There are also likely to be genes that affect only particular aspects of allergic disease. In asthma, for example, there is evidence that different genes affect at least three aspects of the disease—IgE production, the inflammatory response, and clinical responses to particular treatments. On chromosome 20, polymorphism of the gene encoding ADAM33, a metalloproteinase expressed by bronchial smooth muscle cells and lung fibroblasts, has been associated with asthma and bronchial hyperreactivity. This is likely to be an example of genetic variation in the pulmonary inflammatory response and in the pathological anatomical changes that occur in the airways (airway remodeling). In the skin, filaggrin importantly contributes to normal skin barrier function by binding keratin molecules into the lipid envelope of cornifying keratinocytes. Loss-of-function mutations in the gene encoding filaggrin lead to the development of eczema. Through unknown mechanisms, filaggrin mutations also can contribute to the development of asthma. Almost half of people in the United States who suffer from severe eczema have at least one mutated filaggrin allele. Between 7 and 10% of Caucasians carry a loss-of-function mutation in filaggrin, and the frequency of this mutation is considerably higher in individuals with asthma.
14-4 Environmental factors may interact with genetic susceptibility to cause allergic disease.
Studies of susceptibility suggest that environmental factors and genetic variation each account for about 50% of the risk of developing atopy. The prevalence of atopic allergic diseases, and of asthma in particular, is increasing in economically advanced regions of the world, and this is likely due to the impact of changes in certain environmental factors on individuals with genetic backgrounds that predispose them toward atopy. Interestingly, although the incidence of asthma is lower in economically underdeveloped regions of Africa, Americans of African ancestry show increased asthma frequency and severity compared with Americans not of African ancestry. This shows a clear impact of environment on the expressivity of genetic influences.
The prevalence of atopy and especially allergic asthma has been steadily increasing in the developed world for the past 50–60 years. One hypothesis for this steady increase is changes in exposure to infectious diseases in early childhood as our population has moved increasingly from rural into urban environments. This shift has meant less early-life exposure to microorganisms associated with farm animals and microorganisms in the soil. This change in exposure is thought to lead to alterations in the intestinal microbiota, which performs an important immunomodulatory function (discussed in Chapter 12). Changes in exposure to ubiquitous microorganisms as a possible cause of increased atopy was first suggested in 1989, ultimately giving rise to the hygiene hypothesis (Fig. 14.7). The original proposition was that less hygienic environments, particularly those encountered in less developed rural settings, predispose to infections early in childhood, which help to protect against the development of atopy and allergic asthma. It was originally proposed that the protective effect might be due to mechanisms that skew immune responses away from the production of TH2 cells (and their associated cytokines, which dispose toward IgE production) and toward the production of TH1 cells. This would impede responses that favor the production of IgE and promote responses that suppress class switching to IgE.
Suggesting that this interpretation was overly simplistic was the strong negative correlation between infection by helminths (such as hookworms and schistosomes) and the development of allergic disease. A study in Venezuela showed that children treated for a prolonged period with antihelminthic agents had