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Start Over Author "Bismuth, Jacky" Journal journal of clinical investigation
2 results on '"Bismuth, Jacky"'

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

Author

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

Subjects
Genetic regulation -- Health aspects, Estrogen -- Health aspects, Transcription factors -- Properties, Autoimmune diseases -- Genetic aspects -- Development and progression, Health care industry
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 a-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., Introduction Autoimmune diseases, a group of 70 different diseases, represent the fifth leading cause of death by disease among females of reproductive age (1, 2). As suggested by several studies, [...]

Published
2016
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Author

Dragin, Nadine, Bismuth, Jacky, Cizeron-Clairac, Géraldine, Biferi, Maria Grazia, Berthault, Claire, Serraf, Alain, Nottin, Rémi, Klatzmann, David, Cumano, Ana, Barkats, Martine, Le Panse, Rozen, Berrih-Aknin, Sonia, Centre de recherche en myologie, Université Pierre et Marie Curie - Paris 6 (UPMC)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Remodelage tissulaire et fonctionnel : signalisation et physio-pathologie (RTFSPP), Centre National de la Recherche Scientifique (CNRS)-Centre chirurgical Marie Lannelongue-Université Paris-Sud - Paris 11 (UP11), Cellule Pasteur, Université Paris Diderot - Paris 7 (UPD7)-PRES Sorbonne Paris Cité, Lymphopoïèse, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Chirurgical Marie Lannelongue (CCML), Centre chirurgical Marie Lannelongue, Immunologie - Immunopathologie - Immunothérapie (I3), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut de Myologie, Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Association française contre les myopathies (AFM-Téléthon)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Pierre et Marie Curie - Paris 6 (UPMC), This work was supported by MYASTAID (LSHM-CT-2006-037833) and FIGHT-MG (HEALTH-2009-242-210) grants from the European Community and a grant from the Association Française contre les Myopathies obtained by S. Berrih-Aknin., European Project: 38962,MYASTAID, European Project: 242210,EC:FP7:HEALTH,FP7-HEALTH-2009-single-stage,FIGHT-MG(2009), Université Paris-Sud - Paris 11 (UP11)-Centre Chirurgical Marie Lannelongue (CCML)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), HAL UPMC, Gestionnaire, Development of models to improve management of Myasthenia Gravis: From basic knowledge to clinical application - MYASTAID - 38962 - OLD, and Myasthenias, a group of immune mediated neurological diseases: from etiology to therapy. - FIGHT-MG - - EC:FP7:HEALTH2009-12-01 - 2014-05-31 - 242210 - VALID

Subjects
0301 basic medicine, medicine.medical_specialty, medicine.drug_class, Population, Estrogen receptor, Biology, MESH: Estrogens, 03 medical and health sciences, MESH: DNA Methylation, 0302 clinical medicine, MESH: Autoimmune Diseases, MESH: Child, Internal medicine, Male castration, medicine, MESH: Animals, MESH: Mice, Inbred C3H, MESH: CpG Islands, education, MESH: Mice, MESH: Estrogen Receptor alpha, MESH: Adolescent, education.field_of_study, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, MESH: Humans, MESH: Middle Aged, MESH: Child, Preschool, MESH: Adult, MESH: Thymus Gland, MESH: Transcription Factors, General Medicine, Autoimmune regulator, MESH: Gene Expression Regulation, MESH: Infant, MESH: Male, Thymic Tissue, 030104 developmental biology, Endocrinology, Estrogen, Central tolerance, MESH: Female, Estrogen receptor alpha, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, MESH: Sex Characteristics, MESH: Cells, Cultured, 030215 immunology
Abstract

International audience; 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.

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