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Page 1: Prof. Dr. Dominique A. Vuitton€¦ · • Also found in urban children drinking raw milk Raw milk and allergy: a non-expected protective association… Observations in cross-sectional

www.milkscienceconference.comVALENCIA

24 · 25 OCTUBRE 2019

Prof. Dr.

Dominique A. VuittonBourgogne Franche-Comté University, France

Profesora Emérita de Inmunología Clínica en la Universidad Bourgogne Franche-Comté, Francia.

Raw milk, allergies, asthma and respiratory infections: main results of the «PASTURE » international project.

Leche cruda, alergias, asma e infecciones respiratorias: principales resultados del proyecto internacional «PASTURE».

with the support of / con el apoyo de:

Page 2: Prof. Dr. Dominique A. Vuitton€¦ · • Also found in urban children drinking raw milk Raw milk and allergy: a non-expected protective association… Observations in cross-sectional

Rawmilk,allergies,asthmaandrespiratoryinfections:mainresultsofthe«PASTURE»internationalproject

DominiqueAngèleVUITTONProfessoremeritusofClinicalImmunology

UniversityBourgogneFranche-Comté,FranceCorrespondingmemberoftheFrenchNationalAcademyofMedicine,

Inmemoryto

Jean-CharlesDalphin,Onbehalfof

Marie-LaureDalphin,AmandineDivaret-Chauveau,SophieNicklaus,ErikavonMutius

Page 3: Prof. Dr. Dominique A. Vuitton€¦ · • Also found in urban children drinking raw milk Raw milk and allergy: a non-expected protective association… Observations in cross-sectional

Urbanization&

Development

Increasedstandardofliving

significantlyassociatedwith

DecreasedfamilysizeDecreasednumberofinfectionsinearlylife:

bacteriaandviruses:vaccination,antibiotics,parasites:slaughteringandmeatcontrol…

Increasedhygiene(‘hygiene’hypothesis)Majorchangesinfeedinghabits

From1960to2000:unprecedentedincreaseinallergic/atopicdiseases

Page 4: Prof. Dr. Dominique A. Vuitton€¦ · • Also found in urban children drinking raw milk Raw milk and allergy: a non-expected protective association… Observations in cross-sectional

•  Beingbornandlivingonafarm:majorcircumstancesofprotectionagainstallergy–  Timespentwithanimals,inthestable,inthebarn

– Drinkingrawmilk(cf.Braun-FahrländerandvonMutius,2011;vonMutius,2012)

•  forthepregnantwomanandherchildinearlylife•  Associationfoundincross-sectionalstudiesinmanydifferent

countries

•  Alsofoundinurbanchildrendrinkingrawmilk

Rawmilkandallergy:anon-expectedprotectiveassociation…

Page 5: Prof. Dr. Dominique A. Vuitton€¦ · • Also found in urban children drinking raw milk Raw milk and allergy: a non-expected protective association… Observations in cross-sectional

Observationsincross-sectionalstudies

11.8

1.4

14.8

2.8

16

3.2

19.8

5.1

32.9

12.4

0

5

10

15

20

25

30

35

Asthmadiagnosis

Asthmasymptoms

Hay feverdiagnosis

Hay feversymptoms

Atopy

No exposureMilk onlyStable onlyStable and milk

The‘Alex’study[Riedleretal,TheLancet,2001]

Page 6: Prof. Dr. Dominique A. Vuitton€¦ · • Also found in urban children drinking raw milk Raw milk and allergy: a non-expected protective association… Observations in cross-sectional

1,000sofquestionnairesonenvironment,diet,behaviour,occupation,health…Blood,milk,andenvironmentalsamplesMedicalvisitsat1,3,4.5,6,10.5,17yearsMicrobiological,immunological,andgenomicstudies

The‘PASTUREcohort’LongitudinalstudyofruralEuropeanchildren(from2002)ü  500bornandlivingonafarmü  500notbornandlivingona

farmFollow-upfrompregnancyto17yrs-old

Page 7: Prof. Dr. Dominique A. Vuitton€¦ · • Also found in urban children drinking raw milk Raw milk and allergy: a non-expected protective association… Observations in cross-sectional

Rawmilk,rawmilk-products,…rawmilk-cheeses

ThePASTUREstudydidnotspecificallyaddresstheissueofrawmilk-cheeses!Why??

ü Studiesbasedoncorrelationsbetweenü environmentalandbiologicaldata(labmeasurements),ü medicaldata(questionnairesandmedicalvisits),andü datacollectedbytheparents(yearlyquestionnaires,‘first-yeardiary’)

ü ExceptforFrance,differentiationbetweentheoriginofthemilktopreparecheeseswasjudgednon-reliable

ü Thequestionon‘farm-madecheese’didnotcoverallrawmilk-cheeses(mostarepreparedoutsidethefarm)

Page 8: Prof. Dr. Dominique A. Vuitton€¦ · • Also found in urban children drinking raw milk Raw milk and allergy: a non-expected protective association… Observations in cross-sectional

17yearslater,themessagesofPASTURE

ResultsofthePASTUREcohortconfirm:– Contactwithanimals– Stableandbarnenvironment– Drinkingrawmilk

actuallyandindependentlyprotectagainstoccurrenceofallergicdiseaseslaterinlife–  Atopicdermatitis–  Asthma–  Allergicrhinitis–  Allergicsensitization

