Complement as a Mediator of Recurrent Miscarriages

描述(由申请者提供)：1%至3%的美国女性反复流产。虽然大多数妇女反复流产的原因尚不清楚，但已经提出了一种免疫机制，涉及母亲免疫系统对受孕的不适当和有害的识别。我们最近在小鼠模型中开发的数据表明，先天免疫机制会触发堕胎。具体地说，我们已经确定了补体激活在导致与胎盘炎症相关的妊娠丢失的途径中作为早期效应者的新作用。我们的工作表明，补体激活是导致抗磷脂抗体诱导的妊娠丢失和胎儿生长受限的中心机制，补体激活是肿瘤坏死因子-α升高所必需的，也是先于肿瘤坏死因子-α升高的。在这一应用中，我们将在免疫介导性流产小鼠模型中检验补体激活是胎儿丢失发病机制中必要的中间事件的假设，该模型既代表着床期丢失，也代表着植入后丢失。我们的总体目标是阐明调节复发性自然流产的补体途径，并确定干预措施的目标，以防止复发性人类流产。因此，我们的目标是： 目的1.在DBA/2交配的雌性CBA/J小鼠自然流产模型中，明确补体在胚胎丢失中的作用。(A)确定C3(和其他补体成分)的沉积与蜕膜内炎症细胞的渗透和肿瘤坏死因子-Q的产生之间的时间关系；(B)利用补体缺乏小鼠和特异性补体抑制剂，确定启动(S)补体激活并导致C3在蜕膜沉积的途径(S)；(C)确定小鼠补体调节蛋白在蜕膜中的表达减少是否参与局部补体激活；(D)确定介导胎儿损伤的补体途径激活产物和受体；(E)确定哪些导致胎儿丧失的细胞和细胞因子有助于蜕膜中有害的补体激活。 目的2.在DBA/2交配的肿瘤坏死因子-α处理的C57BL/6雌性动物模型中，明确补体在胎儿丢失中的作用，并寻找介导体内组织损伤和胎儿丢失的特异性补体激活产物。(A)确定C3是否沉积在蜕膜内；流产是否需要C3激活；以及肿瘤坏死因子-α治疗、C3沉积和细胞浸润之间的关系；(B)使用补体缺陷小鼠和特异性补体抑制剂确定导致细胞因子依赖型流产的补体成分或受体 如果补体激活是反复妊娠丢失的必要机制，阐明特定补体成分的作用将为开发新的治疗方法提供基础，为在这些治疗方法中进行选择提供理论基础，并提供改善患者结局的能力。此外，我们的研究将对补体诱导疾病的机制提供见解，并提出预防、阻止或修改补体介导的炎性疾病的方法。

DESCRIPTION (provided by applicant): Between 1% and 3% of U. S. women suffer recurrent miscarriages. Although the cause of recurrent miscarriages in most women is unknown, an immune mechanism involving inappropriate and injurious recognition of the conceptus by the mother's immune system has been proposed. We have recently developed data in murine models indicating that innate immune mechanisms trigger abortion. Specifically, we have identified a novel role for complement activation as an early effector in the pathway leading to pregnancy loss associated with placental inflammation. Our work shows that complement activation is a central mechanism contributing to antiphospholipid antibody-induced pregnancy loss and fetal growth restriction and that complement activation is required for and precedes increases in TNF-alpha. In this application, we will test the hypothesis that complement activation is a necessary intermediary event in the pathogenesis of fetal loss in murine models of immunologically-mediated abortion representing both peri-implantation and postimplantation loss. Our overall goals are to elucidate the complement pathways that mediate recurrent spontaneous abortion and to define targets for interventions to prevent recurrent human miscarriage. Accordingly, our aims are: Aim 1. To define the role of complement in fetal loss in the DBA/2-mated female CBA/J murine model of spontaneous abortion. (a) To determine the temporal relationships between deposition of C3 (and of other complement components) and infiltration of inflammatory cells and production of TNF-q within decidua; (b) To identify the pathway(s) that initiate(s) complement activation and lead to C3 deposition in the decidua using complement deficient mice and specific complement inhibitors; (c) To determine whether diminished expression of murine complement regulatory proteins occurs in decidua and contributes to local complement activation; (d) To identify the complement pathway activation products and receptors that mediate fetal injury; (e) To determine which cellular and cytokine mediators of fetal loss contribute to deleterious complement activation in the deciduas. Aim 2. To define the role of complement in fetal loss in the DBA/2-mated TNF-a-treated female C57BL/6 model and to identify the specific complement activation products that mediate in vivo tissue injury and fetal loss. (a) To determine whether C3 is deposited within deciduas; whether C3 activation is required for abortion; and the relationship between TNF-alpha treatment, C3 deposition, and cellular infiltration; (b) To define the complement components or receptors that contribute to cytokine-dependent abortion using complement deficient mice and specific complement inhibitors If complement activation is a necessary mechanism in repeated pregnancy loss, elucidating the roles of specific complement components will provide a basis for developing new therapies, a rationale for choosing among them, and the capacity to improve patient outcomes. In addition, our studies will provide insights into mechanisms by which complement-induces disease and suggest means to prevent, arrest, or modify complement-mediated inflammatory disorders.