Mechanisms of aPL antibody-induced pregnancy loss

描述(由申请人提供)： 抗磷脂综合征(APS)的特征是在抗磷脂(APL)抗体存在的情况下发生血栓形成和妊娠丢失，是流产和母婴发病率的主要原因。APS妇女的妊娠并发症包括胎儿死亡、先兆子痫和宫内生长受限(IUGR)。导致体内损伤的致病机制尚不完全清楚，治疗APS的孕妇也只取得了部分成功。我们在被动转移人APL抗体诱导的小鼠APS模型上的研究表明，补体激活在胎儿丧失和生长受限中起着重要的致病作用。此外，肝素是妊娠APS患者的标准治疗方法，可以防止补体激活并保护小鼠免受APL抗体引起的妊娠并发症的影响，而不抑制补体的抗凝剂不能保护怀孕。这些研究表明，APS是一种炎症性疾病，补体抑制疗法可能是一种有效的治疗方法。我们的总体目标是使用APS的小鼠模型来确定补体是如何被激活的，哪些补体产物介导了与APL抗体相关的临床并发症，以及补体激活在整个炎症级联反应中的相对作用。此外，我们建议检验母胎界面补体激活在IUGR中起病因学作用的假设。因此，我们的目标是： 目的1.确定哪些补体成分和受体在介导APL抗体诱导的胎盘损伤、胎儿丢失和/或IUGR中是必需的或充分的。(A)确定启动补体激活和导致(S)补体在蜕膜沉积和不良妊娠结局的途径；(B)确定介导胎儿损伤的补体激活产物和受体；(C)评估小鼠补体调节蛋白在控制局部补体激活中的作用。 目的2.明确APL抗体介导的补体激活在整个炎症级联反应中的作用，以确定补体依赖和补体非依赖的机制，(A)确定Fc？R在APL抗体介导的损伤中的作用；(B)确定在蜕膜补体激活、IUGR和胎儿丧失中起作用的细胞和细胞因子。 这项拟议的研究，连同我们正在进行的确定补体和细胞因子在APS患者妊娠并发症中的作用的工作，将为补体诱发疾病的机制提供见解，并确定干预措施的目标，以防止APL抗体相关的胎儿死亡和IUGR。此外，了解APL抗体是如何“导致”妊娠丢失的，可能会转化为关于母胎耐受和流产的新概念，并使患有非APL相关妊娠并发症的妇女受益。

DESCRIPTION (provided by applicant): The antiphospholipid syndrome (APS), characterized by thrombosis and pregnancy loss that occurs in the presence of antiphospholipid (aPL) antibodies, is a leading cause of miscarriage and maternal and fetal morbidity. Pregnancy complications in women with APS include fetal death, preeclampsia, and intrauterine growth restriction (IUGR). The pathogenic mechanisms that lead to injury in vivo are incompletely understood and the therapy for pregnant women with APS is only partially successful. Our studies in a murine model of APS, induced by passive transfer of human Apl antibodies, indicate that complement activation plays an essential and causative role in fetal loss and growth restriction. In addition, treatment with heparin, the standard therapy for pregnant patients with APS, prevents complement activation and protects mice from pregnancy complications induced by aPL antibodies, while anticoagulants that do not inhibit complement do not protect pregnancies. These studies indicate that APS is an inflammatory disease and, they suggest that complement inhibitory therapy might be an effective treatment. Our overall goals are to use the murine model of APS to determine how complement is activated, which complement products mediate the clinical complications associated with aPL antibodies, and the relative role of complement activation within the overall inflammatory cascade. In addition, we propose to test the hypothesis that activation of complement at the maternal-fetal interface plays an etiologic role in IUGR. Accordingly, our aims are: Aim 1. To determine which complement components and receptors are necessary or sufficient to mediate aPL antibody-induced placental injury, fetal loss and/or IUGR. (a) To identify the pathways that initiate complement activation and lead(s) to complement deposition in deciduas and poor pregnancy outcomes; (b) To identify the complement activation products and receptors that mediate fetal injury; (c) To assess the role of murine complement regulatory proteins in the control of local complement activation. Aim 2. To define the role of aPL antibody-mediated complement activation within the overall inflammatory cascade in order to identify complement-dependent vs. complement-independent mechanisms, (a) To define the contribution of Fc?R to aPL antibody-mediated injury; (b) To define the cellular and cytokine mediators which contribute to complement activation in deciduas, to IUGR and to fetal loss. The proposed study, together with our ongoing work to define the role of complement and cytokines in pregnancy complications in APS patients, will provide insights into the mechanisms by which complement induces disease and define targets for interventions to prevent aPL antibody-associated fetal demise and IUGR. Additionally, understanding how aPL antibodies "cause" pregnancy loss may translate into new concepts about maternal-fetal tolerance and miscarriages in general and benefit women with non-aPL-related pregnancy complications.