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 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.
Clinical implications The identification of sICs as drivers of an escalating immunopathology in predisposed patients opens new avenues regarding intervention strategies to alleviate critical COVID-19 progression.
Graphical abstractA vicious cycle of immunopathology in COVID-19 patients is driven by soluble multimeric immune complexes (sICs). SARS-CoV-2 infection triggers sIC formation in prone individuals. Activation of FcγRIII/CD16 expressing immune cells by sICs precedes a humoral response to SARS-CoV2 infection. sICs and infection add to IgG afucosylation, further enhancing FcγRIII/CD16 activation by opsonized targets. High inflammation induces further sIC mediated immune cell activation ultimately leading to an escalating immunopathology.
Competing Interest Statement
The authors declare the following competing financial interest(s): InVivo BioTech Services is a biotechnology company producing antibodies and proteins, including SARS-CoV-2 antigens.
Footnotes
Conflict of interest The authors declare the following competing financial interest(s): InVivo BioTech Services is a biotechnology company producing antibodies and proteins, including SARS-CoV-2 antigens.
Funding This work was supported by the Bundesministerium fuer Bildung und Forschung (BMBF) through the Deutsches Zentrum fuer Luft- und Raumfahrt, Germany, (DLR, grant number 01KI2077) and by the Federal State of Baden-Wuerttemberg, Germany, MWK-Sonderfoerdermaßnahme COVID-19/AZ.:33-7533.-6-21/7/2 to M.S.. This work was also supported by an intramural junior investigator fund of the Faculty of Medicine to P.K. (EQUIP - Funding for Medical Scientists, Faculty of Medicine, University of Freiburg) and “NaFoUniMedCovid19” (FKZ: 01KX2021 - COVIM to H.H., FKZ 100493916 B-FAST to H.H.) and DFG HE2526/9-1 to H.H.. RE.V. was funded by DFG research grant TRR130. A.L. is a member of SFB1425, funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation #422681845). The funders had no role in the study design, data analysis, data interpretation, and in the writing of this report. All authors had full access to the data in the study and accept responsibility to submit for publication.
Added SLE dataset for reference (addition of REV as contributing author). Changes to the main text accordingly. Discussion was shortened. Minor changes to title.
