Allergy and Gene–Environment Interactions
Many features of allergic inflammation resemble those of the inflammation that results from immune responses to infection with enteric helminths1 or from cutaneous responses to the bites of ectoparasites such as ticks2. Similarities to aspects of immune responses to parasites or environmental allergens have also been identified, notably that both involve TH2 cells and are associated with antigen-specific IgE. These similarities have led to the idea that in allergic disorders the immune system is ‘tricked’ into reacting to otherwise inconsequential allergens in the same way as it does to signals derived from enteric helminths or ectoparasites.
In addition to the benefits conferred on the host by TH2-cell responses to parasites, such as the development and enhancement of effector mechanisms that contribute to parasite clearance, chronic infection with certain parasites often also turns on immunological mechanisms that downregulate the inflammation and tissue damage that is associated with that infection1,3. Such mechanisms include the development of regulatory T cells that secrete interleukin 10 (IL-10), which has many immunosuppressive and anti-inflammatory effects1,3,4,. In allergic disorders, it is thought that such downregulatory mechanisms do not fully develop, are lost or might be overwhelmed by inflammatory factors1,3,4. Indeed, observations of this type support the ‘hygiene hypothesis’5,13,15,16. This hypothesis is based on the observation that, as living standards advance, there is reduced exposure to parasitic infections and to other pathogenic and non-pathogenic microorganisms (and their products). Such infections usually promote the normal development of immune responses (with a bias towards TH1 cells rather than TH2 cells) and favour the development of appropriate control of potentially harmful immune responses by various populations of regulatory T cells. However, as exposure to infections is reduced, and exposure to certain otherwise harmless environmental allergens is increased, there is a propensity for genetically predisposed individuals to develop TH2-cell-type responses to a variety of common environmental allergens1,3,4,.
The molecular mechanisms underlying the hygiene hypothesis continue to be explored1,3,5, but there can be no doubt that the recent marked increase in allergic disorders reflects recent changes in the interactions between the external environment and those individuals who are genetically predisposed to develop allergic diseases. Accordingly, many researchers are attempting to understand the gene–environment interactions that promote the development, increase the severity or limit the resolution of allergic inflammation7,8. There is already evidence that exposure to the same microbial products can have the opposite effect on an individual’s propensity to develop allergic disorders, depending on an individual’s genotype7
Asthma and asthma-related traits are complex diseases with strong genetic and environmental components. Rapid progress in asthma genetics has led to the identification of several candidate genes that are associated with asthma-related traits. Typically the phenotypic impact of each of these genes, including the ones most often replicated in association studies, is mild, but larger effects may occur when multiple variants synergize within a permissive environmental context. Despite the achievements made in asthma genetics formidable challenges remain. The development of novel, powerful tools for gene discovery, and a closer integration of genetics and biology, should help to overcome these challenges7.
- Yazdanbakhsh M, Kremsner PG, van Ree R. Allergy, parasites, and the hygiene hypothesis. Science. 2002;296:490–494.
- Galli SJ, Askenase PW. The Reticuloendothelial System: A Comprehensive Treatise. In: Abramoff P, Phillips SM, Escobar MR, editors. Hypersensitivity. IX. Plenum; 1986. pp. 321–369.
- Fallon PG, Mangan NE. Suppression of TH2-type allergic reactions by helminth infection. Nature Rev Immunol. 2007;7:220–230
- Hawrylowicz CM, O’Garra A. Potential role of interleukin-10-secreting regulatory T cells in allergy and asthma. Nature Rev Immunol. 2005;5:271–283. This review provides an introduction to the mechanisms by which regulatory T cells that produce the anti-inflammatory and immunosuppressive cytokine IL-10 might limit the pathology associated with allergy and allergic inflammation of the airways in asthma.
- Romagnani S. Coming back to a missing immune deviation as the main explanatory mechanism for the hygiene hypothesis. J Allergy Clin Immunol. 2007;119:1511–1513.
- Cookson W. The immunogenetics of asthma and eczema: a new focus on the epithelium. Nature Rev Immunol. 2004;4:978–988.
- Vercelli D. Discovering susceptibility genes for asthma and allergy. Nature Rev Immunol. 2008;8:169–182. This review presents the current understanding of the many genes that have been implicated in asthma and allergy, including evidence that exposure to the same microbial products may have opposite effects on susceptibility to developing allergic disorders, depending on an individual’s genotype.