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

ABSTRACT: BackgroundSome 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.MethodsIn 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.ResultsAnti-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.ConclusionWe identify anti-ACE2 IgM as a mechanism-based biomarker strongly associated with severe clinical outcomes in SARS-CoV-2 infection, which has therapeutic implications.FUNDINGBill & 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).

SUBMITTER: Casciola-Rosen L

PROVIDER: S-EPMC9090251 | biostudies-literature | 2022 May

REPOSITORIES: biostudies-literature

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

Casciola-Rosen Livia L Thiemann David R DR Andrade Felipe F Trejo-Zambrano Maria I MI Leonard Elissa K EK Spangler Jamie B JB Skinner Nicole E NE Bailey Justin J Yegnasubramanian Srinivasan S Wang Rulin R Vaghasia Ajay M AM Gupta Anuj A Cox Andrea L AL Ray Stuart C SC Linville Raleigh M RM Guo Zhaobin Z Searson Peter C PC Machamer Carolyn E CE Desiderio Stephen S Sauer Lauren M LM Laeyendecker Oliver O Garibaldi Brian T BT Gao Li L Damarla Mahendra M Hassoun Paul M PM Hooper Jody E JE Mecoli Christopher A CA Christopher-Stine Lisa L Gutierrez-Alamillo Laura L Yang Qingyuan Q Hines David D Clarke William A WA Rothman Richard E RE Pekosz Andrew A Fenstermacher Katherine Zj KZ Wang Zitong Z Zeger Scott L SL Rosen Antony A

JCI insight 20220509 9

BackgroundSome 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.MethodsIn an opportunity sample of 118 COVID-19 inpatients, autoantibodies recognizing ACE2 were detected by ELISA. Binding prop ...[more]

PMID: 35349483

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

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

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