A central role for central tolerance.
Recent elucidation of the role of central tolerance in preventing organ-specific autoimmunity has changed our concepts of self/nonself discrimination. This paradigmatic shift is largely attributable to the discovery of promiscuous expression of tissue-restricted self-antigens (TRAs) by medullary thymic epithelial cells (mTECs). TRA expression in mTECs mirrors virtually all tissues of the body, irrespective of developmental or spatio-temporal expression patterns. This review summarizes current knowledge on the cellular and molecular regulation of TRA expression in mTECs, outlines relevant mechanisms of antigen presentation and modes of tolerance induction, and discusses implications for the pathogenesis of autoimmune diseases and other biological processes such as fertility, pregnancy, puberty, and tumor defense.
Division of Developmental Immunology, Tumor Immunology Program, German Cancer Research Center, 69120 Heidelberg, Germany. b.kyewski@dkfz.de
Bruno
B
Kyewski
Ludger
L
Klein
D000818:Animals; D017951:Antigen Presentation; D000940:Antigenic Variation / Q000235:genetics; D001324:Autoantigens / Q000235:genetics; D015551:Autoimmunity / Q000235:genetics; D002454:Cell Differentiation; D004847:Epithelial Cells / Q000166:cytology / Q000276:immunology; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D007108:Immune Tolerance / Q000235:genetics; D051379:Mice; D008957:Models, Genetic; D018448:Models, Immunological; D009369:Neoplasms / Q000276:immunology; D017634:Self Tolerance / Q000235:genetics; D017154:Stromal Cells / Q000166:cytology / Q000276:immunology; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology; D013950:Thymus Gland / Q000166:cytology / Q000276:immunology
D001324:Autoantigens