Development of autoimmunity against transcriptionally unrepressed target antigen in the thymus of aire-deficient mice
Development of autoimmunity against transcriptionally unrepressed target antigen in the thymus of aire-deficient mice
复制标题
DOI：
10.4049/jimmunol.174.4.1862
复制
发表时间：
2005-02-15
影响因子：
4.4
通讯作者：
Matsumoto, M
中科院分区：
文献类型：
--
作者：
Kuroda, N;Mitani, T;Matsumoto, M
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疾病的发病机制。尽管Aire已被认为通过胸腺上皮细胞中组织特异性Ags的转录控制来调节自身反应性T细胞的消除，但Aire依赖性耐受的其他机制仍有待研究。我们建立了缺乏空气的小鼠，并研究了自我耐受性崩溃的机制。免疫调节性T细胞的产生和/或功能在空气缺陷小鼠中被保留。这些小鼠的外分泌器官出现了干燥综合征样的病理变化，这与对一种普遍存在的蛋白a-fodrin的自身免疫有关。值得注意的是，α -fodrin的转录表达在缺乏空气的胸腺中得以保留。这些结果表明，在胸腺中，Aire调节自身反应性T细胞的存活，至少对这种普遍存在的蛋白质有抑制作用，而不是对自身蛋白表达的转录控制。相反，Aire可能调节自身蛋白的加工和/或呈递，使成熟的T细胞能够以能够有效触发自身反应性T细胞的形式识别自身ags。通过使用近亲繁殖的空气缺乏小鼠品系，我们也证明了一些额外因素的存在，这些因素决定了由空气缺乏引起的自身免疫性疾病的靶器官特异性。
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 Ags in thymic epithelial cells, other mechanisms of AIRE-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 alpha-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-Ags in a form capable of efficiently triggering autoreactive T cells. With the use of inbred Aire-deficient mouse strains, we also demonstrate the presence of some additional factor(s) that determine the target-organ specificity of the autoimmune disease caused by Aire deficiency.