IgM autoantibodies recognizing ACE2 are associated with severe COVID-19

Casciola-Rosen, Livia; Thiemann, David R.; Andrade, Felipe; Trejo Zambrano, Maria Isabel; Hooper, Jody E.; Leonard, Elissa K.; Spangler, Jamie B.; Cox, Andrea L.; Machamer, Carolyn E.; Sauer, Lauren; Laeyendecker, Oliver; Garibaldi, Brian T.; Ray, Stuart C.; Mecoli, Christopher A.; Christopher-Stine, Lisa; Gutierrez-Alamillo, Laura; Yang, Qingyuan; Hines, David; Clarke, William A.; Rothman, Richard; Pekosz, Andrew; Fenstermacher, Katherine J.; Wang, Zitong; Zeger, Scott L.; Rosen, Antony

SARS-CoV-2 infection induces severe disease in a subpopulation of patients, but the underlying mechanisms remain unclear. We demonstrate robust IgM autoantibodies that recognize angiotensin converting enzyme-2 (ACE2) in 18/66 (27%) patients with severe COVID-19, which are rare (2/52; 3.8%) in hospitalized patients who are not ventilated. The antibodies do not undergo class-switching to IgG, suggesting a T-independent antibody response. Purified IgM from anti-ACE2 patients activates complement. Pathological analysis of lung obtained at autopsy shows endothelial cell staining for IgM in blood vessels in some patients. We propose that vascular endothelial ACE2 expression focuses the pathogenic effects of these autoantibodies on blood vessels, and contributes to the angiocentric pathology observed in some severe COVID-19 patients. These findings may have predictive and therapeutic implications.