M. Latex allergy: clinical features andcross-reactivity with fruits.Ann Allergy 1994;73(4):309-14

32. Fernandez de Corres L, Moneo I, Munoz D, et al.Sensitization from chestnuts and bananas inpatients with urticaria and anaphylaxis fromcontact with latex.Ann Allergy 1993;70:35-9

33. Saraclar Y, Cetinkaya F, Tuncer A, Sekerel B,Hovanec-Burns D, Unver E. Latex sensitivityamong hospital employees and atopicchildren. Turk J Pediatr 1998;40(1):61-8

34. Monreal P, Server MT, et al. Hipersensitivityto fruits in latex allergic patients. AllergolImmunopathol (Madr) 1996;24(1):33-5

35. Blanco C, Carrillo T, Castillo R, Quiralte J,Cuevas M. Avocado hypersensitivity.Allergy 1994;49:454-9

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37. Zapatero L, Baeza ML, Sierra Z, Molero MI.Anaphylaxis by fruits of the Fagaceae family:acorn and chestnut. Allergy 2005;60(12):12


39. Tucke J, Posch A, Baur X, Rieger C, Raulf-Heimsoth M. Latex type I sensitization andallergy in children with atopic dermatitis.Evaluation of cross-reactivity to some foods.Pediatr Allergy Immunol 1999;10(3):160-7

40. Antico A. Oral allergy syndrome induced bychestnut (Castanea sativa).Ann Allergy 1996;76(1):37-40

41. Tomitaka A, Matsunaga K, Akita H, Suzuki K,Ueda H. Four cases with latex allergyfollowed by anaphylaxis to chestnut.[Japanese] Arerugi 2000;49(4):327-34

42. Stricker WE, Anorve-Lopez E, Reed CE. Foodskin testing in patients with idiopathicanaphylaxis.J Allergy Clin Immunol 1986;77:516-9

43. Estrada JL, Gozalo F, Cecchini C, Casquete E.Contact urticaria from hops (Humuluslupulus) in a patient with previous urticaria-angioedema from peanut, chestnut andbanana. Contact Dermatitis 2002;46(2):127

44. Laurent J, Lafay M, Lattanzi B, Legall C,Sauvaget J. Evidence for Chestnut Pollinosisin Paris. Clin Exp Allergy 1993;23:1;29-43

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Juglans regiaFamily: JuglandaceaeSourcematerial: Shelled nutsSee also: Walnut t10The Juglandaceae family contains 2important genera: Hickory/Pecan(Carya) and Walnut (Juglans). Walnut isthe common name for 20 species ofdeciduous trees in the Juglans genus(native to south-western Asia, easternAsia, and the Americas). Those specieshave been separated into 4 taxonomicsections: Dioscaryon (English walnut),Rhysocaryon (Black walnut),Cardiocaryon (Asian butternut), andTrachycaryon (American butternut).Section Dioscaryon contains a singlespecies, J. regia, and this nut iscommonly called the English walnut orPersian walnut. Section Rhysocaryonincludes all of the Black walnuts: forexample, the species J. nigra (Easternblack walnut), J. californica (SouthernCalifornia black walnut), J. hindsii(Northern California black walnut), J.major (Arizona black walnut) and J.microcarpa (Texas black walnut).Section Cardiocaryon contains J.ailantifolia (Japanese walnut), J.cathayensis (Chinese walnut), and J.mandshurica (Manchurian walnut),among others. Section Trachycaryoncomprises a single species native toNorth America, J. cinerea, known asthe Butternut or White walnut. Withinsome species there are also differentcultivars (1)For continuous updates:www.immunocapinvitrosight.com

f256 Walnut

Allergen Exposure


Walnut is one of the most important nutcrops. The leading commercial producers ofWalnuts are the United States, Turkey,China, Iran, France and Romania.

The Walnut tree is up to 20 m tall, with alarge, spreading, rounded top and thick,massive stem. Walnut trees are monoecious,with male flowers borne in long,unbranched, drooping catkins, and femaleflowers borne singly or in short spikes. Theleaves and outer green husks are poisonousto fish and most animals. The flowers appearin May, and the yellow leaves turn green bymid-June.

The Walnut fruit is a nut, borne singly orin pairs and enclosed in a solid, non-splittinggreen husk. The fruit is oval in shape, 4 to 5cm across. The outer, slightly soft coat,which is called a husk or shuck, is shiny andgreen at first. It changes to dark brown whenit is ripe. Inside this fruit is a single seed, theWalnut, which has an edible, oil-rich, white,two-lobed, wrinkled kernel enclosed in athick, hard, ridged, and brown to black shell.In mid-September the nuts can be harvestedwith their husks still on. By October, thehusks fall off, and the hard-shelled nuts canbe gathered.

Walnut shells are composed of 2 halves.Between the halves is the “shell seal”, whichis usually tight, to protect the nut frommoisture and pests. But the shell of freshlypicked Walnuts can easily be cracked openby hand. After washing and drying, the shellbecomes very hard and must be broken openwith a tool such as a nutcracker or hammer.

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f256 WalnutA hard, fibrous membrane lines the insideof the shell, runs between the two halves ofthe nut, and is removed before eating. TheWalnut itself is covered by a thin edible skincalled the pellicle, which can be removed byblanching the nut in rapidly boiling waterfor 30 to 60 seconds. The pellicle containstannins; the darker the pellicle, the moretannins it contains. Walnut has a very highpolyunsaturated fat content, which makesthe nut extremely perishable, requiringcareful storage.

While there are numerous species ofedible Walnuts, the 3 main ones consumedare the English (or Persian) walnut (J. regia),the Black Walnut (J. nigra), and the White(or Butternut) Walnut (J. cinerea). TheEnglish walnut is the most popular andfeatures a large nut and thinner shell, whichis easily broken with a nutcracker. The Blackwalnut has thicker shells that are harder tocrack; the nuts are oilier and richer-tasting,with a much more pungent and distinctiveflavour than that of the English walnut. Theyare harder to extract from the shell in largepieces. The much less available White walnuthas a sweeter and oilier taste than the other2 types, and very high protein content.

Environment

The nuts are rich in oil, particularly in alpha-linoleic acid (omega 3 fatty acid) and linoleicacid (polyunsaturated fatty acids), and arewidely eaten both fresh and in cookery.Walnuts can be eaten directly from the shell,but more often they are eaten as aningredient in baked goods, ice cream or otherfoods. They are used in salads and in meat,poultry, fish and pasta dishes. Immatureyoung fruits are pickled in vinegar andconsidered a delicacy. A liqueur is made inFrance from the husks. Greeks and Romansused Walnuts to cure headaches, because ofthe shape, which resembles the two halvesof the brain.

The oil is used in salads and pasta. Theallergenicity of this oil and various othergourmet nut oils depends on the extractionmethod and the purity of the end product (2).

Oil paint often contains Walnut oil as aneffective binding medium, known for itsclear, glossy consistency and non-toxicity.

Walnut husks can produce a rich yellow-brown to dark brown dye that is used fordyeing fabric and for other purposes. Husksshould be handled wearing rubber gloves,to avoid dyeing one's fingers.

Allergens


Jug r 1, a 14-16 kDa protein, a 2S albumin,a major allergen (1,3-9).

Jug r 2, a 44-48 kDa protein, a 7S vicilinglobulin, a major allergen (1,3,5-7,10).

Jug r 3, a 9 kDa protein, a lipid transferprotein, a major allergen (5-7,11).

Jug r 4, a legumin-like protein. (5-6,12-13).

Jug r profilin (14).

Jug r 1, a 2S albumin, was shown to be amajor allergen in a study of 20 AmericanWalnut-allergic individuals; the allergenbound 75% of the patients' sera (4).Similarly, IgE binding to Jug r 1 wasdemonstrated in 12 of 16 (75%) sera fromWalnut-allergic patients (3). The IgE bindinginhibition study suggested that the Walnut2S protein precursor undergoes post-translational modification into a large anda small subunit similar to Castor seed,Cottonseed, Mustard seed, and Brazil nut2S seed storage protein allergens (3).

However, contrasting results were seen ina study of 46 Italian patients, either with oralallergy syndrome confirmed by open oralchallenge, or with systemic symptoms afteringestion of Walnut; a comparison of theWalnut IgE binding profile in patients withand without pollen allergy showed that theonly major allergen recognised was a lipidtransfer protein (LTP) (Jug r 3), which wasrecognised by 36 patients (78.2%). Two otherminor allergens of approximately 9 kDa, bothbelonging to the vicilin family, wererecognised by 10 patients (21.7%). Ninepatients reacted to vicilin A, and 1 patientto vicilin B (which has 90% homology withCocoa). Two patients exclusively allergic to

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f256 WalnutWalnut were sensitised to vicilin A. IgEbinding to Walnut LTP was completelyinhibited by Peach LTP. The study concludedthat in the Italian population, the LTP is amajor allergen (7).

Jug r 4 has been shown to be a majorallergen and was found in sera from 15 of 23(65%) Walnut-allergic patients. (12) rJug r 4has been cloned and was demonstrated tobind to serum IgE antibodies from 21 of 37(57%) Walnut-allergic patients (13).

Allergens similar to the English walnutallergens Jug r 1 and Jug r 2 have been shownto be present in Walnuts of other closelyrelated Juglans species (1). However, althoughcross-reactivity between the Jug r 1 allergenand a similar allergen in other Juglans speciesoccurs, and appears to be extensive, speciesother than J. regia were shown to be unableto completely inhibit binding to therecombinant form of Jug r 1. The authorssuggest that perhaps the other species had less2S albumin and left more Jug r 1-specific IgEantobodies available in solution for bindingto the immobilised rJug r 1, or that bindingaffinities differ slightly. They also proposedthat the reduction and partial linearisationof rJug r 1 by the SDS in the gel or the non-natural folding of a precursor fusion protein(the 2S albumin precursor is normallyprocessed into large and small subunits inWalnut) introduces additional IgE epitopesthat are still present when membrane-bound.The authors suggested that, in any case,subtle differences in the 2S albumins can beinferred (1).


