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.
Highlights
Male gender is protective against multiple sclerosis and other T-cell-mediated autoimmune diseases
Since Autoimmune regulator (Aire) plays a critical role in protecting from autoimmunity, we hypothesized that increased androgen in males may upregulate Aire expression to contribute to this protection
Relative Aire messenger RNA expression was determine by quantitative PCR with reverse transcription (RT–PCR) and normalized to cytokeratin 5 (KRT) 5, a housekeeping gene expressed by thymic medulla
Summary
Male gender is protective against multiple sclerosis and other T-cell-mediated autoimmune diseases. Aire polymorphisms in humans that incrementally decrease Aire expression are associated with increased development of autoimmune disease[16] Together, these findings suggest that factors that quantitatively regulate Aire expression may determine autoimmunity predisposition. On the basis of these findings, we hypothesized that androgen/ AR complexes may upregulate Aire expression to protect against autoimmune disease In support of this hypothesis, we show that male mice and humans express increased Aire in the thymus. We show that androgen administration and male gender protected against autoimmunity in a mouse model of multiple sclerosis through an Aire-dependent mechanism. Together, these results suggest that androgen regulation of the intrathymic Aire tolerance mechanisms alters predisposition to autoimmunity
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