Molecular mechanisms and therapeutic targeting of Fc receptor activation in acute and chronic inflammatory diseases

Antibodies play a crucial role in the host immune response against invading pathogens. By facilitating specific effector functions, they contribute to pathogen clearance and modulation of the immune response. Beyond well-known functions like neutralization, antibodies can trigger a powerful cytokine response mediated by Fc receptor (FcR) activation through a mechanism called antibody-dependent inflammation (ADI). ADI facilitates the rapid secretion of pro-inflammatory cytokines, which, in a pathological situation, plays an important role in effective pathogen clearance. In contrast, if mis-regulated, due to its ability to induce high levels of pro-inflammatory molecules, aberrant ADI can contribute to extensive tissue damage and worsening of disease pathology. In severe COVID-19, aberrantly glycosylated antibodies induce mis-regulated ADI, contributing to a hyperinflammatory phenotype, microvascular thrombosis and pulmonary edema. To successfully counteract aberrant ADI-induced pathology, it is important to understand the underlying molecular mechanisms causing these deteriorating effects. In this thesis, I set out to investigate the molecular mechanisms, as well as potential therapeutic targets, of pathological FcR activation in severe COVID-19 progression. Apart from antibodies, pentraxins can induce the secretion of pro-inflammatory cytokines via FcR activation in a mechanism similar to ADI. CRP-induced pathology has been described in several chronic inflammatory conditions, such as rheumatoid arthritis (RA) and inflammatory bowel disease (IBD). Thus, I investigated the molecular mechanism of CRP-induced cytokine induction to explore potential indications for the treatment of chronic inflammatory diseases.