A high degree of cross-reactivity occursamong the different Walnut species (1).

Early inhibition studies suggested cross-reactivity between Walnut and Pecan when7 tree nuts (Walnut, Pecan Almond, Hazelnut, Brazil nut, Cashew, Pistachio) andPeanut were evaluated (15). Other studieshave also reported a higher risk of cross-reactivity between Walnut and Pecan (16)and among Walnut, Pecan, and Hazel nut(17). The allergens resulting in thisrelationship were not elucidated. Cross-reactivity among Walnut, Hazel nut and

Brazil nut was reported in a patient withWalnut-induced anaphylaxis (18).

A high degree of cross-reactivity among thetree nuts is most likely to be a result of the 2Salbumin and other storage proteins. Jug r 1has been shown to have a 46.1% identity withthe Brazil nut 2S albumin Ber e 1 (3). A majorallergen in Cashew nut, a 2S albumin, wasreported to be the possible basis for cross-reactivity with Walnut 2S albumin (19).Cross-reactivity among the 2S albumin inAlmond, Walnut and Hazel nut has beendemonstrated (20).

There are reports of cross-reactivityamong allergens in Sesame and allergens inWalnut (21). This may occur as a result ofthe presence of a 2S albumin (Ses i 2) or a7S vicilin-type globulin (Ses i 3) found inSesame seed; both kinds of storage proteinsare found in Walnut (22). Other studies havereported that the Sesame 11S globulin showsonly partial immunological cross-reactivitywith Walnut (23).

Vicilin allergens of Peanut (Ara h 1),Walnut (Jug r 2), Hazel nut (Cor a 11) andCashew nut (Ana o 1) share structurallyrelated IgE-binding epitopes, and authorshave suggested that avoidance or restrictedconsumption of other tree nuts should berecommended to Peanut-sensitisedindividuals (9). Ana o 1, a 7S vicilin-likeglobulin from Cashew, has a 52-62%similarity to Walnut (6). A 19 kDa proteinof Buckwheat has been shown to have aweak homology to the vicilin-like proteinof Walnut (Jug r 2), Cashew (Ana o 1), andto 7 S globulin from Sesame seed (24). A 7Sglobulin from Coconut has also been shownto be cross-reactive with Walnut and Hazelnut (25).

Linear IgE-binding epitopes identified inlegumin allergens of Peanut (Ara h 3) andother allergenic tree nuts (Jug r 4 of Walnut,Cor a 9 of Hazel nut, Ana o 2 Cashew nut)were mapped.

Conformational analysis has shown thatthe legumin allergens of Peanut (Ara h 3),Walnut (Jug r 4), Hazel nut (Cor a 9), andCashew nut (Ana o 2) have consensualsurface-exposed IgE-binding epitopes thatexhibit some structural homology, whichaccounts for the IgE-binding cross-reactivity

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f256 Walnutobserved among Peanut and tree nutallergens. IgE-binding epitopes similar tothose found in 11S globulin allergens do notapparently occur in other vicilin allergenswith the cupin fold, as in Peanut (Ara h 1),Walnut (Jug r 2), Hazel nut (Cor a 1), andCashew nut (Ana o 3) (26).

Jug r 3 from Walnut is a lipid transferprotein. As LTP-hypersensitive patientsexperience adverse reactions after ingestionof botanically unrelated plant-derived foodsas well, in view of the high prevalence andseverity of the reactions, authors haverecommended that Hazel nut, Walnut, andPeanut should be regarded as potentiallyhazardous for these patients (7,11). In astudy of 20 LTP-monosensitive patients witha clinical history of allergic reactionsfollowing the ingestion of Rosaceae fruits(Apple, Pear, Peach, Cherry, Apricot, Plum,or Almond), 80% reported clinical reactivityto nuts (Hazel nut, Walnut, Pistachio); in11 cases (55%) nuts caused systemicsymptoms, with urticaria/angioedema in 9cases and anaphylaxis in 2. Maize and beerwere not tolerated by 4 (20%) and 2 (10%)respectively. After ingesting Grapes, 2patients experienced immediate gastro-enteritis/rhinitis and oral allergy syndrome,respectively. Cashew and Pistachio inducedan anaphylactic reaction in a single patient,but Cashew is rarely eaten in Italy. Only 2patients had ever eaten Pistachio, and 1reacted; hence the study conclusion thatthese 2 nuts may be significant LTP-containing foods for adverse reactions (11).The relevance of LTP in cross-reactivityamong Walnut and other LTP-containingfoods, e.g., Apple (Mal d 3), has beenreported (27).

Jug r 4, a legumin-like protein, has beenshown to have significant sequencehomology to Hazel nut and Cashew leguminallergens, and in vitro cross-reactivity wasdemonstrated with Hazel nut, Cashew, andPeanut protein extracts (13). Legumin-likeseed storage proteins have been implicatedin cross-reactivity between Coconut andWalnut, Almond and Peanut (28).

Walnut profilin may result in cross-reactivity with other profiling-containingfood, but this has not been established yet.

Clinical Experience


Tree nuts and Peanuts are frequent causesof severe IgE-mediated food hypersensitivityand anaphylaxis. In particular, tree nutallergies are potentially life-threatening,rarely outgrown, and appear to be increasingin prevalence. Peanut and tree-nut allergicreactions coexist in a third of Peanut-allergicpatients, frequently occur on first knownexposure, and may be life-threatening (29).

The frequency of Walnut allergy inchildren with IgE-mediated food allergy hasbeen reported as 4.2% (30). Walnut wasmost commonly reported to be allergenic byparticipants in the Food Allergy andAnaphylaxis Network (FAAN) Peanut andTree Nut registry in the United States. Aquestionnaire of 5,149 patients (mainlychildren) found that of allergic reactions totree nuts, 34% of reactions were to Walnut(31). In 1,000 British patients allergic to nut,30 cases of severe allergic reactions toWalnut occurred (32). Random telephonesurveys found that the importance of Walnutallergy and other nut allergies is related notonly to the severity of the allergic reactionsbut also to the high prevalence in the generalpopulation, estimated to be around 0.2%to 0.7% (33-34). In a SPT study of 1,286allergic patients, aged 2-79 years, in thesoutheast part of Iran, it was found that30.33% of the subjects were sensitised toHen's egg, 29.16% to Walnut, 21.46% toCow's milk, 19.21% to Beef, and 15.32%to and Hazel nut (35).

As Walnuts are promoted as part of ahealthy diet because of their polyunsaturatedfat and antioxidant content, consumptionof Walnuts and the addition of them toprocessed foods can be expected to increase.

In a study based on a patientquestionnaire, hypersensitivity to Walnutswas shown to be more common in patientswith Birch pollen allergy (26%) than inpatients without Birch pollen allergy (6%)(36). Similarly, in a study of grass pollenallergy in Northern Italy, where this allergyis the most common, IgE antibodies to Bet v 1were more strongly associated with nuts and

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f256 Walnutlegumes, while Bet v 2 was more stronglyrelated to allergy to fresh fruits andvegetables (37).

Anaphylaxis to Walnut has beenfrequently reported. In a case series, 10 of 32fatal anaphylactic reactions to foods resultedfrom ingestion of a tree nut, and Walnut wasnamed in 3 cases (38). In the United Kingdomregister of anaphylaxis deaths between 1992and 1998, 37 food-induced fatalities wererecorded, 5 caused by Walnut (39-40). Of 55severe or fatal food-allergic reactions reportedin a British paediatric population, 1 near-fatalreaction was caused by Walnut (41).Nevertheless, the prevalence of severe allergymay vary according to population groups. Ina retrospective review of 213 Australianchildren with Peanut or tree nut allergy, therewas only 1 reported case of anaphylaxis toWalnut alone, and 3 to a mixture of nuts (42).

Walnut-induced anaphylaxis wasreported in an 11-year-old boy whodeveloped gastric pain followed by severeasthma, generalised urticaria and collapse15 minutes after eating home-baked cookiesmade with Walnuts, Pistachios, dried Figsand raisins. Skin reactivity and IgEantibodies were detected to Walnut andHazel nut (18). Significantly, accidentalintake of foods containing small amountsof Walnuts not listed on the food labels caninduce anaphylaxis (43).

In particular, patients with an initialdiagnosis of “idiopathic” anaphylaxis mayhave in fact reacted to Walnut. A hundredand two patients with an initial diagnosis ofidiopathic anaphylaxis were evaluated with79 food allergens using SPT; only thosepatients were included whose episodesconsisted of at least 2 of the following:angioedema with or without urticaria,laryngeal oedema leading to severedyspnoea, hypotension, and loss ofconsciousness; 32 patients (31%) hadpositive tests to 1 or more foods. Walnutwas among the foods implicated. Theauthors concluded that some instances of“idiopathic” anaphylaxis are not trulyidiopathic (44).

Importantly, delayed anaphylaxis toWalnut following epinephrine administrationmay occur, as documented in a 7-year-old girlwith known Walnut allergy. Five minutesafter the accidental ingestion of a bite of aWalnut-containing salad, the patient's motherinjected her with 0.15 mg epinephrine,although no clinical reaction was noted priorto administration. After 90 minutes ofobservation, she suddenly developed diffusepruritus, cough, wheeze, erythema, andurticaria. Further treatment resulted inresolution of symptoms (45).

Walnut food-dependant exercise-inducedanaphylaxis has been reported (46-47).

Cross-reactivity may have severeconsequences. An 18-year-old maleexperienced generalised urticaria,angioedema of the face, wheezing, dyspnoeaand hypotension a few minutes after eatinga cake containing Walnut. He had previouslyexperienced episodes of urticaria and oralitching after eating Walnuts. During SPTevaluation for Walnut and Brazil nut allergy,a severe episode of anaphylaxis occurredimmediately after pricking with fresh Brazilnut. The subject had never eaten Brazil nutbefore. The authors hypothesise that thisadverse reaction was a result of cross-reactive mechanisms (48).

Anaphylaxis to Walnuts and Pine nutinduced by angiotensin-converting enzymeinhibitors (ACE) has been described (49).

