Estrogen-mediated downregulation of AIRE influences sexual dimorphism in autoimmune diseases

Abstract

Autoimmune diseases affect 5% to 8% of the population, and females are more susceptible to these diseases than males. Here, we analyzed human thymic transcriptome and revealed sex-associated differences in the expression of tissue-specific antigens that are controlled by the autoimmune regulator (AIRE), a key factor in central tolerance. We hypothesized that the level of AIRE is linked to sexual dimorphism susceptibility to autoimmune diseases. In human and mouse thymus, females expressed less AIRE (mRNA and protein) than males after puberty. These results were confirmed in purified murine thymic epithelial cells (TECs). We also demonstrated that AIRE expression is related to sexual hormones, as male castration decreased AIRE thymic expression and estrogen receptor α-deficient mice did not show a sex disparity for AIRE expression. Moreover, estrogen treatment resulted in downregulation of AIRE expression in cultured human TECs, human thymic tissue grafted to immunodeficient mice, and murine fetal thymus organ cultures. AIRE levels in human thymus grafted in immunodeficient mice depended upon the sex of the recipient. Estrogen also upregulated the number of methylated CpG sites in the AIRE promoter. Together, our results indicate that in females, estrogen induces epigenetic changes in the AIRE gene, leading to reduced AIRE expression under a threshold that increases female susceptibility to autoimmune diseases.

Prédisposition aux pathologies auto-immmunes

“…Afin d'explorer cette hypothèse, une étude comparative du transcriptome thymique a été réalisée chez l'homme en fonction du sexe [9]. L'analyse par familles de gènes a ainsi révélé une différence importante, en fonction du sexe, du nombre et du niveau d'expression des gènes codant les TSA.…”

“…En revanche, une supplémentation androgénique des femelles les protège des maladies auto-immunes [22]. La castration physique de souris mâles induit une diminution de l'expression de AIRE [9]. L'oestradiol contrôle négativement les niveaux d'expression de la protéine et ceux des TSA AIRE-dépendants dans les CET.…”

“…L'oestradiol contrôle négativement les niveaux d'expression de la protéine et ceux des TSA AIRE-dépendants dans les CET. Au contraire, la dihydrotestostérone (DHT), métabolite actif de la testostérone, les stimule [9,10] (Figure 2). Il apparaît donc que les hormones stéroïdiennes, en modulant l'expression de AIRE, jouent un rôle actif dans la mise en place ou le maintien de la tolérance centrale thymique, dans l'efficacité de la sélection négative et, par consé-quent, dans l'échappement des lymphocytes autoréactifs thymiques vers la périphérie.…”

Forbearance of the Immune System during pregnancy: Fetal parasite takes an estrogenic way!

“…A recent work from our lab has identified the expression of AIRE in decidua and has substantially proved the role of AIRE in decidualization [36]. Estrogen mediated down regulation of AIRE in thymic epithelial cells linking it to increased susceptibility of females to autoimmune diseases is also known [37].…”

A vestigial pathway for sex differences in immune regulation

“…[6][7][8] Autoimmune regulator (AIRE), a key factor in central tolerance that promotes self-antigen expression in medullary thymic epithelial cells, has been shown to be upregulated by androgens and downregulated by estrogen. 9,10 However, intriguingly, in humans, mutations in AIRE, which cause autoimmune polyendocrinopathycandidiasis-ectodermal dystrophy, are characterized by combinations of autoimmune diseases such as Addison's disease, vitiligo, type I diabetes and alopecia, which are diseases that do not generally show gender bias. 11 To understand the mechanism of sex differences in susceptibility to immune diseases, we have investigated sexual dimorphisms in immune processes on a molecular level.…”