Role of defective clearance of apoptotic beta-cell in pathogenesis of T1D

描述(申请人提供)：1型糖尿病(T1D)是一种自身免疫性疾病，由选择性破坏胰岛β细胞引起。导致T1D的病因步骤是复杂的、不清楚的和有争议的。我们的长期目标是阐明β细胞特异性自身抗原在遗传易感个体中触发自身免疫的机制。细胞凋亡是细胞死亡的一种程序性和生理性形式。细胞凋亡程序的最终目标是清除凋亡细胞，以防止其成分的释放。如果不能及时做到这一点，将导致炎症和自身免疫的严重后果。最近的研究表明，凋亡细胞是潜在的自身抗原储存库，可能启动和推动易感宿主的全身自身免疫。已有研究表明，在自身免疫性NOD小鼠中，生理性的β细胞死亡触发树突状细胞(DC)启动自身反应性T细胞。NOD小鼠的DC对死亡细胞的摄取令人惊讶，因为巨噬细胞被认为是清除凋亡细胞碎片的专家，这表明NOD小鼠对死亡的β细胞的清除受到损害。根据这些观察结果，我们推测，在NOD幼年小鼠或易感人类中，经历发育凋亡的β细胞未能释放“Find-Me”信号或呈现“Eat-Me”信号，会导致对凋亡的β细胞的缺陷清除，从而导致触发自身免疫的免疫原性细胞内成分的释放。钙非依赖性磷脂酶A2(IPLA2)是凋亡细胞产生溶血磷脂酰胆碱(LPC)的关键分子。本研究的目的是验证一个新的假说，即iPLA2不能产生“Find-Me”信号LPC会导致对凋亡的β细胞的缺陷清除，从而使易感个体中易患T1D的β细胞特异性自身抗原可用。其具体目的是：1)验证iPLA2对凋亡的β细胞释放趋化因子LPC募集巨噬细胞起重要作用的假说；2)检验NOD小鼠iPLA2水平降低导致无法清除凋亡的β细胞，从而获得β细胞特异性自身抗原的假说。通过开展这项研究，我们将能够阐明激活和促进T细胞侵袭胰岛的关键事件，从而特异性地杀伤β细胞，并开发防止T1D启动自身免疫的治疗策略。通过开展这项研究，我们将能够阐明激活和促进T细胞侵袭胰岛的关键事件，从而特异性地杀伤β细胞，并开发防止T1D启动自身免疫的治疗策略。

DESCRIPTION (provided by applicant): Type 1 diabetes (T1D) is an autoimmune disease resulting from a selective destruction of the pancreatic beta-cells. The etiologic steps leading to T1D are complex, unclear, and controversial. Our long-term goal is to elucidate the mechanisms by which beta-cell specific autoantigens are made available in the genetically susceptible individuals to trigger the autoimmunity. Apoptosis is a programmed and physiological form of cell death. The ultimate objective of apoptotic program is to remove apoptotic cells to prevent release of their components. Failure to do so promptly has serious consequences for inflammation and autoimmunity. Recent studies have implicated apoptotic cells as being potential reservoirs of autoantigens that might initiate and drive systemic autoimmunity in susceptible hosts. It has been shown that physiological beta-cell death triggers priming of self-reactive T cells by dendritic cells (DCs) in autoimmune NOD mice. The uptake of dying cells by DCs in NOD mice came as a surprise because macrophages are thought to be the specialists in clearing apoptotic cellular debris, suggesting the impaired clearance of dying beta-cells in NOD mice. In light of these observations, we hypothesize that failure to release "find-me" signals or to present the "eat-me" signals by beta-cells undergoing developmental apoptosis in juvenile NOD mice or susceptible humans results in defective clearance of apoptotic beta-cells, which subsequently results in release of immunogenic intracellular components triggering autoimmunity. Ca2+independent PLA2 (iPLA2) is key player in generating lysophosphatidylcholine (LPC) as a "find-me" signal by apoptotic cells to attract phagocytes. The goal of this study is to test a novel hypothesis that failure to produce "find-me" signal LPC by iPLA2 leads to the defective clearance of apoptotic beta-cells, which makes beta-cell specific autoantigens available predisposing to T1D in the susceptible individuals. The specific aims are to: 1) test the hypothesis that iPLA2 plays an important role for apoptotic beta-cells to release chemotactic factor LPC to recruit macrophages and 2) test the hypothesis that the decreased level of iPLA2 in NOD mice leads to failure to clear apoptotic beta-cells, which makes beta- cell specific autoantigens available. By conducting this study, we will be able to elucidate the critical events that activate and promote T cell invasion of the islets to specifically kill beta-cell and to develop therapeutic strategy preventing the initiation of autoimmunity in T1D. By conducting this study, we will be able to elucidate the critical events that activate and promote T cell invasion of the islets to specifically kill beta-cell and to develop therapeutic strategy preventing the initiation of autoimmunity in T1D.