AIRE: a missing link to explain female susceptibility to autoimmune diseases

Abstract

Women are more susceptible to autoimmune diseases than men. Autoimmunity results from tolerance breakdown toward self-components. Recently, three transcription modulators were identified in medullary thymic epithelial cells that orchestrate immune central tolerance processes: the autoimmune regulator (AIRE), FEZ family zinc finger 2 (FEZF2 or FEZ1), and PR domain zinc finger protein 1 (PRDM1). Interestingly, these three transcription modulators regulate nonredundant tissue-specific antigen subsets and thus cover broad antigen diversity. Recent data from different groups demonstrated that sex hormones (estrogen and testosterone) are involved in the regulation of thymic AIRE expression in humans and mice through direct transcriptional modulation and epigenetic changes. As a consequence, AIRE displays gender-biased thymic expression, with females showing a lower expression compared with males, a finding that could explain the female susceptibility to autoimmune diseases. So far, FEZF2 has not been related to an increased gender bias in autoimmune disease. PRDM1 expression has not been shown to display gender-differential thymic expression, but its expression level and its gene polymorphisms are associated with female-dependent autoimmune disease risk. Altogether, various studies have demonstrated that increased female susceptibility to autoimmune diseases is in part a consequence of hormone-driven reduced thymic AIRE expression.

Characteristics and reference ranges of CD4+T cell subpopulations among healthy adult Han Chinese in Shanxi Province, North China

“…Deficiency in either the number or the function of Treg cells may lead to the breakdown of immune homeostasis and development of autoimmune diseases [22]. Most autoimmune diseases, such as systemic lupus erythematosus and rheumatoid arthritis, have a strong female predilection and preferably occur in young women [23]. In the present study, Treg cells displayed age-and sex-biased expression, with younger females showing a lower expression than older males, a finding that may explain the susceptibility of young females to autoimmune diseases.…”

Myasthenia Gravis: Pathogenic Effects of Autoantibodies on Neuromuscular Architecture

“…It is thought that thymic abnormalities such as follicular hyperplasia or thymoma contribute to defects in central tolerance mechanisms and the escape of AChR specific T-cells [235]. These include: (1) a defective AIRE expression in mTECs [236,237]; (2) the downregulation of AIRE transcription by estrogen, which may explain the female predominance [232,238]; (3) an absence of thymic medulla and cells involved in the negative selection in thymoma [239,240,241,242]; (4) hyperplastic or neoplastic mTECs presenting autoantigen [243,244] or downregulating MHC II expression [239,245,246], and (5) aberrant expression of pro-inflammatory cytokines (reviewed by [235,247]).…”

Mechanisms of sex hormones in autoimmunity: focus on EAE

“…Furthermore, in addition to repressive effects on lymphopoiesis, estrogens and testosterone can directly modulate the expression of autoimmune regulator (AIRE) protein that has a pivotal role in the thymic expression of self-antigens [105]. While estrogen suppresses AIRE via epigenetic changes [106,107], androgens promote AIRE's expression, an effect that can be abolished by castration [106,108]. Whether enhanced expression of AIRE in the male thymus can be directly related to their low susceptibility to autoimmune diseases needs further clarifications.…”