【作者】 于春雷；

【导师】 李一；

【作者基本信息】 吉林大学 ， 免疫学， 2006， 博士

【摘要】 AIRE(Autoimmune Regulator)控制着组织特异性抗原在胸腺髓质上皮细胞上表达，从而影响胸腺阴性选择，在维持中枢耐受中发挥作用的一种转录因子。该基因的突变可导致自身免疫病APECED(autoimmune-polyendocrinopathy-candidiasis-ectodermal-dystrophy，APECED)，又称为自身免疫性多腺体综合症Ⅰ(autoimmune polyglandular syndrome type Ⅰ，APSI)。目前对于AIRE蛋白的详细的亚细胞分布、表达调节以及AIRE基因与常见的自身免疫病中的作用还不是很清楚。 为了探讨AIRE蛋白的分子动态学及Aire基因与T1D的相关性，首先，我们建立了稳定表达GFP-AIRE融合基因的Hela细胞株，在此基础上对AIRE的亚细胞定位及表达调节进行了分析，并且对NOD鼠及T1D病人PBMC中Aire基因的表达进行了研究。 研究结果显示：1．在稳定转染的细胞中，AIRE以核体形式存在于细胞核中；2．AIRE NBs与细胞周期相关，在G2期表达明显：3．AIRE NBs明显与核基质相关；4．在蛋白酶体抑制剂的作用下表达AIRE核体明显出现在核内，并同核仁聚集，并且AIRE蛋白的表达水平是被蛋白酶体部分调节的；5．NOD鼠Aire基因相关表达明显减少，并且在T1D病人PBMC中有部分病人AIRE基因表达缺失。 结果表明：1．AIRE蛋白在本转染细胞中以核体方式存在，这种AIRE核体受细胞周期影响，明显与核基质相关，并且AIRE蛋白表达受蛋白酶体调节。这些特点表明，AIRE蛋白很可能在核基质部分发挥它的转录活性，并且AIRE蛋白的调节是部分以蛋白酶体依赖的蛋白水解方式降解。2．Aire的表达异常与T1D的发病相关，说明Aire在免疫耐受的维持中发挥作用。更多还原

【Abstract】 Immunological self-tolerance can be defined as a meta-stable state in which the immune system does not react destructively against self-molecules, cells or tissues. Lack or loss of self-tolerance is likely to result in autoimmune response, cellular and tissue damage, and eventually the clinical onset of autoimmune disease.The mechanism underlying the generation of T and B autoreactive clones in autoimmune diseases is still unknown. Among genetic factors implicated in autoimmunity, Autoimmune Regulator gene (AIRE) is one of the candidates to better understand the complex scenario of autoimmune manifestations.Mutations in the autoimmune regulator (AIRE) gene result in the rare autoimmune syndrome APECED (autoimmune polyendocrinoathy candidiasis ectodermal dystrophy). The disease is charactreised by autoimmune distruction mainly targeting endocrine organs, including Addison’s disease , hypoparathyroidism,, thyroiditis,, and type I diabetes. APECED also involves immune dysfunction manifesting as chronic mucocutaneous candidiasis.The AIRE protein is a transcriptional regulator carrying several conserved protein domains commonly seen in transcription factors, such as the PHD type zinc fingers and the LXXLL nuclear receptor interaction motif AIRE is a transcription factor that controls the ectopic expression of tissue-specfic genes in the thmus. resulting in deletion of T-cells autoreactive to these genes. Deletion of AIRE by mutations thus leads to defective negative selection of a multitude of autoreactive T-cells and subsequent autoimmunity.It has recently been shown that the PHD1 domain of AIRE gene acts as E3 ubiquitin ligase, mediating transfer of ubiquitine to specific proteins.Because AIRE gene mutation is responsible for the development of APECED, independent of HLA types, understanding the relationship between AIRE gene malfunction and the breakdown of self-tolerance promises to help unravel the pathogenesis of not only APECED, but also other common types of autoimmune disease(such as type 1 diabete). However, the rare tissue expression as well as the low更多还原