Paradoxical development of polymyositis-like autoimmunity through augmented expression of autoimmune regulator (AIRE)
Paradoxical development of polymyositis-like autoimmunity through augmented expression of autoimmune regulator (AIRE)
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DOI：
10.1016/j.jaut.2017.09.006
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发表时间：
2018-01-01
影响因子：
12.8
通讯作者：
Matsumoto, Mitsuru
中科院分区：
文献类型：
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作者：
Nishijima, Hitoshi;Kajimoto, Tatsuya;Matsumoto, Mitsuru
自身免疫被自身免疫调节因子[AIRE(小鼠的AIRE)]的功能所阻止，该调节因子促进髓质胸腺上皮细胞(MTECs)和外周抗原提呈细胞(APC)亚群的各种组织限制性抗原(Tras)的表达。我们在NOD小鼠的自身免疫性糖尿病模型中检测了人类AIRE(HuAIRE)的相加表达的影响。出乎意料的是，我们观察到，表达增强的AIRE/Aire的小鼠发生了肌肉特异性自身免疫，与mTECs的不成熟以及Aire依赖的tras的表达受损有关。这导致自身反应性T细胞的删除失败，同时胸腺中调节性T细胞的产量显著减少。在外周APC中，共刺激分子的表达增强。我们建议，为了维持免疫耐受，需要严格控制Aire的表达水平。我们的结果也强调了在Aire的共同控制下，中枢耐受和外周耐受之间协调行动的重要性。(C)2017年作者。爱思唯尔有限公司出版。
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. (C) 2017 The Authors. Published by Elsevier Ltd.