Antibodies and complement are key drivers of thrombosis

IF 25.5 1区 医学 Q1 IMMUNOLOGY Immunity Pub Date : 2024-09-02 DOI:10.1016/j.immuni.2024.08.007
Konstantin Stark, Badr Kilani, Sven Stockhausen, Johanna Busse, Irene Schubert, Thuy-Duong Tran, Florian Gaertner, Alexander Leunig, Kami Pekayvaz, Leo Nicolai, Valeria Fumagalli, Julia Stermann, Felix Stephan, Christian David, Martin B. Müller, Birgitta Heyman, Anja Lux, Alexandra da Palma Guerreiro, Lukas P. Frenzel, Christoph Q. Schmidt, Steffen Massberg
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Abstract

Venous thromboembolism (VTE) is a common, deadly disease with an increasing incidence despite preventive efforts. Clinical observations have associated elevated antibody concentrations or antibody-based therapies with thrombotic events. However, how antibodies contribute to thrombosis is unknown. Here, we show that reduced blood flow enabled immunoglobulin M (IgM) to bind to FcμR and the polymeric immunoglobulin receptor (pIgR), initiating endothelial activation and platelet recruitment. Subsequently, the procoagulant surface of activated platelets accommodated antigen- and FcγR-independent IgG deposition. This leads to classical complement activation, setting in motion a prothrombotic vicious circle. Key elements of this mechanism were present in humans in the setting of venous stasis as well as in the dysregulated immunothrombosis of COVID-19. This antibody-driven thrombosis can be prevented by pharmacologically targeting complement. Hence, our results uncover antibodies as previously unrecognized central regulators of thrombosis. These findings carry relevance for therapeutic application of antibodies and open innovative avenues to target thrombosis without compromising hemostasis.

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抗体和补体是血栓形成的关键因素
静脉血栓栓塞症(VTE)是一种常见的致命疾病,尽管已采取了预防措施,但其发病率仍在不断上升。临床观察发现,抗体浓度升高或基于抗体的疗法与血栓事件有关。然而,抗体如何导致血栓形成尚不清楚。在这里,我们发现血流减少能使免疫球蛋白 M(IgM)与 FcμR 和聚合免疫球蛋白受体(pIgR)结合,启动内皮活化和血小板募集。随后,活化血小板的促凝表面容纳了抗原和不依赖 FcγR 的 IgG 沉积。这导致了经典的补体激活,引发了促血栓形成的恶性循环。这一机制的关键因素存在于人类的静脉瘀血以及 COVID-19 的失调免疫血栓中。这种抗体驱动的血栓形成可以通过药物靶向补体来预防。因此,我们的研究结果揭示了抗体是以前未曾认识到的血栓形成的核心调节因子。这些发现对抗体的治疗应用具有重要意义,并为在不影响止血的情况下靶向血栓形成开辟了创新途径。
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来源期刊
Immunity
Immunity 医学-免疫学
CiteScore
49.40
自引率
2.20%
发文量
205
审稿时长
6 months
期刊介绍: Immunity is a publication that focuses on publishing significant advancements in research related to immunology. We encourage the submission of studies that offer groundbreaking immunological discoveries, whether at the molecular, cellular, or whole organism level. Topics of interest encompass a wide range, such as cancer, infectious diseases, neuroimmunology, autoimmune diseases, allergies, mucosal immunity, metabolic diseases, and homeostasis.
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