Estrogen turns down “the AIRE”
Pearl Bakhru, Maureen A. Su
Pearl Bakhru, Maureen A. Su
Published March 21, 2016
Citation Information: J Clin Invest. 2016;126(4):1239-1241. https://doi.org/10.1172/JCI86800.
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Commentary

Estrogen turns down “the AIRE”

Abstract

Genetic alterations are known drivers of autoimmune disease; however, there is a much higher incidence of autoimmunity in women, implicating sex-specific factors in disease development. The autoimmune regulator (AIRE) gene contributes to the maintenance of central tolerance, and complete loss of AIRE function results in the development of autoimmune polyendocrinopathy syndrome type 1. In this issue of the JCI, Dragin and colleagues demonstrate that AIRE expression is downregulated in females as the result of estrogen-mediated alterations at the AIRE promoter. The association between estrogen and reduction of AIRE may at least partially account for the elevated incidence of autoimmune disease in women and has potential implications for sex hormone therapy.

Authors

Pearl Bakhru, Maureen A. Su

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Figure 1

Estrogen downregulates AIRE-mediated central (thymic) tolerance.

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Estrogen downregulates AIRE-mediated central (thymic) tolerance. (A) AIR...
(A) AIRE in mTECs plays a major role in protection against autoimmunity. AIRE upregulates expression of TSAs, so that high-affinity T cells (Teff) that recognize these TSAs are triggered to undergo negative selection. Additionally, AIRE induces Treg development. AIRE expression is regulated by NF-κB responsive enhancer elements (~3 kB upstream of AIRE), transcription factors (Sp1, AP-1, NF-Y, ETS family transcription factors [ETS/TF], and AR [not shown]), and DNA methylation of the AIRE promoter region. (B) Estrogen (E)/ER complexes downregulate AIRE through DNA methylation. Although the mechanism is not known, ER may potentially facilitate DNMT activity or bind to other transcription factors to induce DNA methylation. DNA methylation results in AIRE gene silencing with decreased AIRE-dependent TSA expression, escape of self-reactive T cells from negative selection, and decreased Treg development. These estrogen effects contribute to increased susceptibility to autoimmunity.