Paradoxical development of polymyositis-like autoimmunity through augmented expression of autoimmune regulator (AIRE).
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.
['Nishijima|Hitoshi|H|', 'Kajimoto|Tatsuya|T|', 'Matsuoka|Yoshiki|Y|', 'Mouri|Yasuhiro|Y|', 'Morimoto|Junko|J|', 'Matsumoto|Minoru|M|', 'Kawano|Hiroshi|H|', 'Nishioka|Yasuhiko|Y|', 'Uehara|Hisanori|H|', 'Izumi|Keisuke|K|', 'Tsuneyama|Koichi|K|', 'Okazaki|Il-Mi|IM|', 'Okazaki|Taku|T|', 'Hosomichi|Kazuyoshi|K|', 'Shiraki|Ayako|A|', 'Shibutani|Makoto|M|', 'Mitsumori|Kunitoshi|K|', 'Matsumoto|Mitsuru|M|']
D000818:Animals D001324:Autoantigens D015551:Autoimmunity D003922:Diabetes Mellitus, Type 1 D004195:Disease Models, Animal D006801:Humans D007108:Immune Tolerance D051379:Mice D016688:Mice, Inbred NOD D008822:Mice, Transgenic D009132:Muscles D009928:Organ Specificity D017285:Polymyositis D013950:Thymus Gland D014157:Transcription Factors
AIRE Medullary thymic epithelial cell (mTEC) Tolerance Muscle