tetano
Editor, Senior Moderator
JCI Insight
. 2022 Mar 29;e158362.
doi: 10.1172/jci.insight.158362. Online ahead of print.
IgM anti-ACE2 autoantibodies in severe COVID-19 activate complement and perturb vascular endothelial function
Livia Casciola-Rosen[SUP] 1 [/SUP], David R Thiemann[SUP] 2 [/SUP], Felipe Andrade[SUP] 1 [/SUP], Maria I Trejo-Zambrano[SUP] 1 [/SUP], Elissa K Leonard[SUP] 3 [/SUP], Jamie B Spangler[SUP] 3 [/SUP], Nicole E Skinner[SUP] 4 [/SUP], Justin Bailey[SUP] 4 [/SUP], Srinivasan Yegnasubramanian[SUP] 5 [/SUP], Rulin Wang[SUP] 5 [/SUP], Ajay M Vaghasia[SUP] 5 [/SUP], Anuj Gupta[SUP] 5 [/SUP], Andrea L Cox[SUP] 4 [/SUP], Stuart C Ray[SUP] 4 [/SUP], Raleigh M Linville[SUP] 6 [/SUP], Zhaobin Guo[SUP] 6 [/SUP], Peter C Searson[SUP] 7 [/SUP], Carolyn E Machamer[SUP] 8 [/SUP], Stephen Desiderio[SUP] 9 [/SUP], Lauren M Sauer[SUP] 10 [/SUP], Oliver Laeyendecker[SUP] 4 [/SUP], Brian T Garibaldi[SUP] 11 [/SUP], Li Gao[SUP] 12 [/SUP], Mahendra Damarla[SUP] 11 [/SUP], Paul M Hassoun[SUP] 11 [/SUP], Jody E Hooper[SUP] 13 [/SUP], Christopher A Mecoli[SUP] 1 [/SUP], Lisa Christopher-Stine[SUP] 1 [/SUP], Laura Gutierrez-Alamillo[SUP] 1 [/SUP], Qingyuan Yang[SUP] 1 [/SUP], David Hines[SUP] 1 [/SUP], William A Clarke[SUP] 13 [/SUP], Richard E Rothman[SUP] 10 [/SUP], Andrew Pekosz[SUP] 14 [/SUP], Katherine Zj Fenstermacher[SUP] 15 [/SUP], Zitong Wang[SUP] 16 [/SUP], Scott L Zeger[SUP] 16 [/SUP], Antony Rosen[SUP] 1 [/SUP]
Affiliations
Abstract
Background: 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.
Methods: 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.
Results: 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.
Conclusions: 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.
Keywords: Autoimmunity; COVID-19; Rheumatology.
. 2022 Mar 29;e158362.
doi: 10.1172/jci.insight.158362. Online ahead of print.
IgM anti-ACE2 autoantibodies in severe COVID-19 activate complement and perturb vascular endothelial function
Livia Casciola-Rosen[SUP] 1 [/SUP], David R Thiemann[SUP] 2 [/SUP], Felipe Andrade[SUP] 1 [/SUP], Maria I Trejo-Zambrano[SUP] 1 [/SUP], Elissa K Leonard[SUP] 3 [/SUP], Jamie B Spangler[SUP] 3 [/SUP], Nicole E Skinner[SUP] 4 [/SUP], Justin Bailey[SUP] 4 [/SUP], Srinivasan Yegnasubramanian[SUP] 5 [/SUP], Rulin Wang[SUP] 5 [/SUP], Ajay M Vaghasia[SUP] 5 [/SUP], Anuj Gupta[SUP] 5 [/SUP], Andrea L Cox[SUP] 4 [/SUP], Stuart C Ray[SUP] 4 [/SUP], Raleigh M Linville[SUP] 6 [/SUP], Zhaobin Guo[SUP] 6 [/SUP], Peter C Searson[SUP] 7 [/SUP], Carolyn E Machamer[SUP] 8 [/SUP], Stephen Desiderio[SUP] 9 [/SUP], Lauren M Sauer[SUP] 10 [/SUP], Oliver Laeyendecker[SUP] 4 [/SUP], Brian T Garibaldi[SUP] 11 [/SUP], Li Gao[SUP] 12 [/SUP], Mahendra Damarla[SUP] 11 [/SUP], Paul M Hassoun[SUP] 11 [/SUP], Jody E Hooper[SUP] 13 [/SUP], Christopher A Mecoli[SUP] 1 [/SUP], Lisa Christopher-Stine[SUP] 1 [/SUP], Laura Gutierrez-Alamillo[SUP] 1 [/SUP], Qingyuan Yang[SUP] 1 [/SUP], David Hines[SUP] 1 [/SUP], William A Clarke[SUP] 13 [/SUP], Richard E Rothman[SUP] 10 [/SUP], Andrew Pekosz[SUP] 14 [/SUP], Katherine Zj Fenstermacher[SUP] 15 [/SUP], Zitong Wang[SUP] 16 [/SUP], Scott L Zeger[SUP] 16 [/SUP], Antony Rosen[SUP] 1 [/SUP]
Affiliations
- PMID: 35349483
- DOI: 10.1172/jci.insight.158362
Abstract
Background: 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.
Methods: 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.
Results: 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.
Conclusions: 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.
Keywords: Autoimmunity; COVID-19; Rheumatology.