Page 9: Prof. Dr. Dominique A. Vuitton€¦ · • Also found in urban children drinking raw milk Raw milk and allergy: a non-expected protective association… Observations in cross-sectional

Inaddition,drinkingrawmilkprotectsagainstacuteinfectionsofthe1styearoflife

17yearslater,themessagesofPASTURE

Correlationsbetweentypeofmilkandoccurrenceofinfectionsinthe1styearoflife[Lossetal,JACI,2014]

Page 10: Prof. Dr. Dominique A. Vuitton€¦ · • Also found in urban children drinking raw milk Raw milk and allergy: a non-expected protective association… Observations in cross-sectional

1.Diversitymatters!Inthefarmenvironment:– Diversityofexposure•  stable,barn,house•  Microbes+pollen(hay),plantparticles(straw)

– Diversityofanimals•  Farmanimals++,dogsandcats

– Diversityofmicro-organisms•  Grampositiveetnegativebacteria,actinomycetes,•  Fungi:Absidiaspp.,Eurotiumspp.,Cladosporiumspp.,Penicilliumspp.,•  Highdiversityintraditionalfarms

Page 11: Prof. Dr. Dominique A. Vuitton€¦ · • Also found in urban children drinking raw milk Raw milk and allergy: a non-expected protective association… Observations in cross-sectional

•  Earlyfooddiversificationinthe1styearoflife1.Diversitymatters!

Predictiveeffectofafooddiversityscore

onasthma onfoodallergy[Roduitetal,JACI,2014]

Page 12: Prof. Dr. Dominique A. Vuitton€¦ · • Also found in urban children drinking raw milk Raw milk and allergy: a non-expected protective association… Observations in cross-sectional

1.Bothdiversityandquantitymatter…forcheeses

[Nicklausetal,Allergy,2018]

ü  Childrenwhoneverorrarelyatecheesehadhigherriskoffoodallergyandallergicrhinitis

ü  Finnishchildrenhadthehighestfrequencyofcheeseconsumption

ü  Frenchchildrenhadthemostdiverseconsumptionofcheeses

ü  Farmers’andnon-farmers’childrenhadsimilarcheeseconsumption

ü  Cheeseconsumptiondiversitywascorrelatedwiththemother’slevelofeducation

Page 13: Prof. Dr. Dominique A. Vuitton€¦ · • Also found in urban children drinking raw milk Raw milk and allergy: a non-expected protective association… Observations in cross-sectional

2.Rawmilk:THEprotectivefactor

•  Mostconstantlyfoundinanalyses•  Independentofother‘farm-associated’factors

•  Additionaleffectof‘farmmilk-’butter,yoghurt,andcheese

•  Mother’sconsumptionisalsoprotectiveforherchild

•  Consumptioninearlylife(<6years)ismostimportant

Page 14: Prof. Dr. Dominique A. Vuitton€¦ · • Also found in urban children drinking raw milk Raw milk and allergy: a non-expected protective association… Observations in cross-sectional

Roleofthemilkmicroflora?Thefirsthypothesis:bacterialendotoxins

2.Rawmilk:THEprotectivefactor

Unboiled raw milk

UHT milk

Pasteurized milk

Boiled raw milk

[Lossetal-GABRIELA.JACI,2011]

ü Nomoreendotoxinsintherawmilkofthestudiedfarmsthanin‘shopmilk’keptbyfamilies

ü Highernumberanddiversityof

micro-organismsinrawmilkü Noassociationbetween

numbersoforganisms(orsinglespecies)andclinicalparameters(allergy,infectionetc.)

ü Associationwithdiversity

(organismssimilartothosefoundinthefarmenvironment)

Page 15: Prof. Dr. Dominique A. Vuitton€¦ · • Also found in urban children drinking raw milk Raw milk and allergy: a non-expected protective association… Observations in cross-sectional

Roleofnon-microbialcomponents?ü Wheyproteins:changesinα-lactalbumin,etβ-lactoglobulinü Immunitycomponents:lactoferrin,IgA,TGF-βü Lipids:ConjugatedLinoleicAcids(CLA),Ω-3FattyAcids,ShortChainFattyAcids

2.Rawmilk:THEprotectivefactorCo

nten

tinom

éga-3Fa

ttyac

ids

[Bricketal,JACI,2016]

Non-asthmatics Asthmatics

Percen

tage

ofc

hildrenwith

allergen

icsen

sitiz

ation

[Roduitetal,Allergy,2018]

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3.Earlyexposureisassociatedwithimmunologicalchanges

•  Influenceofmother’sexposuretoprotectivefactorsduringpregnancyonimmuneresponse:trueforrawmilkandrawmilkproducts

Nbofanimalspecies

Unskimmedrawmilk

Farmbutter

FarmYoghurt

Nbofanimalspecies

Nbofhoursinthebarn

Interféron-γ

TNF-αFarmbutter

FarmYoghurt

Productionofcytokinesbytheimmunecellsofthecordblood,accordingtomaternalexposureduringpregnancy

[Pfefferleetal.JACI,2010]

Page 17: Prof. Dr. Dominique A. Vuitton€¦ · • Also found in urban children drinking raw milk Raw milk and allergy: a non-expected protective association… Observations in cross-sectional

