A dysregulated immune response with high levels of SARS-CoV-2 specific IgG antibodies characterizes patients with severe or critical COVID-19. Although a robust IgG response is traditionally considered to be protective, excessive triggering of activating Fc-gamma-receptors (FcγRs) could be detrimental and cause immunopathology. Here, we document that patients who develop soluble circulating IgG immune complexes (sICs) during infection are subject to enhanced immunopathology driven by FcγR activation. Utilizing cell-based reporter systems we provide evidence that sICs are predominantly formed prior to a specific humoral response against SARS-CoV-2. sIC formation, together with increased afucosylation of SARS-CoV-2 specific IgG eventually leads to an enhanced CD16 (FcγRIII) activation of immune cells reaching activation levels comparable active systemic lupus erythematosus (SLE) disease. Our data suggest a vicious cycle of escalating immunopathology driven by an early formation of sICs in predisposed patients. These findings reconcile the seemingly paradoxical findings of high antiviral IgG responses and systemic immune dysregulation in severe COVID-19.

中文翻译：

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循环多聚体免疫复合物驱动 COVID-19 的免疫病理学

具有高水平 SARS-CoV-2 特异性 IgG 抗体的免疫反应失调是 COVID-19 重症或危重症患者的特征。尽管传统上认为强大的 IgG 反应具有保护作用，但过度触发激活 Fc-γ-受体 (FcγRs) 可能是有害的并导致免疫病理学。在这里，我们记录了在感染期间产生可溶性循环 IgG 免疫复合物 (sIC) 的患者受到 FcγR 激活驱动的增强免疫病理学的影响。利用基于细胞的报告系统，我们提供了证据，证明 sIC 主要在针对 SARS-CoV-2 的特定体液反应之前形成。sIC形成，连同 SARS-CoV-2 特异性 IgG 的无岩藻糖基化增加，最终导致免疫细胞的 CD16（FcγRIII）活化增强，达到与活动性系统性红斑狼疮（SLE）疾病相当的活化水平。我们的数据表明，易感患者中 sIC 的早期形成导致免疫病理学不断升级的恶性循环。这些发现调和了严重 COVID-19 中高抗病毒 IgG 反应和全身免疫失调的看似矛盾的发现。