Although the storage proteins are ingeneral major allergens responsible foradverse reactions to Walnut, in Italianpatients the lipid transfer proteins are majorallergens and responsible for oral allergysyndrome. In a study of 46 Italian patientseither with oral allergy syndrome confirmedby open oral challenge or with systemicsymptoms after ingestion of Walnut, the onlymajor allergen recognised was a lipidtransfer protein that bound serum of 37patients. Two other minor allergens, bothbelonging to the vicilin family, wererecognised by 10 patients. IgE binding toWalnut LTP was completely inhibited byPeach LTP, and the authors suggested thatthe sensitisation to this protein seemed tobe secondary to the sensitisation to Peach

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f256 WalnutLTP, which would act as the primarysensitiser. Symptoms of oral allergysyndrome were reported in 24 patients,gastrointestinal symptoms in 1, glotticedema in 13, urticaria in 6, angioedema in8, shock in 10, atopic dermatitis in 2, andasthma in 1 (7). The importance of lipidtransfer proteins in Walnut-allergic patientshas been reported in other studies (11,18).

Walnut allergy may occur as part of a truemultifood allergy. A 4-year-old male, whofirst experienced urticaria and asthmarelated to the ingestion of eggs at the age of2, in subsequent years developed rhinitis,angioedema, headache, and gastroenteritis.Symptoms started between a few minutes to2 hours after the ingestion of a number offoods. SPT and IgE antibody determinationswere positive for a number of foods,including Walnut, and this was confirmedby DBPCFC (50).

Walnut may also exacerbate atopicdermatitis. Over half of paediatric patientswith atopic eczema were found to be haveIgE antibodies to Walnut (51).

Occupational contact urticaria fromWalnut associated with hand eczema hasbeen reported (52).

Other reactions

Juglone is the active ingredient of the greenflesh of Walnuts and is known to be a strongirritant. Two young nursery-schoolplaymates developed contact pigmentationand acute irritant contact dermatitis as aresult of contact with the “juice” of greenWalnut husks (53).

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26. Barre A, Jacquet G, Sordet C, Culerrier R,Rouge P. Homology modelling andconformational analysis of IgE-bindingepitopes of Ara h 3 and other leguminallergens with a cupin fold from tree nuts.Mol Immunol 2007;44(12):3243-55

27. Zuidmeer L, van Leeuwen WA, Kleine B,Cornelissen J, Bulder I, Rafalska I, Tellez BN,Akkerdaas JH, Asero R, Fernandez RM,Gonzalez ME, van RR. Lipid Transfer Proteinsfrom Fruit: Cloning, Expression andQuantification. Int Arch Allergy Immunol2005;137(4):4-281

28. Teuber SS, Peterson WR. Systemic allergicreaction to coconut (Cocos nucifera) in 2subjects with hypersensitivity to tree nut anddemonstration of cross-reactivity to legumin-like seed storage proteins: new coconut andwalnut food allergens.J Allergy Clin Immunol 1999;103(6):1185


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32. Clark AT, Ewan PW. Interpretation of tests fornut allergy in one thousand patients, inrelation to allergy or tolerance.Clin Exp Allergy 2003;33(8):1041-5

33. Sicherer SH, Munoz-Furlong A, Sampson HA.Prevalence of peanut and tree nut allergy inthe United States determined by means of arandom digit dial telephone survey: a 5-yearfollow-up study.J Allergy Clin Immunol 2003;112(6):1203-7

34. Emmett SE, Angus FJ, Fry JS, Lee PNPerceived prevalence of peanut allergy inGreat Britain and its association with otheratopic conditions and with peanut allergy inother household members.Allergy 1999;54(4):380-5

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235

Triticum aestivumFamily: Poaceae (Gramineae)Commonnames: Wheat, Common wheat,

Bread wheatSynonyms: Triticum hybernum L.,

Triticum macha Dekap.& Menab., Triticumsativum Lam., TriticumsphaerococcumPercival, Triticumvulgare Vill

Sourcematerial: Untreated planting seedsSee also: Cultivated wheat g15,

Gluten f79 andrTri a 19; Omega-5Gliadin f416

The following are important varieties ofWheat:Common Wheat – Triticum aestivum L.Club Wheat – T. aestivum compactumDurum Wheat, Macaroni Wheat – T. durumSpelt Wheat – T. spelta L.Rivet Wheat – Triticum turgidum L.Emmer Wheat – T. dicoccoidesPoulard Wheat – T. turgidum L.Polish Wheat – T. polonicum L.Persian Wheat – T. carthlicum NevskiOriental Wheat – T. turanicum Jakubz.Einkorn Wheat – T. monococcum L.Wild Einkorn Wheat – T. boeoticum Boiss

For continuous updates:www.immunocapinvitrosight.com

f4 Wheat

Allergen Exposure

Expected exposure

Wheat is one of the major cereal grainsbelonging to the grass family (Poaceae orGramineae) and is a staple food item in mostdiets worldwide.

Wheats are freely tillering, usually robustgrasses 60 - 120 cm tall. The inflorescencehas a typical single spike on each node. Thereare very many distinct types of Wheat thathave been named as species. They areseparable into three groups – diploid,tetraploid and hexaploid, according to thenumber of sets of chromosomes. The mostimportant Wheats today are hexaploids,

having 6 sets. These Wheats are in most caseslarger and higher-yielding than diploids andtetraploids, and they also adapt to a widerrange of climates.

The hexaploid Triticum aestivum is byfar the most important of all Wheat species,the highest yielding and the widest ranging,as well as the one most suited to breadmaking. Its centre of origin is thought to besomewhere south of the Caspian sea, but itsrise to prominence came only after Wheatcultivation had spread to more humid areas.During the last 2,000 years, it has come toreplace almost all other species and hasspread to almost all parts of the world whereWheat can be grown.

All varieties pf Wheat contain soluble andinsoluble (gluten) proteins. The softer Wheatwith the lowest protein content is used forbiscuits, cakes and pastry. This is T. aestivumand the varieties closest to it. Harder Wheatwith higher protein content is used for bread,semolina, cous-cous, macaroni and pasta. T.durum (Durum wheat) is a source of Italianpasta, Indian chappatis and Chinese noodles.

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f4 WheatEnvironment

Common Wheat, the best known and mostwidely cultivated of the Wheats, is cultivatedfor the grain and used whole or ground. Itis processed into Wheat berries or kernels,Wheat bran, Wheat flakes, flour, and Wheatgerm. Finely ground, it is the source of flourfor the world's softer bread-stuffs, such ascakes. Harder Wheat, on the other hand, ismuch better suited for breads, and for pastasand other products that need to maintaintexture and flavour under the stress of heat.Wheat also is the source of alcoholicbeverages such as beer, and the industrialalcohol is made into synthetic rubber andexplosives. Bran and germ from flour millingare also important in livestock feed, and thegrain itself is fed to livestock whole orcoarsely ground. Wheat starch is used forpastes and sizing textiles. The straw is madeinto mats, carpets, and baskets, and is usedfor packing material, cattle bedding, andpaper manufacturing. Some Wheat is cut forhay. Wheat is sometimes grown for pasture.

Unexpected exposure


Allergens

Wheat, like all other foods, contains anumber of proteins: over 300 have beenmatched to established protein databaseinformation (1), and some have beenidentified as allergens. The types andproportions of proteins in a cereal have amajor impact on the quality and end useproperties of the cereal. The major proteinsin Wheat vary in proportion according tothe type of Wheat, and this variability is onereason reactions to different Wheat productsare not consistent.

Wheat protein can be classified intodifferent proteins:

• albumins (water-soluble; not similarto egg or milk albumin)

• globulins (salt-soluble, water-insoluble)

• glutens (composed of gliadin andglutelin, the water/salt-insolublewheat proteins)

Glutens can be further divided into:

• gliadins (28-42%; the majorprolamin protein in Wheat, solublein 70-90% alcohol)

• glutenins (42-62.5%; the majorglutelin proteins in Wheat, soluble indilute acid or alkali solutions)

Wheat flour contains between 7% and12% gluten proteins by weight. All glutenproteins are high in proline and glutaminecontents, and that is the predominant basisfor calling them prolamins. Cereal prolaminshave no known function apart from storage.Prolamins consist of a heterogeneousmixture of proteins of a molecular weight30-90 kDa (2). There are specific names forindividual prolamins from different species:secalins from Rye, hordeins from Barley,zeins from Maize, and avenins from Oats.

The 70% ethanol-soluble gliadins of asingle Wheat grain can be separated into upto 50 components and are a heterogeneousmixture of single-chained polypeptides. Theyare divided into 4 groups, here in descendingorder of mobility in accordance with acid-PAGE studies: alpha-, beta-, gamma-, andomega-gliadins (3). Their molecular weightranges from around 30 to 75 kDa.

The 70% ethanol-insoluble glutenins aredivided into high-molecular-weight (HMW)and low-molecular-weight (LMW) glutenins.

Another way of classify the prolamins isby sequence information into three groups:sulphur-poor (S-poor), sulphur-rich (S-rich),and high-molecular-weight (HMW)prolamins. The S-poor prolamins comprisethe omega-gliadins. The S-rich prolamins arethe major group of prolamins in Wheat andthey comprise the alpha-gliadins, thegamma-gliadins and LMW glutenins. TheHMW prolamins play an important role indetermining the bread making quality ofWheat. HMW prolamins are also present inBarley and Rye, where they are called Dhordein and HMW secalins, respectively.

237

f4 WheatThe following is a list of the type of

prolamin in each grain and the percentagethat the prolamin contributes to the grain'sprotein content:

Wheat: Gliadin 69%

Corn: Zein 55%

Barley: Hordein 46-52%

Sorghum: Kafirin 52%

Rye: Secalinin 30-50%

Millet: Panicin 40%

Oats: Avenin 16%

Rice: Orzenin 5%

Data suggest that the different prolaminsmay share regions of amino acid sequencehomology with each other and with someof the water/salt soluble albumin/globulinproteins (4).

