Compelling support for the hygiene hypothesis in asthmagenesis

The hygiene hypothesis is certainly in the category of “grand old theories” stacked nicely on a shelf with other grand old theories, waiting for its eureka moment. There has been a decent effort in the scientific community to validate it over the last 10-15 years, but definitive evidence is wanting. A small group of investigators have continued the pursuit of supportive evidence for this very intuitive, but minimally substantiated, theory and have been rewarded with an exceptional finding, published in this month’s issue (J Allergy Clin Immunol 2011;128:618-625.e7).

Brand et al. report the results of a mouse study designed to determine if maternal microbial exposure during pregnancy works epigenetically to confer asthma protection to their offspring. Using an accepted mouse model of airway hyper-reactivity and inflammation, the authors demonstrate that intranasal delivery of Acinetobacter lwoffi to pregnant mice significantly shifted the TH1/TH2 profile in the offspring. In vitro stimulation of mononuclear cells from the offspring of A. lwoffi-exposed mothers showed a marked decrease in production of TH2 cytokines, IL-4, IL-5, and IL-13 in conjunction with increased IFN-γ production and responsiveness. This resulted in protection from the asthma phenotype in the F1.

Further, Brand et al. demonstrate, using antibody blockade that histone modifications to the IFNG promoter and, to a lesser extent, the IL4 and IL5 promoters, directly modifies the TH1/TH2 balance towards TH1. They note that CpG methylation of these sites is not affected.

The authors present the first-ever findings that asthma protection is mediated epigenetically by maternal exposure to environmental microbes, and, in particular, that the effect of A. lwoffi exposure is mediated by histone acetylation of the IFNG promoter. Noting that other genetic and environmental factors must be considered, Brand et al. suggest that maternal epigenetic interventions may be preventative in offspring with asthma risk.

We asked senior author Harald Renz, MD, to comment on the implications of the study:
Dr. Renz: “With this study the books are far from being closed. [Quite] the contrary, our results raise many questions for future research ranging from the whole mechanistic machinery of epigenetic regulation to possible therapeutic implications in the future. We are convinced that many other research teams will joining this exciting journey of transgenerational asthma and allergy development.”