Estrogen-mediated downregulation of AIRE influences sexual dimorphism in autoimmune diseases
Nadine Dragin, … , Rozen Le Panse, Sonia Berrih-Aknin
Nadine Dragin, … , Rozen Le Panse, Sonia Berrih-Aknin
Published March 21, 2016
Citation Information: J Clin Invest. 2016;126(4):1525-1537. https://doi.org/10.1172/JCI81894.
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Research Article Autoimmunity Endocrinology

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

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, Sonia Berrih-Aknin

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Figure 6

Modulation of AIRE thymic expression by AIRE-miRNAi and its effect on male susceptibility to EAT.

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Modulation of AIRE thymic expression by AIRE-miRNAi and its effect on ma...
Aire (A) and AIRE-dependent TSA (B) mRNA expression in SJL mouse thymuses at day 6 after scAAV9-miRNAi (850) injection (n = 4–5). Percentage of cells expressing the AIRE protein in the thymic section area (C) of SJL mouse after AIRE scAAV9-miRNAi intrathymic injection (n = 4–6). SJL mice were immunized with 100 nmol of p2340 in CFA emulsion by subcutaneous injections 7 days after intrathymic injection of 2 different AIRE scAAV9-miRNAi. Sera were collected at day 30 and the levels of antibodies to the thyroglobulin peptide p2340 in male, female, and AIRE scAAV9-miRNAi treated-male SJL mice were assessed by ELISA (D) (n = 4–8 sera per group). Bilaterally castrated SJL male mice were thymectomized (TX) and received a subcutaneous injection of 1 μg of estradiol (E2) every 2 days, and were challenged for EAT. Sera were collected at day 30, and the levels of antibodies to the thyroglobulin peptide p2340 were assessed by ELISA (E) (n = 5–7 sera per group). Number of infiltrating CD8-positive cells per μm2 of thyroid (F) (n = 4–8 mice per group). Representative photographs of mouse thyroid immunostaining labeled with an anti-CD8 antibody (red) of nonimmunized and immunized mice (G) for EAT challenge. Images were acquired with a Zeiss Axio Observer Z1 inverted microscope (F). P values were obtained using the Mann-Whitney U test (A–C) and the 1-way ANOVA test (D–F). *P < 0.05; **P < 0.01; ***P < 0.001.