Early studies demonstrated that a numberof Wheat allergens play diverse roles inallergy to Wheat: their sizes include 12, 15,16, 17, 21, 26, 27, 30, 33, 38, 47 and69 kDa (5-10).

The water/salt-soluble albumins andglobulins are important proteinscontributing to immediate hypersensitivityreactions (such as baker's asthma) to Wheatprotein in those exposed in an occupationalsetting (6-7,11) In such cases, these proteinsexhibit about 70% to 80% of the allergen-specific IgE-binding activity (7,12-13). Theyare also important in atopic dermatitis (13-14). Nevertheless, although up to 70different IgE-binding proteins can bedemonstrated to exist in the water/salt-soluble Wheat fraction, only a few of theseallergens have been identified andcharacterised on a molecular basis (15). Tothe latter belong various 14- to 17-kDaproteins of the alpha-amylase/trypsininhibitor family, including subunits of thetetrameric alpha-amylase inhibitor (9), 2highly homologous dimeric alpha-amylaseinhibitors (9,15-17) the monomeric alpha-amylase inhibitor (9,16) and a homologueto a barley trypsin inhibitor (16). In a study,the highest in vivo allergenic activity wasshown to a glycosylated subunit CM 16* ofthe tetrameric alpha-amylase inhibitor, withskin reactivity detected to this allergen in

14 of 31 patients allergic to Wheat flour. A36 kDa Wheat glycoprotein with peroxidaseactivity and similarity to a Barley seed-specific peroxidase has also been isolatedfrom 6 of 10 patients with Wheat allergyand baker's asthma demonstrating specificIgE to this enzyme (70).

Other proteins in the water/salt-solublefraction, such as peroxidase, glycerin-aldehyde-3-phosphate dehydro-genase,serpin (a serine proteinase inhibitor), andtriosephosphate isomerase, have beenregarded as major allergens in patients withbaker's asthma, but great inter-individualvariation of IgE-binding patterns of Wheatflour proteins in baker's asthma has beenshown (16,18-19). Other Wheat allergenssimilar to the 27 kDa acyl-CoA oxidasevariants of Rice and Barley or to 39 kDafructose-bisphosphate-aldolase in Maize andRice have been identified in pooled sera fromWheat-allergic individuals, but theirfrequency of sensitisation was not evaluated(15,18,20).

Although the albumin and globulinfractions are the most prevalent allergens inWheat-allergic individuals, IgE binding hasbeen demonstrated to both gliadin andglutenin fractions (13).

LMW glutenin, alpha-gliadin, andgamma-gliadin have been identified asallergens in Wheat-allergic patients (21).Alpha-gliadin and omega-gliadin (e.g. fastomega-gliadin) have been reported to be theallergens associated with baker's asthma (2).LMW glutenin has been reported to be themajor allergen for patients allergic to Wheat(22-23). Other studies have shown thatalpha-gliadin and gamma-gliadin, inaddition to LMW glutenin, are allergens forpatients with Wheat allergies (21).

The following allergens have beenidentified and characterised:

Tri a 12, a profilin, an actin-binding protein,found in Wheat seed and pollen (24-27).

Tri a 14, a lipid transfer protein, resultingin allergic reactions via ingestion, skincontact, and inhalation of Wheat flour(24,28-32).

238

f4 WheatTri a 18, a hevein-like protein (24-25).

Tri a Gluten, also known as Gluten,Gliadin, Gamma-gliadin, Omega-gliadin(21,23,33-46).

Tri a Chitinase, a chitinase (47).

Tri a Bd 17K, an alpha-amylase inhibitorCM16 (48-49).

Tri a 25, a thioredoxin (24-25,50-51).

Tri a 26, a glutenin.

Tri a aA/TI, an alpha-amylase / trypsininhibitor, an approximately 14-15 kDa low-molecular-weight (LMW) allergen, resultingin allergic reactions via ingestion, andinhalation of Wheat, e.g., as flour (5,9,16,52-54).

Tri a Bd36K, a peroxidase purified fromWheat albumin and an inhalant allergen. A36 kDa protein (19).

Tri a LMW Glu, a glutenin (24,34,46,55-60).

Tri a Germin, a germin (61).

Tri a Peroxidase, a peroxidase (62).

Tri a TPIS, a triosephosphate isomerase, anallergen via inhalation in bakers (63).

Tri a alphabeta Gliadin, a gliadin, alsoknown as gliadin or gluten, resulting inallergic reactions via inhalation of Wheat,e.g., as flour (64).

Tri a alpha Gliadin, a gliadin, also known asgliadin, gluten (2,21,25,33-35,46,55,60,65-66).

Tri a beta Gliadin (2,34,46,60,65-66).

Tri a gamma Gliadin (2,21,33-34,41-42,46,55,57,60,65).

Tri a omega-2 Gliadin (2,33-34,37,46,55,65-66).

The following allergens have beencharacterised in Wheat pollen: Tri a 1, Tri a 2,Tri a 3, Tri a 4, Tri a 5, Tri a CBP and Tri a 12.Tri a 12, a profilin, is also found in Wheatseed. (See Cultivated wheat g15.)

Tri a 14, a lipid transfer protein, has beenshown to be heat-stable and to lack cross-reactivity to grass pollen allergens. In a studyof sera of 16 Wheat challenge-positive

patients and 6 patients with Wheatanaphylaxis recruited from Italy, Denmarkand Switzerland, LTP was a major allergenonly in Italian patients (58). In a study of40 patients with occupational baker'sasthma resulting from Wheat flourinhalation, IgE antibodies to Tri a 14 wasfound in 60% of 40, and the purified allergenelicited positive skin reactions in 62% of 24of these patients. Tri a 14 and Peach LTP,Pru p 3, showed a sequence identity of 45%,but the low cross-reactivity between the 2allergens detected in several individual serareflected great differences in their 3-dimensional IgE-binding regions (28).

Tri a Gluten is composed of gliadin andglutelin, i.e., the gliadin and glutenin proteinsform a “complex” and have been termedGluten. Originally thought to be a singleprotein, gliadin is now known to consist of anumber of isoforms or unique proteins, e.g.,Tri a alphabeta Gliadin, Tri a alpha Gliadin,Tri a beta Gliadin and Tri a omega-2 Gliadin.See below for individual descriptions. Wheatflour contains between 7% and 12% Glutenproteins by weight. By definition, Gluten isfound only in Wheat, although the term iscommonly used to refer to any similarprolamin protein in any grain that is harmfulto a person with coeliac disease. Other grainssuch as Rye, Barley, Oats and triticale (aWheat-Rye hybrid) each contain their ownprolamin, which causes the same intestinaldamage in coeliac disease that gliadin causes.This is due to the similarity in proteinstructure. See Gluten f79.

Enzymatic hydrolysis of Wheat glutendemonstrated that the polymeric gluteninand monomeric gliadin in the glutencomplex showed different behaviour afterenzymatic hydrolysis: the monomericprotein (gliadin) and soluble glutenin wereprone to enzymatic hydrolysis, whileinsoluble glutenin was resistant to enzymatichydrolysis (67).

Tri a 19 (omega 5-gliadin) has beenreported to cause sensitisation for betweenapproximately 66% and 92% of Wheat-allergic patients. It has been reported to be amajor allergen in Wheat-dependent exercise-induced anaphylaxis (WDEIA) (33).

239

f4 WheatTri a 25, a thioredoxin, was reported to

be an allergen in 8 out of 17 patient sera.The authors speculated that this family ofallergens might play a role in themaintenance of allergic inflammation inbaker's asthma (25). A more recentpublication questioned whether this proteinis a true allergen, since it had been foundthat thioredoxin alleviates the allergicresponse and that there was no evidence thatthioredoxin acted as an allergen (68).

Tri a 26, a glutenin subunit, and Wheatomega-5 gliadin have been reported as majorallergens in Wheat-dependent exercise-induced anaphylaxis. In a study, 29 of 30patients with Wheat-dependent exercise-induced anaphylaxis had IgE antibodies tothese epitope peptides. Twenty-five patientswith atopic dermatitis who had IgEantibodies to Wheat and/or Gluten had verylow or nonexistent levels of epitope peptide-specific IgE antibodies, suggesting thatmeasurement of IgE levels specific to omega-5 gliadin (Tri a 19) and Tri a 26 is useful forthe assessment of patients with Wheat-dependent exercise-induced anaphylaxis (55).

Tri a aA/TI is an alpha-amylase/trypsininhibitor. This glycosylated form of alpha-amylase inhibitor may be more potent thanthe non-glycosylated form (8-9). This is asensitising allergen whether it is ingested orinhaled, having been implicated as a majorallergen associated with baker's asthma (9),and, less commonly, with food allergy (69).In particular, the subunits of the tetramericalpha-amylase inhibitor, CM2, CM3 andCM16, are known to be major allergens forbaker's asthma. In Japanese patients withatopic dermatitis, serum IgE bound only toCM3 and not to CM2 or CM16, suggestingthat CM3 may be involved in both atopicdermatitis and baker's asthma (52).

Tri a Bd 36K, a peroxidase, is an allergenvia inhalation (19).

Tri a LMW Glu appears to be a majorallergen. In sera of 28 patients with foodallergy to Wheat, 60% of sera were shownto have IgE antibodies against alpha- andbeta-gliadins and LMW glutenin subunits(Tri a LMW Glu); 55% against gamma-gliadins; 48% against omega-gliadins; and26% against HMW glutenins (46).

Tri a Germin is a germin, a glycoproteinexpressed in many plants in response tobiotic and abiotic stress. Wheat germin(expressed in transgenic tobacco plants)bound IgE from 6 of 12 patients sensitisedto Wheat, and elicited skin- reactions in 4out of 5 cases (61).

Tri a Peroxidase occurs in Wheat (T.aestivum). This 36 kDa seed-specificperoxidase is found specifically in T.monococcum but is also present in flourfrom diploid, tetraploid (pasta) andhexaploid (bread) Wheats. Sensitisationoccurs via inhalation. Sera from 6 out of 10patients hypersensitive to Wheat flour wereshown to have IgE antibodies directed to thisallergen (70). This allergen is one of the mostreactive with some patients' sera (14).