Influenceofearlyrawmilkconsumptionbythechildrenonthedevelopmentof‘innate’and‘adaptive’immunity

3.Earlyexposureisassociatedwithimmunologicalchanges

No raw milk

Unboiled raw milk

Boiled raw milk

StimulusMarkerFarmersvsnon-farmersStayinthestablesRawmilkconsumption

[Lluisetal.JACI,2014]

TLR4TLR5TLR6

[Lossetal.JACI,2012]InfluenceontheexpressionoftheToll-likereceptors

Nb

InfluenceonthedevelopmentofT-regulatorlymphocytes

Page 18: Prof. Dr. Dominique A. Vuitton€¦ · • Also found in urban children drinking raw milk Raw milk and allergy: a non-expected protective association… Observations in cross-sectional

The‘bigpicture’

Page 19: Prof. Dr. Dominique A. Vuitton€¦ · • Also found in urban children drinking raw milk Raw milk and allergy: a non-expected protective association… Observations in cross-sectional

Possiblemechanismsoftheeffectsoftraditionalcheesesonhealth?

Gutmicroflora(‘microbiota’):atthecentreoftheimmunesystemregulationaswellasavarietyofmetabolismsIntestinalmicrobiota:-  differentinchildrenlivingin‘developed’vs‘traditional’environment-  differentinchildrenwithandwithoutallergy;-  morediversein‘protectedruralchildren’Confirmationfromcohortstudies[Azad,ClinExpAllergy.2015]

Page 20: Prof. Dr. Dominique A. Vuitton€¦ · • Also found in urban children drinking raw milk Raw milk and allergy: a non-expected protective association… Observations in cross-sectional

ThePasturestudyü  Confirmedtheprotectiveeffectofrawmilk

consumedbythemotherduringpregnancyandbythechildreninthefirst6yearsofageü  Againstallergicdisordersü  Againstacuteinfectionsofthefirstyearof

ageü  Showedthatthiseffectwasincreasedbythe

child’sconsumptionoffarmdairyproductsforthefirstyearoflifeandbythechild’sconsumptionofavarietyofcheeses(includingrawmilk-cheeses+++)forthefirst18months

ü  Demonstratedanassociationwithimmunologicalparameters

ü  Suggestedinterferencewithgeneticfactorsandintestinalandrespiratorymicrobiota

Page 21: Prof. Dr. Dominique A. Vuitton€¦ · • Also found in urban children drinking raw milk Raw milk and allergy: a non-expected protective association… Observations in cross-sectional

Thankstothe«PASTURE»team!Prof.Jean-CharlesDalphin

–  DrMarie-LaureDalphin–  DrVincentKaulek–  DrJean-JacquesLaplante–  DrAmandineDivaret-Chauveau–  DrGabrielReboux–  DrBertrandSudre–  DrSandrineRoussel–  DrSophieNicklaus–  CécileTravers–  NadiaGuillou–  clinicalresearchtechniciansandengineers–  Prof.ErikavonMutiusandthecountrycoordinators

Andall‘PASTURE’familiesonboard!

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Page 23: Prof. Dr. Dominique A. Vuitton€¦ · • Also found in urban children drinking raw milk Raw milk and allergy: a non-expected protective association… Observations in cross-sectional

ScientificreferencesofthePASTUREstudy

1.  KruscheJ,TwardziokM,RehbachK,BöckA,TsangMS,SchröderPC,KumbrinkJ,KirchnerT,XingY,RiedlerJ,DalphinJC,PekkanenJ,LauenerR,RoponenM,LiJ,WongCK,WongGWK,SchaubB;PASTUREstudygroup.TNF-α-inducedprotein3isakeyplayerinchildhoodasthmadevelopmentandenvironment-mediatedprotection.JAllergyClinImmunol.2019Aug2.pii:S0091-6749(19)30978-9.

2.  TaftD,HoS,TancrediD,StephensenC,HindeK,vonMutiusE,KirjavainenP,DalphinJC,LauenerR,RiedlerJ,MorrowA,LewisZ,MillsD.PopulationdurationofbreastfeedingandprevalenceofBifidobacteriumlongumsubspeciesinfantis.CurrDevNutr2019;3:pii:nzz040.OR01-01-19.

3.  BrickT,HoseA,WawretzkaK,vonMutiusE,RoduitC,LauenerR,RiedlerJ,KarvonenAM,PekkanenJ,Divaret-ChauveauA,DalphinJC,EgeMJ;PASTUREstudygroup.Parentsknowitbest:Predictionofasthmaandlungfunctionbyparentalperceptionofearlywheezingepisodes.PediatrAllergyImmunol.2019Aug23.doi:10.1111/pai.13118.[Epubaheadofprint]PubMedPMID:31441979.

4.  MetzlerS,FreiR,Schmaußer-HechfellnerE,vonMutiusE,PekkanenJ,KarvonenAM,KirjavainenPV,DalphinJC,Divaret-ChauveauA,RiedlerJ,LauenerR,RoduitC;PASTURE/EFRAIMstudygroup.Associationbetweenantibiotictreatmentduringpregnancy&infancyandthedevelopmentofallergicdiseases.PediatrAllergyImmunol.2019Feb8.

