IgM anti-ACE2 autoantibodies in severe COVID-19 activate complement and perturb vascular endothelial function
Livia Casciola-Rosen, … , Scott L. Zeger, Antony Rosen
Livia Casciola-Rosen, … , Scott L. Zeger, Antony Rosen
Published March 29, 2022
Citation Information: JCI Insight. 2022;7(9):e158362. https://doi.org/10.1172/jci.insight.158362.
View: Text | PDF
Clinical Medicine COVID-19

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

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)

Authors

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

×

Figure 3

Clinical features of anti-ACE2 IgM–positive COVID-19 patients compared with those who do not have these antibodies.

Options: View larger image (or click on image) Download as PowerPoint
Clinical features of anti-ACE2 IgM–positive COVID-19 patients compared w...
(A) Age, (B) BMI, (C) sex, and levels of (D) temperature, (E) CRP, (F) D-dimer, and (G) neutrophils were compared between the anti-ACE2 IgM–positive and –negative COVID-19 patient groups. Red and blue colors denote anti-ACE2 IgM antibody–positive and –negative status, respectively. Box plots show median, 25th and 75th percentiles, and whiskers min to max. (D–G) Anti-ACE2 IgM-positive patients had higher average body temperature beginning early after hospital admission, followed by elevated CRP and D-dimer measurements. The IgM anti-ACE2–positive group had statistically significantly higher average temperatures, CRP, and D-dimer levels over the first 10 days of hospitalization than the IgM-negative group (P = 0.0001, 0.02, and 0.001, respectively). Average absolute neutrophil levels (G) were not statistically different between the 2 groups. Analyses in panels D–G use linear mixed effects model Wald test with 4 degrees of freedom (see Statistics). (H) Longitudinal analysis of anti-ACE2 IgM antibodies. For all those anti-ACE2 IgM–positive patients with multiple banked sera available (16/18), anti-ACE2 IgM and IgG antibodies were quantitated over time. Red and blue lines on each plot denote anti-ACE2 IgM and IgG antibodies, respectively. Solid black bars represent steroid treatment periods. Additional examples are shown in Supplemental Figure 4.