Tri a TPIS, a triosephosphate isomerase,is an allergen via inhalation, mainly inbakers (63).

Tri a alphabeta Gliadin has been shownto be present in sera of 12% of bakers withoccupational asthma, and it wasdemonstrated that water-insoluble proteinsmight also represent causative allergens (64).

Tri a alpha Gliadin, an alpha-gliadin,appears to be a major allergen and wasreported to be present in 60% of sera of 28patients with food allergy to Wheat (46). Ina study of patients with WDEIA, IgEantibodies to alpha-gliadin weredemonstrated in 13 of 18. The study alsodemonstrated cross-reactivity between thisallergen and gamma-gliadin, suggesting thattreatment with a Gluten-free diet, i.e., a dietexcluding Wheat, Rye, and Barley, isindicated for all patients with WDEIA (35).

Tri a beta Gliadin, a beta-gliadin, wasreported to be present in 60% of sera of 28patients with food allergy to Wheat (46).

Tri a gamma Gliadin, a gamma-gliadin, wasreported to be present in 55% of sera of 28patients with food allergy to Wheat (46). In astudy of 4 male Japanese patients, aged 39 to53, with WDEIA, gamma-gliadin appeared tobe a dominant allergen, causing theanaphylactic symptoms in these patients (41).

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f4 WheatTri a omega-2 Gliadin is an omega-gliadin.

Among the allergens of the gliadin group, theomega-5 gliadin, a component of fast omega-gliadin, is a major allergen of Wheat-dependent exercise-induced anaphylaxis/asthma (WDEIA) (33-35,38,41-42,45,71). Ina study to determine IgE binding against apanel of purified gluten proteins by using serafrom 15 patients with WDEIA, approximately80% of the patients reacted to fast omega-gliadin, strongly confirming that this allergenis a predominant allergen for WDEIA (33).The sera of all of these 15 patients also reactedto slow omega-gliadin, LMW, and HMWglutenin, apart from the strong reactivity tofast omega-gliadin (33). See also rTri a 19;Omega-5 Gliadin f416.

Omega-5 gliadin is also an allergen forchildren with an immediate-type allergy toWheat (38). Transglutaminase-mediatedcross-linking of a pepsin-trypsin-digestedomega-5 gliadin was shown to cause amarked increase in IgE-binding both in vitroand in vivo. (36) Allergen-specific IgE showsfast omega-gliadin cross-reacting withgamma-gliadin and slow omega-gliadin(34,41-42). Gamma-70 and gamma-35secalins in Rye and gamma-3 hordein inBarley cross-react with omega-5 gliadin (37).Fast gamma-gliadin is also called 1B-typeomega-gliadin (72). Fast omega gliadins,which correspond to omega-5 gliadins, havealso been suspected to be allergenic inbakers' asthma (2).


An extensive cross-reactivity among thedifferent individual species of the genuscould be expected (73). Studies have alsoreported various degrees of cross-reactivityamong different Wheat allergens. Water/salt-soluble proteins were reported to cross-reactwith alpha-gliadin and total glutenins, thewater/salt-soluble proteins sharing cross-reacting epitopes with water/salt-insolubleproteins. The authors suggested that thedevelopment of IgE antibodies to alpha-gliadin may in part depend on the presenceof cross-reacting antibodies to water/salt-soluble Wheat allergens (2). Clear cross-reactivity was also reported between gliadinand other fractions; the authors concluded

that identical epitopes are found in severaldifferent allergenic molecules of the cerealflours despite their different solubility (2).

Fast omega-gliadin is a major allergenamong water/salt-insoluble proteins in thecase of WDEIA in Japanese patients, and IgEagainst fast omega-gliadin cross-reacts togamma-gliadin and slow omega-gliadin (34).Further studies have reported that gamma-70 and gamma-35 secalins in Rye andgamma-3 hordein in Barley cross-react withomega-5 gliadin, suggesting that Rye andBarley may elicit symptoms in patients withWheat-dependent exercise-induced ana-phylaxis. In immunoblotting, anti-omega-5gliadin antibodies bound to 70 kDa and 32 kDaproteins in Rye and to a 34-kDa protein inBarley, but not to proteins in Oats. Theseproteins were identified as Rye gamma-70secalin, Rye gamma-35 secalin and Barleygamma-3 hordein, respectively. In ELISAstudies, 21/23 (91%) patients with WDEIAshowed IgE antibodies to purified gamma-70 secalin, 19/23 (83%) to gamma-35secalin and 21/23 (91%) to gamma-3hordein. Skin prick testing gave positivereactions to gamma-70 secalin in 10/15(67%) patients, to gamma-35 secalin in 3/15 (20%) patients and to gamma-3 hordeinin 7/15 (47%) patients (37).

Considerable similarity has been reportedamong the major allergenic protein ofmaturing Rice seeds, Barley trypsin inhibitor,and Wheat alpha-amylase inhibitor (74).

Although extensive cross-reactivity canbe expected among the varieties of Wheat,Einkorn wheats, particularly T.monococcum, are suspected to be less toxicthan bread and pasta Wheats to patientswith coeliac disease (75). Most lines ofEinkorn wheats have been reported to lackthe highly allergenic components of thealpha-amylase inhibitor family, but theirflour/salt-soluble extracts show levels of IgE-binding similar to those of bread and pastaWheats. Putative major allergens withmolecular sizes from 20 to 60 kDa inEinkorn Wheats are responsible for the latterresult (76).

241

f4 WheatLaboratory investigation has reported

that Wheat flour allergens wereimmunologically partially identical toantigens of Rye flour and of common grasspollen (77-78). Further RAST inhibitionexperiments showed cross-reactivitybetween grain extracts of Wheat, Rye, Barleyand Oats, suggesting that the bran layers ofcereal grains are at least as allergenic as theflour (79). Cross-reactivity has been reportednot only among the flours of Wheat, Rye,Barley and Oats, but also Corn and Rice, asshown by RAST inhibition tests (80).Synthetic Lol p 5 from Rye grass recognisedproteins of other clinically important grasspollens, including Wheat, further indicatingthe presence of cross-reactivity at the levelof allergenic epitope (81).

A putative class I chitinase recognised bysera from patients with Latex-fruit allergywas described in Chestnut, Cherimoya,Passion fruit, Kiwi, Papaya, Mango,Tomato, and Wheat flour extracts (47).

A lipid transfer protein, found in Spelt,was reported to be highly homologous toother LTPs from Wheat, Barley, Rice, Maizeand Peach (29-30).

Clinical Experience


Wheat is among the 6 most important fooditems accounting for hypersensitivityreactions in children. Special adversereactions to Wheat protein include:

1. Baker's asthma (an IgE-mediatedreaction to inhaled flour from Wheatand other grains)

2. Coeliac disease, a non-IgE-mediatedenteropathy caused by Wheat gliadin,and

3. Wheat-dependant exercise-inducedasthma or anaphylaxis.

The onset of adverse reactions may beimmediate, delayed, or both immediate anddelayed (17). Differences in the specificallergens, the routes of sensitisation, and theend-organ responsiveness have not beencompletely understood or elucidated. Wheathypersensitivity has been reported in bothoccupational and non-occupational settings andmay occur to Wheat or Wheat flour (7,82- 84).

Overview of food allergy to Wheat

Hypersensitivity reactions to ingested Wheatprotein have been commonly reported,including by investigators performingblinded food challenges in children (17,85).In Japan, for example, Wheat is reported tobe the food allergen causing the mostreactions (86). Hypersensitivity reactions toingested Wheat protein typically occurwithin an hour after Wheat ingestion andinclude gastrointestinal, respiratory andcutaneous symptoms (87). Adverse reactionstypically occur within an hour after Wheatingestion and include cutaneous, gastro-intestinal, and respiratory symptoms.Affected individuals are usually sensitisedduring infancy (88) and unlike in Peanut andshellfish allergy, the clinical reactivitytypically resolves before adulthood.

Sensitisation to Wheat by ingestion canlead to food allergy symptoms and WDEIA,whereas sensitisation by inhalation can causebaker's asthma and rhinitis. Wheat omega-5 gliadin (Tri a 19) has been shown to be amajor allergen in children with immediateallergy to ingested Wheat. Of 40 childrenwith suspected Wheat allergy who presentedwith atopic dermatitis and/or gastro-intestinal and/or respiratory symptoms, afteroral Wheat challenge, 19 children (48%) hadimmediate reactions and 8 children (20%)had delayed hypersensitivity symptoms.Sixteen (84%) of those with immediatesymptoms had IgE antibodies to omega-5gliadin. In contrast, IgE antibodies to omega-5 gliadin were not detected in any of thechildren with delayed or negative challengetest results. Skin prick testing with omega-5gliadin was positive in 6 of 7 children withimmediate challenge symptoms and negativein 2 children with delayed challengesymptoms (38). In a study, 60% of 28patients with food allergy to Wheat had IgEantibodies directed against alpha- and beta-gliadins and LMW glutenin subunits, 55%of the affected group to gamma-gliadins,48% to omega-gliadins and 26% to HMWglutenins. Further analysis also showed that67% of patients had IgE antibodies to thealbumin/globulin fraction (46).

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f4 WheatAnaphylaxis

Wheat exposure may result in life-threatening anaphylactic reactions. (89)Minute residual Wheat protein may beresponsible. A Wheat-allergic boyexperienced systemic urticaria andangioedema within 40 minutes after theingestion of 9 g of packed rice crackerswhich contained a trace quantity of Wheatprotein, 1.50 µg/g. Three of 8 other kindsof processed rice crackers werecontaminated by Wheat protein, with levelsranging from 0.26 to 1.13 µg/g. The authorsconcluded that approximately 13.5 µg ofWheat protein can elicit a systemic adversereaction in highly sensitive Wheat-allergicindividuals (90).

