High titers and low fucosylation of early human anti-SARS-CoV-2 IgG promote inflammation by alveolar macrophages.
High titers and low fucosylation of early human anti-SARS-CoV-2 IgG promote inflammation by alveolar macrophages.
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DOI：
10.1126/scitranslmed.abf8654
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发表时间：
2021-06-02
影响因子：
17.1
通讯作者：
den Dunnen J
中科院分区：
文献类型：
--
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
人抗刺突蛋白IgG的高滴度和低岩藻糖基化促进肺泡巨噬细胞活化和炎症。被诊断患有2019冠状病毒病（COVID-19）的患者主要在适应性免疫反应激活时变得危重。在这里，我们提供的证据表明，抗体在血清转换时的疾病恶化中发挥作用。我们发现，重症COVID-19患者血清中早期严重急性呼吸窘迫综合征冠状病毒2（SARS-CoV-2）刺突蛋白特异性IgG诱导人肺泡巨噬细胞过度炎症反应。我们发现，这种过度的炎症反应依赖于两种对严重COVID-19患者具有特异性的抗体特征。首先，炎症是由高滴度的抗刺突IgG驱动的，这是严重疾病的标志。其次，我们发现来自严重COVID-19患者的抗刺突IgG本质上更促炎，因为抗体Fc尾的不同糖基化，特别是低岩藻糖基化。值得注意的是，抗刺突IgG的低岩藻糖基化在SARS-CoV-2初始感染后几周内恢复正常，表明增加的抗体依赖性炎症主要发生在血清转化时。我们确定Fcγ受体（FcγR）IIa和FcγRIII是两种主要的IgG受体，负责诱导关键的COVID-19相关细胞因子，如白细胞介素-6和肿瘤坏死因子。此外，我们表明，抗刺IgG激活的人巨噬细胞可以随后打破肺内皮屏障的完整性和诱导微血管血栓形成体外。最后，我们证明了抗刺突IgG诱导的炎症反应可以被fostamatinib特异性抵消，fostamatinib是FDA和EMA批准的Syk激酶治疗性小分子抑制剂。
High titers and low fucosylation of human anti-spike protein IgG promote alveolar macrophage activation and inflammation. Patients diagnosed with coronavirus disease 2019 (COVID-19) become critically ill primarily around the time of activation of the adaptive immune response. Here, we provide evidence that antibodies play a role in the worsening of disease at the time of seroconversion. We show that early phase severe acute respiratory distress syndrome coronavirus 2 (SARS-CoV-2) spike protein-specific IgG in serum of critically ill COVID-19 patients induces excessive inflammatory responses by human alveolar macrophages. We identified that this excessive inflammatory response is dependent on two antibody features that are specific for patients with severe COVID-19. First, inflammation is driven by high titers of anti-spike IgG, a hallmark of severe disease. Second, we found that anti-spike IgG from patients with severe COVID-19 is intrinsically more pro-inflammatory because of different glycosylation, particularly low fucosylation, of the antibody Fc tail. Notably, low fucosylation of anti-spike IgG was normalized in a few weeks after initial infection with SARS-CoV-2, indicating that the increased antibody-dependent inflammation mainly occurs at the time of seroconversion. We identified Fcγ Receptor (FcγR) IIa and FcγRIII as the two primary IgG receptors that are responsible for the induction of key COVID-19-associated cytokines such as interleukin-6 and tumor necrosis factor. In addition, we show that anti-spike IgG-activated human macrophages can subsequently break pulmonary endothelial barrier integrity and induce microvascular thrombosis in vitro. Finally, we demonstrate that the inflammatory response induced by anti-spike IgG can be specifically counteracted by fostamatinib, an FDA- and EMA-approved therapeutic small molecule inhibitor of Syk kinase.
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影响因子：
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作者：
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Gnjatic S
影响因子：
64.8
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通讯作者：
Krummel MF