Complement C5a receptors and neutrophils mediate fetal injury in the antiphospholipid syndrome
Complement C5a receptors and neutrophils mediate fetal injury in the antiphospholipid syndrome
复制标题
DOI：
10.1172/jci18817
复制
发表时间：
2003-12-01
影响因子：
15.9
通讯作者：
Salmon, JE
中科院分区：
文献类型：
--
作者：
Girardi, G;Berman, J;Salmon, JE
抗磷脂综合征(APS)是指在抗磷脂(APL)抗体存在的情况下反复发生的妊娠丢失和血栓形成。目前，对APS孕妇的治疗主要集中在预防血栓形成，但抗凝在避免流产方面只有部分成功。我们假设补体激活是APS妊娠丢失的主要机制，并在怀孕小鼠接受含有APL抗体的人免疫球蛋白的模型中进行了验证。在这里，我们确定补体成分CS(特别是其切割产物C5a)和中性粒细胞是胎儿损伤的关键介质，我们证明了阻断C5a-C5a受体相互作用的抗体或多肽可以预防妊娠并发症。事实上，APL抗体的F(Ab)‘2片段并不介导胎儿损伤，C4缺陷小鼠不受胎儿损伤的影响，这表明补体级联的激活是通过经典途径启动的。然而，在因子B缺陷小鼠的研究表明，替代途径激活是必需的，并放大补体激活。相反，激活FcGammaRs在介导APL抗体诱导的胎儿损伤中并不起重要作用。我们的发现确定了致病自身抗体参与APS不良妊娠结局的关键先天免疫效应，并为APS预防妊娠丢失提供了新的重要靶点。
Antiphospholipid syndrome (APS) is defined by recurrent pregnancy loss and thrombosis in the presence of antiphospholipid (aPL) Ab's. Currently, therapy for pregnant women with APS is focused on preventing thrombosis, but anticoagulation is only partially successful in averting miscarriage. We hypothesized that complement activation is a central mechanism of pregnancy loss in APS and tested this in a model in which pregnant mice receive human IgG containing aPL Ab's. Here we identify complement component CS (and particularly its cleavage product C5a) and neutrophils as key mediators of fetal injury, and we show that Ab's or peptides that block C5a-C5a receptor interactions prevent pregnancy complications. The fact that F(ab)'2 fragments of aPL Ab's do not mediate fetal injury and that C4-deficient mice are protected from fetal injury suggests that activation of the complement cascade is initiated via the classical pathway. Studies in factor B-deficient mice, however, indicate that alternative pathway activation is required and amplifies complement activation. In contrast, activating FcgammaRs do not play an important role in mediating aPL Ab-induced fetal injury. Our findings identify the key innate immune effectors engaged by pathogenic autoantibodies that mediate poor pregnancy outcomes in APS and provide novel and important targets for prevention of pregnancy loss in APS.