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

点击翻译按钮获取中文摘要

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.