Complement C5 but not C3 is expendable for tissue factor activation by cofactor-independent antiphospholipid antibodies
Complement C5 but not C3 is expendable for tissue factor activation by cofactor-independent antiphospholipid antibodies
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DOI：
10.1182/bloodadvances.2018017095
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发表时间：
2018-05-08
期刊：
影响因子：
7.5
通讯作者：
Ruf, Wolfram
中科院分区：
文献类型：
--
作者：
Mueller-Calleja, Nadine;Ritter, Svenja;Ruf, Wolfram
在血栓形成和炎性疾病中，补体和凝血级联在多个水平上相互作用。在静脉血栓形成中，补体因子3（C3）对于依赖于蛋白质二硫键异构酶（PDI）的血小板和组织因子（TF）促凝血激活至关重要。此外，C5选择性地促进白细胞促凝血磷脂酰丝氨酸（PS）的暴露，这是血栓形成中单核细胞TF和纤维蛋白形成快速活化的先决条件。在这里，我们表明，单克隆辅因子非依赖性抗磷脂抗体（aPLs）迅速激活TF对骨髓单核细胞。TF活化被PDI抑制剂和干扰PDI与TF结合的抗TF抗体阻断，并且需要C3但出乎意料地不需要C5。其他促血栓形成的补体固定抗体，例如抗胸腺细胞球蛋白，通常依赖于单核细胞外膜上C5 b-7介导的PS暴露来诱导TF活化。我们发现，APLs直接诱导促凝血PS暴露独立于C5。因此，C3缺陷的小鼠，而不是C5缺陷的小鼠，被保护免于由辅因子非依赖性aPL诱导的体内血栓形成。只有来自抗磷脂综合征（APS）患者的具有辅因子非依赖性抗心磷脂反应性的免疫球蛋白G（IgG）组分诱导补体非依赖性单核细胞PS暴露和PDI依赖性TF活化。针对β 2-糖蛋白I（β 2GPI）的人单克隆aPL和对β 2GPI具有选择性反应性的患者IgG都不能快速激活单核细胞TF。这些结果表明，PDI和TF的抑制剂，但不一定是临床上可用的靶向C5的药物，在预防与APS相关的血栓形成方面具有治疗益处，所述血栓形成由主要与脂质反应的致病性aPL引起，不依赖于β 2GPI。
The complement and coagulation cascades interact at multiple levels in thrombosis and inflammatory diseases. In venous thrombosis, complement factor 3 (C3) is crucial for platelet and tissue factor (TF) procoagulant activation dependent on protein disulfide isomerase (PDI). Furthermore, C5 selectively contributes to the exposure of leukocyte procoagulant phosphatidylserine (PS), which is a prerequisite for rapid activation of monocyte TF and fibrin formation in thrombosis. Here, we show that monoclonal cofactor-independent antiphospholipid antibodies (aPLs) rapidly activate TF on myelomonocytic cells. TF activation is blocked by PDI inhibitor and an anti-TF antibody interfering with PDI binding to TF, and requires C3 but unexpectedly not C5. Other prothrombotic, complement-fixing antibodies, for example, antithymocyte globulin, typically induce TF activation dependent on C5b-7-mediated PS exposure on the outer membrane of monocytes. We show that aPLs directly induce procoagulant PS exposure independent of C5. Accordingly, mice deficient in C3, but not mice deficient in C5, are protected from in vivo thrombus formation induced by cofactor-independent aPLs. Only immunoglobulin G (IgG) fractions with cofactor-independent anticardiolipin reactivity from patients with antiphospholipid syndrome (APS) induce complement-independent monocyte PS exposure and PDI-dependent TF activation. Neither a human monoclonal aPL directed against beta 2-glycoprotein I (beta 2GPI) nor patient IgG with selective reactivity to beta 2GPI rapidly activated monocyte TF. These results indicate that inhibitors of PDI and TF, but not necessarily clinically available drugs targeting C5, have therapeutic benefit in preventing thrombosis associated with APS caused by pathogenic aPLs primarily reactive with lipid, independent of beta 2GPI.