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

• Published in: The Journal of clinical investigation Vol. 126; no. 4; pp. 1525 - 1537
• Main Authors: Dragin, Nadine, Bismuth, Jacky, Cizeron-Clairac, Géraldine, Biferi, Maria Grazia, Berthault, Claire, Serraf, Alain, Nottin, Rémi, Klatzmann, David, Cumano, Ana, Barkats, Martine, Le Panse, Rozen, Berrih-Aknin, Sonia
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 01-04-2016
• Subjects: Adolescent; Adult; Agreements; AIRE Protein; Animals; Autoimmune Diseases; Autoimmune Diseases - genetics; Autoimmune Diseases - metabolism; Biomedical research; Cells, Cultured; Child; Child, Preschool; CpG Islands; Development and progression; Disease; DNA Methylation; Estrogen; Estrogen Receptor alpha; Estrogen Receptor alpha - genetics; Estrogen Receptor alpha - metabolism; Estrogens; Estrogens - genetics; Estrogens - metabolism; Experiments; Female; Females; Flow cytometry; Gene Expression Regulation; Genetic aspects; Genetic regulation; Health aspects; Human health and pathology; Humans; Hypotheses; Infant; Keratin; Laboratory animals; Life Sciences; Lymphocytes; Male; Males; Mice; Mice, Inbred C3H; Middle Aged; Properties; Protein expression; Proteins; Sex Characteristics; Studies; Thymus Gland; Thymus Gland - metabolism; Transcription Factors; Transcription Factors - biosynthesis; Transcription Factors - genetics
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/jci81894

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.