Circulating multimeric immune complexes contribute to immunopathology in COVID-19

Area of Science:

• Immunology
• Virology
• Pathology

Background:

• Severe COVID-19 is linked to dysregulated immune responses and high SARS-CoV-2 specific IgG antibodies.
• While IgG is typically protective, excessive Fc-gamma-receptor (FcγR) activation can cause immunopathology.

Purpose of the Study:

• To investigate the mechanisms behind excessive FcγR activation in severe COVID-19.
• To identify ligands responsible for FcγRIIIA/CD16A overactivation in COVID-19 patients.

Main Methods:

• Quantification of FcγRIIIA/CD16A activation in patients with varying COVID-19 severity.
• Detection and characterization of soluble IgG immune complexes (sICs).
• Assessment of IgG afucosylation and its impact on FcγR activation using cell-based reporter systems.

Main Results:

• Excessive FcγRIIIA/CD16A activation was observed in severe/critical COVID-19, but not mild cases.
• High levels of soluble circulating IgG immune complexes (sICs) were found in ~80% of severe/critical patients.
• Afucosylation of SARS-CoV-2 specific IgG enhanced FcγRIIIA/CD16A activation; sICs formation can precede specific antiviral responses.

Conclusions:

• Early sIC formation may drive a cycle of immunopathology in predisposed individuals, explaining high IgG responses alongside immune dysregulation in severe COVID-19.
• Targeting sICs offers a potential strategy to mitigate severe COVID-19 progression.