Roles of Dendritic Cells in Immune Regulation

描述（由申请人提供）：了解自身免疫中自身耐受性破坏的机制对于开发预防和治疗自身免疫性疾病的策略至关重要。大量证据表明，免疫系统中的缺陷性细胞凋亡与人类和小鼠的系统性自身免疫性疾病的发展有关。然而，单独抑制淋巴细胞中的凋亡不足以打破免疫耐受，表明其他细胞类型中受损的凋亡在自身耐受的破坏中起关键作用。靶向抑制树突状细胞（DC）中的凋亡已被证明可诱导全身性自身免疫反应。本实验旨在验证DCs中的细胞凋亡对于限制淋巴细胞活化和预防自身免疫是必不可少的这一假设，具体目的如下：1）表征DCs中的细胞凋亡途径。死亡受体介导的凋亡途径和凋亡相关蛋白依赖的凋亡途径将在DC中表征。初步研究表明，体内DC亚群的寿命与抗凋亡和促凋亡bcl-2家族成员之间的分子比例相关。将进行实验以进一步表征bcl-2调节的线粒体凋亡途径在调节DC凋亡中的作用; 2）检验DC中的缺陷性凋亡有助于失调的淋巴细胞活化的假设。DC的寿命可以通过影响DC刺激淋巴细胞的持续时间来潜在地影响免疫应答。将检查凋亡缺陷型DC在过度活化淋巴细胞中的潜力;和3）检验DC中的缺陷型凋亡有助于自身免疫发展的假设。本研究将探讨树突状细胞在线粒体凋亡途径中的凋亡缺陷是否会导致自身免疫的发生。提出实验来检验凋亡调节DC稳态和免疫原性的假设，并且DC中的缺陷性凋亡有助于自身免疫的发生。从长远来看，从这些研究中获得的知识将被用来开发更具体和有效的策略，以防止自身免疫的发生，通过靶向细胞凋亡的DC。

DESCRIPTION (provided by applicant): Understanding the mechanisms for the breakdown of self-tolerance in autoimmunity is essential for the development of strategies to prevent and treat autoimmune diseases. Abundant evidence has shown that defective apoptosis in the immune system is associated with the development of systemic autoimmune diseases in humans and mice. However, inhibition of apoptosis in lymphocytes alone is not sufficient to break immune tolerance, indicating that impaired apoptosis in other cell types plays a critical role in the breakdown of self-tolerance. Targeted inhibition of apoptosis in dendritic cells (DCs) has been shown to induce systemic autoimmune responses. Experiments are proposed to test the hypothesis that apoptosis in DCs is essential for limiting lymphocyte activation and preventing autoimmunity in the following specific aims: 1) to characterize the apoptosis pathways in DCs. Death receptor-mediated and mitochondrion-dependent apoptosis pathways will be characterized in DCs. Preliminary studies suggested that the lifespan of DC subsets in vivo was correlating to the molecular ratios between anti-apoptotic and pro-apoptotic bcl-2 family members. Experiments will be performed to further characterize the bcl-2-regulated mitochondrial apoptosis pathways in regulating DC apoptosis; 2) to test the hypothesis that defective apoptosis in DCs contributes to dysregulated lymphocyte activation. The lifespan of DCs can potentially influence immune responses by affecting the duration of DCs in stimulating lymphocytes. The potentials for apoptosis-deficient DCs in over- activating lymphocytes will be examined; and 3) to test the hypothesis that defective apoptosis in DCs contributes to the development of autoimmunity. Studies will be performed to examine whether DCs harboring apoptosis deficiency in the mitochondrial apoptosis pathways leads to the development of autoimmunity. Experiments are proposed to test the hypothesis that apoptosis regulates DC homeostasis and immunogenicity, and defective apoptosis in DCs contributes to the onset of autoimmunity. In the long term, the knowledge gained from these studies will be used to develop more specific and effective strategies to prevent the onset of autoimmunity by targeting apoptosis in DCs.