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

被引:148
作者
Dragin, Nadine [1 ,2 ,3 ,4 ]
Bismuth, Jacky [1 ,2 ,3 ,4 ]
Cizeron-Clairac, Geraldine [5 ]
Biferi, Maria Grazia [1 ,2 ,3 ,4 ]
Berthault, Claire [6 ,7 ]
Serraf, Alain [8 ]
Nottin, Remi [8 ]
Klatzmann, David [9 ]
Cumano, Ana [6 ]
Barkats, Martine [1 ,2 ,3 ,4 ]
Le Panse, Rozen [1 ,2 ,3 ,4 ]
Berrih-Aknin, Sonia [1 ,2 ,3 ,4 ]
机构
[1] Univ Paris 06, Sorbonne Univ, Paris, France
[2] INSERM, U974, Paris, France
[3] CNRS, FRE 3617, Paris, France
[4] Inst Myol, AIM, Paris, France
[5] CNRS, UMR 8162, Le Plessis Robinson, France
[6] Inst Pasteur, INSERM, U668, Unit Lymphopoiesis,Immunol Dept, F-75724 Paris, France
[7] Univ Paris Diderot, Sorbonne Paris Cite, Cellule Pasteur, Paris, France
[8] Hop Marie Lannelongue, 133 Ave Resistance, F-92350 Le Plessis Robinson, France
[9] Grp Hosp Pitie Salpetriere, AP HP, Biotherapy, F-75634 Paris, France
关键词
THYMIC EPITHELIAL-CELLS; TISSUE ANTIGEN GENES; THYROTROPIN RECEPTOR; ANIMAL-MODELS; T-CELLS; EXPRESSION; MICE; DEFICIENT; TOLERANCE; AGE;
D O I
10.1172/JCI81894
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
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 alpha-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.
引用
收藏
页码:1525 / 1537
页数:13
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