Microbial exposure, interferon gamma gene demethylation in naive T-cells, and the risk of allergic disease

The period of immune programming during early life presents a critical window of opportunity for the prevention of allergic diseases. There is mounting evidence that inappropriate immune programming may involve disruption of specific epigenetic modifications (switches) at immune-related genes. This novel area of research has great potential, as epigenetic changes are known to be sensitive to environmental factors and may therefore provide a mechanistic link for the observed association between specific environmental cues, faulty immune development, and the risk of allergic disease. In addition, the dynamic and potentially reversible nature of epigenetic modifications offers potentially novel targets for therapeutic and/or preventative interventions. We review the evidence that (1) failure to up-regulate the interferon gamma (IFN gamma) response during infancy is an important determinant of the risk of allergic disease, (2) expression of the IFN gamma gene in naive T-cells is regulated by epigenetic mechanisms, and (3) failure to up-regulate IFN gamma gene expression of naive T-cells associated with low early life microbial exposure. Taken together, these lines of evidence suggest that low microbial exposure during early life increases the risk of allergic disease by reducing demethylation (activation) of the IFN gamma gene of naive T-cells.