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)的人类在 AIRE基因，它编码一种具有转录的结构和功能特征的蛋白质 监管因素。携带a/re基因座工程零突变的小鼠也会患上多发性... 器官自身免疫性疾病。在上一次资助期间在这些小鼠身上进行的机械学研究 R01 DK60027循环建立了AIRE通过促进 胸腺细胞分化的负选择。它主要是通过诱导表达来运作的 编码外周组织抗原或PTT的转录本，特别是在胸腺髓质中 上皮细胞(MECs)。其次，它增强了MECs向T细胞递送抗原的能力 并克隆删除自我反应性胸腺细胞--通过一种目前未知的可分离机制 来自PTT诱导。这份竞争性续签申请建议进一步阐明这两个 AIRE行动模式的各个方面--具体地说，我们打算： I)评估MEC PTT曲目的可塑性； Ii)概括和定位AIRE阴性的MECs的抗原提呈缺陷； Iii)评估AIRE作为E3泛素连接酶的作用的相关性。 这些研究的结果应该阐明中央(即 胸腺)介导的免疫耐受，潜在地改善了预防或 治疗自身免疫性疾病，如1型糖尿病和多发性硬化症。

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.