Functional analysis ofAIRE, a gene responsible for the hereditary type of autoimmune disease

决定自身免疫性破坏的靶器官谱的因素知之甚少。虽然胸腺上皮细胞自身免疫调节因子（AIRE）功能的丧失是自身免疫的原因，但AIRE在调节靶器官特异性方面的致病作用仍然是未知的。为了深入了解这个问题，我们建立了NOD小鼠，这是一种由针对B细胞胰岛的自身免疫攻击引起的I型糖尿病的动物模型，其中Aire已被废除。值得注意的是，腺泡细胞而不是β细胞胰岛是Aire缺陷NOD小鼠中自身免疫破坏的主要靶点，并且胰腺内靶器官特异性的这种改变与针对胰腺特异性蛋白二硫键异构酶（PDIP）的自身抗体的产生相关，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，动物对糖尿病的发展具有抵抗力。结果表明，Aire不仅是控制自身耐受性的关键，而且是通过调节T细胞库多样化的靶器官特异性的强修饰剂。我们还表明，PDIp的转录表达保留在Aire缺陷的NOD胸腺，进一步支持的概念，Aire可以调节自身反应性T细胞的生存超出自身蛋白表达在胸腺中的转录控制。

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 I diabetes caused by autoimmune attack against b-cell islets, in which Aire has been abrogated. Remarkably, acinar cells rather than β-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 auto-Ab against pancreas-specific protein disulfide isomerase (PDIp), an antigen expressed predominantly by acinar cells. Consistent with this pathologic change, the animals were resistant to the development of diabetes. The results suggest that Aire is not only 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.