According to an analysis of a group of580 patients in France with reactions tofood, 60 presented with severe, near-fatalreactions. The foods most frequentlyincriminated in anaphylactic reactions wereCelery (30%), crustaceans (17%), fish(13%), Peanuts (12%), Mango (6%), andMustard (3%). Sensitisation to foods in thegroup tested was as follows: Wheat (39%),Peanuts (37%), Crab (34%), Celery (30%),and Soy (30%) (91).

Anaphylaxis to Wheat flour was alsodescribed in a 9-month-old child who hadeaten cereal baby food. The allergensresponsible were attributed to the Wheatalpha-amylase inhibitor subunits CM3 andCM16. CM2, CM3 and CM16 were foundto be involved in baker's asthma (92).

Nonsteroidal anti-inflammatory drugsenhanced allergic reactions in a patient withWheat-induced anaphylaxis (93).

Anaphylaxis has also been reported toWheat isolates (60).

Wheat-dependent exercise-inducedanaphylaxis (WDEIA)

WDEIA is a severe IgE-mediated allergicreaction provoked by the combination ofWheat or Wheat flour ingestion withintensive physical exercise during the nextfew hours (39,41-43,86,94-98). Typicalsymptoms are generalised urticaria andsevere allergic reactions such a shock orhypotension (33). Wheat allergy is common

in children but rare in adults, but Wheat-dependant exercise-induced anaphylaxis iscommon across the spectrum (99). Eighteenpatients were described who hadexperienced recurrent episodes ofgeneralised urticaria during exercise, 17patients in association with collapse and 15patients with an anaphylactic reaction. Thesymptoms appeared only when the patientshad eaten food containing Wheat beforeexercise (35). WDEIA may occur to multiplefood intake (100).

The threshold amount of ingested Wheatresulting in WDEIA has not yet beenelucidated, but in a report of a 24-year-oldJapanese woman who suffered for 2 yearsfrom attacks of urticaria, dyspnoea andsyncope associated with exercise after theingestion of Wheat, symptoms were inducedfollowing the ingestion of 64 g of bread, butnot 45 g (101). Although ingestion of Wheatalone may result in WDEIA, there is a reportof a 14-year-old boy who was shown todevelop food-dependant exercise-inducedanaphylaxis only on provocation testingwith simultaneous intake of Wheat andumeboshi, but not when each food was eatensingly (102). A study reports on a 48-year-old female who developed urticaria,angioedema, dyspnoea and loss ofconsciousness after a restaurant meal. Asecond episode occurred. These reactionscould be elicited in the ward only with acombination of Wheat flour, ethanol,additives and exercise (99).

Food-dependent exercised-inducedcholinergic urticaria to Wheat occurring in a24-year-old woman has been described (103).

Of the Wheat proteins, omega-5 gliadin(Tri a 19), one of the components of fastomega-gliadin, has been reported as a majorallergen in WDEIA (19). Although themechanism is not fully understood, a studyreports that omega-5 gliadin-derived peptidesare cross-linked by tissue transglutaminase(tTG), which causes a marked increase in IgEbinding both in vitro and in vivo. Activationof tTG, during exercise, in the intestinalmucosa of patients with WDEIA could leadto the formation of large allergen complexescapable of eliciting anaphylactic reactions(36). A study suggests that, in addition to IgE

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f4 Wheatantibodies against omega-5 gliadin, IgAantibodies may be involved in thepathogenesis of WDEIA (40).

Although omega-5 gliadin is thepredominant allergen in WDEIA and is acomponent of gluten, in a study of patientswith WDEIA, some were reported to benegative in IgE antibody tests for gluten,suggesting unreliable sensitivity of the testfor the diagnosis of WDEIA; the findingsimplied that the measurement of IgEantibodies to gluten is not alwayssatisfactory for the screening as well asdiagnosis of WDEIA (33).

Pre-treatment with sodium bicarbonateappears to inhibit the reappearance ofanaphylactic symptoms following Wheatingestion and exercise provocation (104).

Although this is not an instance ofWDEIA, a male athlete is described whosuffered respiratory arrest following a runthrough a Wheat field, a run which hadcaused Wheat pollen to be released. He hadmultiple wheals on both legs and complainedof severe breathlessness before collapsing.The authors suggest that it was possible thatthe symptoms were triggered either by therunning itself, inhalation of allergens otherthan Wheat pollen, skin abrasions causedby contact with Wheat stalks, or acombination of these factors (105).

Atopic Eczema

Wheat allergy may result in or exacerbateatopic eczema (85,106).

In 34 children with atopic dermatitis, 33were SPT-positive with Wheat, and 18 withOats. Positive IgE antibody tests to Wheatand Oats could be detected in 32 and 30samples respectively. SPT with Rice, Corn,Millet or Buckwheat was positive in 16/34patients (10). The strong association betweenpositive oral Wheat challenge and positiveskin reactivity with ethanol-soluble gliadinsuggests that gliadin is an important allergenin Wheat-allergic children with AD (107).

SPT with a NaCl Wheat suspension andethanol-soluble Wheat gliadin wasperformed on 18 Wheat-challenge-positiveor -negative children with AD, 6 adult ADpatients with suspected cereal allergy, and 1

adult with Wheat-dependent exercise-induced urticaria/anaphylaxis. It wasreported that 13 of the AD children wereWheat-challenge-positive, that 11 werepositive for gliadin SPT, and that all hadelevated gluten-specific IgE. Those who werechallenge-negative were negative with bothgliadin SPT and gluten-specific IgE. Four ofthe adult patients responded to a cereal-freediet, although only 2 of them appeared tobe positive with gliadin SPT and gluten-specific IgE determinations (107).

Ocular-type atopic dermatitis belongs tothe most severe end of the spectrum of AD,and IgE antibodies to Rice and Wheat weresignificantly higher in this form of AD. Theauthors suggest that food antigens maycontribute to severe AD, resulting in ocularcomplications (108).

Allergic contact dermatitis fromhydrolyzed Wheat protein in cosmetic creamhas been reported (109).

Other cutaneous reactions

Chronic urticaria to ingestion of Wheat hasbeen reported (110).

Other IgE-mediated food reactions

A significant association has been reportedbetween recurrent serous otitis media andfood allergy in 81 of 104 patients. Anelimination diet resulted in a significantamelioration of the disease in 86% of thepatients, and a challenge diet provokedrecurrence of symptoms in 94%. The highestfrequency was seen with Cow's milk, Wheat,egg, Peanut, Soy and Maize, and <10%frequency was seen with Orange, Tomato,Chicken and Apple (111).

Allergy to Wheat may also result ineosinophilic esophagitis (112).

Wheat may be a “hidden allergen” (113).

Baker's asthma

Baker's asthma is a frequent allergy in thebaking industry. In Germany, approximately1,800 bakers annually claim compensationfor baker's asthma (114). The prevalence ofasthma among bakers has been shown to bearound 10%, and the prevalence of cerealallergy 15-25% (115-116). Of those bakers

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who have cereal allergy, up to 35%experience asthma (78). In Japan in recentyears, the number of patients suffering frombaker's asthma caused by bread Wheat hasbeen increasing, and includes not onlypeople engaged in food industries, but alsothose who live near a factory producingWheat flour products (117).

Several protein components of saltextracts of Wheat flour weighing from 10to 100 kDa have been identified as majorIgE-binding proteins in occupational asthma(118). Allergen-specific IgE antibodies to anumber of flour components have beendemonstrated in allergic bakers' sera withthe strongest reactivities occurring to water-soluble Wheat albumins and globulins, theformer being shown in inhibition studies tobe more reactive than the latter (12-13,119).However, further analyses havedemonstrated that major IgE-bindingproteins are found in other fractions (gliadinand glutenin) as well. (13) Therefore, it isno surprise that serum IgE antibodies fromdifferent allergic bakers have markedlydifferent specificities and bind to numerousWheat proteins (119). The major allergensare reported to be 15, 17, and 47 kDaallergens of Wheat (6) the 15 kDa Wheatallergen belonging to the alpha-amylase/trypsin inhibitor family (5,82). In ingestedcereal allergy and atopic dermatitis, the IgEresponses have appeared more poly-specific,being directed against over 30 individualbands of Wheat, Rye and Barley in IgEimmunoblotting (10,14). Wheat flourperoxidase has also been reported to be aprominent allergen associated with baker'sasthma (70). Several water-soluble Wheatmolecules exhibit identical epitopes (120).Wheat flour proteins are allergens for 60%to 70% of bakers with workplace-relatedrespiratory symptoms. Nevertheless, a greatinter-individual variation of IgE-bindingpatterns of Wheat flour proteins occurs inbaker's asthma (18).

Although baker's asthma (121-123) is anoccupational hypersensitivity disease primarilycaused by the inhalation of flour proteins,which are mainly derived from Wheat, thedisease may also be caused by flour proteinsfrom Rye, Barley or Soya (83-84). However,

the allergens involved in baker's asthma arenot limited to cereal allergens. Exposurepossibilities in a bakery range from mouldand mite contaminants to several additiveagents used in the baking. For example, in astudy of bakers with workplace-relatedrespiratory symptoms, sensitisation toWheat flour was demonstrated in 64%, toRye flour in 52%, to Soy flour in 25%, andto alpha-amylase in 21% (114).

Cereal alpha- and beta-amylases may bemore important allergens than fungal alpha-amylase. IgE antibody determinationanalysis showed that 29 of 30 subjects withinhalant-induced cereal allergy had IgEantibodies to cereal amylases, but that only16 were positive to fungal alpha-amylase;RAST inhibition showed little cross-reactivity between cereal and fungal alpha-amylases (124).

Other occupational conditions

Occupational exposure to Wheat or Wheatdust may result in a number of other allergicconditions besides baker's asthma, and mayinvolve animal workers, bakers and bakery,food industry, and mill workers.

In bakers, rhinitis, itching, skin eruptions,ocular symptoms (including tearing, itchingand conjunctival injection) and respiratorysymptoms (including cough and sputumproduction) have been reported. In a study,44.4% of affected individuals were shownto have Wheat flour-specific IgE (125).

