Tissue-specific autoimmunity controlled by Aire in thymic and peripheral tolerance mechanisms
Tissue-specific autoimmunity controlled by Aire in thymic and peripheral tolerance mechanisms
复制标题
DOI：
10.1093/intimm/dxz066
复制
发表时间：
2020-02-01
影响因子：
4.4
通讯作者：
Nishijima, Hitoshi
中科院分区：
文献类型：
--
作者：
Matsumoto, Minoru;Tsuneyama, Koichi;Nishijima, Hitoshi
组织特异性自身免疫性疾病被认为是由于免疫耐受的两个检查点的故障引起的：胸腺中自身反应性T细胞的缺陷消除和外周相应自身抗原对这些T细胞的激活。然而，这一模型的证据以及这种改变在每一种或两种耐受机制中的结果还没有得到充分的研究。我们通过在NOD小鼠中表达人AIRE(HuAIRE)作为耐受功能的调节剂来研究这些问题，在NOD小鼠中，胸腺和外周耐受缺陷共同导致I型糖尿病(T1D)。胸腺基质中添加的huAIRE表达对胸腺中促糖尿病T细胞的产生没有重大影响。相比之下，外周抗原提呈细胞(APC)中huAIRE的表达使小鼠对T1D产生了抵抗力，同时保持了其他组织特异性自身免疫反应和针对外源蛋白抗原的抗体产生，这是因为失去了Xcr1(+)树突状细胞，这是激活外周糖尿病T细胞的基本成分。这些结果与我们最近发现的胸腺基质和外周APC中huAIRE的表达导致肌肉特异性自身免疫的矛盾发展形成了鲜明对比。我们的结果表明，组织特异性自身免疫是由胸腺功能和外周耐受的组合来控制的，这可以通过huAIRE/Aire在两种耐受机制中的表达来控制。
Tissue-specific autoimmune diseases are assumed to arise through malfunction of two checkpoints for immune tolerance: defective elimination of autoreactive T cells in the thymus and activation of these T cells by corresponding autoantigens in the periphery. However, evidence for this model and the outcome of such alterations in each or both of the tolerance mechanisms have not been sufficiently investigated. We studied these issues by expressing human AIRE (huAIRE) as a modifier of tolerance function in NOD mice wherein the defects of thymic and peripheral tolerance together cause type I diabetes (T1D). Additive huAIRE expression in the thymic stroma had no major impact on the production of diabetogenic T cells in the thymus. In contrast, huAIRE expression in peripheral antigen-presenting cells (APCs) rendered the mice resistant to T1D, while maintaining other tissue-specific autoimmune responses and antibody production against an exogenous protein antigen, because of the loss of Xcr1(+) dendritic cells, an essential component for activating diabetogenic T cells in the periphery. These results contrast with our recent demonstration that huAIRE expression in both the thymic stroma and peripheral APCs resulted in the paradoxical development of muscle-specific autoimmunity. Our results reveal that tissue-specific autoimmunity is differentially controlled by a combination of thymic function and peripheral tolerance, which can be manipulated by expression of huAIRE/Aire in each or both of the tolerance mechanisms.