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 Article has an altmetric score of 20

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 4

Influence of estrogen on AIRE and TSA expression in cultured human TECs, human thymic tissue grafted to NSG mice, and mouse fetal thymic organ culture.

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Influence of estrogen on AIRE and TSA expression in cultured human TECs,...
Representative flow cytometry plot of estrogen effect (1 nM) on AIRE protein level in human primary TECs; the control isotype is shown (red histogram) (A). Effect of estrogen on the percentage of AIRE-positive cells (B) and AIRE fluorescence geometric mean (geomean) (C) in cultured human primary TECs. For each experiment, control untreated cells were normalized to 100 (n = 8–9). Effect of daily intraperitoneal injections of estrogen (200 μg) on AIRE, thyroglobulin, and GAD67 mRNA expression in human thymic tissue grafted to NSG female mice aged of 5 to 6 weeks (n = 8) (D). Effect of the mouse sex recipient on AIRE mRNA expression in human thymic tissue engrafted subcutaneously in NSG mice for 4 days (E) (n = 3 individual human thymuses) and 20 days (F) (n = 4 individual human thymuses). Effect of estrogen on the mRNA expression of Aire, in mouse fetal thymic organ cultures (G). Each point represents the mean value of an experiment using thymuses from 4 to 5 different fetuses. Representative picture of mouse FTOC labeled with anti-K14 (red) and anti-AIRE (green) antibodies. Images were acquired with a Zeiss Axio Observer Z1 inverted microscope (H). Effect of estrogen (estro) (10–7 M) on the number of cells expressing AIRE protein in the mouse FTOC (I). Cont, control. P values were obtained using the 1-way ANOVA test (B and C), nonparametric Mann-Whitney U test for unpaired data (D and I), and the Wilcoxon test for paired data (E–G). *P < 0.05; **P < 0.01; ***P < 0.005 to 0.001.