R E V I E W : I M M U N O L O G Y

Allergy, Parasites, and the Hygiene HypothesisMaria Yazdanbakhsh,1* Peter G. Kremsner,2,3 Ronald van Ree4

The increase of allergic diseases in the industrialized world has often been explainedby a decline in infections during childhood. The immunological explanation has beenput into the context of the functional T cell subsets known as T helper 1 (TH1) and Thelper 2 (TH2) that display polarized cytokine profiles. It has been argued thatbacterial and viral infections during early life direct the maturing immune systemtoward TH1, which counterbalance proallergic responses of TH2 cells. Thus, a reductionin the overall microbial burden will result in weak TH1 imprinting and unrestrainedTH2 responses that allow an increase in allergy. This notion is contradicted byobservations that the prevalence of TH1-autoimmune diseases is also increasing andthat TH2-skewed parasitic worm (helminth) infections are not associated with allergy.More recently, elevations of anti-inflammatory cytokines, such as interleukin-10, thatoccur during long-term helminth infections have been shown to be inversely corre-lated with allergy. The induction of a robust anti-inflammatory regulatory network bypersistent immune challenge offers a unifying explanation for the observed inverseassociation of many infections with allergic disorders.

T here has been a significant increase inthe prevalence of allergic diseases overthe past 2 to 3 decades. Currently,

more than 130 million people suffer fromasthma, and the numbers are increasing (1);nevertheless, there is a considerably lowerprevalence of allergic diseases in developingcountries (2). There are also clear differencesin the prevalence of allergies between ruraland urban areas within one country. For ex-ample, in Ethiopia, asthma is more prevalentin urban areas than in rural villages (3), andasthma is more common in residents of urbanGermany than in farmers living in rural Ba-varia (4). To explain these observations, en-vironmental factors associated with more in-dustrialized and urban living have been stud-ied intensively, but there is little consistentevidence to suggest that obvious risk factors,such as increased exposure to indoor aller-gens, pollution, or changes in diet and breast-feeding, could account for the rise in atopicdiseases. However, another category of envi-ronmental factors, childhood infections,shows an overwhelming and consistent neg-ative association with atopy and allergic dis-eases. Allergic sensitization is overrepresent-ed among first-born but is less frequent inchildren from large families (5) and thoseattending day care (6), suggesting that a fre-quent exchange of infections may have aprotective effect (5).

Atopy, characterized by raised immuno-globulin (Ig)E levels, underlies allergic dis-eases such as asthma, rhinoconjunctivitis, andeczema. The interaction of an environmentalallergen with the innate immune system, itsuptake by antigen-presenting cells, and thesubsequent T cell priming leads to the stim-ulation of cytokines such as interleukin (IL)-4, IL-5, and IL-13. These cytokines interactwith their receptors to stimulate IgE produc-tion and increased numbers of eosinophilsand mast cells; all of these components arecapable of precipitating inflammation in therespiratory tract (Fig. 1) (7).

Exposure to food and orofecal patho-gens, such as hepatitis A, Toxoplasma gon-dii, and Helicobacter pylori, reduces therisk of atopy by .60% (8). Studies of gutcommensals indicate differences in the rateof microbial colonization, as well as thebacterial type involved (clostridia versuslactobacilli) in children with and without apredisposition to allergy (9). On the basisof these data, it has been proposed that thelack of intense infections in industrializedcountries owing to improved hygiene, vac-cination, and use of antibiotics may alterthe human immune system such that it re-sponds inappropriately to innocuous sub-stances. This so-called “hygiene hypothe-sis” (5) has been given an immunologicalframework in which the balance betweentype 1 (TH1, associated with bacterial andviral infections and autoimmune diseases)and type 2 (TH2, associated with helminthinfections and allergic diseases) immuneresponses is pivotal (10). It has been pos-tulated that limited exposure to bacterialand viral pathogens during early childhoodresults in an insufficient stimulation of TH1cells, which in turn cannot counterbalance

the expansion of TH2 cells and results in apredisposition to allergy (Fig. 1).