5.  RoduitC,FreiR,FerstlR,LoeligerS,WestermannP,RhynerC,SchiaviE,BarcikW,Rodriguez-PerezN,WawrzyniakM,ChassardC,LacroixC,Schmausser-HechfellnerE,DepnerM,vonMutiusE,Braun-FahrländerC,KarvonenA,KirjavainenP,PekkanenJ,DalphinJC,RiedlerJ,AkdisC,LauenerR,O'MahonyL;PASTURE/EFRAIMstudygroup.Highlevelsofbutyrateandpropionateinearlylifeareassociatedwithprotectionagainstatopy.Allergy.2018Nov3.doi:10.1111/all.13660.[Epubaheadofprint]

6.  GorlanovaO,IlliS,TonchevaAA,UsemannJ,LatzinP,KabeschM,DalphinJC,LauenerR,PekkanenJR,VonMutiusE,RiedlerJ,KuehniCE,RöösliM,FreyU;BILDandPASTUREstudygroups.Protectiveeffectsofbreastfeedingonrespiratorysymptomsininfantswith17q21asthmariskvariants.Allergy.2018Dec;73(12):2388-2392.

7.  KarvonenAM*,TischerC*,KirjavainenPV,RoponenM,HyvärinenA,IlliS,MustonenK,PfefferlePI,RenzH,RemesS,SchaubB,vonMutius,E,PekkanenJ.Earlyageexposuretomoisturedamageandsystemicinflammationattheageof6years.IndoorAir.2018May;28(3):450-458.

8.  Delgado-EckertE,FuchsO,KumarN,PekkanenJ,DalphinJC,RiedlerJ,LauenerR,KabeschM,KupczykM,DahlenSE,MutiusEV,FreyU;PASTUREandBIOAIRStudygroups.Functionalphenotypesdeterminedbyfluctuation-basedclusteringoflungfunctionmeasurementsinhealthyandasthmaticcohortparticipants.Thorax.2018Feb;73(2):107-115.

9.  TwardziokM,SchröderPC,KruscheJ,CasacaVI,IlliS,BöckA,LossGJ,KabeschM,TonchevaAA,RoduitC,DepnerM,GenuneitJ,RenzH,RoponenM,WeberJ,Braun-FahrländerC,RiedlerJ,LauenerR,VuittonDA,DalphinJC,PekkanenJ,vonMutiusE,SchaubB;PASTUREStudyGroup:,HyvärinenA,KarvonenAM,KirjavainenPV,RemesS,KaulekV,DalphinML,EgeM,PfefferlePI,DoekesG.AsthmaticfarmchildrenshowincreasedCD3(+)CD8(low)T-cellscomparedtonon-asthmaticfarmchildren.ClinImmunol.2017Oct;183:285-292.

Page 24: Prof. Dr. Dominique A. Vuitton€¦ · • Also found in urban children drinking raw milk Raw milk and allergy: a non-expected protective association… Observations in cross-sectional

10.  FreiR,FerstlR,RoduitC,ZieglerM,SchiaviE,BarcikW,Rodriguez-PerezN,WirzOF,WawrzyniakM,PuginB,NehrbassD,JutelM,SmolinskaS,KoniecznaP,BieliC,LoeligerS,WaserM,PershagenG,RiedlerJ,DepnerM,SchaubB,GenuneitJ,RenzH,PekkanenJ,KarvonenAM,DalphinJC,vanHageM,DoekesG,AkdisM,Braun-FahrländerC,AkdisCA,vonMutiusE,O'MahonyL,LauenerRP;PreventionofAllergyRiskfactorsforSensitizationinChildrenRelatedtoFarmingandAnthroposophicLifestyle(PARSIFAL)studygroup;ProtectionAgainstAllergyStudyinRuralEnvironments(PASTURE)/MechanismsofEarlyProtectiveExposuresonAllergyDevelopment(EFRAIM)studygroup.ExposuretononmicrobialN-glycolylneuraminicacidprotectsfarmers'childrenagainstairwayinflammationandcolitis.JAllergyClinImmunol.2018Jan;141(1):382-390.e7.

11.  RoduitC,FreiR,DepnerM,KarvonenAM,RenzH,Braun-FahrländerC,Schmausser-HechfellnerE,PekkanenJ,RiedlerJ,DalphinJC,vonMutiusE,LauenerRP;thePASTUREstudygroup,HyvärinenA,KirjavainenP,RemesS,RoponenM,DalphinML,KaulekV,EgeM,GenuneitJ,IlliS,KabeschM,SchaubB,PfefferlePI,DoekesG.PhenotypesofAtopicDermatitisDependingontheTimingofOnsetandProgressioninChildhood.JAMAPediatr.2017Jul1;171(7):655-662.

12.  ChauveauA,DalphinML,MaunyF,KaulekV,Schmausser-HechfellnerE,RenzH,RiedlerJ,PekkanenJ,KarvonenAM,LauenerR,RoduitC,VuittonDA,vonMutiusE,DalphinJC;PASTUREStudyGroup.SkinpricktestsandspecificIgEin10-year-oldchildren:Agreementandassociationwithallergicdiseases.Allergy.2017Sep;72(9):1365-1373.

