Circulating multimeric immune complexes drive immunopathology in COVID-19

Abstract

A dysregulated immune response with high levels of SARS-CoV-2 specific IgG antibodies is a common and distinctive feature of severe or critical COVID-19. Although a robust IgG response is typically considered to be beneficial, an overshooting activation mediated by immune receptors recognizing the Fc part of IgG (FcγRs) is thought to be detrimental and associated with immunopathology. However, direct evidence of FcγR driven immunopathology in COVID-19 is still sparse. Here, we used a cell-based FcγR activation reporter system to systematically analyze SARS-CoV-2 specific IgG responses and IgG-mediated FcγRIII (CD16) activation profiles in COVID-19 patient cohorts categorized by severity of disease. We found that increased CD16 activation by SARS-CoV-2 specific IgG is associated with a known pro-inflammatory IgG modification, namely afucosylation. Further, we identified CD16-reactive soluble IgG immune complexes (sICs) to be present in the serum of COVID-19 patients and show that the resulting CD16 activation by sICs is strongly related to disease severity. Our results provide evidence that CD16 activation by pro-inflammatory SARS-CoV-2 specific IgG together with circulating sICs is a major contributor to COVID-19 immunopathology. These findings highlight the importance of FcγR driven immunopathology in COVID-19. Further, our data highly warrant the development of targeted intervention strategies against IgG driven immunopathology following SARS-CoV-2 infection.

Protective and pathogenic role of humoral responses in COVID-19

“…This indicated that the pathogenic IgG-related immune complex is associated with ARDS in fatal COVID-19 cases. This observation is consistent with other studies showing immune complex deposition inside vascular walls or increased soluble immune complex in serum samples from critical COVID-19 patients (Roncati et al, 2020;Ankerhold et al, 2021;Chakraborty et al, 2021b).…”

“…Several studies have found an aberrant glycosylation, afucosylation, in the Fc glycan region of S-specific IgG in critical COVID-19 patients (Ankerhold et al, 2021;Bye et al, 2021;Chakraborty et al, 2021b). Increased afucosylated IgG in immune complexes may facilitate the interaction with FcγRIIIa or FcγRIIa expressed on macrophages, enhancing their activation (Nazy et al, 2020;Chakraborty et al, 2021b).…”

Immune complexes as culprits of immunopathology in severe COVID-19

“…However, continuous antigen production is required for sustained sIC formation. In line with this, a recent study proved the presence of serum-derived sICs in severe COVID-19, which were devoid of SARS-CoV-2 antigen [ 43 ]. Although not directly identifying autoantibodies as culprits, the authors show that sICs are not formed following administration of either heterologous (Vaxzevria/Spikevax) or homologous (Comirnaty) prime-boost vaccination, demonstrating that spike-antigen expression per se does not induce sIC formation.…”

Early and rapid identification of COVID-19 patients with neutralizing type I-interferon auto-antibodies by an easily implementable algorithm

“…Currently discussed therapeutic options tailored to IFN-AAB-positive COVID-19 patients comprise mainly TPE and IFN-β administration. TPE in the context of COVID-19 has been analyzed in individual case reports and case-control studies, including IFN-AABpositive and negative patients ) and might efficiently remove soluble circulating Fc gamma receptor-activating immune complexes (Ankerhold et al 2021). TPE effectively decreased circulating IFN-AAB, but not SARS-CoV-2 antibody concentrations in four IFN-AAB-positive, severely ill patients (de and in a child with APS-1 suffering from severe COVID-19 .…”