Paradoxical development of polymyositis-like autoimmunity through augmented expression of autoimmune regulator (AIRE). (January 2018)

• Record Type: Journal Article
• Authors: Nishijima, Hitoshi; Kajimoto, Tatsuya; Matsuoka, Yoshiki; Mouri, Yasuhiro; Morimoto, Junko; Matsumoto, Minoru; Kawano, Hiroshi; Nishioka, Yasuhiko; Uehara, Hisanori; Izumi, Keisuke; Tsuneyama, Koichi; Okazaki, Il-mi; Okazaki, Taku; Hosomichi, Kazuyoshi; Shiraki, Ayako; Shibutani, Makoto; Mitsumori, Kunitoshi; Matsumoto, Mitsuru
• Is Part Of: Journal of autoimmunity. Volume 86(2018)
• Page Start: 75
• Page End: 92
• Publication Date: 2018-01
• Subjects: Medullary thymic epithelial cell (mTEC) -- AIRE -- Muscle -- Tolerance; Ab antibody -- APC antigen-presenting cell -- BM bone marrow -- Crp C-reactive protein -- cTEC cortical thymic epithelial cell -- DC dendritic cell -- EpCAM epithelial cell adhesion molecule 1 -- eTAC extrathymic Aire-expressing cell -- FISH fluorescence in situ hybridization -- huAIRE human AIRE -- Ins2 insulin 2 -- mAb monoclonal Ab -- MHC-II MHC class II -- mTEC medullary thymic epithelial cell -- Myh7 myosin heavy chain 7 -- OVA ovalbumin -- RIP rat insulin promoter -- Sap salivary protein 1 -- Tg transgenic mice -- TRA tissue-restricted antigen -- Treg regulatory T cell -- UEA-1 Ulex europaeus agglutinin 1; Autoimmunity -- Periodicals; Autoimmune diseases -- Periodicals; Autoantibodies -- Periodicals; Autoimmune Diseases -- Periodicals; Auto-immunité -- Périodiques; Maladies auto-immunes -- Périodiques; Electronic journals; 616.978005
• DOI: 10.1016/j.jaut.2017.09.006
• Languages: English
• ISSNs: 0896-8411

Abstract

Abstract: Autoimmunity is prevented by the function of the autoimmune regulator [ AIRE ( Aire in mice)], which promotes the expression of a wide variety of tissue-restricted antigens (TRAs) from medullary thymic epithelial cells (mTECs) and from a subset of peripheral antigen-presenting cells (APCs). We examined the effect of additive expression of human AIRE (huAIRE) in a model of autoimmune diabetes in NOD mice. Unexpectedly, we observed that mice expressing augmented AIRE/Aire developed muscle-specific autoimmunity associated with incomplete maturation of mTECs together with impaired expression of Aire-dependent TRAs. This led to failure of deletion of autoreactive T cells together with dramatically reduced production of regulatory T cells in the thymus. In peripheral APCs, expression of costimulatory molecules was augmented. We suggest that levels of Aire expression need to be tightly controlled for maintenance of immunological tolerance. Our results also highlight the importance of coordinated action between central tolerance and peripheral tolerance under the common control of Aire. Graphical abstract: Highlights: Aire in the thymus and periphery prevents autoimmunity by self-antigen expression. Mice overexpressing AIRE/Aire paradoxically developed muscle-specific autoimmunity due to the altered development of mTEC. Level of Aire expression must be tightly controlled to maintain self-tolerance. Altered AIRE expression might be a feasible mechanism of autoimmunity.