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.
【초록키워드】 COVID-19, coronavirus disease, SARS-CoV-2, IgG, Inflammation, Necrosis, Macrophage, Tumor, Respiratory distress syndrome, Coronavirus disease 2019, coronavirus, Cytokines, thrombosis, macrophages, severe COVID-19, acute respiratory distress syndrome, glycosylation, antibody, interleukin-6, cytokine, in vitro, FDA, Spike protein, Fcγ receptor, excessive inflammatory response, serum, Seroconversion, interleukin, tumor necrosis factor, Critically ill, anti-Spike IgG, therapeutic, Patient, fostamatinib, small molecule, receptor, Adaptive immune response, human macrophage, inhibitor, disease, macrophage activation, alveolar macrophage, Anti-spike, acute respiratory distress, Evidence, Inflammatory response, severe disease, COVID-19 patient, critically ill COVID-19 patients, Alveolar macrophages, respiratory distress, tumor necrosis, Microvascular thrombosis, Activation, early phase, worsening, syndrome, hallmark, FcγR, second, alveolar, pulmonary endothelial, pro-inflammatory, anti-spike protein IgG, feature, initial, responsible, addition, diagnosed, occur, dependent on, promote, induce, driven by, intrinsically, IIa, infection with SARS-CoV-2, was normalized, 【제목키워드】 anti-SARS-CoV-2 IgG, promote inflammation,