Location: Children's Nutrition Research CenterTitle: Epigenetic regulation in murine offspring as a novel mechanism for transmaternal asthma protection induced by microbes Author
Submitted to: Journal of Allergy Clinical Immunology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 4/22/2011
Publication Date: 4/22/2011
Citation: Brand, S., Teich, R., Dicke, T., Harb, H., Yildirim, A.O., Tost, J., Schneider-Stock, R., Waterland, R.A., Bauer, U., Mutius, E., Garn, H., Pfefferle, P.I., Renz, H. 2011. Epigenetic regulation in murine offspring as a novel mechanism for transmaternal asthma protection induced by microbes. Journal of Allergy Clinical Immunology. 128(3):618-625. Interpretive Summary: This study explores fundamental mechanisms underlying the "hygiene hypothesis", which suggests that natural microbial exposure of human infants during prenatal and early postnatal development may actually be beneficial, essentially by 'training' the immune system to deal with immune challenges later in life. According to the hygiene hypothesis, the much cleaner environment to which pregnant women and infants are now exposed, compared to 100 years ago, may explain increases in immune-related diseases such as asthma. This study explored a mouse model of the hygiene hypothesis in relation to asthma. Pregnant mice were exposed to the bacterium Acinebacter lwoffi (often found on farms), and asthma symptoms and epigenetic outcomes were evaluated in the offspring. (Epigenetic mechanisms are developmental mechanisms that stably regulate the expression potential of specific genes.) The results showed that prenatal exposure to the bacterium prevented the development of asthma later in life, and identified epigenetic alterations that might explain this persistent effect. Overall, the study supports the hygiene hypothesis, and suggests that epigenetic mechanisms may play a central role in maintaining persistent immunological "memory" of early microbial exposures.
Technical Abstract: Bronchial asthma is a chronic inflammatory disease resulting from complex gene-environment interactions. Natural microbial exposure has been identified as an important environmental condition that provides asthma protection in a prenatal window of opportunity. Epigenetic regulation is an important mechanism by which environmental factors might interact with genes involved in allergy and asthma development. This study was designed to test whether epigenetic mechanisms might contribute to asthma protection conferred by early microbial exposure. Pregnant maternal mice were exposed to the farm-derived gram-negative bacterium Acinetobacter lwoffii F78. Epigenetic modifications in the offspring were analyzed in TH1- and TH2-relevant genes of CD4+ T cells. Prenatal administration of A. lwoffii F78 prevented the development of an asthmatic phenotype in the progeny, and this effect was IFN-' dependent. Furthermore, the IFNG promoter of CD4+ T cells in the offspring revealed a significant protection against loss of histone 4 (H4) acetylation, which was closely associated with IFN-' expression. Pharmacologic inhibition of H4 acetylation in the offspring abolished the asthma-protective phenotype. Regarding TH2-relevant genes only at the IL4 promoter, a decrease could be detected for H4 acetylation but not at the IL5 promoter or the intergenic TH2 regulatory region conserved noncoding sequence 1 (CNS1). These data support the hygiene concept and indicate that microbes operate by means of epigenetic mechanisms. This provides a new mechanism in the understanding of gene-environment interactions in the context of allergy protection.