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

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 end...

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Detalles Bibliográficos
Autores principales: Casciola-Rosen, Livia, Thiemann, David R., Andrade, Felipe, Trejo-Zambrano, Maria I., Leonard, Elissa K., Spangler, Jamie B., Skinner, Nicole E., Bailey, Justin, Yegnasubramanian, Srinivasan, Wang, Rulin, Vaghasia, Ajay M., Gupta, Anuj, Cox, Andrea L., Ray, Stuart C., Linville, Raleigh M., Guo, Zhaobin, Searson, Peter C., Machamer, Carolyn E., Desiderio, Stephen, Sauer, Lauren M., Laeyendecker, Oliver, Garibaldi, Brian T., Gao, Li, Damarla, Mahendra, Hassoun, Paul M., Hooper, Jody E., Mecoli, Christopher A., Christopher-Stine, Lisa, Gutierrez-Alamillo, Laura, Yang, Qingyuan, Hines, David, Clarke, William A., Rothman, Richard E., Pekosz, Andrew, Fenstermacher, Katherine Z.J., Wang, Zitong, Zeger, Scott L., Rosen, Antony
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Clinical Investigation 2022
Materias:
Clinical Medicine
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9090251/
https://www.ncbi.nlm.nih.gov/pubmed/35349483
http://dx.doi.org/10.1172/jci.insight.158362
Descripción
Sumario: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 K(D) 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)

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