Alteration of intra-pancreatic target-organ specificity by abrogation of Aire in NOD mice
Alteration of intra-pancreatic target-organ specificity by abrogation of Aire in NOD mice
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DOI：
10.1172/jci26971
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发表时间：
2006-05-01
影响因子：
15.9
通讯作者：
Matsumoto, M
中科院分区：
文献类型：
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作者：
Niki, S;Oshikawa, K;Matsumoto, M
人们对决定参与自身免疫破坏的靶器官范围的因素知之甚少。尽管胸腺上皮细胞中自身免疫调节因子（AIRE）功能的丧失是导致自身免疫的原因，但 AIRE 在调节靶器官特异性中的致病作用仍然难以捉摸。为了深入了解这个问题，我们建立了NOD小鼠，这是一种由自身免疫攻击P细胞胰岛引起的1型糖尿病动物模型，其中Aire已被废除。值得注意的是，在 Aire 缺陷型 NOD 小鼠中，腺泡细胞而不是 P 细胞胰岛是自身免疫破坏的主要目标，这种胰腺内靶器官特异性的改变与针对胰腺特异性蛋白二硫键异构酶 (PDIp) 的自身抗体的产生有关，PDIp 是一种主要由腺泡细胞表达的抗原。与这种病理变化一致的是，这些动物对糖尿病的发展具有抵抗力。结果表明，Aire 不仅对于自我耐受的控制至关重要，而且还通过调节 T 细胞库多样化，成为靶器官特异性的强大调节剂。我们还证明，PDIp 的转录表达保留在 Aire 缺陷的 NOD 胸腺中，进一步支持了这样的观点：Aire 可能调节自身反应性 T 细胞的存活，超越胸腺中自身蛋白表达的转录控制。
Factors that determine the spectrum of target organs involved in autoimmune destruction are poorly understood. Although loss of function of autoimmune regulator (AIRE) in thymic epithelial cells is responsible for autoimmunity, the pathogenic roles of AIRE in regulating target-organ specificity remain elusive. In order to gain insight into this issue, we have established NOD mice, an animal model of type 1 diabetes caused by autoimmune attack against P cell islets, in which Aire has been abrogated. Remarkably, acinar cells rather than P cell islets were the major targets of autoimmune destruction in Aire-deficient NOD mice, and this alteration of intra-pancreatic target-organ specificity was associated with production of autoantibody against pancreas-specific protein disulfide isomerase (PDIp), an antigen expressed predominantly by acinar cells. Consistent with this pathological change, the animals were resistant to the development of diabetes. The results suggest that Aire not only is critical for the control of self-tolerance but is also a strong modifier of target-organ specificity through regulation of T cell repertoire diversification. We also demonstrated that transcriptional expression of PDIp was retained in the Aire-deficient NOD thymus, further supporting the concept that Aire may regulate the survival of autoreactive T cells beyond transcriptional control of self-protein expression in the thymus.