Broad auto-reactive IgM responses are common in critically ill patients, including those with COVID-19

• Published in: Cell reports. Medicine 2021-06, Vol.2 (6), p.100321-100321, Article 100321
• Main Authors: Wong, Andrew Kam Ho, Woodhouse, Isaac, Schneider, Frank, Kulpa, Deanna A., Silvestri, Guido, Maier, Cheryl L.
• Format: Article
• Language: English
• Subjects: Autoantibodies - blood; Autoantibodies - immunology; Cell Line; Complement C4 - metabolism; COVID-19 - immunology; COVID-19 - pathology; COVID-19 - virology; Critical Illness; Humans; Immunoglobulin M - blood; Immunoglobulin M - immunology; Intensive Care Units; Lung - metabolism; Protein Array Analysis; Proteome - analysis; SARS-CoV-2 - isolation & purification
• ISSN: 2666-3791; 2666-3791
• DOI: 10.1016/j.xcrm.2021.100321

The pathogenesis of severe coronavirus disease 2019 (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-IgMs 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 lactose dehydrogenase (LDH)-release cytotoxicity assays, we identify high-affinity, complement-fixing, auto-reactive IgM directed against 260 candidate autoantigens, 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. [Display omitted] More than 90% of critically ill COVID-19 patients have auto-reactive IgM antibodiesAuto-reactive IgM binds diverse targets across multiple organ typesIgM and complement component C4d are abundant in COVID-19 non-survivor lung tissueCOVID-19-associated auto-IgM fixes complement to induce cell death in vitro Critical illness can be associated with immune dysregulation; yet, mediators contributing to disease severity in COVID-19 are unclear. Wong et al. show a high percentage of critically ill patients possess auto-reactive IgM, which, in SARS-CoV-2 infection, are capable of binding diverse targets across key organs and inflicting complement-dependent cytotoxicity.