Infections and allergy — helminths, hygiene and host immune regulation

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There is increasing evidence that helminth infections can protect the host against Th2-mediated allergic pathologies, even though helminths themselves are strong Th2 inducers. In murine model systems, alleviation of allergy is not achieved through immune deviation to Th1, but is linked to expansion of regulatory T cell activity. Parasite infection does not prevent allergen sensitisation, but restricts the Th2 effector phase responsible for inflammation. Suppression of allergic inflammation can be transferred by Treg phenotype cells from an infected, allergen-naïve animal to an uninfected, sensitized recipient. Patent allergy in humans is also known to be modulated by helminth infections, suggesting that a similar regulatory network may be controlling immunopathologic disease in man.

Introduction

The unbounded capacity of our immune system to react to exogenous antigen challenge equips us to recognize all manner of pathogenic agents, but also exposes us to the risk of undesirable pathological reactions to innocuous allergens and autoantigens. Responses to antigenic challenges of different types are by no means autonomous, however, and there are now numerous examples of how the presence of a major infection can greatly influence the manner of immune responsiveness to unrelated antigens, or indeed other infections [1]. The proposition that the character and cadence of infections in humans can critically influence the development of allergies and other immunopathologies — known as the ‘hygiene hypothesis’ — is one that has attracted much critical comment. Nevertheless, it is increasingly accepted that infection history and status is one of the major factors, against a background of profound changes in environmental conditions and significant genetic diversity, likely to determine whether individuals progress to allergic disease [2].

The original ‘hygiene hypothesis’ centred around the role of Th1-inducing microbial infections in inhibiting Th2-mediated allergies, and this subject has been well reviewed [3]. In this review, I will focus on a different interplay that has excited much recent interest: that of Th2-driving helminth parasites and their ability to suppress Th2-related allergic pathology. As is now becoming apparent from bacterial and viral systems, the interaction between infection and allergy often involves regulatory T cell (Treg) activity [4, 5]. With the emergence of Tregs as a major facet of helminth infections [6], it is timely to summarize the evidence for a regulatory ‘hygiene hypothesis’ as it relates to the immunology of helminths.

Section snippets

Allergies and immunopathology

Allergies are classically considered to be Th2-mediated inflammatory diseases, involving, in the case of allergic asthma, eosinophil infiltration into the airway epithelium, the release of long-lasting inflammatory mediators (such as arachidonic acid metabolites), the elaboration of goblet cells and their production of secretory mucins, and incremental tissue damage and remodelling which causes longer-term compromise of airway function. Therapies based on switching the allergen-specific

Allergy and Tregs

Can allergies be blocked by suppressive Treg cells? In some cases, at least, it appears so. For example, Karlsson et al. [15] studied infants allergic to cow's milk, of whom ∼60% became milk tolerant after some months of milk-free diet. Tolerant children had higher numbers of CD25+ Tregs with greater suppressive function than those who remained allergic. In a study of adult atopics reactive to pollen or mite allergens, Akdis et al. [16••] reported that the frequency of IL-10-producing Treg

Immunology of helminths

Helminths are multicellular worm parasites from two distinct invertebrate phyla (nematodes and flatworms), within which parasitic clades have independently evolved over a long evolutionary time. In general, parasites are well tolerated and infection is highly prevalent in natural populations, indicating that helminths have evolved sophisticated molecular methods of immune evasion and suppression [22]. Equally, helminths have exerted a major influence on the evolution of the vertebrate immune

Do helminths downmodulate bystander pathologies?

It has been widely noted that the incidence of asthma and other allergic disorders has not risen as sharply in environments with high levels of helminth infections as in more developed countries [25]. Moreover, within the populations of helminth-endemic areas, an inverse association between helminthiasis and allergy has been clearly established [26, 27]. The most recent studies, on hookworm-infected children in Ethiopia [28] and Ascaris-infected pupils in Ecuador [29], confirm the trend that

Control of both Th1 and Th2 pathologies

Allergies and autoimmunities are often considered to have opposing aetiologies (Th1 vs Th2), although epidemiological evidence does not show a clear discordance between the two. For example, the incidence of asthma and diabetes have shown parallel increases over the past half-century [40], and in one of the few studies to report on individual incidence, the risk of autoimmune disease is actually higher in allergic patients not lower [41, 42], demonstrating that, even in the single individual,

Tregs, dendritic cells and infectious tolerance

From the human and animal model data, which indicate both that Treg cells are activated in helminth infection and that cells of a similar phenotype can actively suppress airway allergic inflammation, we have proposed that a major component of the immunological interaction between infection and allergy is mediated by Tregs [6, 43]. Several key unanswered questions are raised by this model, concerning, for example, the antigen specificity of the helminth-stimulated Treg population, and the

Non-Treg mechanisms

One should also consider other mechanisms by which parasite infection could impede the expression of allergic pathology [52]. One simple explanation for cross-suppression between infection and allergy is that the immune system has a limited capacity for responsiveness and, through competition or division of effort, the anti-allergic response is reduced in the presence of infection. This homeostatic model [53] is consistent with the observed quantitative reduction without a qualitative shift in

The evolutionary balance between allergy and infection

Most recently, the overlap between allergy and helminth infection has become apparent in another arena: that of human polymorphisms governing susceptibility to disease. Examples are now emerging of alleles that were originally described as predisposing towards asthma and are now significantly linked to resistance to helminthiasis. Thus, a polymorphism in the 3′ UTR of STAT-6 is linked to differential resistance to Ascaris in a Chinese population as well as to asthma in Japan [59]. Similarly,

Conclusions

The past two years have seen accelerating activity on the issue of whether helminth infections impact on the allergic status of the host, and new studies have been published regarding model systems, in which it is possible to dissect the interplay between these separate and complex responses. Although mechanistic explanations have yet to be provided in any detail, there is satisfactory evidence that regulatory T cells play at least some part in the crossover from the ‘suppressive’

Update

The work referred to in the text as (MW Wilson et al., unpublished) is now in press [61].

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

I would like to warmly thank our colleagues Judith Allen, Adam Balic, Constance Finney, Matt Taylor, Mark Wilson and Maria Yazdanbakhsh for their many constructive discussions and for sharing unpublished data; and the Wellcome Trust for research grant support.

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