Complement activity and complement regulatory gene mutations are associated with thrombosis in APS and CAPS
Complement activity and complement regulatory gene mutations are associated with thrombosis in APS and CAPS
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DOI：
10.1182/blood.2019003863
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发表时间：
2020-01-23
期刊：
影响因子：
20.3
通讯作者：
Brodsky, Robert A.
中科院分区：
文献类型：
--
作者：
Chaturvedi, Shruti;Braunstein, Evan M.;Brodsky, Robert A.
抗磷脂综合征（APS）的特点是在存在抗磷脂抗体的情况下形成血栓和/或妊娠发病率，包括抗β 2-糖蛋白- i（抗β 2GPI），这被认为是APS发病机制的核心。基于补体在APS相关临床事件中的作用的动物研究，我们使用改进的Ham （mHam）测定（补体依赖性细胞杀伤）和C5b-9的细胞表面沉积来验证补体激活与APS血栓形成事件相关的假设。mHam阳性（和相应的C5b-9沉积）存在于85.7%的灾难性APS (CAPS)， 35.6%的APS（和68.5%的血栓形成1年内收集的样本），只有6.8%的系统性红斑狼疮（SLE）血清中。mHam检测阳性与三重阳性（狼疮抗凝血剂、抗心磷脂和抗- 2GPI抗体）和复发性血栓形成相关。患者源性抗- β - 2GPI抗体也诱导C5b-9沉积，C5b-9沉积被抗- c5单克隆抗体完全阻断，但不被因子D抑制剂阻断，这表明抗- β - 2GPI抗体激活补体主要通过经典补体途径发生。最后，与APS患者（21.8%）、SLE患者（28.6%）或正常对照（23.3%）相比，CAPS患者补体调节基因的罕见种系变异率（60%）较高，突变率与非典型溶血性尿毒症综合征患者（51.5%）相似。综上所述，我们的数据表明抗- 2GPI抗体激活补体并导致APS患者血栓形成，而CAPS患者的补体调节基因存在潜在突变，作为“第二次打击”，导致补体激活失控和更严重的血栓表型。
The antiphospholipid syndrome (APS) is characterized by thrombosis and/or pregnancy morbidity in the presence of antiphospholipid antibodies, including anti-beta 2-glycoprotein-I (anti-beta 2GPI), that are considered central to APS pathogenesis. Based on animal studies showing a role of complement in APS-related clinical events, we used the modified Ham (mHam) assay (complement-dependent cell killing) and cell-surface deposition of C5b-9 to test the hypothesis that complement activation is associated with thrombotic events in APS. A positive mHam (and corresponding C5b-9 deposition) were present in 85.7% of catastrophic APS (CAPS), 35.6% of APS (and 68.5% of samples collected within 1 year of thrombosis), and only 6.8% of systemic lupus erythematosus (SLE) sera. A positive mHam assay was associated with triple positivity (for lupus anticoagulant, anticardiolipin, and anti-beta 2GPI antibodies) and recurrent thrombosis. Patient-derived anti-beta 2GPI antibodies also induced C5b-9 deposition, which was blocked completely by an anti-C5 monoclonal antibody, but not by a factor D inhibitor, indicating that complement activation by anti-beta 2GPI antibodies occurs primarily through the classical complement pathway. Finally, patients with CAPS have high rates of rare germline variants in complement regulatory genes (60%), compared with patients with APS (21.8%) or SLE (28.6%) or normal controls (23.3%), and have mutations at a rate similar to that of patients with atypical hemolytic uremic syndrome (51.5%). Taken together, our data suggest that anti-beta 2GPI antibodies activate complement and contribute to thrombosis in APS, whereas patients with CAPS have underlying mutations in complement regulatory genes that serve as a "second hit," leading to uncontrolled complement activation and a more severe thrombotic phenotype.