The immunological explanation for thehygiene hypothesis has been very influentialin directing strategies to prevent allergic dis-eases. Induction of allergen-specific TH1 re-sponses by Bacille Calmette-Guerin (BCG)or DNA vaccination is being advocated (11)on the basis of the promising results obtainedin experimental animals (11). However, inthe face of discrepancies that have come tolight from studies involving autoimmune dis-eases and helminth infections, it is importantto reevaluate the immunological basis of thehygiene hypothesis.

The prevalence of type 1 diabetes, a TH1-mediated disease, has been progressively in-creasing in the past few decades, and thereare data to support an association between theoccurrence of type 1 diabetes and asthma atthe population level (12). Such data suggestthat the root cause of the increase in allergicdiseases is also responsible for the escalationof autoimmune disorders and that this cannotmerely be accounted for by the TH1 versusTH2 imbalance, but instead must have a com-mon immunological denominator. Similarconcerns arise when considering helminth in-fections, which are the most potent naturalstimuli for TH2 responses.

Worldwide, helminth infections and aller-gic diseases do not overlap despite both con-ditions being accompanied by strong TH2immune responses (2, 13). Here, we reviewthe relation between parasitic infections andallergy and focus on insights that may presentan alternative immunological framework forthe hygiene hypothesis and have im-portant implications for future research andtherapeutics.

Risk Factors or Protection?Helminth infections are universally associat-ed with responses stimulated by TH2-typecytokines, such as high levels of IgE, eosin-ophilia, and mastocytosis (14). Thus, al-though helminth infections and atopic diseas-es are associated with similar immunologicalphenomena, the clinical outcome with respectto immediate hypersensitivity and inflamma-tion is clearly not the same (Fig. 1). Whenone considers that the 1 billion or so peoplewho are heavily infected with helminthsworldwide and suffer from the resultant nu-tritional, growth, and cognital deficienciesare rarely afflicted by allergic diseases, then itis clear that a strong TH2 response is not thesole factor in precipitating an allergic attack.

1Department of Parasitology, Leiden University Med-ical Center, Leiden, Netherlands. 2Department of Par-asitology, Institute for Tropical Medicine, Universityof Tuebingen, Germany. 3Research Unit, AlbertSchweitzer Hospital, Lambarene, Gabon. 4Departmentof Immunopathology, Sanquin Research at CLB, Am-sterdam, Netherlands.

*To whom correspondence should be addressed. E-mail: M.Yazdanbakhsh@LUMC.NL

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The 1960s and 1970s were marked by livelydebates about the notion that helminths havea protective effect against allergy. In additionto anecdotal reports of protection from hayfever by ingestion of Ascaris spp. (round-worm) eggs (15), a meta-analysis of datafrom early surveys showed that, despite thevariation in methodology and clinical assess-ment of allergy, the prevalence of parasiticinfections was negatively associated with theprevalence of asthma (13).

More recent studies have reevaluatedfindings in South America and Africa using acombination of parameters to assess allergywith careful parasitological diagnosis andhave shown a consistent inverse relation be-tween helminth infections (schistosomiasisand intestinal helminths) and either skin re-activity to environmental allergens or clinicalscores, such as airway hyperresponsiveness,wheeze, and asthma (16–20) (Fig. 2A). Inmost of these studies, .30% of the studied