13.  HoseAJ,DepnerM,IlliS,LauS,KeilT,WahnU,FuchsO,PfefferlePI,Schmaußer-HechfellnerE,GenuneitJ,LauenerR,KarvonenAM,RoduitC,DalphinJC,RiedlerJ,PekkanenJ,vonMutiusE,EgeMJ;MAS.,BauerCP,ForsterJ,ZeppF,WahnV,SchusterA,BergmannRL,BergmannKE,ReichA,GrabenhenrichL;PASTUREstudygroupmembers.,SchaubB,LossGJ,RenzH,KabeschM,RoponenM,HyvärinenA,TiittanenP,RemesS,Braun-FahrländerC,FreiR,KaulekV,DalphinML,DoekesG,BlümerN,FreyU.Latentclassanalysisrevealsclinicallyrelevantatopyphenotypesintwobirthcohorts.JAllergyClinImmunol.2017Jun;139(6):1935-1945.e12

14.  BergrothE,RoponenM,KarvonenAM,Keski-NisulaL,RemesS,RiedlerJ,RoduitC,DalphinJC,KaulekV,LossGJ,LauenerR,HirvonenMR,GenuneitJ,Schmaußer-HechfellnerE,RenzH,PfefferlePI,Krauss-EtschmannS,SchaubB,vonMutiusE,PekkanenJ;PASTUREStudyGroup..EnhancedThelper1and2cytokineresponsesatbirthassociatewithlowerriskofmiddleearinfectionsininfancy.PediatrAllergyImmunol.2016Feb;28(1):53-59.

15.  SchröderPC,CasacaVI,IlliS,SchieckM,MichelS,BöckA,RoduitC,FreiR,LluisA,GenuneitJ,PfefferleP,RoponenM,WeberJ,Braun-FahrländerC,RiedlerJ,LauenerR,VuittonDA,DalphinJC,PekkanenJ,vonMutiusE,KabeschM,SchaubB;PASTUREStudygroup.IL-33polymorphismsareassociatedwithincreasedriskofhayfeverandreducedregulatoryTcellsinabirthcohort.PediatrAllergyImmunol.2016Nov;27(7):687-695.

16.  SchröderPC,IlliS,CasacaVI,LluisA,BöckA,RoduitC,DepnerM,FreiR,GenuneitJ,PfefferlePI,RoponenM,WeberJ,Braun-FahrländerC,RiedlerJ,DalphinJC,PekkanenJ,LauenerR,vonMutiusE,SchaubB;PASTUREstudygroup.AswitchinregulatoryTcellsthroughfarmexposureduringimmunematurationinchildhood.Allergy.2017Apr;72(4):604-615.

17.  ChauveauA.,DalphinM.,KaulekV.,RoduitC.,PuginA.,vonMutiusE.,VuittonD.,DalphinJ.DisagreementbetweenskinpricktestsandspecificIgEinearlychildhood.IntArchAllergyImmunol.2016;170(2):69-74

18.  BrickT,SchoberY,BöckingC,PekkanenJ,GenuneitJ,LossG,DalphinJC,RiedlerJ,LauenerR,NockherWA,RenzH,VaaralaO,Braun-FahrländerC,vonMutiusE,EgeMJ,PfefferlePI;PASTUREstudygroup.ω-3fattyacidscontributetotheasthma-protectiveeffectofunprocessedcow'smilk.JAllergyClinImmunol.2016Jun;137(6):1699-1706.e13

19.  KääriöH,NieminenJK,KarvonenAM,HuttunenK,SchröderPC,VaaralaO,vonMutiusE,PfefferlePI,SchaubB,PekkanenJ,HirvonenMR,RoponenM.CirculatingDendriticCells,FarmExposureandAsthmaatEarlyAge.ScandJImmunol.2016Jan;83(1):18-25.

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20.  KääriöH,HuttunenK,KarvonenAM,SchaubB,vonMutiusE,PekkanenJ,HirvonenMR,RoponenM.ExposuretoafarmenvironmentisassociatedwithThelper1andregulatorycytokinesatage4.5years.ClinExpAllergy.2016Jan;46(1):71-7.

21.  KirjavainenPV,TäubelM,KarvonenAM,SulyokM,TiittanenP,KrskaR,HyvärinenA,PekkanenJ.Microbialsecondarymetabolitesinhomesinassociationwithmoisturedamageandasthma.IndoorAir.2016Jun;26(3):448-56.

22.  LossGJ,DepnerM,HoseAJ,GenuneitJ,KarvonenAM,HyvärinenA,RoduitC,KabeschM,LauenerR,PfefferlePI,PekkanenJ,DalphinJC,RiedlerJ,Braun-FahrländerC,vonMutiusE,EgeMJ;PASTUREstudygroup.TheEarlyDevelopmentofWheeze:EnvironmentalDeterminantsandGeneticSusceptibilityat17q21.AmJRespirCritCareMed.2016Apr15;193(8):889-97.

23.  MustonenK,KarvonenAM,KirjavainenP,RoponenM,SchaubB,HyvärinenA,FreyU,RenzH,PfefferlePI,GenuneitJ,VaaralaO,PekkanenJ.Moisturedamageinhomeassociateswithsystemicinflammationinchildren.IndoorAir.2016Jun;26(3):439-47

24.  MartikainenMV,KääriöH,KarvonenA,SchröderPC,RenzH,KaulekV,DalphinJC,vonMutiusE,SchaubB,PekkanenJ,HirvonenMR,RoponenM.Farmexposuresareassociatedwithlowerpercentageofcirculatingmyeloiddendriticcellsubtype2atage6.Allergy.2015Oct;70(10):1278-87.

