Do rogue antibodies make the difference between mild versus severe COVID-19?

To shed light on the immunological mechanisms underlying the mild/severe distinction in COVID-19 pathology, Combes et al. performed single-cell RNA-seq analysis on blood samples from patients with mild/moderate or severe COVID-19. In patients with mild/moderate COVID-19, they found populations of immune cells that displayed a coordinated pattern of interferon-stimulated gene (ISG) expression, but these cells were systemically absent in patients with severe disease. Surprisingly, patients with severe disease had higher virus-specific antibody titres and lower viral loads than patients with mild/moderate disease. However, they uniquely produced antibodies that appeared to functionally block the production of ISG-expressing cells by engaging FcγRIIβ. This Fc receptor antagonizes IFNα receptor (IFNAR) signalling and thereby disrupts a positive-feedback loop that would otherwise enhance interferon responses.