subjects carried substantial levels of IgE tohouse dust mite (HDM-IgE); these valuescorrespond to those seen in many industrial-ized countries. In high-income countries, al-lergen-specific IgE leads to skin reactivity tomite, but in less developed countries, thepresence of specific IgE does not alwaystranslate into equivalent numbers of atopicskin reactions. In Gabon, only 11% of theschool children reacted to mite in a skin pricktest (SPT), whereas 32% were positive forHDM IgE (19). High levels of IgE and SPTpositivity in affluent societies in central Eu-rope (33%) (21) and Australia (32.5%) (22)are associated with high prevalences of air-way disease (12% asthma in central Europeand 21.9% wheeze in Australia). By contrast,in many low-income countries, such as TheGambia (20) and Nigeria (22), 35.3% and28.2% atopic reactions translated into only3.6% asthma and 6% wheeze, respectively. Ina recent study in Ethiopia, atopy to HDM

was common, but in the presence of high-intensity intestinal helminth infections wasunrelated to wheeze (23). It is clear, there-fore, that despite IgE sensitization to envi-ronmental allergens, helminth-infested sub-jects are somehow protected from mast celldegranulation and inflammatory responsesin affected organs.

The burden and chronicity of helminthinfections is an important variable that maydetermine whether helminths act as a riskfactor for, or confer protection against, aller-gic diseases. In Venezuela, the classificationof helminth-infested populations into thosewith none, light, or heavy worm burdensshows that light helminth infections are asso-ciated with the amplification of allergen-spe-cific IgE responses and a high skin reactivity,whereas heavily parasitized subjects are pro-tected from atopic skin reactivity despite ahigh degree of sensitization to mite (16).Clinical allergic symptoms in those with light

Fig. 1. Divergent outcome of TH2 responses in industrialized (lowpathogen exposure) and developing countries (high pathogen expo-sure). It has been argued that improved hygiene, frequent use ofantibiotics, and vaccination has led to reduced bacterial and viralinfections in industrialized countries and therefore to insufficientstimulation of TH1 responses, which in turn allows the expansion ofTH2 cells. TH2 responses are characterized by increased IgE to aller-gens, mastocytosis, and eosinophilia. Mast cell degranulation andrelease of inflammatory mediators leads to mucus production andsmooth muscle cell contraction, precipitating allergic diseases of theairways. Helminths are prevalent in developing countries and lead to

strong TH2 responses. Nevertheless, helminth-infected populationsshow little signs of allergic disorders. This difference may be explainedby the differences in exposure to pathogens. A high prevalence ofchronic infections in developing countries results in persistent im-mune challenge, with cycles of infection and inflammation, which isfollowed by the triggering of anti-inflammatory molecules to restrictimmunopathology. This dynamic interaction educates the immunesystem to establish a robust regulatory network, possibly the key tocontrolling allergic diseases. Such a network would be weakly devel-oped in industrialized countries with a low pathogen load, allowinginappropriate immunopathological reactions to develop more readily.

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helminth infections were alleviated after de-worming with drugs (24) but were exacerbat-ed in individuals who had had heavy wormburdens (17). This reinforces the view thatheavy helminth infections protect against al-lergy. These observations may also explainthe situation in industrialized countries whereexposure to helminths such as Toxocara spp.(25), leading to seropositivity, is associatedwith an increased prevalence of airway symp-toms. Such infections are presumably lightand sporadic, allowing exposure to helminthantigens that potentiate TH2 responses with-out the inhibitory component that is associat-ed with heavy and chronic infections.

Polyclonal IgE and Allergic ResponsesThe first scenario that was favored to explainthe negative association between helminths andallergy was the “IgE blocking hypothesis.”Clinical allergy requires efficient cross-linkingof high-affinity IgE receptors (FcεRI) on mastcells and basophils (7). At least two FcεRI-bound IgE molecules must capture a singleallergen (bivalent interaction) to induce media-tor release. Helminth infections are often asso-ciated with highly polyclonal IgE, which is notspecific for parasite antigen. If IgE, for whichno antigen is available, saturates FcεRI on mastcells and blocks the binding of specific IgEdirected either to parasite antigen or to environ-mental allergens, it could inhibit degranulationand immediate hypersensitivity responses to al-lergens. In an editorial in the Lancet in 1976, itwas proposed that “one theoretical approach toprevention or treatment of allergic diseaseswould be deliberately to induce high IgE re-sponsiveness—for example, by artificial infec-tion with parasites” (26). In numerous immu-