25.  OrivuoriL,MustonenK,deGoffauMC,HakalaS,PaaselaM,RoduitC,DalphinJC,GenuneitJ,LauenerR,RiedlerJ,WeberJ,vonMutiusE,PekkanenJ,HarmsenHJ,VaaralaO;PASTUREStudyGroup.Highleveloffecalcalprotectinatage2monthsasamarkerofintestinalinflammationpredictsatopicdermatitisandasthmabyage6.ClinExpAllergy.2015May;45(5):928-39

26.  LossG,DepnerM,UlfmanLH,vanNeervenRJ,HoseAJ,GenuneitJ,KarvonenAM,HyvärinenA,KaulekV,RoduitC,WeberJ,LauenerR,PfefferlePI,PekkanenJ,VaaralaO,DalphinJC,RiedlerJ,Braun-FahrländerC,vonMutiusE,EgeMJ;PASTUREstudygroup.Consumptionofunprocessedcow'smilkprotectsinfantsfromcommonrespiratoryinfections.JAllergyClinImmunol.2015Jan;135(1):56-62.

27.  KarvonenAM,HyvärinenA,KorppiM,Haverinen-ShaughnessyU,RenzH,PfefferlePI,RemesS,GenuneitJ,PekkanenJ.Moisturedamageandasthma:abirthcohortstudy.Pediatrics.2015Mar;135(3):e598-606.

28.  OrivuoriL,MustonenK,RoduitC,Braun-FahrländerC,DalphinJC,GenuneitJ,LauenerR,PfefferleP,RiedlerJ,WeberJ,vonMutiusE,PekkanenJ,VaaralaO;PASTUREStudyGroup.ImmunoglobulinAandimmunoglobulinGantibodiesagainstβ-lactoglobulinandgliadinatage1associatewithimmunoglobulinEsensitizationatage6.PediatrAllergyImmunol.2014Jun;25(4):329-37.

29.  RoduitC,FreiR,DepnerM,SchaubB,LossG,GenuneitJ,PfefferleP,HyvärinenA,KarvonenAM,RiedlerJ,DalphinJC,PekkanenJ,vonMutiusE,Braun-FahrländerC,LauenerR;PASTUREstudygroup.Increasedfooddiversityinthefirstyearoflifeisinverselyassociatedwithallergicdiseases.JAllergyClinImmunol.2014Apr;133(4):1056-64.

30.  DepnerM,FuchsO,GenuneitJ,KarvonenAM,HyvärinenA,KaulekV,RoduitC,WeberJ,SchaubB,LauenerR,KabeschM,PfefferlePI,FreyU,PekkanenJ,DalphinJC,RiedlerJ,Braun-FahrländerC,vonMutiusE,EgeMJ;PASTUREStudyGroup.Clinicalandepidemiologicphenotypesofchildhoodasthma.AmJRespirCritCareMed.2014Jan15;189(2):129-38.

31.  NwaruBI,VirtanenSM,AlfthanG,KarvonenAM,GenuneitJ,LauenerRP,DalphinJC,HyvärinenA,PfefferleP,RiedlerJ,WeberJ,RoduitC,KaulekV,Braun-FahrländerC,vonMutiusE,PekkanenJ;PASTUREstudygroup.SerumvitaminEconcentrationsat1yearandriskofatopy,atopicdermatitis,wheezing,andasthmainchildhood:thePASTUREstudy.Allergy.2014Jan;69(1):87-94.

32.  OrivuoriL,LossG,RoduitC,DalphinJC,DepnerM,GenuneitJ,LauenerR,PekkanenJ,PfefferleP,RiedlerJ,RoponenM,WeberJ,vonMutiusE,Braun-FahrländerC,VaaralaO;PASTUREStudyGroup.SolubleimmunoglobulinAinbreastmilkisinverselyassociatedwithatopicdermatitisatearlyage:thePASTUREcohortstudy.ClinExpAllergy.2014Jan;44(1):102-12.

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33.  Leppänen HK, Täubel M, Roponen M, Vepsäläinen A, Rantakokko P, Pekkanen J, Nevalainen A, von Mutius E, Hyvärinen A. Determinants,reproducibility,andseasonalvariationofbacterialcellwallcomponentsandviablecountsinhousedust.IndoorAir.2015Jun;25(3):260-72.

34.  LluisA,DepnerM,GauglerB,SaasP,CasacaVI,RaedlerD,MichelS,TostJ,LiuJ,GenuneitJ,PfefferleP,RoponenM,WeberJ,Braun-FahrländerC,Riedler J, LauenerR,VuittonDA,Dalphin JC,Pekkanen J, vonMutiusE, SchaubB;ProtectionAgainstAllergy:Study inRuralEnvironmentsStudyGroup.IncreasedregulatoryT-cellnumbersareassociatedwithfarmmilkexposureandloweratopicsensitizationandasthmainchildhood.JAllergyClinImmunol.2014Feb;133(2):551-9

35.  KarvonenAM,HyvärinenA,RintalaH,KorppiM,TäubelM,DoekesG,GehringU,RenzH,PfefferlePI,GenuneitJ,Keski-NisulaL,RemesS,LampiJ,vonMutiusE,PekkanenJ.Quantityanddiversityofenvironmentalmicrobialexposureanddevelopmentofasthma:abirthcohortstudy.Allergy.2014Aug;69(8):1092-101.