Occupational protein contact dermatitishas been described (126).

Cereal flours are used in the wood industryto improve the quality of the glues necessaryto produce veneer panels. Three individualswere found to be allergic to cereal alpha-amylase inhibitors found in Wheat, which areimportant occupational allergens responsiblefor baker's asthma (127).

Asthma can be related to exposure tocereal flour contained in animal formulafeeds (128).

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Other reactions

Non-IgE immune reactions to gluten mayresult in coeliac disease. Even low levels ofimmuno-reactive gliadin (0.75 mg/100 g)found in Wheat starch may affect theseindividuals. In one study, the majority of thepatients with coeliac disease (11 of 17) whohad never consumed Wheat starchpreviously developed symptoms, whichresolved within weeks of discontinuing theoffending product (129).

In an Indian study, 39 children sufferingfrom Wheat harvest-period respiratoryallergy, along with randomly selectedcontrols, were investigated for allergysymptoms. Of the allergic children, 81% hadskin reactivity to antigen of Wheat threshingdust, 30% to fungal antigens, 14% to Wheatdust antigens and none to Wheat plantantigens (130).

Various Wheat and Soy protein sources,including the Soy protein isolates used tomake infant formulas, may be related tojuvenile or insulin-dependent diabetesmellitus (131-132).

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79. Baldo BA, Krilis S, Wrigley CW.Hypersensitivity to inhaled flour allergens.Comparison between cereals.Allergy 1980;35:45-56

80. Block G, Tse KS, Kijek K, Chan H, Chan-Yeung M. Baker's asthma. Studies of thecross-antigenicity between different cerealgrains. Clin Allergy 1984; 14:177-85

81. Suphioglu C, Blaher B, Rolland JM,McCluskey J, Schappi G, Kenrick J, Singh MB,Knox RB. Molecular basis of IgE-recognitionof Lol p 5, a major allergen of rye-grasspollen. Mol Immunol 1998;35(5):293-305

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85. Sampson HA, Ho DG Relationship betweenfood-specific IgE concentrations and the riskof positive food challenges in children andadolescents.J Allergy Clin Immunol 1997;100(4):444-51

86. Dohi M, Suko M, Sugiyama H, Yamashita N,et al. Food-dependant exercise-inducedanaphylaxis; a study on 11 Japanese cases.J Allergy Clin Immunol 1991;87:34-40


88. Sampson HA. Food allergy.J Allergy Clin Immunol 1989;84:1062-7

89. Vichyanond P, Visitsuntorn N, Tuchinda M.Wheat-induced anaphylaxis.Asian Pac J Allergy Immunol 1990;8:49-52

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f4 Wheat90. Matsumoto T, Miyazaki T. Systemic urticaria

in an infant after ingestion of processed foodthat contained a trace quantity of wheat. AnnAllergy Asthma Immunol 2004;93(1):98-100

91. Andre F, Andre C, Colin L, Cacaraci F,Cavagna S. Role of new allergens and ofallergens consumption in the increasedincidence of food sensitizations in France.Toxicology 1994;93(1):77-83

92. Zapatero L, Martinez MI, Alonso E, Salcedo G,Sanchez-Monge R, Barber D, Lombardero M.Oral wheat flour anaphylaxis related to wheatalpha-amylase inhibitor subunits CM3 andCM16. Allergy 2003;58(9):956

93. Shirai T, Matsui T, Uto T, Chida K, Nakamura H.Nonsteroidal anti-inflammatory drugsenhance allergic reactions in a patient withwheat-induced anaphylaxis.Allergy 2003;58(10):1071

94. Perkins DN, Keith PK. Food- and exercise-induced anaphylaxis: importance of history indiagnosis. Ann Allergy Asthma Immunol2002;89:15-23

95. Armentia A, Martin Santos JM, Blanco M, et al.Exercise-induced anaphylactic reaction tograin flours. Ann Allergy 1990;65:149-51

96. Murakami R, Nakahara I, Kanemoto H,Suzuki T, Kasahara K, et al. Case of food-dependent exercise-induced anaphylaxiscaused by wheat. [Japanese] Nippon NaikaGakkai Zasshi 1997

97. Guinnepain MT, Eloit C, Raffard M, BrunetMoret MJ, et al. Exercise-inducedanaphylaxis: useful screening of foodsensitization. Ann Allergy 1996;77(6):491-6


99. Fiedler EM, Zuberbier T, Worm M. Acombination of wheat flour, ethanol and foodadditives inducing FDEIA.Allergy 2002;57(11):1090-1


101.Hanakawa Y, Tohyama M, et al. Food-dependent exercise-induced anaphylaxis: acase related to the amount of food allergeningested .Br J Dermatol 1998;138(5):898-900

102.Aihara Y, Kotoyori T, Takahashi Y, Osuna H,Ohnuma S, Ikezawa Z. The necessity for dualfood intake to provoke food-dependentexercise-induced anaphylaxis (FEIAn): A casereport of FEIAn with simultaneous intake ofwheat and umeboshi.J Allergy Clin Immunol 2001;107(6):1100-5

103.Napoli D, Neeno T. Wheat dependentexercise-induced cholinergic urticaria. AAAAI56th Annual Meeting 2000;March 3-8

104.Katsunuma T, Iikura Y, et al. Wheat-dependent exercise-induced anaphylaxis:inhibition by sodium bicarbonate.Ann Allergy 1992;68(2):184-8

105.Swaine IL, Riding WD. Respiratory arrest in amale athlete after running through a wheatfield. Int J Sports Med 2001;22(4):268-9

106.Burks AW, James JM, Hiegel A, et al. Atopicdermatitis and food hypersensitivityreactions. J Pediatr 1998;132(1):132-6

107.Varjonen E, Vainio E, Kalimo K AntigliadinIgE – indicator of wheat allergy in atopicdermatitis. Allergy 2000;55(4):386-91

108.Uchio E, Miyakawa K, Ikezawa Z, Ohno SSystemic and local immunological features ofatopic dermatitis patients with ocularcomplications.Br J Ophthalmol 1998;82(1):82-7

109.Sanchez-Perez J, Sanz T, Garcia-Diez A.Allergic contact dermatitis from hydrolyzedwheat protein in cosmetic cream.Contact Dermatitis 2000;42(6):360

110.Kanny G, Chenuel B, Moneret-Vautrin DA.Chronic urticaria to wheat.Allergy 2001;56(4):356-7


112.Spergel JM, Beausoleil JL, Mascarenhas M,Liacouras CA. The use of skin prick tests andpatch tests to identify causative foods ineosinophilic esophagitis.J Allergy Clin Immunol 2002;109(2):363-8

113.Steinman HA. Hidden Allergens in Foods.J Allergy Clin Immunol 1996;98(2):241-50

114.Baur X, Degens PO, Sander I. Baker'sasthma: still among the most frequentoccupational respiratory disorders. J AllergyClin Immunol 1998;102(6 Pt 1):984-97

115.Savolainen J. Baker's Asthma: diversity ofallergens. [Editorial] Clin Exp Allergy1997;27:1111-3

116. Armentia A, Martin-Santos JM, Quintero A. et al.Baker's asthma: prevalence and evaluation ofimmunotherapy with a wheat flour extract.Ann Allergy 1990; 65:265-72

117.Kamidaira T, Suetsugu S, Umeda H. Clinicaland immunologic studies on patients withbaker's asthma. [Japanese] Arerugi1986;35(1):47-59

118.Sandiford CP. Cereal-induced occupationalasthma. Clin Exp Allergy 1996;26(2):128-31

119.Sutton R, Skerritt JH, Baldo BA, Wrigley CW.The diversity of allergens involved in baker'sasthma. Clin Allergy 1984;14:93-107

120.Theobald K, Thiel H, Kallweit C, Ulmer W,Konig W. Detection of proteins in wheat flourextracts that bind human IgG, IgE, andmouse monoclonal antibodies.J Allergy Clin Immunol 1986; 78:470-7

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121.Prichard MG, Ryan G, Musk AW. Wheat floursensitization and airways disease in urbanbakers. Brit J Ind Med 1984;41:450-4

122.De Zotti R, Larese F, Bovenzi M, Negro C,Molinari S. Allergic airway disease in Italianbakers and pastry makers.Occup Environ Med 1994; 51:548-52

123.Valero Santiago A, Amat Par P, Sanosa Vails Jet al. Hypersensitivity to wheat flour inbakers.Allergol et Immunopathol 1988; 16:309-14

124.Sandiford CP, Tee RD, Taylor AJ. The role ofcereal and fungal amylases in cereal flourhypersensitivity.Clin Exp Allergy 1994; 24:549-57

125.Matsumura Y, Niitsuma T, Ito H. A study offactors contributing to bakers' allergysymptoms. Arerugi 1994;43(5):625-33

126.Iliev D, Wüthrich B. Occupational proteincontact dermatitis with type I allergy todifferent kinds of meat and vegetables.Int Arch Occup Environ Health.1998;71(4):289-92

127.Lopez-Rico R, Moneo I, Rico A, Curiel G,Sanchez-Monge R, Salcedo G. Cereal alpha-amylase inhibitors cause occupationalsensitization in the wood industry.Clin Exp Allergy 1998;28(10):1286-91

128.Valdivieso R, Pola J, Zapata C, Puyana J,Cuesta J et al. Farm animal feeders: anothergroup affected by cereal flour asthma.Allergy 1988;43(6):406-10

129.Chartrand LJ, Russo PA, Duhaime AG,Seidman EG. Wheat starch intolerance inpatients with celiac disease.J Am Diet Assoc 1997;97(6):612-8

130.Lavasa S, Kumar L, Kaushal SC, Ganguli NK.Wheat threshing dust – a "new allergen" inApril-May nasobronchial allergy. IndianPediatr 1996;33(7):566-70

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f4 Wheat

251

Phaseolus vulgarisFamily: Fabaceae (Leguminosae)Commonnames: White bean, Cannellini

bean, Marrow bean,Great northern bean,White kidney bean,Haricot bean

Sourcematerial: Dried beansSynonym: P. vulgaris var. humilisSee also: Red kidney bean f287

and Green bean f315For continuous updates:www.immunocapinvitrosight.com

f15 White bean

Allergen Exposure


White bean (the beans actually range incolour from pale green to creamy white) isa term given to varieties of beans that havelight-coloured seeds. They are less robust inflavour than the Green bean and Red kidneybean, but in some countries they are a staplefood. There are several varieties of Whitebeans, each tending to be used in differentdishes. For example, White beans may beused as “Haricot beans” in stews, or ascanned baked beans.

