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

自身免疫调节因子(AIRE)基因突变是单基因常染色体隐性遗传的器官特异性自身免疫性疾病的发病机制。虽然Aire被认为通过转录控制胸腺上皮细胞中的组织特异性抗原来调节自身反应性T细胞的消除，但ALRE依赖耐受的其他机制仍有待研究。我们已经建立了Aire缺陷小鼠，并研究了导致自我耐受崩溃的机制。Aire基因缺陷小鼠保留了免疫调节性T细胞的产生和/或功能。小鼠的外分泌器官出现了类似干燥综合征的病理变化，这与对一种普遍存在的蛋白质a-fodrin的自身免疫有关。值得注意的是，在AIRE缺陷的胸腺中，α-fodrin的转录表达保持不变。这些结果表明，Aire对自身反应性T细胞的存活的调控超出了胸腺中自我蛋白表达的转录控制，至少对这种普遍存在的蛋白是如此。相反，Aire可能调节自身蛋白的加工和/或呈现，以便成熟的T细胞能够以一种能够有效地触发自身反应性T细胞的形式识别自身抗原。我们还发现，AIRE的第一个PhD(Phd1)调节E3连接酶的活性。PhD1(C311Y和P326Q)的致病错义突变使其E3连接酶活性丧失，这一事实突显了这一发现的重要性。这些结果为AIRE增加了一种新的酶功能，并提示泛素-蛋白酶体途径在建立自我耐受性中起着不可或缺的作用，而AIRE参与其中。

Autoimmune regulator (AIRE) gene mutation is responsible for the development of organ-specific autoimmune disease with monogenic autosomal recessive inheritance. Although Aire has been considered to regulate the elimination of autoreactive T cells through transcriptional control of tissue-specific antigens in thymic epithelial cells, other mechanisms of AlRE-dependent tolerance remain to be investigated. We have established Aire-deficient mice, and examined the mechanisms underlying the breakdown of self-tolerance. The production and/or function of immunoregulatory T cells were retained in the Aire-deficient mice. The mice developed Sjogren's syndrome-like pathologic changes in the exocrine organs, and this was associated with autoimmunity against a ubiquitous protein, a-fodrin. Remarkably, transcriptional expression of α-fodrin was retained in the Aire-deficient thymus. These results suggest that Aire regulates the survival of autoreactive T cells beyond transcriptional control of self-protein expression in the thymus, at least against this ubiquitous protein. Rather, Aire may regulate the processing and/or presentation of self-proteins so that the maturing T cells can recognize the self-antigens in a form capable of efficiently triggering autoreactive T cells. We also show that the first PHD (PHD1) of AIRE mediates E3 ligase activity. The significance of this finding was underscored by the fact that disease-causing missense mutations in the PHD1 (C311Y and P326Q) abolished its E3 ligase activity. These results add a novel enzymatic function for AIRE, and suggest an indispensable role of the ubiquitin-proteasome pathway in the establishment of self-tolerance in which AIRE is involved.