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

By Nadine Dragin, Jacky Bismuth, Géraldine Cizeron-Clairac, Maria Grazia Biferi, Claire Berthault, Alain Serraf, Rémi Nottin, David Klatzmann, Ana Cumano, Martine Barkats, Rozen Le Panse and Sonia Berrih-Aknin


International audienceAutoimmune 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

Topics: MESH : Adolescent, MESH : Adult, MESH : Estrogens, MESH : Female, MESH : Gene Expression Regulation, MESH : Humans, MESH : Infant, MESH : Male, MESH : Mice, MESH : Mice, Inbred C3H, MESH : Middle Aged, MESH : Sex Characteristics, MESH : Animals, MESH : Thymus Gland, MESH : Transcription Factors, MESH : Autoimmune Diseases, MESH : Cells, Cultured, MESH : Child, MESH : Child, Preschool, MESH : CpG Islands, MESH : DNA Methylation, MESH : Estrogen Receptor alpha, [ SDV.MHEP ] Life Sciences [q-bio]/Human health and pathology
Publisher: HAL CCSD
Year: 2016
DOI identifier: 10.1172/JCI81894
OAI identifier: oai:HAL:hal-01310502v1
Provided by: Hal-Diderot

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