Autoantibodies to host proteins can trigger or exacerbate disease by perturbing target-dependent biological pathways, directing cell lysis and/or triggering inflammation. Although the generation of these antibodies is constrained by tolerance mechanisms, some autoantibody production is detectable in healthy individuals. An increased prevalence of more diverse autoantibodies has been reported in several inflammatory settings, including chronic viral infections. However, the breadth of antigens that are targeted and the ensuing pathophysiological effects are poorly understood.

In this preprint (non-peer-reviewed), Wang et al. used a novel high-throughput assay to quantitate circulating antibodies reactive with 2,770 secreted and cell surface-expressed human proteins in individuals infected with SARS-CoV-2 and control subjects. This work provided unprecedented insight into pre-existing and COVID-19-associated autoantibody reactivities and their contribution to pathogenesis. More proteins were targeted in infected individuals, with patients with severe COVID-19 exhibiting higher-level reactivity to the greatest number of antigens.

Notably, autoantibody reactivities found in patients with COVID-19 included many that targeted immune-relevant proteins such as cytokines (for example, type I interferons), chemokines or their receptors, as well as particular leukocyte subsets (B cells, T cells, natural killer cells and monocytes). These antibodies had immunomodulatory effects in vitro and were associated with virological and immune parameters in vivo. Blockade of key innate cytokine pathways exacerbated disease in a murine model of SARS-CoV-2 infection. Other autoantibodies in individuals infected with SARS-CoV-2 recognized tissue-associated antigens from sites including blood vessels and the brain and correlated with clinical markers of inflammation and disease severity.

The findings reported suggest pivotal immune-modulatory and effector roles for diverse autoantibodies in COVID-19 pathogenesis and prompt future work to investigate the persistence of tissue-targeted autoantibodies and their putative contribution to the long-term effects of COVID-19. It is unclear whether the remarkable breadth of autoantibody reactivities in patients with COVID-19 highlighted by this study reflects enrichment for individuals with rare pre-existing autoantibodies and/or perturbation of humoral immunoregulation in the inflammatory environment induced during infection. Understanding the mechanisms that drive these autoantibody responses could inform strategies to ameliorate severe COVID-19 and to treat ‘long COVID’.