Circulating multimeric immune complexes contribute to immunopathology in COVID-19

Jakob Ankerhold, Sebastian Giese, Philipp Kolb, Andrea Maul-Pavicic, Reinhard E. Voll, Nathalie Göppert, Kevin Ciminski, Clemens Kreutz, Achim Lother, Ulrich Salzer, Wolfgang Bildl, Tim Welsink, Nils G. Morgenthaler, Andrea Busse Grawitz, Florian Emmerich, Daniel Steinmann, Daniela Huzly, Martin Schwemmle, Hartmut Hengel () and Valeria Falcone ()
Additional contact information
Jakob Ankerhold: Albert-Ludwigs-University of Freiburg
Sebastian Giese: Albert-Ludwigs-University of Freiburg
Philipp Kolb: Albert-Ludwigs-University of Freiburg
Andrea Maul-Pavicic: Freiburg University Medical Center, Faculty of Medicine, Albert-Ludwigs-University of Freiburg
Reinhard E. Voll: Freiburg University Medical Center, Faculty of Medicine, Albert-Ludwigs-University of Freiburg
Nathalie Göppert: Albert-Ludwigs-University of Freiburg
Kevin Ciminski: Albert-Ludwigs-University of Freiburg
Clemens Kreutz: Freiburg University Medical Center, Faculty of Medicine, Albert-Ludwigs-University of Freiburg
Achim Lother: University Heart Center, Freiburg University Medical Center, Faculty of Medicine, Albert-Ludwigs-University of Freiburg
Ulrich Salzer: Freiburg University Medical Center, Faculty of Medicine, Albert-Ludwigs-University of Freiburg
Wolfgang Bildl: Albert-Ludwigs-University of Freiburg
Tim Welsink: InVivo BioTech Services GmbH
Nils G. Morgenthaler: InVivo BioTech Services GmbH
Andrea Busse Grawitz: Albert-Ludwigs-University of Freiburg
Florian Emmerich: Freiburg University Medical Center, Faculty of Medicine, University of Freiburg
Daniel Steinmann: Freiburg University Medical Center, Faculty of Medicine, Albert-Ludwigs-University of Freiburg
Daniela Huzly: Albert-Ludwigs-University of Freiburg
Martin Schwemmle: Albert-Ludwigs-University of Freiburg
Hartmut Hengel: Albert-Ludwigs-University of Freiburg
Valeria Falcone: Albert-Ludwigs-University of Freiburg

Nature Communications, 2022, vol. 13, issue 1, 1-15

Abstract: Abstract 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.

Date: 2022
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DOI: 10.1038/s41467-022-32867-z

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