The study was done in an opportunity sample of 118 COVID-19 inpatients. Autoantibodies recognizing ACE2 were detected by ELISA. Binding properties of anti-ACE2 IgM from patients were analyzed via biolayer interferometry. The effects of anti-ACE2 IgM on complement activation and endothelial function were demonstrated in a tissue-engineered pulmonary microvessel model.
Anti-ACE2 IgM (but not IgG) were associated with severe COVID-19, found in 18/66 (27.2%) patients with severe disease compared to 2/52 (3.8%) of patients with moderate disease (OR 9.38, 95% CI 2.38-42.0; p=0.0009, Fisher's exact test). Anti-ACE2 IgM were rare (2/50) in non-COVID-19 ventilated patients with ARDS. Unexpectedly, ACE2-reactive IgM in COVID-19 do not undergo class-switching to IgG, and have apparent KD values of 5.6-21.7nM, indicating that they are T-independent. Anti-ACE2 IgM activated complement and initiated complement-binding and functional changes in endothelial cells in microvessels, suggesting that they contribute to the angiocentric pathology of COVID-19.
Our results identify anti-ACE2 IgM as a mechanism-based biomarker strongly associated with severe clinical outcomes in SARS-CoV-2 infection, which has therapeutic implications. We anticipate that additional IgM responses may identify other COVID-19 subgroups with severe disease, and potentially other serious pandemic illnesses.
COVID-19 is a global pandemic caused by the novel coronavirus SARS-CoV-2. Some clinical features of severe COVID-19 represent blood vessel damage induced by activation of host immune responses, initiated by the virus. We hypothesized that 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.
Casciola-Rosen L, Thiemann DR, Andrade F, Trejo-Zambrano MI, Leonard EK, Spangler JB, Skinner NE, Bailey J, Yegnasubramanian S, Wang R, Vaghasia AM, Gupta A, Cox AL, Ray SC, Linville RM, Guo Z, Searson PC, Machamer CE, Desiderio S, Sauer LM, Laeyendecker O, Garibaldi BT, Gao L, Damarla M, Hassoun PM, Hooper JE, Mecoli CA, Christopher-Stine L, Gutierrez-Alamillo L, Yang Q, Hines D, Clarke WA, Rothman RE, Pekosz A, Fenstermacher KZ, Wang Z, Zeger SL, Rosen A. (2022). IgM anti-ACE2 autoantibodies in severe COVID-19 activate complement and perturb vascular endothelial function. JCI insight