Classical complement activation as a footprint for murine and human antiphospholipid antibody-induced fetal loss
Classical complement activation as a footprint for murine and human antiphospholipid antibody-induced fetal loss
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DOI：
10.1002/path.2893
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发表时间：
2011-12-01
影响因子：
7.3
通讯作者：
Bajema, Ingeborg M.
中科院分区：
文献类型：
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作者：
Cohen, Danielle;Buurma, Aletta;Bajema, Ingeborg M.
反复流产、胎儿生长受限和宫内死胎是系统性红斑狼疮（SLE）和抗磷脂综合征（APS）患者常见的妊娠并发症。小鼠模型表明，补体激活在抗磷脂抗体介导的妊娠发病中起着关键作用，但补体激活的确切途径及其在人类妊娠中的潜在作用尚不清楚。我们假设经典途径在诱导胎儿丢失中起主要作用。怀孕的 C57BL/6 小鼠和缺乏 C1q 和 D 因子的小鼠被注射抗磷脂抗体或正常人 IgG。随后用抗 C4 抗体和抗正常人 IgG 对小鼠胎盘进行染色，以确定经典补体激活和 IgG 结合的存在。在小鼠中的研究结果在 83 名女性的 88 个人类胎盘中得到了验证（SLE 和 APS 病例与对照），这些胎盘对 C4d、C1q、备解素和 MBL 进行了免疫组织化学染色。将染色模式与妊娠结局进行比较。在用抗磷脂抗体预处理的小鼠胎盘中，观察到 C4 沉积增加，这与不良胎儿结局相关，但与 IgG 结合无关。在人类中，胎儿-母体界面处的弥漫性 C4d 染色几乎只出现在 SLE 和/或 APS 患者中 (p < 0.001)，并且与宫内胎儿死亡相关 (p = 0.03)。我们的数据表明，小鼠和人类胎盘中 C4d 的存在与 SLE 和 APS 情况下的不良胎儿结局密切相关。 C4d 的过度沉积支持了胎儿-母体界面处自身抗体介导的严重损伤的概念。我们建议 C4d 作为 SLE 和 APS 中自身抗体介导的胎儿丢失的潜在生物标志物。版权所有 (C) 2011 大不列颠及爱尔兰病理学会。由约翰·威利父子有限公司出版
Recurrent miscarriage, fetal growth restriction and intrauterine fetal death are frequently occurring complications of pregnancy in patients with systemic lupus erythaematosus (SLE) and antiphospholipid syndrome (APS). Murine models show that complement activation plays a pivotal role in antiphospholipid antibody-mediated pregnancy morbidity, but the exact pathways of complement activation and their potential role in human pregnancy are insufficiently understood. We hypothesized that the classical pathway would play a major role in inducing fetal loss. Pregnant C57BL/6 mice and mice deficient in C1q and factor D were injected with antiphospholipid antibodies or normal human IgG. Mouse placentas were subsequently stained with an anti-C4 antibody and anti-normal human IgG to determine the presence of classical complement activation and IgG binding. Findings in mice were validated in 88 human placentae from 83 women (SLE and APS cases versus controls), which were immunohistochemically stained for C4d, C1q, properdin and MBL. Staining patterns were compared to pregnancy outcome. In murine placentae of mice pretreated with antiphospholipid antibodies, increased C4 deposition was observed, which was associated with adverse fetal outcome but not with IgG binding. In humans, diffuse C4d staining at the feto-maternal interface was present almost exclusively in patients with SLE and/or APS (p < 0.001) and was related to intrauterine fetal death (p = 0.03). Our data show that presence of C4d in murine and human placentae is strongly related to adverse fetal outcome in the setting of SLE and APS. The excessive deposition of C4d supports the concept of severe autoantibody-mediated injury at the fetal-maternal interface. We suggest C4d as a potential biomarker of autoantibody-mediated fetal loss in SLE and APS. Copyright (C) 2011 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.