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

被引：40

作者：

Casciola-Rosen, Livia ^{[1
]}

Thiemann, David R. ^{[2
]}

Andrade, Felipe ^{[1
]}

Trejo-Zambrano, Maria, I ^{[1
]}

Leonard, Elissa K. ^{[3
]}

Spangler, Jamie B. ^{[3
,4
,5
]}

Skinner, Nicole E. ^{[6
]}

Bailey, Justin ^{[6
]}

Yegnasubramanian, Srinivasan ^{[7
]}

Wang, Rulin ^{[7
]}

Vaghasia, Ajay M. ^{[7
]}

Gupta, Anuj ^{[7
]}

Cox, Andrea L. ^{[6
]}

Ray, Stuart C. ^{[6
]}

Linville, Raleigh M. ^{[8
,9
]}

Guo, Zhaobin ^{[8
]}

Searson, Peter C. ^{[3
,8
,9
]}

Machamer, Carolyn E. ^{[10
]}

Desiderio, Stephen ^{[11
]}

Sauer, Lauren M. ^{[12
,13
]}

Laeyendecker, Oliver ^{[6
,14
]}

Garibaldi, Brian T. ^{[13
,15
]}

Gao, Li ^{[16
]}

Damarla, Mahendra ^{[15
]}

Hassoun, Paul M. ^{[15
]}

Hooper, Jody E. ^{[17
]}

Mecoli, Christopher A. ^{[1
]}

Christopher-Stine, Lisa ^{[1
]}

Gutierrez-Alamillo, Laura ^{[1
]}

Yang, Qingyuan ^{[1
]}

Hines, David ^{[1
]}

Clarke, William A. ^{[17
]}

Rothman, Richard E. ^{[12
]}

Pekosz, Andrew ^{[18
,19
]}

Fenstermacher, Katherine Zj ^{[18
]}

Wang, Zitong ^{[20
]}

Zeger, Scott L. ^{[1
,20
]}

Rosen, Antony ^{[1
,10
,17
]}

机构：

[1] Johns Hopkins Univ, Div Rheumatol, Dept Med, Sch Med, Baltimore, MD USA

[2] Johns Hopkins Univ, Div Cardiol, Dept Med, Sch Med, Baltimore, MD USA

[3] Johns Hopkins Univ, Sch Med, Dept Biomed Engn, Baltimore, MD 21205 USA

[4] Johns Hopkins Univ, Whiting Sch Engn, Dept Chem & Biomol Engn, Baltimore, MD USA

[5] Johns Hopkins Univ, Sch Med, Translat Tissue Engn Ctr, Baltimore, MD USA

[6] Johns Hopkins Univ, Div Infect Dis, Dept Med, Sch Med, Baltimore, MD USA

[7] Johns Hopkins Univ, Sch Med, Dept Oncol, Baltimore, MD 21205 USA

[8] Johns Hopkins Univ, Whiting Sch Engn, Inst NanoBioTechnol, Baltimore, MD USA

[9] Johns Hopkins Univ, Whiting Sch Engn, Dept Mat Sci & Engn, Baltimore, MD USA

[10] Johns Hopkins Univ, Sch Med, Dept Cell Biol, Baltimore, MD USA

[11] Johns Hopkins Univ, Sch Med, Dept Mol Biol & Genet, Baltimore, MD 21205 USA

[12] Johns Hopkins Univ Hosp, Adult Emergency Dept, Baltimore, MD USA

[13] Johns Hopkins Univ, Johns Hopkins Biocontainment Unit, Sch Med, Baltimore, MD USA

[14] NIAID, Div Intramural Med, NIH, Baltimore, MD USA

[15] Johns Hopkins Univ, Div Pulm & Crit Care Med, Dept Med, Sch Med, Baltimore, MD USA

[16] Johns Hopkins Univ, Div Allergy & Clin Immunol, Dept Med, Sch Med, Baltimore, MD USA

[17] Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21205 USA

[18] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Environm Hlth & Engn, Baltimore, MD USA

[19] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Mol Microbiol & Immunol, Baltimore, MD USA

[20] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Biostat, Baltimore, MD USA

来源：

JCI INSIGHT | 2022年 / 7卷 / 09期

基金：

比尔及梅琳达.盖茨基金会; 美国国家科学基金会;

关键词：

DERMATOMYOSITIS; ANTIBODIES; PROTEIN; CORONAVIRUS; MECHANISMS; RESPONSES; IMMUNITY; PATHWAY;

D O I：

10.1172/jci.insight.158362

中图分类号：

R-3 [医学研究方法]; R3 [基础医学];

学科分类号：

1001 ;

摘要：

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 a ngiotensin-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, 950/0 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 K-D 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.