noepidemiological stud-ies, the protective effect ofhelminth infections on al-lergic reactivity was asso-ciated with high levels oftotal polyclonal IgE (16,17, 27, 28). What wasconsidered compellingdata for the ability of totalIgE to protect againstmast cell degranulationcame from early studiesusing the Prausnitz-Kust-ner (P-K) test, which isbased on passive sensiti-zation of mast cells by thedermal injection of a se-rum containing high aller-gen-specific IgE, followedby a skin challenge withthe allergen to induce awheal and flare reaction.With one exception (29),the studies showed that, inrecipients with high levelsof IgE, it was not possible

to sensitize for skin reactivity to an allergen (16,17).

Several arguments have been raisedagainst this model. First, the epidemiologicalassociation studies did not take into accountthe effect of confounding factors such as age,sex, nutrition, socioeconomic factors, or theimmunological parameters tested. Recentstudies in Gabon and Ethiopia, where con-founders were included in the statistical anal-ysis, failed to show any significant effect oftotal IgE on parasite-mediated suppression ofatopy (19, 23). Second, with respect to theP-K test studies, there may be a difference inhow total IgE influences the mast cell Fcεreceptor occupancy by allergen-specific anti-bodies administered passively, as opposed towhen allergen-specific IgE antibodies are ac-tively produced in vivo. This has been ele-gantly shown in an experimental model,where IgE induced by a helminth infectionwas capable of blocking passive sensitizationbut did not inhibit skin hypersensitivity reac-tions to an allergen by endogenous, activelyproduced IgE (30). Furthermore, clinical tri-als with antibodies to IgE have provided di-rect evidence that the FcεRI numbers on mastcells respond to the concentration of circulat-ing IgE by changing receptor concentrationand accommodating additional binding (31).

Clinically Irrelevant Allergen-SpecificIgE Antibodies: Cross-ReactivityThe characteristics of the specific IgE anti-bodies against common inhalant allergensmay contribute to a high prevalence of sen-sitization to allergens without clinical symp-toms in parasite-infected subjects. Clinicallyirrelevant specific IgE antibodies are not

unique to parasite-infected patients. Pollen-allergic patients often have IgE antibodiesagainst foods without any sign of clinicalfood allergy (32). Common structural ele-ments, such as peptides in Betula verrucosaallergen 1 and profilins or a(1,3)-linked fu-cose on proximal N-acetyl-glucosamine inglycoproteins play an important role in IgEcross-reactivity between pollen and food al-lergens (33). Pollen-allergic patients with IgEantibodies against these sugars or against thecross-reactive peptides are positive for invitro diagnostic tests for many vegetablefoods, yet skin reactivity with vegetablefoods is low or absent in many of thesepollinosis patients (32). Whether cross-reac-tive IgE is of low affinity and therefore un-able to induce efficient mediator release frommast cells is not yet known.

In most studies of allergy in the tropics,prominent reactions to the HDM are reported.Although structural data on the N-glycans ofthese invertebrates has not been reported,a(1,3)-linked fucose is present on glycoproteinsof other arthropods (34). This substitution hasrecently been identified as an IgE-bindingstructure in helminths (35). Similarly, parasiticantigens, such as tropomyosins and glutathioneS-transferases, have their allergenic homologsin HDMs (36). It is therefore tempting to spec-ulate that chronic helminth infections result inIgE responses that are cross-reactive to HDM;hence, by analogy with cross-sensitization frompollen to foods, sensitization to parasites mayinduce clinically irrelevant cross-reactions toHDMs. Preliminary studies of one cohort inGabon do not support an important role forcross-reactivity between helminth and mite an-tigens (37), but more research is needed on thebiochemical characterization of IgE to HDM intropical populations. With the availability ofreagents, both recombinant allergens, and syn-thetic glycans, it is now possible to study thebimolecular interactions of IgE with well-de-fined epitopes.

