Fig. 14.7 Genes, the environment, and atopic allergic diseases. Both inherited and environmental factors are important determinants of the likelihood of developing allergic disease. Many genes are known to influence the development of asthma (see Fig. 14.6). The postulate of the ‘hygiene hypothesis’ is that exposure to some infections and to common environmental microorganisms in infancy and childhood drives the immune system toward a general state of non-atopy. In contrast, children who have a genetic susceptibility to atopy and who live in an environment with low exposure to infectious disease and environmental microorganisms, or who received multiple courses of antibiotics in infancy and early childhood, are thought not to develop efficient immunoregulatory mechanisms and to be most susceptible to the development of atopic allergic disease.
a higher prevalence of atopy than did untreated and heavily parasitized children. As helminths provoke a strong TH2-mediated IgE response, this seemed inconsistent with the hygiene hypothesis.
One possible explanation for this apparent inconsistency suggests that all types of infection might protect against the development of atopy because the host responses they elicit include the production of cytokines such as IL-10 and TGF-β, perhaps as part of the homeostatic responses that occur as the infection is being controlled. IL-10 and TGF-β suppress the formation of both TH1 and TH2 responses, and IL-10 suppresses TH17 responses (see Sections 9-21 and 9-23). A large proportion of allergic reactions are initiated by antigens that enter though mucosal surfaces such as the respiratory or intestinal epithelium. As described in Chapter 12, the human mucosal immune system has evolved mechanisms of regulating responses to commensal flora and environmental antigens (such as food antigens) that involve the generation of IL-10/TGF-βproducing Treg cells. The idea underlying the current version of the hygiene hypothesis is that decreased early exposure to common microbial pathogens and commensals in some way makes the body less efficient at producing these Treg cells, thus increasing the risk of making an allergic response to a common environmental antigen.
In support of a role for disturbed immunoregulatory pathways in susceptibility to asthma is evidence that exposure to certain types of childhood infection, with the important exception of some respiratory infections that we consider below, helps to protect against the development of allergic disease. Younger children from families with three or more older siblings and children aged less than 6 months who are exposed to other children in daycare facilities— situations linked to a greater exposure to infections—appear to be partially protected against atopy and asthma. Additionally, children with early-life exposure to a farm or ones having a dog are also somewhat protected against development of atopy and asthma, presumably because of their exposure to farmor pet-associated microbes. Furthermore, early colonization of the gut by commensal bacteria such as lactobacilli and bifidobacteria, or infection by gut pathogens such as Toxoplasma gondii or Helicobacter pylori, is associated with a reduced prevalence of allergic disease. There is also emerging evidence that, conversely, repeated exposure to antibiotics in early life increases the risk of developing asthma.
A history of infection with hepatitis A virus also seems to have a negative association with atopy. A possible explanation for this association is that the human counterpart of the murine Tim-1 protein (see Section 14-3) is the cellular receptor for hepatitis A virus (designated HAVCR1). The infection of T cells by hepatitis A virus could thus directly influence their differentiation and cytokine production, limiting the development of an IgE-generating response.