JCI Insight (May 2022)

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

  • 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

Journal volume & issue
Vol. 7, no. 9

Abstract

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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)

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