title: 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.
authors.forename: Nadine
authors.initials: N
authors.lastname: Dragin
authors.forename: Jacky
authors.initials: J
authors.lastname: Bismuth
authors.forename: Géraldine
authors.initials: G
authors.lastname: Cizeron-Clairac
authors.forename: Maria Grazia
authors.initials: MG
authors.lastname: Biferi
authors.forename: Claire
authors.initials: C
authors.lastname: Berthault
authors.forename: Alain
authors.initials: A
authors.lastname: Serraf
authors.forename: Rémi
authors.initials: R
authors.lastname: Nottin
authors.forename: David
authors.initials: D
authors.lastname: Klatzmann
authors.forename: Ana
authors.initials: A
authors.lastname: Cumano
authors.forename: Martine
authors.initials: M
authors.lastname: Barkats
authors.forename: Rozen
authors.initials: R
authors.lastname: Le Panse
authors.forename: Sonia
authors.initials: S
authors.lastname: Berrih-Aknin
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D001327:Autoimmune Diseases / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D018899:CpG Islands; D019175:DNA Methylation; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism; D004967:Estrogens / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D007223:Infant; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008875:Middle Aged; D012727:Sex Characteristics; D013950:Thymus Gland / Q000378:metabolism; D014157:Transcription Factors / Q000096:biosynthesis* / Q000235:genetics; D000096927:AIRE Protein
chemical_list: D047628:Estrogen Receptor alpha; D004967:Estrogens; D014157:Transcription Factors; D000096927:AIRE Protein