In contrast to these negative associations between childhood infection and the development of atopy and asthma is evidence that children who have had attacks of bronchiolitis associated with respiratory syncytial virus (RSV) infection are more prone to developing asthma later on. Children hospitalized with RSV infection have a skewed ratio of cytokine production away from IFN-γ toward IL-4, presumably increasing their likelihood of developing TH2 responses and increased production of IgE. This effect of RSV appears to depend on age at first infection. Experimental infection of neonatal mice with RSV was followed by lower increases in the production of IFN-γcompared with mice that received experimental RSV infection at 4 or 8 weeks of age. When the mice were rechallenged at 12 weeks of age with RSV infection, animals that had been primarily infected as neonates had more severe lung inflammation than animals first infected at 4 or 8 weeks of age.
Other environmental factors that might contribute to the increase in atopic disease are changes in diet, allergen exposure, atmospheric pollution, and tobacco smoke. Pollution has been blamed for an increase in the prevalence of nonallergic cardiopulmonary diseases such as chronic bronchitis, but an association with allergic disease has been more difficult to demonstrate. There is, however, increasing evidence for an interaction between allergens and pollution, particularly in genetically susceptible individuals. Diesel exhaust particles are the best-studied pollutant in this context; they increase IgE production 20to 50-fold when combined with allergen, with an accompanying shift to TH2 cytokine production. Reactive oxidant chemicals such as ozone are generated as a result of such pollution, and individuals less able to deal with this onslaught may be at increased risk of allergic disease.
Genes that might be governing this aspect of susceptibility are GSTP1 and GSTM1, members of the glutathione-S-transferase superfamily that are important in preventing oxidant stress. Individuals who were allergic to ragweed pollen and who carried particular variant alleles of these genes showed an increased airway hyperreactivity when challenged with the allergen-plus-diesel exhaust particles, compared with the allergen alone. A study in Mexico City on the effects of atmospheric ozone levels on atopic children with allergic asthma also found that the children carrying the null allele of GSTM1 were more susceptible than noncarriers to airway hyperreactivity when exposed to given levels of ozone. Underscoring the potential for reactive oxygen species such as ozone and superoxide to contribute to asthma exacerbation, studies using mice indicate that airway myeloid cells that produce high levels of super-oxide worsen antigen-induced airway hyperreactivity. Inhibitors of NADPH oxidase, required for the production of superoxide, reduce antigen-induced airway hyperreactivity in sensitized and challenged animals, whereas adoptive transfer of superoxide-producing myeloid cells into the airways of sensitized and challenged mice causes marked exacerbation of hyperresponsiveness.
14-5 Regulatory T cells can control allergic responses.