Immune complexes as culprits of immunopathology in severe COVID-19

Infection with the pandemic human coronavirus SARS-CoV-2 elicits a respiratory tract disease, termed Coronavirus disease 2019 (COVID-19). While a variable degree of disease-associated symptoms may emerge, severe COVID-19 is commonly associated with respiratory complications such as acute respiratory distress syndrome (ARDS), the necessity for mechanical ventilation or even extracorporeal membrane oxygenation (ECMO). Amongst others, disease outcome depends on age and pre-existing conditions like cardiovascular diseases, metabolic disorders but also age and biological sex. Intriguingly, increasing experimental and clinical evidence suggests that an exacerbated inflammatory response and in particular IgG immune complexes (ICs), significantly contribute to severe and prolonged COVID-19 disease progression. Vast amounts of deposited, unresolved ICs in tissue are capable to initiate an exaggerated Fc gamma receptor (FcγR) mediated signalling cascade which eventually results in common IC-associated organ diseases such as vasculitis, glomerulonephritis and arthritis, comorbidities that have been frequently reported for COVID-19. Moreover and independent of deposited ICs, very recent work identified soluble ICs (sIC) to be also present in the circulation of a majority of severely ill patients, where their systemic abundance correlated with disease severity. Thus, detection of circulating sICs in patients represents a potential marker for critical COVID-19 disease progression. Their detection early after clinical deterioration might become an indicator for the requirement of prompt anti-inflammatory treatment. Here, we review the role of ICs in COVID-19 progression, their possible origins and potential intervention strategies. GRAPHICAL ABSTRACT: [Image: see text]