Abstract
Abstract Estrogen contributes to the elevated antibody response to vaccines in women and the female bias of autoimmune responses, likely by increasing class-switched and hypermutated antibodies and pathogenic autoantibodies. As we have shown, estrogen potentiates the induction of AID, which is critical for class switch DNA recombination (CSR) and somatic hypermutation (SHM), through upregulation of HoxC4. Estrogen may also alter AID gene expression through epigenetic modifications. As we have also shown, short-chain fatty acid (SCFA) histone deacetylase inhibitors (HDIs), including valproic acid and butyrate, upregulated miRNAs that silence AID expression, resulted in reduction of T-dependent and T-independent antibody responses in C57BL/6 mice and autoantibody responses in lupus-prone mice. Here we found that the HDI-mediated downregulation of antibody and autoantibody responses was reversed by estrogen but significantly enhanced by deletion or inhibition of estrogen receptor α (ERα). In B cells, estrogen downregulated the expression of miR-26a, which we found to target the 3′UTR Aicda mRNA. miR-26a was highly expressed in activated B cells and significantly upregulated by SCFA HDIs. Estrogen enhanced cytoplasm to nuclear translocation of HDAC4/HDAC5, and decreased histone acetylation of the host gene of miR-26, and possibly, other selective miRNAs. Finally, The estrogen-mediated enhancement of AID was abrogated by selective inhibition of HDAC4/HDAC5 by LMK258, which decreased CSR. Collectively, our findings provide mechanistic insights into the immunomodulating activity of estrogen and its potential use as therapeutic target in systemic autoimmunity. Supported by the NIH grants AI 105813, AI 079705.
Published Version
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