Environment

White beans are traditionally eaten alone,without the pods. They are usually availableonly canned, dried or (occasionally) frozen.They are baked with sauces, or added tosoups, stews and baked dishes. The seed maybe sprouted and used in salads or cooked.White beans are an excellent source of ironand folate and a good source of magnesium,phosphorus, potassium, and copper.

The green or dried mature pods, or theseeds alone, are reported to have diuretic,hypoglycaemic and hypotensive actions. Theseeds or the whole plant may be used as ahomeopathic remedy for a variety ofdiseases. Ground into flour, the seeds areused externally in the treatment of ulcers.

Allergens


An alpha-amylase inhibitor has beenisolated (1). The allergenicity of this proteinhas not been determined yet.

Phaseolus vulgaris contains a chitinase ofunknown allergenicity (2).


An extensive cross-reactivity among thedifferent individual species of the genuscould be expected but in fact is not seenfrequently (3).

Legumes have structurally homologousproteins, but they are not all equally allergenic,making it difficult to distinguish in vitro andin vivo cross-reactivity. In SPT serum IgEantibody tests, most patients are shown to besensitised to more than 1 species, but this maybe clinically irrelevant. For example, in an invitro study, the specific IgE binding by proteinextracts of 11 food legumes was examined byIgE antibody determination and RASTinhibition. Cross-allergenicity wasdemonstrated to be most marked between theextracts of Peanut, Garden pea, Chick pea,and Soybean (4-5), and between Pea andSoybean (6). However, clinical studies havefound that there is little cross-reactivitybetween members of the legume family (7-9).

252

f15 White beanIn a recent Spanish study, a high degree of

cross-reactivity was demonstrated byinhibition studies among Lentil, Chick pea, Peaand Peanut. The majority of the study grouphad had symptoms with more than 1 legume(median 3 legumes). Thirty-nine patients werechallenged (open or simple blind) with 2 ormore legumes and 32 (82%) reacted to 2 ormore legumes: 43.5% to 3, 25.6% to 2, 13%to 4 legumes. Seventy-three per cent of thepatients challenged with Lentil and Pea hadpositive challenges to both, 69.4% to Lentiland Chick pea, 60% to Chick pea, and64.3% to Lentil, Chick pea and Peasimultaneously. However, White bean,Green bean and Soy were generally welltolerated by children allergic to otherlegumes. The authors argued that, unlike inthe Anglo-Saxon population, thisphenomenon implies clinical sensitisation formany Spanish children (10).

The Peanut vicilin storage protein sharessignificant sequence homology with thevicilin storage proteins of other legumes, e.g.,Soybean, Pea, and Common bean (11). Thisdoes not necessarily indicate clinical cross-reactivity but would explain why IgEantibodies to other legumes may be foundin serum.

A study investigated the in vitro cross-reactivity of allergens from Mesquite treepollen (Honey locust tree; Prosopis juliflora)and Lima bean (Phaseolus limensis/Phaseolus lunatus). Of 110 patients withasthma, rhinitis or both, as evaluated byintradermal test, 20 were highly positive toMesquite pollen extract. Of these, 12patients showed elevated IgE antibody levelto Mesquite pollen extract alone, and 4 toboth Lima bean and pollen extract. Limabean extract could inhibit IgE binding toMesquite in a dose-dependent manner. Also,humoral and cellular cross-reactivity wasdemonstrated (12). Although cross-reactivity was not investigated betweenMesquite and White bean per se, cross-reactivity may exist between pollen from thistree and other species of Phaseolus.

Clinical Experience


White bean may uncommonly inducesymptoms of food allergy in sensitisedindividuals.

A study reports on a 33-year-old womanwho developed tongue swelling and burningand mouth itching minutes after eatingbaked Beans. Similar symptoms occurred aday after ingesting Pea soup, on anotheroccasion within 15 minutes of eating a Beanburrito, and again 20 minutes after eatingchilli containing Kidney and Pinto beans. Inthis last instance, she also developed chesttightness, wheezing, generalised erythema,urticaria, abdominal pain, a feeling ofimpending doom and light-headedness. SPTwas positive to Red kidney and White bean,but negative to Pea, Green and Lima bean.IgE antibodies were found to Red kidney,Pinto and White bean, and to Chick pea,Pea and Black-eyed pea (13).

A 7-year-old boy was described whodeveloped angioedema associated withinhalation of vapours from cooked Whitebean. SPT evaluation using the prick-to-prick method was positive for White bean.IgE antibody determination was positive forWhite bean and Green bean. The patient alsodeveloped angioedema after ingestingcooked White bean (14).

Other reactions

The root is dangerously narcotic. Largequantities of the raw mature seed may bepoisonous. Flatulence is also a hazard.

253

References1. Lee SC, Gepts PL, Whitaker JR. Protein

structures of common bean (Phaseolusvulgaris) alpha-amylase inhibitors.J Agric Food Chem 2002;50(22):6618-27

2. Verburg JG, Smith CE, Lisek CA, Huynh QK.Identification of an essential tyrosine residuein the catalytic site of a chitinase isolatedfrom Zea mays that is selectively modifiedduring inactivation with 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide.J Biol Chem 1992;267(6):3886-93



5. Bardare M, Magnolfi C, Zani G.Soy sensitivity: personal observation on 71children with food intolerance.Allerg Immunol (Paris) 1988;20(2):63-6



f15 White bean




11. Stanley JS, Bannon GA. Biochemistry of foodallergens. Clin Rev Allergy Immunol1999;17(3):279-91



14. Martinez AJ, Callejo MA, Fuentes Gonzalo MJ,Martin GC. Angioedema induced byinhalation of vapours from cooked white beanin a child. Allergol Immunopathol (Madr )2005;33(4):4-230

254

MixesThese tests consist of a mixture of differentallergens, related or unrelated. For specificinformation about the included allergensconsult the separate descriptions.

Refers to other books in the serie Allergy – Which Allergens?1Food of Animal Origin2Food of Plant Origin – Fruits & Vegetables3Food of Plant Origin – Additives, Spices & Miscellaneous

fx1Peanut (f13) page 132Hazel nut (f17) page 81Brazil nut (f18) page 26Almond (f20) page 9Coconut (f36) page 54

fx3Wheat (f4) page 235Oat (f7) page 126Maize (f8) page 114Sesame seed (f10) page 192Buckwheat (f11) page 32

fx5Egg white (f1)1

Milk (f2)1

Fish (f3)1

Wheat (f4) page 235Peanut (f13) page 132Soybean (f14) page 200

fx8Hazel nut (f17) page 81Brazil nut (f18) page 26Orange (f33)2

Apple (f49)2

Cacao (f93)3

fx9Almond (f20) page 9Kiwi (f84)2

Melons (f87)2

Banana (f92)2

Grape (f259)2

255

Mixes

fx11Maize (f8) page 114Pea (f12) page 126White bean (f15) page 251Carrot (f31)2

Broccoli (f260)2

fx12Rye (f5) page 184Rice (f9) page 175Potato (f35)2

Mushroom (f212)3

Pumpkin (f225)2

fx13Pea (f12) page 126White bean (f15) page 251Carrot (f31)2

Potato (f35)2

fx18Pea (f12) page 126Peanut (f13) page 132Soybean (f14) page 200

fx20Wheat (f4) page 235Rye (f5) page 184Barley (f6) page 15Rice (f9) page 175

fx22Pecan nut (f201) page 150Cashew nut (f202) page 41Pistachio (f203) page 157Walnut (f256) page 227

fx24Hazel nut (f17) page 81Shrimp (f24)1

Kiwi fruit (f84)2

Banana (f92)2

256

Mixes

Refers to other books in the serie Allergy – Which Allergens?1Food of Animal Origin2Food of Plant Origin – Fruits & Vegetables3Food of Plant Origin – Additives, Spices & Miscellaneous

fx25Sesame seed (f10) page 192Yeast (f45)3

Garlic (f47)2

Celery (f85)2

fx26Egg white (f1)1

Cow's milk (f2)1

Peanut (f13) page 132Mustard (f89)3

fx27Fish (f3)1

Wheat (f4) page 235Soybean (f14) page 200Hazel nut (f13) page 81

fx28Sesame seed (f10) page 192Shrimp (f24)1

Beef (f27)1

Kiwi (f84)2

ISBN

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9704

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-452

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, 200

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Phadia AB. P O Box 6460, SE-751 37 Uppsala, SwedenTel +46 18 16 50 00. www.phadia.com

Head office Sweden +46 18 16 50 00 Austria +43 1 270 20 20 Belgium +32 2 749 5515 Brazil +55 11 3340 1800 Denmark +45 7023 3306 Finland +358 9 430 040France +33 1 61 37 34 30 Germany +49 761 47 805-0 Great Britain/Ireland +44 1 908 84 70 34 Italy +39 02 641 634 11 Japan +81 3 5365 8332Korea +82 2 2027 5400 Netherlands +31 30 602 3700 Norway +47 21 67 32 80 Portugal +351 21 423 53 50 South Africa +27 11 793 5337 Spain +34 93 589 69 79Sweden +46 18 16 50 00 Switzerland +41 43 343 40 50 Taiwan +886 2 2516 0925 United States +1 800 346 4364 Other countries +46 18 16 56 16

Legumes, Nuts & Seeds - ImmunoCAP Explorer€¦ · Legumes Both grain legumes and nuts consist of a...

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Transcript of Legumes, Nuts & Seeds - ImmunoCAP Explorer€¦ · Legumes Both grain legumes and nuts consist of a...