ANTIPHOSPHOLIPID ANTIBODIES AND DISORDERS OF PREGNANCY

天然存在的抗磷脂抗体（aPL）通常是 与妊娠中断相关，其特征为 先兆子痫、宫内生长受限或胎儿死亡。 抗磷脂酰丝氨酸（PS）和心磷脂（CL）的APL 依赖性抗原通常与妊娠有关 并发症 我们以前的研究表明， 单克隆和人多克隆抗磷脂酰丝氨酸抗体 (aPS)直接与滋养层抗原结合，包括绒毛和 绒毛外的 这些PS依赖性抗原以一种 滋养层的分化相关方式。 我们还 显示单克隆aPS抑制体外测定， 滋养层融合、激素产生和滋养层 入侵，以及诱导IUGR的怀孕小鼠。 我们假设 在分化过程中，PS依赖性抗原被外化到 aPS抑制滋养层细胞的活动， 是成功怀孕的必要条件。 我们的长期目标是 了解调节PS外部化的机制- 依赖性抗原，外部PS在滋养层中的作用 发展，以及杀伤人员地雷干扰这一发展的机制 过程 在这个竞争的延续中，我们将1）确定 aPL的特异性及其抗原的性质，2）确定 控制滋养层PS外化的机制及其 分化的意义，和3）确定的机制， aPLs~对滋养层功能的影响。 这些后续研究将 包括与滋养层结合的aPL的定位， aPL对滋养层细胞凋亡的影响，并评估其影响 APLs对体外滋养层细胞融合的影响， 妊娠相关激素，滋养细胞侵袭细胞外 基质，滋养层介导的母体凝血控制，和 通过蛋白激酶C进行滋养细胞信号转导。 这些 研究应阐明磷脂外化在 滋养层分化和apl影响的机制 这些功能。

Naturally occurring antiphospholipid antibodies (aPLs) are commonly associated with disruption of pregnancy, characterized by preeclampsia, intrauterine growth restriction, or death of the fetus. APLs against phosphatidylserine (PS)- and cardiolipin (CL)- dependent antigens are most commonly associated with pregnancy complications. Our previous studies have demonstrated that mouse monoclonal and human polyclonal antiphosphatidylserine antibodies (aPS) bind directly to antigens on trophoblast, both villous and extravillous. These PS-dependent antigens are expressed in a differentiation-related manner on the trophoblast. We have also shown that monoclonal aPS inhibits in vitro assays for intertrophoblastic fusion, hormone production, and trophoblastic invasion, as well a induces IUGR in pregnant mice. We hypothesize that during differentiation PS-dependent antigens are externalized on trophoblastic cells and that aPS inhibits trophoblastic activities that are necessary for successful pregnancy. Our long-range goals are to understand the mechanisms that regulate the externalization of PS- dependent antigens, the role of external PS in trophoblast development, and the mechanism by which aPLs interfere with this process. In this competing continuation, we will 1) determine the specificity of aPLs and the nature of their antigens, 2) determine the mechanisms that control trophoblastic PS externalization and its significance to differentiation, and 3) determine the mechanisms of aPLs~ effects on trophoblast function. These later studies will include localization of aPL binding to trophoblast, determining the effects of aPLs on trophoblast apoptosis, and evaluating the effects of aPLs on in vitro intertrophoblastic fusion, the production of pregnancy-related hormones, trophoblast invasion of extracellular matrix, trophoblast-mediated control of maternal coagulation, and trophoblastic signal transduction through protein kinase C. These studies should clarify the role of phospholipid externalization in trophoblast differentiation and the mechanisms by which aPLs affect those functions.