Journal
INTERNATIONAL IMMUNOLOGY
Volume 31, Issue 3, Pages 141-156Publisher
OXFORD UNIV PRESS
DOI: 10.1093/intimm/dxy074
Keywords
female; ligand; male; nuclear hormone receptor; vaccine
Categories
Funding
- National Institutes of Health (NIH) National Cancer Institute (NCI) [NCI CA21765]
- Intramural Research Program of the NIH National Institute on Aging
- ALSAC
- NATIONAL INSTITUTE ON AGING [ZIAAG000732] Funding Source: NIH RePORTER
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Nuclear hormone receptors including the estrogen receptor (ER) and the retinoic acid receptor regulate a plethora of biological functions including reproduction, circulation and immunity. To understand how estrogen and other nuclear hormones influence antibody production, we characterized total serum antibody isotypes in female and male mice of C57BL/6J, BALB/cJ and C3H/HeJ mouse strains. Antibody levels were higher in females compared to males in all strains and there was a female preference for IgG2b production. Sex-biased patterns were influenced by vitamin levels, and by antigen specificity toward influenza virus or pneumococcus antigens. To help explain sex biases, we examined the direct effects of estrogen on immunoglobulin heavy chain sterile transcript production among purified, lipopolysaccharide-stimulated B cells. Supplemental estrogen in B-cell cultures significantly increased immunoglobulin heavy chain sterile transcripts. Chromatin immunoprecipitation analyses of activated B cells identified significant ER binding to estrogen response elements (EREs) centered within enhancer elements of the immunoglobulin heavy chain locus, including the E mu enhancer and hypersensitive site 1,2 (HS1,2) in the 3 regulatory region. The ERE in HS1,2 was conserved across animal species, and in humans marked a site of polymorphism associated with the estrogen-augmented autoimmune disease, lupus. Taken together, the results highlight: (i) the important targets of ER in regulatory regions of the immunoglobulin heavy chain locus that influence antibody production, and (ii) the complexity of mechanisms by which estrogen instructs sex-biased antibody production profiles.
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