36.  MustonenK,OrivuoriL,Keski-NisulaL,HyvärinenA,PfefferlePI,RiedlerJ,DalphinJC,GenuneitJ,LauenerR,RoduitC,Braun-FahrländerC,WeberJ,Schaub B,vonMutiusE,PekkanenJ,VaaralaO;PASTUREStudyGroup.Inflammatory responseandIgEsensitizationatearlyage.PediatrAllergyImmunol.2013Jun;24(4):395-401.

37.  MichelS,BusatoF,GenuneitJ,PekkanenJ,DalphinJC,RiedlerJ,MazaleyratN,WeberJ,KarvonenAM,HirvonenMR,Braun-FahrländerC,LauenerR,vonMutiusE,KabeschM,TostJ;PASTUREstudygroup.FarmexposureandtimetrendsinearlychildhoodmayinfluenceDNAmethylationingenesrelatedtoasthmaandallergy.Allergy.2013Mar;68(3):355-64.

38.  DepnerM,EgeMJ,Genuneit J, Pekkanen J,RoponenM,HirvonenMR,Dalphin JC,KaulekV,Krauss-EtschmannS,Riedler J,Braun-FahrländerC,RoduitC,LauenerR,PfefferlePI,WeberJ,vonMutiusE;PASTUREStudyGroup.Atopicsensitizationinthefirstyearoflife.JAllergyClinImmunol.2013Mar;131(3):781-8.

39.  LossG,BitterS,WohlgensingerJ,FreiR,RoduitC,GenuneitJ,PekkanenJ,RoponenM,HirvonenMR,DalphinJC,DalphinML,RiedlerJ,vonMutiusE,WeberJ,KabeschM,MichelS,Braun-FahrländerC,LauenerR;PASTUREstudygroup.Prenatalandearly-lifeexposuresalterexpressionofinnateimmunitygenes:thePASTUREcohortstudy.JAllergyClinImmunol.2012Aug;130(2):523-30.

40.  KarvonenAM,HyvärinenA,GehringU,KorppiM,DoekesG,RiedlerJ,Braun-FahrländerC,BitterS,SchmidS,Keski-NisulaL,RoponenM,KaulekV,Dalphin JC, Pfefferle PI, Renz H, Büchele G, vonMutius E, Pekkanen J; PASTURE Study Group. Exposure tomicrobial agents in house dust andwheezing,atopicdermatitisandatopicsensitizationinearlychildhood:abirthcohortstudyinruralareas.ClinExpAllergy.2012Aug;42(8):1246-56.

41.  MustonenK,Keski-NisulaL,VaaralaO,PfefferlePI,RenzH,RiedlerJ,DalphinJC,BuecheleG,LauenerR,Braun-FahrländerC,vonMutiusE,PekkanenJ; PASTUREStudyGroup.Fewassociationsbetweenhigh-sensitivityC-reactiveproteinandenvironmentalfactorsin4.5-year-oldchildren.PediatrAllergyImmunol.2012Sep;23(6):522-8.

42.  Respiratorytractillnessesduringthefirstyearoflife:effectofdogandcatcontacts.BergrothE,RemesS,PekkanenJ,KauppilaT,BücheleG,Keski-NisulaL.Pediatrics.2012Aug;130(2):211-20.

43.  RoduitC,FreiR,LossG,BücheleG,Weber J,DepnerM,LoeligerS,DalphinML,RoponenM,HyvärinenA,Riedler J,Dalphin JC,PekkanenJ,vonMutiusE,Braun-FahrländerC,LauenerR;ProtectionAgainstAllergy–Study inRuralEnvironmentsstudygroup.Developmentofatopicdermatitisaccordingtoageofonsetandassociationwithearly-lifeexposures.JAllergyClinImmunol.2012Jul;130(1):130-6.

44.  RousselS,SudreB,RebouxG,WaserM,BucheleG,VacheyrouM,DalphinJC,MillonL,Braun-FahrländerC,vonMutiusE,PiarrouxR.ExposuretomouldsandactinomycetesinAlpinefarms:anestedenvironmentalstudyofthePASTUREcohort.EnvironRes.2011Aug;111(6):744-50.

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45.  RoduitC,WohlgensingerJ,FreiR,BitterS,BieliC,LoeligerS,BücheleG,RiedlerJ,DalphinJC,RemesS,RoponenM,PekkanenJ,KabeschM,SchaubB,vonMutiusE,Braun-FahrländerC,LauenerR;PASTUREStudyGroup.Prenatalanimalcontactandgeneexpressionofinnateimmunityreceptorsatbirthareassociatedwithatopicdermatitis.JAllergyClinImmunol.2011Jan;127(1):179-85

46.  Analytical performance of a multiplexed, bead-based cytokine detection system in small volume samples. Bomert M, Köllisch G, Roponen M,LauenerR,RenzH,PfefferlePI,Al-FakhriN.ClinChemLabMed.2011Oct;49(10):1691-3.

