학술논문
IgM anti-ACE2 autoantibodies in severe COVID-19 activate complement and perturb vascular endothelial function
Document Type
article
Author
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
Source
JCI Insight, Vol 7, Iss 9 (2022)
Subject
Language
English
ISSN
2379-3708
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)