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Circulating multimeric immune complexes contribute to immunopathology in COVID-19.

Jakob AnkerholdSebastian GiesePhilipp KolbAndrea Maul-PavicicReinhard E VollNathalie GöppertKevin CiminskiClemens KreutzAchim LotherUlrich SalzerWolfgang BildlTim WelsinkNils G MorgenthalerAndrea Busse GrawitzFlorian EmmerichDaniel SteinmannDaniela HuzlyMartin SchwemmleHartmut HengelValeria Falcone
Published in: Nature communications (2022)
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 considered to be protective, excessive triggering of activating Fc-gamma-receptors (FcγRs) could be detrimental and cause immunopathology. Here, we document excessive FcγRIIIA/CD16A activation in patients developing severe or critical COVID-19 but not in those with mild disease. We identify two independent ligands mediating extreme FcγRIIIA/CD16A activation. Soluble circulating IgG immune complexes (sICs) are detected in about 80% of patients with severe and critical COVID-19 at levels comparable to active systemic lupus erythematosus (SLE) disease. FcγRIIIA/CD16A activation is further enhanced by afucosylation of SARS-CoV-2 specific IgG. Utilizing cell-based reporter systems we provide evidence that sICs can be formed prior to a specific humoral response against SARS-CoV-2. Our data suggest a cycle of immunopathology driven by an early formation of sICs in predisposed patients. These findings suggest a reason for the seemingly paradoxical findings of high antiviral IgG responses and systemic immune dysregulation in severe COVID-19. The involvement of circulating sICs in the promotion of immunopathology in predisposed patients opens new possibilities for intervention strategies to mitigate critical COVID-19 progression.
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