Although the IgE-blocking hypothesis ap-pears to be obsolete, and the proposition that thephysiochemical characteristics of the IgE-rec-ognizing allergens in parasitized populationscontributes to the low incidence of clinical al-lergy has yet to be tested, data from recentstudies on hyporesponsiveness and anti-inflam-matory cytokines have indicated attractive ex-planations for the low levels of allergy in TH2-skewed populations.

Alternative TH2 Responses: TheIgG4 IsotypeFor helminth parasites, it is known thatasymptomatic infections are correlatedwith high levels of IgG4, another TH2-dependent isotype, and it has been shownthat parasite-specific IgG4 antibodies caninhibit IgE-mediated degranulation of ef-fector cells (38). Originally, this concept of

Fig. 2. Parasites pro-tect from allergy. (A)The prevalence ofSchistosoma haema-tobium (19), Ascarislumbricoides/hook-worm (20), and hook-worm (23) infectionswas significantly high-er in individuals whowere free from allergy(atopy or wheeze)compared to those who were allergic. (B) The Plasmodium falciparumreinfection scores in young Gabonese children who were eitherpositive or negative in skin testing to HDM (58). In the Kaplan-Meieranalysis of the data, it was found that nonatopic children (blue line)had significantly shorter periods to reinfection and therefore higherincidences of infection than did atopic children (black line).

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“blocking” antibodies was proposed as apossible mechanism of allergen immuno-therapy in the 1930s and 1940s (39). Effi-cient treatment of allergic patients by im-munotherapy consists of immunizationwith increasing doses of allergen up to amaintenance dose, which is then adminis-tered at regular intervals (fortnightly ormonthly) for at least 3 years. It has beennoted that one of the characteristics of suc-cessful immunotherapy is the induction ofallergen-specific IgG4 antibodies, evenwith the persistence of allergen-specificIgE (40). A recent report from Platts-Millsshowed that a high exposure to cat aller-gens results in high IgG4 titres and de-creased atopy, supporting a role for IgG4antibodies in down-regulating allergic re-sponses (41). Platts-Mills et al. propose theterm “alternative TH2 responses” to de-scribe a modified TH2 response not associ-ated with clinical allergy, a concept that hasalso been invoked in autoimmunity (42). Itis therefore tempting to propose that thelack of skin reactivity in parasitized indi-viduals may be due to the presence ofblocking IgG4 antibodies. Although not in-vestigated extensively, a study in Gabonfound no evidence for an inverse correla-tion between IgG4 and skin reactivity (37 ).The question of whether IgG4 competes forallergen or whether its occurrence reflectsanother immunologic event that underliesthe lack of allergy should be consideredgiven that the immunosuppressory cytokineIL-10 has recently been shown to stimulateIgG4 differentially (43). High levels of IL-10 are seen in individuals chronically in-fected with helminths (44 ) and subjectsreceiving allergen immunotherapy (45),conditions that are associated with highIgG4.

The Anti-Inflammatory Network MayBe Central to the Hygiene HypothesisT cell hyporesponsiveness is a well-knowncorollary of chronic parasitic infections inhumans. Helminth parasites in particular areassociated with poor antigen-specific T cell–proliferative responses, as well as with re-duced cytokine production (44). Down-regu-latory molecules such as IL-10 (44–46, 47),transforming growth factor beta (TGF-b)(47), and nitric oxide (48) have been impli-cated in this immunosuppression, and clearevidence for elevated IL-10 has come fromstudies on filarial and schistosomiasis pa-tients. The helminth antigen–specific immu-nological hyporesponsiveness appears to spillover to nonrelated antigens. Work on immu-nological responses to a purified protein de-rivative of Mycobacterium tuberculosis(PPD) and to tetanus toxoid after BCG ortetanus vaccination has shown that responsesare weaker in patients with concurrent hel-

