IgM anti-ACE2 autoantibodies in severe COVID-19 activate complement and perturb vascular endothelial function

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Abstract

Background Some clinical features of severe COVID-19 represent blood vessel damage induced by activation of host immune responses initiated by the coronavirus SARS-CoV-2. We hypothesized autoantibodies against angiotensin-converting enzyme 2 (ACE2), the SARS-CoV-2 receptor expressed on vascular endothelium, are generated during COVID-19 and are of mechanistic importance.Methods In an opportunity sample of 118 COVID-19 inpatients, autoantibodies recognizing ACE2 were detected by ELISA. Binding properties of anti-ACE2 IgM were analyzed via biolayer interferometry. Effects of anti-ACE2 IgM on complement activation and endothelial function were demonstrated in a tissue-engineered pulmonary microvessel model.Results Anti-ACE2 IgM (not IgG) autoantibodies were associated with severe COVID-19 and found in 18/66 (27.2%) patients with severe disease compared with 2/52 (3.8%) of patients with moderate disease (OR 9.38, 95% CI 2.38–42.0; P = 0.0009). Anti-ACE2 IgM autoantibodies were rare (2/50) in non-COVID-19 ventilated patients with acute respiratory distress syndrome. Unexpectedly, ACE2-reactive IgM autoantibodies in COVID-19 did not undergo class-switching to IgG and had apparent KD values of 5.6–21.7 nM, indicating they are T cell independent. Anti-ACE2 IgMs activated complement and initiated complement-binding and functional changes in endothelial cells in microvessels, suggesting they contribute to the angiocentric pathology of COVID-19.Conclusion We identify anti-ACE2 IgM as a mechanism-based biomarker strongly associated with severe clinical outcomes in SARS-CoV-2 infection, which has therapeutic implications.FUNDING Bill & Melinda Gates Foundation, Gates Philanthropy Partners, Donald B. and Dorothy L. Stabler Foundation, and Jerome L. Greene Foundation; NIH R01 AR073208, R01 AR069569, Institutional Research and Academic Career Development Award (5K12GM123914-03), National Heart, Lung, and Blood Institute R21HL145216, and Division of Intramural Research, National Institute of Allergy and Infectious Diseases; National Science Foundation Graduate Research Fellowship (DGE1746891)

Authors

Livia Casciola-Rosen, David R. Thiemann, Felipe Andrade, Maria I. Trejo-Zambrano, Elissa K. Leonard, Jamie B. Spangler, Nicole E. Skinner, Justin Bailey, Srinivasan Yegnasubramanian, Rulin Wang, Ajay M. Vaghasia, Anuj Gupta, Andrea L. Cox, Stuart C. Ray, Raleigh M. Linville, Zhaobin Guo, Peter C. Searson, Carolyn E. Machamer, Stephen Desiderio, Lauren M. Sauer, Oliver Laeyendecker, Brian T. Garibaldi, Li Gao, Mahendra Damarla, Paul M. Hassoun, Jody E. Hooper, Christopher A. Mecoli, Lisa Christopher-Stine, Laura Gutierrez-Alamillo, Qingyuan Yang, David Hines, William A. Clarke, Richard E. Rothman, Andrew Pekosz, Katherine Z.J. Fenstermacher, Zitong Wang, Scott L. Zeger, Antony Rosen