Apoptosis signals in autoimmune disease

据推测，自身反应性T细胞参与自身免疫性疾病的发展。自体反应性T细胞通常通过胸腺或外周的tcr信号诱导的凋亡从宿主中清除。免疫监视系统功能障碍导致外周出现自身反应性T细胞。在本研究中，我们研究了TCR信号诱导胸腺细胞或T细胞凋亡，以揭示自身免疫性疾病的发生机制。首先，我们分析了线粒体在tcr诱导胸腺细胞凋亡中的作用，发现tcr刺激激活p38激酶通路可诱导Bax易位至线粒体，导致dym破坏，并释放细胞色素c，最终诱导caspase-3介导的胸腺细胞凋亡。其次，我们研究了caspase激活的脱氧核糖核酸酶（CAD）及其抑制剂（ICAD）的定位和功能，它们在凋亡细胞、胸腺细胞在体内tcr刺激之前或之后的染色质断裂中发挥核心作用。我们发现，胸腺细胞的tcr结合诱导了caspase-3依赖性的CAD激活，不仅在细胞质中，而且在微粒体中，导致它们向细胞核转移，并导致DNA和谐地断裂。这些结果将促使我们分析自身免疫性疾病患者T细胞中tcr诱导的凋亡信号。

It is supposed that the auto-reactive T cells are involved in the development of autoimmune diseases. Auto-reactive T cells are usually eliminated from the host by apoptosis that is induced through TCR-signals in the thymus or in the periphery. Dysfunction of the immune surveillance system leads to appearance of auto-reactive T cells in the periphery. In this study, we investigated the TCR signals that induce apoptosis in thymocytes or T cells to unravel the mechanism of the development of autoimmune diseases. First, we analyzed the role of mitochondria in TCR-induced apoptosis of thymocytes and showed that activated p38 kinase pathway by TCR-stimulation induces translocation of Bax to mitochondria, causing DYm-disruption, and the release of cytochrome c, which finally induces caspase-3-mediated apoptosis in thymocytes. Second, we investigated the localization and the function of caspase-activated deoxyribonuclease (CAD) and its inhibitor (ICAD), which play a central role in chromatin fragmentation in apoptotic cells, in thymocytes prior or post in vivo TCR-stimulation. We showed that TCR-engagement of thymocytes induced caspase-3-dependent activation of CAD localized not only in cytosol but also in microsome, leading to their translocation to nuclei and the resulting DNA fragmentation in harmony. These results will prompt us to analyze the TCR-induced apoptosis signals in T cells from patients of autoimmune diseases.