minth infections, as compared with responsesin healthy controls (49, 50). The immunosup-pressive effects of chronic helminth infec-tions can be transferred to a fetus in utero;children born to mothers infected with filarialworms or with schistosomes respond poorlyto BCG (51). Therefore, it is clear that thewiring of immune responses in populationsliving in tropical countries and exposed to amultiplicity of chronic helminth infectionscan be quite distinct from those in subjectsliving in regions where infections havebeen controlled more successfully.

This may have several important implica-tions for the expression of immune-mediateddiseases, such as allergy. As already noted,allergies are inflammatory diseases depen-dent on TH2-type responses and initiated bymast cell degranulation. The release of medi-ators leads to vasodilation, mucus production,and smooth muscle cell contraction and ac-companies the production of pro-inflamma-tory cytokines (Fig. 1). Therefore, the pres-ence of a strong anti-inflammatory regulatorynetwork, characterized by elevated IL-10and TGF-b produced by antigen-presentingcells, and/or the newly discovered regula-tory T cells (52), could help to prevent thecascade of events leading to allergic in-flammation (Fig. 1). Recent data on schis-tosomiasis and atopy in Gabon support thisview (19). When all immunological param-eters are taken into consideration, parasite-induced IL-10 significantly reduces (by

47%) the risk of skin reactivity to mite.Several studies in industrialized coun-

tries of patients with allergic diseases favora central role for anti-inflammatory cyto-kines. Allergic individuals express lowerlevels of IL-10 (53), and the skin-whealsize in response to mite is negatively cor-related with allergen-stimulated IL-10 (54 ).Moreover, successful immunotherapy is as-sociated with a sharp increase in IL-10production by T cells (45) and IL-10 in-creases in atopic children receiving probi-otic supplementation (55). Royer and col-leagues (56 ) have shown that IL-10 caninhibit mast cell degranulation, providing amechanism for the observed negative asso-ciations between IL-10 and atopy.

Nature of the Pathogen and Inductionof the Regulatory NetworkAlthough helminth infections have highlightedthe inability of the TH1-TH2 dichotomy to ex-plain the hygiene hypothesis and have providedan alternative explanation based on the anti-inflammatory network, it has to be emphasizedthat several other chronic infectious diseases areassociated with down-regulated inflammatoryresponses. For example, malarial parasites in-fect a large proportion of children worldwideand is associated with profound immunosup-pression (57). Recently, malaria has beenlinked to allergy; in a study conducted in acohort of young children in Gabon, malariainfections were intensively monitored (every 2

Fig. 3. Education of the immune system by pathogens. Dendritic cells can develop into distinctsubpopulations, depending on the nature of the signals they receive from the microenvironment,and then direct T cell differentiation into polarized subsets. Viruses, bacteria, and helminths carrydistinct signature molecules that interact with dendritic cells to stimulate TH1-type and TH2-typeimmune responses (63). When uncontrolled, strong TH1 and TH2 responses lead to autoimmunityand allergy. High pathogen burden may either change the physiology of the microenvironment orresult in the accumulation of novel signature molecules that together endow dendritic cells withthe ability to induce regulatory T cells. Regulatory T cells produce suppressory cytokines and arepart of an anti-inflammatory network that ensures that inflammatory T cells (both TH1 and TH2)and their downstream effectors are kept under control.

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weeks) for 5 years, at the end of which thepatients were skin tested for mite. As shown inFig. 2B, children who had a negative SPT hadsignificantly shorter periods between infec-tions, and thus higher scores of repeated in-fections in the observation period (58). Theseresults agree with studies showing that re-sponses to other severe infectious diseases inthe tropics such as measles and tuberculosisare inversely associated with atopy (59, 60).Notably, each of these diseases is associatedwith immunosuppression sometimes mediat-ed by IL-10 or TGF-b (61, 62).

