aire a zinc-finger protein that controls autoimmunity

患有多内分泌自身免疫性疾病APECED（或APS-1）的人在其基因组中携带突变。 AIRE基因，其编码具有转录因子的结构和功能特征的蛋白质， 调节因子携带a/re基因座工程无效突变的小鼠也会出现多- 器官自身免疫性疾病在上一次资助期间对这些小鼠进行的机制研究 R 01 DK 60027的循环证实，Aire通过促进自身免疫保护生物体免受自身免疫。 分化中的胸腺细胞的负选择。它主要是通过诱导表达 转录本编码外周组织抗原，或PTTs，特别是在胸腺髓质 上皮细胞（MEC）。其次，它增强了MEC向T细胞呈递抗原的能力 并通过目前未知的机制克隆删除自身反应性胸腺细胞， PTT诱导。这一竞争性更新申请旨在进一步阐明这两个 AIRE行动模式的各个方面-具体而言，我们打算： i）测量MEC PTT库的可塑性; ii）概括和定位由aire-null MEC表现出的抗原呈递缺陷; iii）评估aire作为E3泛素连接酶的作用的相关性。 这些研究的结果应阐明中枢神经系统的关键机制要素（即， 胸腺）介导的免疫耐受，潜在地改善预防性或 自身免疫性疾病如1型糖尿病和多发性硬化症的治愈性治疗。

Humans with the polyendocrine autoimmune disease APECED (or APS-1) harbor mutations in the AIRE gene, which encodes a protein with the structural and functional features of a transcriptional regulatory factor. Mice carrying an engineered null mutation of the a/re locus also develop multi- organ autoimmune disease. Mechanistic studies performed on these mice during the last funding cycle of R01 DK60027 established that aire protects an organism from autoimmunity by promoting the negative selection of differentiating thymocytes. It operates primarily by inducing the expression of transcripts encoding peripheral-tissue antigens, or PTTs, specifically in thymic medullary epithelial cells (MECs). Secondly, it enhances the capacity of MECs to present antigens to T cells and to clonally delete self-reactive thymocytes - via a currently unknown mechanism dissociable from PTT induction. This competitive renewal application proposes to further elucidate these two aspects of aire's mode of action - specifically, we intend: i) to gauge the plasticity of the MEC PTT repertoire; ii) to generalize and localize the antigen-presentation defect exhibited by aire-null MECs; iii) to assess the relevance of aire's role as an E3 ubiquitin ligase. Results from these studies should elucidate critical mechanistic elements of centrally (i.e. thymically) mediated immunological tolerance, potentially improving prospects for preventive or curative therapy for autoimmune diseases such as type-1 diabetes and multiple sclerosis.