ROLE OF BETA 2 GPI IN APOPTOSIS

细胞凋亡，或程序性细胞死亡，是一种活跃的过程，通过这种过程 不需要的细胞被消除了。通过以下方式迅速清除凋亡细胞 吞噬细胞在没有炎症的情况下发生，也没有提供 自身免疫反应。细胞凋亡清除的一个重要机制 涉及细胞膜磷脂不对称性的丧失和 识别磷脂酰丝氨酸(PS)但推测为巨噬细胞PS 感受器。β/2-糖蛋白I(Beta2GPI)，一种磷脂结合血浆 蛋白质，最近已被确定为患者的主要自身抗原 患有系统性红斑狼疮和抗磷脂抗体综合征。尽管它的 生理功能尚不清楚，越来越多的证据表明 Beta2GPI是补体控制蛋白家族的成员之一，可能是 参与凋亡细胞的调理和吞噬作用。 初步研究表明Beta2GPI与细胞凋亡具有特异性结合 小鼠脾细胞导致假设β2GPI可能作为 一种生理性的、非炎症性的调理素，用于凋亡细胞，并且 抗β2GPI抗体可能通过以下途径参与SLE的发病 改变凋亡细胞的正常清除，以及抗Beta2GPI 抗体可能通过改变系统性红斑狼疮患者的 正常清除凋亡细胞。这项提议的目标是 探讨Beta2GPI的作用及抗Beta2GPI的作用 自身抗体，吞噬凋亡细胞。第一个目标是 检测β_2GPI对细胞吞噬功能的影响 细胞。体外吞噬试验将在含血清的 在有无血清存在和不存在的情况下的培养和无血清培养 Beta2GPI。第二个目标是鉴定和鉴定吞噬细胞 β2GPI的表面受体。假设Beta2GPI充当一个 调理素对凋亡细胞的作用需要受体识别β2GPI 在吞噬细胞上。受体介导的Beta2GPI与某些吞噬细胞的结合 最近的一些报告和我们的初步数据表明。噬菌体 显示克隆将用于分离和鉴定Beta2GPI结合 分子。第三个目的是研究自身抗体对人类免疫功能的影响 β2GPI诱导的细胞凋亡清除。多克隆和多克隆抗体的作用 抗Beta2GPI的单抗将在体外进行研究 吞噬试验和体内清除凋亡细胞。 更多的体内实验将调查是否有可能 疾病相关的抗Beta2GPI自身抗体可以刺激 对凋亡细胞抗原的自身免疫反应的发展。

Apoptosis, or programmed cell death, is an active process by which unwanted cells are eliminated. The swift removal of apoptotic cells by phagocytes occurs in the absence of inflammation and without provide an autoimmune response. An important mechanism of apoptotic cell clearance involves the cell's loss of membrane phospholipid asymmetry and recognition of phosphatidylserine (PS) but putative macrophage PS receptors. Beta/2-glycoprotein I (beta2GPI), a phospholipid-binding plasma protein, has recently been identified as a major autoantigen in patients with SLE and the anti-phospholipid antibody syndrome. Although its physiological function is not known, there is growing evidence that Beta2GPI, a member of the complement control protein family, may be involved in the opsonization and phagocytosis of apoptotic cells. Preliminary studies demonstrate specific binding of beta2GPI to apoptotic murine splenocytes leading to the hypothesis the beta2GPI may function as a physiological, non-inflammatory opsonin for apoptotic cells, and that anti-beta2GPI antibodies may contribute to the pathogenesis of SLE by altering the normal clearance of apoptotic cells, and that anti-beta2GPI antibodies may contribute to the pathogenesis of SLE by altering the normal clearance of apoptotic cells. The goals of this proposal are to investigate the role of beta2GPI and the effect of anti-beta2GPI autoantibodies, on the phagocytosis of apoptotic cells. The first aim is to determine the effect of beta2GPI on the phagocytosis of apoptotic cells. In vitro phagocytosis assays will be performed in serum-containing medium and in serum-free medium in the presence and absence of purified beta2GPI. The second aim is to identify and characterize phagocyte cell surface receptors for beta2GPI. The hypothesis that beta2GPI acts as an opsonin for apoptotic cells require recognition for beta2GPI by receptors on phagocytes. Receptor-mediated binding of beta2GPI to certain phagocytes is suggested by a number of recent reports and our preliminary data. Phage display cloning will be used to isolate and identify beta2GPI binding molecules. The third aim is to investigate the effect of autoantibodies of beta2GPI apoptotic cell clearance. The effects of polyclonal and monoclonal autoantibodies to beta2GPI will be investigated in in vitro phagocytosis assays and in the in vivo clearance of apoptotic cells. Additional in vivo experiments will investigate the possibility that disease-related anti-beta2GPI autoantibodies could stimulate the development of an autoimmune response to apoptotic cell antigens.