47.  RochatMK,EgeMJ,PlabstD,SteinleJ,BitterS,Braun-FahrländerC,DalphinJC,RiedlerJ,RoponenM,HirvonenMR,BücheleG,RenzH,LauenerR,Krauss-EtschmannS,vonMutiusE;PASTUREStudygroup.MaternalvitaminDintakeduringpregnancyincreasesgeneexpressionofILT3andILT4incordblood.ClinExpAllergy.2010May;40(5):786-94.

48.  PfefferlePI,BücheleG,BlümerN,RoponenM,EgeMJ,Krauss-EtschmannS,GenuneitJ,HyvärinenA,HirvonenMR,LauenerR,PekkanenJ,RiedlerJ,DalphinJC,BrunekeefB,Braun-FahrländerC,vonMutiusE,RenzH;PASTUREStudyGroup.Cordbloodcytokinesaremodulatedbymaternalfarmingactivitiesandconsumptionoffarmdairyproductsduringpregnancy:thePASTUREStudy.JAllergyClinImmunol.2010Jan;125(1):108-15.

49.  Keski-Nisula L, LappalainenMH,Mustonen K, HirvonenMR, Pfefferle PI, Renz H, Pekkanen J, RoponenM. Production of interleukin-5, -10 andinterferon-γincordbloodisstronglyassociatedwiththeseasonofbirth.ClinExpAllergy.2010Nov;40(11):1658-68.

50.  Keski-Nisula L, Karvonen A, Pfefferle PI, Renz H, Büchele G, Pekkanen J. Birth-related factors and doctor-diagnosed wheezing and allergicsensitizationinearlychildhood.Allergy.2010Sep;65(9):1116-25.

51.  SudreB,VacheyrouM,Braun-FahrländerC,NormandAC,WaserM,RebouxG,RuffaldiP, vonMutiusE,PiarrouxR;PASTUREstudygroup.HighlevelsofgrasspolleninsideEuropeandairyfarms:arolefortheallergy-protectiveeffectsofenvironment?Allergy.2009Jul;64(7):1068-73.

52.  KarvonenAM,HyvärinenA,RoponenM,HoffmannM,KorppiM,RemesS,vonMutiusE,NevalainenA,PekkanenJ.Confirmedmoisturedamageathome,respiratorysymptomsandatopyinearlylife:abirth-cohortstudy.Pediatrics.2009Aug;124(2):e329-38.

53.  EgeMJ,HerzumI,BücheleG,Krauss-EtschmannS,LauenerRP,BitterS,RoponenM,RemesS,VuittonDA,RiedlerJ,BrunekreefB,DalphinJC,Braun-FahrländerC,PekkanenJ,RenzH,vonMutiusE;PASTUREStudyGroup.SpecificIgEtoallergensincordbloodisassociatedwithmaternalimmunitytoToxoplasmagondiiandrubellavirus.Allergy.2008Nov;63(11):1505-11.

54.  PfefferlePI,SelS,EgeMJ,BücheleG,BlümerN,Krauss-EtschmannS,HerzumI,AlbersCE,LauenerRP,RoponenM,HirvonenMR,VuittonDA,RiedlerJ, Brunekreef B, Dalphin JC, Braun-Fahrländer C, Pekkanen J, vonMutius E, Renz H; PASTURE Study Group. Cord blood allergen-specific IgE isassociatedwithreducedIFN-gammaproductionbycordbloodcells:theProtectionagainstAllergy-StudyinRuralEnvironments(PASTURE)Study.JAllergyClinImmunol.2008Oct;122(4):711-6.

55.  EgeMJ,HerzumI,BücheleG,Krauss-EtschmannS,LauenerRP,RoponenM,HyvärinenA,VuittonDA,Riedler J,BrunekreefB,DalphinJC,Braun-FahrländerC,PekkanenJ,RenzH,vonMutiusE;ProtectionAgainstAllergyStudyinRuralEnvironments(PASTURE)Studygroup.Prenatalexposuretoafarmenvironmentmodifiesatopicsensitizationatbirth.JAllergyClinImmunol.2008Aug;122(2):407-12,412.

56.  GehringU,SpithovenJ,SchmidS,BitterS,Braun-FahrländerC,DalphinJC,HyvärinenA,PekkanenJ,RiedlerJ,WeilandSK,BücheleG,vonMutiusE,Vuitton DA,BrunekreefB;PASTURE studygroup.Endotoxin levels in cow'smilk samples from farmingandnon-farming families - thePASTUREstudy.EnvironInt.2008Nov;34(8):1132-6.

57.  GehringU,SpithovenJ,SchmidS,BitterS,Braun-FahrländerC,DalphinJC,HyvärinenA,PekkanenJ,RiedlerJ,WeilandSK,BücheleG,vonMutiusE,VuittonDA,BrunekreefB;PASTUREstudygroup.Endotoxinlevelsincow'smilksamplesfromfarmingandnon-farmingfamilies-thePASTUREstudy.EnvironInt.2008Nov;34(8):1132-6.

58.  von Mutius E, Schmid S; PASTURE Study Group. The PASTURE project: EU support for the improvement of knowledge about risk factors andpreventivefactorsforatopyinEurope.Allergy.2006Apr;61(4):407-13.

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