Allergy, Parasites, and the Hygiene Hypothesis
M. Yazdanbakhsh
2002
Science
by putinto the(;onteXtof the and T hetper2(TH2) that bacterialandv~ral towardTl11,whIch jn theoveraltmi(;robialburdenwil.re inweakTH1 imprinting andun!estrained There has been a significant increase in tIle prevalence of allergic diseases over the past 2 to 3 decades. Currently, more than 130 m:i1lion people suffer from asthma, and tIle numbers are increasing (1); nevertheless, tIlere is a considerably lower prevalence of allergic diseases in developing countries (2). There are also clear
more »
... ences in the prevalence of allergies between rural and urban areas within one country. For ex-ample, in Ethiopia, asthma is more prevalent in urban areas tIlan in rural villages (3), and asthma is more common in residents of urban Germany tIlan in farmers living in rural Ba-varia (4). To explain tIlese observations, en-vironmental factors associated witIl more in-dustrialized and urban living have been stud-ied intensively, but there is little consistent evidence to suggest that obvious risk factors, such as increased exposure to indoor aller-gens, pollution, or changes in diet and breastfeeding, could account for tIle rise in atopic diseases. 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 fJrst-bom but is less frequent in children from large families (5) and those attending day care (6) , suggesting that a fre-quent exchange of infections may have a protective effect (5). Atopy, characterized by raised immuno-globulin (lg)E levels, underlies allergic dis-eases such as asthma, rhinoconjunctivitis, and eczema. The interaction of an environmental allergen with the innate immune system, its uptake by antigen-presenting cells, and the subsequent T cell priming leads to the stinl-ulation of cytokines such as interleukin (IL}-4, IL-5, and IL-13. These cytokines interact with their receptors to stimulate IgE produc-tion and increased numbers of eosinophils and mast cells; all of these components are capable of precipitating inflammation in the respiratory tract ( Fig. I) (7) . Exposure to food and orofecal patho-gens, such as hepatitis A, Toxop/asma gon-dii, and He/icobacter py/ori, reduces the risk of atopy by >600;0 (8). Studies of gut commensals indicate differences in the rate of microbial colonization, as well as the bacterial type involved (clostridia versus lactobacilli) in children with and without a predisposition to allergy (9). On the basis of these data, it has been proposed that the lack of intense infections in industrialized countries owing to improved hygiene, vac-cination, and use of antibiotics may alter the human immune system such that it re-sponds inappropriately to innocuous sub-stances. This so-called "hygiene hypothe-sis" (5) has been given an immunological framework in which the balance between type 1 (TH1, associated with bacterial and viral infections and autoimmune diseases) and type 2 (TH2, associated with helminth infections and allergic diseases) immune responses is pivotal (10). It has been pos-tulated that limited exposure to bacterial and viral pathogens during early childhood results in an insufficient stinlulation ofTHl cells, which in turn cannot counterbalance the expansion of TH2 cells and results in a predisposition to allergy (Fig. I) . The immunological explanation for the hygiene hypothesis has been very influential in directing strategies to prevent allergic dis-eases. Induction of allergenspecific THI re-sponses by Bacille Calmette-Guerin (BCG) or DNA vaccination is being advocated (11) on the basis of the promising results obtained in experimental animals (11). However, in the face of discrepancies that have come to light from studies involving autoimmune dis-eases and helminth infections, it is important to reevaluate the immunological basis of the hygiene hypothesis. The prevalence of type I diabetes, a THI-mediated disease, has been progressively in-creasing in the past few decades, and there are data to support an association between the occurrence of type I diabetes and asthma at the population level (12). Such data suggest that the root cause of the increase in allergic diseases is also responsible for the escalation of autoimmune disorders and that this cannot merely be accounted for by the THI versus T H2 imbalance, but instead must have a com-mon immunological denominator. Similar concerns arise when considering helminth in-fections, which are the most potent natural stimuli for TH2 responses. Worldwide, helminth infections and aller-gic diseases do not overlap despite both con-ditions being accompanied by strong TH2 immune responses (2, 13). Here, we review the relation between parasitic infections and allergy and focus on insights that may present an alternative immunological framework for the hygiene hypothesis and have im-portant implications for future research and therapeutics. Risk Factors or Protection? Helminth infections are universally associat-ed with responses stimulated by TH2-type cytokines, such as high levels of IgE, eosin-ophilia, and mastocytosis (14). Thus, al-though helminth infections and atopic diseas-es are associated with similar immunological phenomena, the clinical outcome with respect to immediate hypersensitivity and inflamma-tion is clearly not the same (Fig. I) . When one considers that the I billion or so people who are heavily infected with helminths worldwide and suffer from the resultant nu-tritional, growth, and cognital deficiencies are rarely affiicted by allergic diseases, then it is clear that a strong T H2 response is not the sole factor in precipitating an allergic attack.
doi:10.1126/science.296.5567.490
pmid:11964470
fatcat:qkmxlmim5fcypk2dp5qlqxbwjm