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. [Display omitted] •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.