Epigenetic regulation in murine offspring as a novel mechanism for transmaternal asthma protection induced by microbes

JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY

卷:128

Article

Teich, Rene³  Yildirim, Ali O.⁴  Tost, Joerg^5,6  Schneider-Stock, Regine⁷  Waterland, Robert A.^8,9  Bauer, Uta-Maria²  von Mutius, Erika¹⁰  Renz, Harald¹ 

[1] Univ Marburg, Dept Clin Chem & Mol Diagnost, Fac Med, D-35043 Marburg, Germany

[2] Univ Marburg, Inst Mol Biol & Tumor Res IMT, D-35043 Marburg, Germany

[3] Helmholtz Ctr Infect Res, Braunschweig, Germany

[4] Helmholtz Ctr Munich, Inst Lung Biol & Dis, Comprehens Pneumol Ctr, Neuherberg, Germany

[5] CEA Inst Genom, Ctr Natl Genotypage, Lab Epigenet, Evry, France

[6] Fdn Jean Dausset CEPH, Lab Funct Gen, Paris, France

[7] Univ Erlangen Nurnberg, Inst Pathol, D-8520 Erlangen, Germany

[8] USDA, Childrens Nutr Res Ctr, Baylor Coll Med, Dept Pediat, Houston, TX USA

[9] USDA, Childrens Nutr Res Ctr, Baylor Coll Med, Dept Mol & Human Genet, Houston, TX USA

[10] Univ Munich, Univ Childrens Hosp, Munich, Germany

关键词: Asthma;    allergy;    epigenetics;    histone acetylation;    hygiene hypothesis;    T cells;   

DOI  :  10.1016/j.jaci.2011.04.035

来源: Elsevier

【 摘 要 】

Background: 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. Objective: This study was designed to test whether epigenetic mechanisms might contribute to asthma protection conferred by early microbial exposure. Methods: Pregnant maternal mice were exposed to the farm-derived gram-negative bacterium Acinetobacter lwoffii F78. Epigenetic modifications in the offspring were analyzed in T(H)1- and T(H)2-relevant genes of CD4(+) T cells. Results: Prenatal administration of A lwoffii F78 prevented the development of an asthmatic phenotype in the progeny, and this effect was IFN-gamma 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-gamma expression. Pharmacologic inhibition of H4 acetylation in the offspring abolished the asthma-protective phenotype. Regarding T(H)2-relevant genes only at the IL4 promoter, a decrease could be detected for H4 acetylation but not at the IL5 promoter or the intergenic T(H)2 regulatory region conserved noncoding sequence 1 (CNS1). Conclusion: 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. (J Allergy Clin Immunol 2011;128:618-25.)

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