Sex bias in CNS autoimmune disease mediated by androgen control of autoimmune regulator

Meng-Lei Zhu, Pearl Bakhru, Bridget Conley, Jennifer S. Nelson, Meghan Free, Aaron Martin, Joshua Starmer, Elizabeth M. Wilson and Maureen A. Su ()
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Meng-Lei Zhu: School of Medicine, University of North Carolina at Chapel Hill
Pearl Bakhru: School of Medicine, University of North Carolina at Chapel Hill
Bridget Conley: School of Medicine, University of North Carolina at Chapel Hill
Jennifer S. Nelson: School of Medicine, University of North Carolina at Chapel Hill
Meghan Free: School of Medicine, University of North Carolina at Chapel Hill
Aaron Martin: School of Medicine, University of North Carolina at Chapel Hill
Joshua Starmer: University of North Carolina at Chapel Hill
Elizabeth M. Wilson: School of Medicine, University of North Carolina at Chapel Hill
Maureen A. Su: School of Medicine, University of North Carolina at Chapel Hill

Nature Communications, 2016, vol. 7, issue 1, 1-14

Abstract: Abstract Male gender is protective against multiple sclerosis and other T-cell-mediated autoimmune diseases. This protection may be due, in part, to higher androgen levels in males. Androgen binds to the androgen receptor (AR) to regulate gene expression, but how androgen protects against autoimmunity is not well understood. Autoimmune regulator (Aire) prevents autoimmunity by promoting self-antigen expression in medullary thymic epithelial cells, such that developing T cells that recognize these self-antigens within the thymus undergo clonal deletion. Here we show that androgen upregulates Aire-mediated thymic tolerance to protect against autoimmunity. Androgen recruits AR to Aire promoter regions, with consequent enhancement of Aire transcription. In mice and humans, thymic Aire expression is higher in males compared with females. Androgen administration and male gender protect against autoimmunity in a multiple sclerosis mouse model in an Aire-dependent manner. Thus, androgen control of an intrathymic Aire-mediated tolerance mechanism contributes to gender differences in autoimmunity.

Date: 2016
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DOI: 10.1038/ncomms11350

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