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

• DOI: 10.1172/jci.insight.158362
• Publication Date: 2022-03-29T16:03:20Z
• Authors: Livia Casciola-Rosen; David R. Thiemann; Felipe Andrade; Maria I. Trejo-Za...; Elissa K. Leonard; Jamie B. Spangler; Nicole E. Skinner; Justin Bailey; Srinivasan Yegnas...; 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. Me...; Lisa Christopher-...; Laura Gutierrez-A...; Qingyuan Yang; David Hines; William A. Clarke; Richard E. Rothman; Andrew Pekosz; Katherine Z.J. Fe...; Zitong Wang; Scott L. Zeger; Antony Rosen
• Keywords: Immunoglobulin M; SARS-CoV-2; R; Medicine; COVID-19; Endothelial Cells; Humans; Autoimmunity; Angiotensin-Converting Enzyme 2; Clinical Medicine; Autoantibodies

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