Immune activation or suppression has beenclosely linked to dendritic cells, which acquiresignals from the microenvironment and conveythese to naıve T cells, instructing their develop-ment into polarized TH1, TH2, or regulatory Tcells (63, 64). Thus, although helminths inducethe development of type 2 responses, and virus-es and bacteria skew toward type 1 (63), it ispossible that high overall infection turnover isinstrumental to the development of the regula-tory network, as depicted in Fig. 3. The modelalso raises the question whether certain patho-gens carry signature molecules that are bettersuited to induce regulatory cells and to protectagainst atopy than other pathogens and predictsthat frequent antigenic challenge from an arrayof pathogens is needed for a balanced develop-ment of the immune system and the preventionof allergic and inflammatory diseases (10, 42).However, instead of TH1 versus TH2, it may bethe pro- versus anti-inflammatory axis with arobust regulatory T cell network that has to beconsidered central to the balance and to theprevention of either TH1 and/or TH2 diseases(Fig. 3) (14, 42).

Implications for Therapeutics andFuture ResearchThe parallels between parasite infections andimmunotherapy strongly suggest that strategiesfor successful prophylaxis should be fo-cused on the induction of an anti-inflam-matory response rather than on active in-duction of an allergen-specific TH1 re-sponse. The latter strategy may be particu-larly dangerous when data are consideredfrom experimental models of asthma thatshow that the transfer of TH1 cells exacer-bates rather than suppresses airway inflam-mation (65). IL-10 therapy to control auto-immune and allergic diseases has beensuggested before (66 ). The most effectivestrategy has yet to be determined, becauseadministration of IL-10 to Chron’s patientsdid not improve clinical scores (67 ), sug-gesting that stimulation of the immune sys-tem for an early and intrinsic production ofIL-10 or other regulators may be essential.It is now well established that recentlydiscovered regulatory T cells, importantplayers in the anti-inflammatory network,can suppress the development of harmful

pathology to specific antigens (52). Effortsshould now focus on more efficient manip-ulation of regulatory T cells to imprintallergen specificity for therapeutic purpos-es without hampering the efficacy of theroutine childhood vaccination. The obser-vation that the repeated stimulation of theimmune system by pathogens is central tothe development of a balanced regulatorysystem also highlights the need to identifymolecular patterns on parasites and to studytheir immunomodulatory potential. The is-sues discussed in this review may also haveimplications for genetic studies. The con-sideration that pro- versus anti-inflammato-ry immune responses may hold the key tothe development of allergic diseases im-plies that the focus of genetic studies mayhave to be upstream of TH1 and TH2, con-centrating on genes involved in the controlof inflammation. With respect to epidemi-ological studies, studies on human popula-tions in the tropics who carry varying bur-dens of diverse pathogens would comple-ment studies on the hygiene hypothesis inindustrialized countries by providing cru-cial information on the optimal dose ofinfection challenging the immune system,the importance of a mother’s infection sta-tus on her infant, and the patho-gens having superior immunomodulatorycapacity.

Parasites are often long-lived and inhabitimmunocompetent hosts for prolonged peri-ods; consequently, it is not surprising thatthey should possess modulatory moleculesthat ameliorate host responses to enhancetheir survival. Understanding the genetics ofhost-parasite interaction and identifying thedistinct parasite molecules that have immu-nomodulatory effects will help us combatallergy without paying the price of becominginfected with noxious pathogens.

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their critical comments; J. Reus and Y. Kruize forphotographs in Fig. 1; B. Lell for providing Fig. 2B; M.Kapsenberg for help with Fig. 3; B. Lell for providingFig. 2B; and D. van der Kleij for help with manuscriptpreparation. Supported by Netherlands Organizationfor Scientific Research (WOTRO section) and LeidenUniversity Medical Center grants.

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