Aberrant glycosylation of anti-SARS-CoV-2 spike IgG is a prothrombotic stimulus for platelets.
Aberrant glycosylation of anti-SARS-CoV-2 spike IgG is a prothrombotic stimulus for platelets.
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DOI：
10.1182/blood.2021011871
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发表时间：
2021-10-21
期刊：
影响因子：
20.3
通讯作者：
Gibbins JM
中科院分区：
文献类型：
--
作者：
Bye AP;Hoepel W;Mitchell JL;Jégouic S;Loureiro S;Sage T;Vidarsson G;Nouta J;Wuhrer M;de Taeye S;van Gils M;Kriek N;Cooper N;Jones I;den Dunnen J;Gibbins JM
COVID-19疾病突出了炎症、免疫、止血和血栓形成之间复杂的相互作用。Bye等人的研究表明，严重急性呼吸综合征冠状病毒2 （SARS-CoV-2）刺突蛋白和抗刺突免疫球蛋白G （IgG）的免疫复合物在体外可增加von Willebrand因子上血小板介导的血栓形成，但仅当IgG Fc结构域的糖基化发生改变时，这种改变是最近在严重COVID-19患者中发现的。这些数据可能有助于解释患者的血栓炎症，并指出预防血栓炎症的新方法。抗sars - cov -2刺突IgG免疫复合物的异常糖基化增加了VWF上血小板血栓的形成。抑制Syk、Btk、P2Y12或FcγRIIA可逆转抗sars - cov -2刺突免疫复合物介导的血栓形成增强2019年冠状病毒病（COVID-19）的一部分患者病情危重，患有严重的呼吸系统疾病，血栓形成率也有所增加。COVID-19重症患者血栓形成的原因仍在不断出现，但危重疾病与适应性免疫启动时间的巧合可能意味着过度的免疫反应。我们假设血小板可能容易被抗严重急性呼吸综合征冠状病毒2（抗sars - cov -2）抗体激活，并可能导致血栓形成。我们发现含有重组SARS-CoV-2刺突蛋白和抗刺突免疫球蛋白G的免疫复合物在体外增强血小板介导的血管性血液病因子血栓形成，但只有当Fc结构域的糖基化状态被修饰为与先前在重症COVID-19患者中发现的异常糖基化相一致时。此外，我们发现活化依赖于FcγRIIA，我们提供的体外证据表明，这种致病性血小板活化可以被治疗性小分子R406 （fostamatinib）和ibrutinib抵消，它们分别抑制酪氨酸激酶Syk和Btk，或P2Y12拮抗剂canrelor。
COVID-19 illness highlights the complex interplay of inflammation, immunity, hemostasis, and thrombosis. Bye et al show that immune complexes of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein and anti-spike immunoglobulin G (IgG) increase the formation of platelet-mediated thrombosis on von Willebrand factor in vitro, but only when the glycosylation of the Fc domain of the IgG is altered in a fashion recently identified in patients with severe COVID-19. These data may help explain the thromboinflammation in patients and point to new approaches to its prevention. Aberrant glycosylation of anti-SARS-CoV-2 spike IgG immune complexes increases platelet thrombus formation on VWF. Inhibition of Syk, Btk, P2Y12, or FcγRIIA reverses enhancement of thrombus formation mediated by anti-SARS-CoV-2 spike immune complexes. A subset of patients with coronavirus disease 2019 (COVID-19) become critically ill, suffering from severe respiratory problems and also increased rates of thrombosis. The causes of thrombosis in severely ill patients with COVID-19 are still emerging, but the coincidence of critical illness with the timing of the onset of adaptive immunity could implicate an excessive immune response. We hypothesized that platelets might be susceptible to activation by anti–severe acute respiratory syndrome coronavirus 2 (anti-SARS-CoV-2) antibodies and might contribute to thrombosis. We found that immune complexes containing recombinant SARS-CoV-2 spike protein and anti-spike immunoglobulin G enhanced platelet-mediated thrombosis on von Willebrand factor in vitro, but only when the glycosylation state of the Fc domain was modified to correspond with the aberrant glycosylation previously identified in patients with severe COVID-19. Furthermore, we found that activation was dependent on FcγRIIA, and we provide in vitro evidence that this pathogenic platelet activation can be counteracted by the therapeutic small molecules R406 (fostamatinib) and ibrutinib, which inhibit tyrosine kinases Syk and Btk, respectively, or by the P2Y12 antagonist cangrelor.
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影响因子：
17.1
作者：
Hoepel W;Chen HJ;Geyer CE;Allahverdiyeva S;Manz XD;de Taeye SW;Aman J;Mes L;Steenhuis M;Griffith GR;Bonta PI;Brouwer PJM;Caniels TG;van der Straten K;Golebski K;Jonkers RE;Larsen MD;Linty F;Nouta J;van Roomen CPAA;van Baarle FEHP;van Drunen CM;Wolbink G;Vlaar APJ;de Bree GJ;Sanders RW;Willemsen L;Neele AE;van de Beek D;Rispens T;Wuhrer M;Bogaard HJ;van Gils MJ;Vidarsson G;de Winther M;den Dunnen J
通讯作者：
den Dunnen J
DOI：
10.1124/jpet.106.109058
发表时间：
2006-12-01
影响因子：
3.5
作者：
Braselmann, Sylvia;Taylor, Vanessa;Masuda, Esteban S.
通讯作者：
Masuda, Esteban S.
DOI：
10.1111/jth.15156
发表时间：
2021-01
期刊：
Journal of thrombosis and haemostasis : JTH
影响因子：
--
作者：
Campbell RA;Boilard E;Rondina MT
通讯作者：
Rondina MT
影响因子：
24.8
作者：
Roschewski, Mark;Lionakis, Michail S.;Wilson, Wyndham H.
通讯作者：
Wilson, Wyndham H.
影响因子：
16.6
作者：
de Witt, Susanne M.;Swieringa, Frauke;Cavill, Rachel;Lamers, Moniek M. E.;van Kruchten, Roger;Mastenbroek, Tom;Baaten, Constance;Coort, Susan;Pugh, Nicholas;Schulz, Ansgar;Scharrer, Inge;Jurk, Kerstin;Zieger, Barbara;Clemetson, Kenneth J.;Farndale, Richard W.;Heemskerk, Johan W. M.;Cosemans, Judith M. E. M.
通讯作者：
Cosemans, Judith M. E. M.