An immune symphony The inflammatory potential of antibody isotypes and subclasses

Antibodies are key mediators of immune defense, orchestrating various protective and inflammatory responses. This thesis investigates the inflammatory capacity of IgG and IgA antibodies and the mechanisms regulating antibody-dependent inflammation. Using COVID-19 as a model, it demonstrates that SARS-CoV-2 anti-spike IgG immune complexes strongly induce hyperinflammation in alveolar-like macrophages. This effect is driven by metabolic reprogramming dependent on glucose and fatty acid metabolism. In parallel, the proinflammatory role of IgA, the more dominant antibody in mucosal tissues, is explored. Anti-spike IgA also promotes inflammation, with the IgA2 subclass inducing stronger proinflammatory responses than IgA1. Similar to IgG, IgA-driven inflammation relies on metabolic reprogramming, with IgA2 additionally engaging mitochondrial activation, adding further complexity to the regulation of these responses. This thesis further examines FcαRI, the IgA receptor encoded by FCAR, and shows that splice variants are differentially expressed by monocytes and alveolar macrophages. These cell type-specific expression profiles correlate with distinct responses to IgA subclasses, suggesting a potential functional role for FCAR splice variants in IgA subclass-dependent inflammation. In addition, IgA subclasses induce tissue-specific inflammatory effects on immune cells corresponding to their local distribution, with IgA1 inducing stronger responses in circulating monocytes, while IgA2 more potently stimulates intestinal CD103+ dendritic cells, reflecting its relative enrichment in the lower intestine. Together, these findings demonstrate that inflammatory outcomes are determined not only by antibody isotype, but also by subclass, receptor variation, tissue context, and cellular metabolism, advancing our understanding of how antibodies contribute to protection as well as pathology.