Complement C5a receptors and neutrophils mediate fetal injury in the antiphospholipid syndrome
Complement C5a receptors and neutrophils mediate fetal injury in the antiphospholipid syndrome
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DOI：
10.1172/jci200318817
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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）抗体存在下反复妊娠丢失和血栓形成。目前，对患有APS的孕妇的治疗集中在预防血栓形成，但抗凝治疗在避免流产方面仅部分成功。我们假设补体激活是APS中妊娠丢失的中心机制，并在妊娠小鼠接受含人IgG的aPL Ab的模型中对此进行了测试。在这里，我们确定补体成分CS（特别是其裂解产物C5 a）和中性粒细胞作为胎儿损伤的关键介质，我们表明，抗体或肽，阻止C5 a-C5 a受体相互作用，防止妊娠并发症。aPL Ab’s的F（ab）2片段不介导胎儿损伤和C4缺陷小鼠受到保护免于胎儿损伤的事实表明，补体级联的激活是通过经典途径启动的。然而，在因子B缺陷小鼠中的研究表明，需要旁路途径激活并放大补体激活。相反，激活Fc γ R在介导aPL Ab诱导的胎儿损伤中不起重要作用。我们的研究结果确定了致病性自身抗体介导APS不良妊娠结局的关键先天免疫效应物，并为预防APS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.