Broad Auto-Reactive IgM Responses are Common in Critically Ill Patients Including Those with COVID-19

Ho Wong, Andrew Kam; Woodhouse, Isaac; Schneider, Frank; Kulpa, Deanna A.; Silvestri, Guido; Maier, Cheryl L.

The pathogenesis of severe COVID-19 remains poorly understood. While several studies suggest that immune dysregulation plays a central role, the key mediators of this process are yet to be defined. Here, we demonstrate that plasma from a high proportion (93%) of critically ill COVID-19 patients, but not healthy controls, contains broadly auto-reactive immunoglobulin M (IgM), and less frequently auto-reactive IgG or IgA. Importantly, these auto-IgM preferentially recognize primary human lung cells in vitro, including pulmonary endothelial and epithelial cells. By using a combination of flow cytometry, analytical proteome microarray technology, and LDH-release cytotoxicity assays, we identify high-affinity, complement-fixing, auto-reactive IgM directed against 260 candidate auto-antigens, including numerous molecules preferentially expressed on the cellular membranes of pulmonary, vascular, gastrointestinal, and renal tissues. These findings suggest that broad IgM-mediated autoimmune reactivity may be involved in the pathogenesis of severe COVID-19, thereby identifying a potential target for therapeutic interventions.