引用

页数：18

共 48 条

[11] EFFECTS OF CYCLOSPORIN-A ON THE IMMUNE-SYSTEM OF THE MOUSE .1. EVIDENCE FOR A DIRECT SELECTIVE EFFECT OF CYCLOSPORIN-A ON B-CELLS RESPONDING TO ANTI-IMMUNOGLOBULIN ANTIBODIES [J].

DONGWORTH, DW ;

KLAUS, GGB .

EUROPEAN JOURNAL OF IMMUNOLOGY, 1982, 12 (12) :1018-1022

[12] Affinity Enhancement of Antibodies: How Low-Affinity Antibodies Produced Early in Immune Responses Are Followed by High-Affinity Antibodies Later and in Memory B-Cell Responses [J].

Eisen, Herman N. .

CANCER IMMUNOLOGY RESEARCH, 2014, 2 (05) :381-392

[13] Thrombotic microangiopathy in aHUS and beyond: clinical clues from complement genetics [J].

Fakhouri, Fadi ;

Fremeaux-Bacchi, Veronique .

NATURE REVIEWS NEPHROLOGY, 2021, 17 (08) :543-553

[14] The mucocutaneous and systemic phenotype of dermatomyositis patients with antibodies to MDA5 (CADM-140): A retrospective study [J].

Fiorentino, David ;

Chung, Lorinda ;

Zwerner, Jeff ;

Rosen, Antony ;

Casciola-Rosen, Livia .

JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY, 2011, 65 (01) :25-34

[15] Patient Trajectories Among Persons Hospitalized for COVID-19 A Cohort Study [J].

Garibaldi, Brian T. ;

Fiksel, Jacob ;

Muschelli, John ;

Robinson, Matthew L. ;

Rouhizadeh, Masoud ;

Perin, Jamie ;

Schumock, Grant ;

Nagy, Paul ;

Gray, Josh H. ;

Malapati, Harsha ;

Ghobadi-Krueger, Mariam ;

Niessen, Timothy M. ;

Kim, Bo Soo ;

Hill, Peter M. ;

Ahmed, M. Shafeeq ;

Dobkin, Eric D. ;

Blanding, Renee ;

Abele, Jennifer ;

Woods, Bonnie ;

Harkness, Kenneth ;

Thiemann, David R. ;

Bowring, Mary G. ;

Shah, Aalok B. ;

Wang, Mei-Cheng ;

Bandeen-Roche, Karen ;

Rosen, Antony ;

Zeger, Scott L. ;

Gupta, Amita .

ANNALS OF INTERNAL MEDICINE, 2021, 174 (01) :33-+

[16] Sphingosine kinase type 2 activation by ERK-mediated phosphorylation [J].

Hait, Nitai C. ;

Bellamy, Andrea ;

Milstien, Sheldon ;

Kordula, Tomasz ;

Spiegel, Sarah .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2007, 282 (16) :12058-12065

[17] Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis [J].

Hamming, I ;

Timens, W ;

Bulthuis, MLC ;

Lely, AT ;

Navis, GJ ;

van Goor, H .

JOURNAL OF PATHOLOGY, 2004, 203 (02) :631-637

[18] Systemic complement activation is associated with respiratory failure in COVID-19 hospitalized patients [J].

Holter, Jan C. ;

Pischke, Soeren E. ;

de Boer, Eline ;

Lind, Andreas ;

Jenum, Synne ;

Holten, Aleksander R. ;

Tonby, Kristian ;

Barratt-Due, Andreas ;

Sokolova, Marina ;

Schjalm, Camilla ;

Chaban, Viktoriia ;

Kolderup, Anette ;

Trand, Trung ;

Gjolberg, Torleif Tollefsrud ;

Skeie, Linda G. ;

Hesstvedt, Liv ;

Ormasen, Vidar ;

Fevang, Borre ;

Austad, Cathrine ;

Muller, Karl Erik ;

Fladeby, Cathrine ;

Holberg-Petersen, Mona ;

Halvorsen, Bente ;

Muller, Fredrik ;

Aukrust, Pal ;

Dudman, Susanne ;

Ueland, Thor ;

Andersen, Jan Terje ;

Lund-Johansen, Fridtjof ;

Heggelund, Lars ;

Dyrhol-Riise, Anne M. ;

Mollnes, Tom E. .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2020, 117 (40) :25018-25025

[19]

Horby P, 2021, NEW ENGL J MED, V384, P693, DOI [10.1056/NEJMoa2022926, 10.1056/NEJMoa2021436]

[20] QUANTITATIVE FLUORESCENCE MICROSCOPY ON SINGLE CAPILLARIES - ALPHA-LACTALBUMIN TRANSPORT [J].

HUXLEY, VH ;

CURRY, FE ;

ADAMSON, RH .

AMERICAN JOURNAL OF PHYSIOLOGY, 1987, 252 (01) :H188-H197

← 1 2 3 4 5 →