ArticleJCI insight2022
IgM anti-ACE2 autoantibodies in severe COVID-19 activate complement and perturb vascular endothelial function.
Article in JCI insight, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 35 papers, 1 of them a synthesis that pooled it.
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Who cites it
35 citing papers in PubMed, 1 synthesis or guideline pooled it, 53 citations in OpenAlex.
- The immunopathological spectrum of COVID-19: from cytokine storm to autoimmunity-a systematic review.Frontiers in medicine · 2026Pooled it
- Xenosialylation as immunological chimerism: a host-centered unifying model for viral and post-vaccination immune complications.European cytokine network · 2026Review
- Mechanisms and impact of long COVID: pathophysiology, neuropsychiatric effects and vaccination.Frontiers in immunology · 2026Review
- COVID-19-associated Autoimmune and Inflammatory Diseases: Molecular Mechanisms and the Role of IVIG Therapy.Clinical reviews in allergy & immunology · 2025Review
- Autoimmune reactions to ACE2 triggered by SARS-CoV-2 S protein and their histopathological consequences.Scientific reports · 2025Article
- ICAM-1 autoantibodies detected in healthy individuals and cross-react with functional epitopes.ImmunoHorizons · 2025Article
- Novel biomarkers of mitochondrial dysfunction in Long COVID patients.GeroScience · 2025Article
- Autoantibodies targeting angiotensin-converting enzyme 2 are prevalent and not induced by SARS-CoV-2 infection.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2025Article
- Sequential SARS-CoV-2 mRNA Vaccination Induces Anti-Idiotype (Anti-ACE2) Antibodies in K18 Human ACE2 Transgenic Mice.Vaccines · 2025Article
- Virus-Induced Pathogenic Antibodies: Lessons from Long COVID and Dengue Hemorrhage Fever.International journal of molecular sciences · 2025Review
- The past, present, and future of anti-idiotype antibodies.Frontiers in immunology · 2025Article
- Screened Fv-Antibodies against the Angiotensin-Converting Enzyme 2 (ACE2) Receptor Neutralizing the Infection of SARS-CoV-2.ACS pharmacology & translational science · 2024Article
- Pathological Sequelae of SARS-CoV-2: A Review for Clinicians.The Yale journal of biology and medicine · 2024Review
- Application of machine learning algorithms to identify serological predictors of COVID-19 severity and outcomes.Communications medicine · 2024Article
- COVID-19 in the Initiation and Progression of Atherosclerosis: Pathophysiology During and Beyond the Acute Phase.JACC. Advances · 2024Review
- Enhancement of NETosis by ACE2-cross-reactive anti-SARS-CoV-2 RBD antibodies in patients with COVID-19.Journal of biomedical science · 2024Article
- Article
- Endothelial Extracellular Vesicles Enriched in microRNA-34a Predict New-Onset Diabetes in Coronavirus Disease 2019 (COVID-19) Patients: Novel Insights for Long COVID Metabolic Sequelae.The Journal of pharmacology and experimental therapeutics · 2024Article
- Autoantibodies to ACE2 and immune molecules are associated with COVID-19 disease severity.Communications medicine · 2024Article
- A guide to complement biology, pathology and therapeutic opportunity.Nature reviews. Immunology · 2024Review
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Authors and funding
38 authors at 9 institutions in 2 countries.
Funding
Abstract
BackgroundSome 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.MethodsIn 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.ResultsAnti-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.ConclusionWe identify anti-ACE2 IgM as a mechanism-based biomarker strongly associated with severe clinical outcomes in SARS-CoV-2 infection, which has therapeutic implications.FUNDINGBill & 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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