title: Sex bias in CNS autoimmune disease mediated by androgen control of autoimmune regulator.
abstract: Male gender is protective against multiple sclerosis and other T-cell-mediated autoimmune diseases. This protection may be due, in part, to higher androgen levels in males. Androgen binds to the androgen receptor (AR) to regulate gene expression, but how androgen protects against autoimmunity is not well understood. Autoimmune regulator (Aire) prevents autoimmunity by promoting self-antigen expression in medullary thymic epithelial cells, such that developing T cells that recognize these self-antigens within the thymus undergo clonal deletion. Here we show that androgen upregulates Aire-mediated thymic tolerance to protect against autoimmunity. Androgen recruits AR to Aire promoter regions, with consequent enhancement of Aire transcription. In mice and humans, thymic Aire expression is higher in males compared with females. Androgen administration and male gender protect against autoimmunity in a multiple sclerosis mouse model in an Aire-dependent manner. Thus, androgen control of an intrathymic Aire-mediated tolerance mechanism contributes to gender differences in autoimmunity.
authors.affiliation: Division of Endocrinology, Department of Pediatrics, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.|Department of Microbiology and Immunology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.|Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.
authors.forename: Meng-Lei
authors.initials: ML
authors.lastname: Zhu
authors.affiliation: Division of Endocrinology, Department of Pediatrics, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.|Department of Microbiology and Immunology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.|Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.
authors.forename: Pearl
authors.initials: P
authors.lastname: Bakhru
authors.affiliation: Division of Endocrinology, Department of Pediatrics, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.|Department of Microbiology and Immunology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.|Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.
authors.forename: Bridget
authors.initials: B
authors.lastname: Conley
authors.affiliation: Division of Cardiothoracic Surgery, Department of Surgery, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.
authors.forename: Jennifer S
authors.initials: JS
authors.lastname: Nelson
authors.affiliation: Department of Medicine, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.
authors.forename: Meghan
authors.initials: M
authors.lastname: Free
authors.affiliation: Department of Microbiology and Immunology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.
authors.forename: Aaron
authors.initials: A
authors.lastname: Martin
authors.affiliation: Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.
authors.forename: Joshua
authors.initials: J
authors.lastname: Starmer
authors.affiliation: Division of Endocrinology, Department of Pediatrics, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.|Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.|Department of Biochemistry and Biophysics, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Wilson
authors.affiliation: Division of Endocrinology, Department of Pediatrics, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.|Department of Microbiology and Immunology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.|Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.
authors.forename: Maureen A
authors.initials: MA
authors.lastname: Su
mesh_terms: D000728:Androgens / Q000494:pharmacology*; D000818:Animals; D000941:Antigens / Q000378:metabolism; D001327:Autoimmune Diseases / Q000378:metabolism* / Q000473:pathology*; D002490:Central Nervous System / Q000473:pathology*; D013196:Dihydrotestosterone / Q000494:pharmacology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D005260:Female; D005455:Fluorescent Antibody Technique; D006801:Humans; D008297:Male; D008810:Mice, Inbred C57BL; D063308:Myelin-Oligodendrocyte Glycoprotein / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011944:Receptors, Androgen / Q000378:metabolism; D063507:Sexism; D013950:Thymus Gland / Q000187:drug effects / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects; D000096927:AIRE Protein
chemical_list: D000728:Androgens; D000941:Antigens; D013196:Dihydrotestosterone; D063308:Myelin-Oligodendrocyte Glycoprotein; D012333:RNA, Messenger; D011944:Receptors, Androgen; D014157:Transcription Factors; D000096927:AIRE Protein