ANTIPHOSPHOLIPID ANTIBODIES AND DISORDERS OF PREGNANCY

自然产生的抗磷脂抗体(APL)通常是 与妊娠中断有关，特征是 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- 依赖抗原最常与怀孕有关。 并发症。我们之前的研究已经证明，小鼠 抗人抗磷脂酰丝氨酸单抗和多克隆抗体 (APS)直接与滋养层细胞上的抗原结合，包括绒毛和 长得太长了。这些PS依赖的抗原在一个 滋养层细胞的分化相关方式。我们还有 结果表明，单抗APS在体外抑制对 滋养层间融合、激素产生与滋养层 侵袭，以及诱导妊娠小鼠宫内发育迟缓。我们假设 在分化过程中，PS依赖的抗原外化于 滋养层细胞，APS抑制滋养层活动， 是成功怀孕所必需的。我们的长期目标是 了解PS外化的调控机制 依赖抗原，外源性PS在滋养层细胞中的作用 发展，以及APL干扰这一过程的机制 进程。在这场竞争的继续中，我们将1)确定 APL的特异性及其抗原的性质，2)决定了 滋养层PS外化的调控机制及其研究进展 对辨证的意义，以及3)确定的机制 APLS~对滋养细胞功能的影响。这些后来的研究将 包括APL与滋养层细胞结合的定位，确定 APLS对滋养层细胞凋亡的影响及效果评价 APL对体外滋养层细胞融合的影响 妊娠相关激素与滋养层细胞外侵袭 基质，滋养层细胞介导的母体凝血控制，以及 滋养层细胞通过蛋白激酶C的信号转导 研究应阐明磷脂外化在 滋养层细胞分化及APL的作用机制 那些功能。

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.