IgM anti-ACE2 autoantibodies in severe COVID-19 activate complement and perturb vascular endothelial function
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 endo...
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| Format: | Article |
| Language: | English |
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American Society for Clinical investigation
2022-05-01
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| Series: | JCI Insight |
| Subjects: | |
| Online Access: | https://doi.org/10.1172/jci.insight.158362 |
| _version_ | 1811238018326986752 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Livia Casciola-Rosen |
| collection | DOAJ |
| description | 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) |
| first_indexed | 2024-04-12T12:34:32Z |
| format | Article |
| id | doaj.art-b514b606a0ee4c42affc7ad2f94c0c67 |
| institution | Directory Open Access Journal |
| issn | 2379-3708 |
| language | English |
| last_indexed | 2024-04-12T12:34:32Z |
| publishDate | 2022-05-01 |
| publisher | American Society for Clinical investigation |
| record_format | Article |
| series | JCI Insight |
| spelling | doaj.art-b514b606a0ee4c42affc7ad2f94c0c672022-12-22T03:32:57ZengAmerican Society for Clinical investigationJCI Insight2379-37082022-05-0179IgM anti-ACE2 autoantibodies in severe COVID-19 activate complement and perturb vascular endothelial functionLivia Casciola-RosenDavid R. ThiemannFelipe AndradeMaria I. Trejo-ZambranoElissa K. LeonardJamie B. SpanglerNicole E. SkinnerJustin BaileySrinivasan YegnasubramanianRulin WangAjay M. VaghasiaAnuj GuptaAndrea L. CoxStuart C. RayRaleigh M. LinvilleZhaobin GuoPeter C. SearsonCarolyn E. MachamerStephen DesiderioLauren M. SauerOliver LaeyendeckerBrian T. GaribaldiLi GaoMahendra DamarlaPaul M. HassounJody E. HooperChristopher A. MecoliLisa Christopher-StineLaura Gutierrez-AlamilloQingyuan YangDavid HinesWilliam A. ClarkeRichard E. RothmanAndrew PekoszKatherine Z.J. FenstermacherZitong WangScott L. ZegerAntony RosenBackground 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)https://doi.org/10.1172/jci.insight.158362AutoimmunityCOVID-19 |
| spellingShingle | 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 IgM anti-ACE2 autoantibodies in severe COVID-19 activate complement and perturb vascular endothelial function JCI Insight Autoimmunity COVID-19 |
| title | IgM anti-ACE2 autoantibodies in severe COVID-19 activate complement and perturb vascular endothelial function |
| title_full | IgM anti-ACE2 autoantibodies in severe COVID-19 activate complement and perturb vascular endothelial function |
| title_fullStr | IgM anti-ACE2 autoantibodies in severe COVID-19 activate complement and perturb vascular endothelial function |
| title_full_unstemmed | IgM anti-ACE2 autoantibodies in severe COVID-19 activate complement and perturb vascular endothelial function |
| title_short | IgM anti-ACE2 autoantibodies in severe COVID-19 activate complement and perturb vascular endothelial function |
| title_sort | igm anti ace2 autoantibodies in severe covid 19 activate complement and perturb vascular endothelial function |
| topic | Autoimmunity COVID-19 |
| url | https://doi.org/10.1172/jci.insight.158362 |
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