Severe COVID-19 patients exhibit elevated levels of autoantibodies targeting cardiolipin and platelet glycoprotein with age: a systems biology approach

Dennyson Leandro Fonseca, Interunit Postgraduate Program on Bioinformatics, Institute of Mathematics and Statistics (IME), University of Sao Paulo (USP), Sao Paulo, SP, Brazil. dennyson@usp.br.
Igor Salerno Filgueiras, Department of Immunology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, SP, Brazil.
Alexandre H. Marques, Department of Immunology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, SP, Brazil.
Elroy Vojdani, Regenera Medical 11860 Wilshire Blvd., Ste. 301, Los Angeles, CA, 90025, USA.
Gilad Halpert, Ariel University, Ari'el, Israel.
Yuri Ostrinski, Ariel University, Ari'el, Israel.
Gabriela Crispim Baiocchi, Department of Immunology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, SP, Brazil.
Desirée Rodrigues Plaça, Department of Clinical and Toxicological Analyses, School of Pharmaceutical Sciences, University of São Paulo, São Paulo, Brazil.
Paula P. Freire, Department of Immunology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, SP, Brazil.
Shahab Zaki Pour, Laboratory of Molecular Evolution and Bioinformatics, Department of Microbiology, Biomedical Sciences Institute, University of São Paulo, São Paulo, 05508-000, Brazil.
Guido Moll, Departament of Nephrology and Internal Intensive Care Medicine, Charité University Hospital, Berlin, Germany.
Rusan Catar, Departament of Nephrology and Internal Intensive Care Medicine, Charité University Hospital, Berlin, Germany.
Yael Bublil Lavi, Scakler faculty of medicine, Tel Aviv University, Tel Aviv, Israel.
Jonathan I. Silverberg, Department of Dermatology, George Washington University School of Medicine and Health Sciences, Washington, DC, USA.
Jason Zimmerman, Maimonides Medical Center, Brooklyn, NY, USA.
Gustavo Cabral-Miranda, Department of Immunology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, SP, Brazil.
Robson F. Carvalho, Department of Structural and Functional Biology, Institute of Biosciences, São Paulo State University (UNESP), Botucatu, São Paulo, Brazil.
Taj Ali Khan, Institute of Pathology and Diagnostic Medicine, Khyber Medical University, Peshawar, Pakistan.
Harald Heidecke, CellTrend Gesellschaft mit beschränkter Haftung (GmbH), Luckenwalde, Germany.
Rodrigo J. Dalmolin, Bioinformatics Multidisciplinary Environment, Federal University of Rio Grande do Norte, Natal, Brazil.
Andre Ducati Luchessi, Department of Clinical and Toxicological Analyses, Federal University of Rio Grande do Norte, R.N., Natal, Brazil.
Hans D. Ochs, Department of Pediatrics, University of Washington School of Medicine, and Seattle Children's Research Institute, Seattle, WA, USA.
Lena F. Schimke, Department of Immunology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, SP, Brazil.
Howard Amital, Ariel University, Ari'el, Israel.
Gabriela Riemekasten, Department of Rheumatology, University Medical Center Schleswig-Holstein Campus Lübeck, Lübeck, Germany.
Israel Zyskind, Maimonides Medical Center, Brooklyn, NY, USA.
Avi Z. Rosenberg, Department of Pathology, Johns Hopkins University, Baltimore, MD, USA.
Aristo Vojdani, Department of Immunology, Immunosciences Laboratory, Inc., Los Angeles, CA, USA.
Yehuda Shoenfeld, Zabludowicz Center for Autoimmune Diseases, Sheba Medical Center, Tel-Hashomer, Israel.
Otavio Cabral-Marques, Interunit Postgraduate Program on Bioinformatics, Institute of Mathematics and Statistics (IME), University of Sao Paulo (USP), Sao Paulo, SP, Brazil. otavio.cmarques@usp.br.

Document Type

Journal Article

Publication Date

8-24-2023

Journal

npj aging

Volume

9

Issue

1

DOI

10.1038/s41514-023-00118-0

Abstract

Age is a significant risk factor for the coronavirus disease 2019 (COVID-19) severity due to immunosenescence and certain age-dependent medical conditions (e.g., obesity, cardiovascular disorder, and chronic respiratory disease). However, despite the well-known influence of age on autoantibody biology in health and disease, its impact on the risk of developing severe COVID-19 remains poorly explored. Here, we performed a cross-sectional study of autoantibodies directed against 58 targets associated with autoimmune diseases in 159 individuals with different COVID-19 severity (71 mild, 61 moderate, and 27 with severe symptoms) and 73 healthy controls. We found that the natural production of autoantibodies increases with age and is exacerbated by SARS-CoV-2 infection, mostly in severe COVID-19 patients. Multiple linear regression analysis showed that severe COVID-19 patients have a significant age-associated increase of autoantibody levels against 16 targets (e.g., amyloid β peptide, β catenin, cardiolipin, claudin, enteric nerve, fibulin, insulin receptor a, and platelet glycoprotein). Principal component analysis with spectrum decomposition and hierarchical clustering analysis based on these autoantibodies indicated an age-dependent stratification of severe COVID-19 patients. Random forest analysis ranked autoantibodies targeting cardiolipin, claudin, and platelet glycoprotein as the three most crucial autoantibodies for the stratification of severe COVID-19 patients ≥50 years of age. Follow-up analysis using binomial logistic regression found that anti-cardiolipin and anti-platelet glycoprotein autoantibodies significantly increased the likelihood of developing a severe COVID-19 phenotype with aging. These findings provide key insights to explain why aging increases the chance of developing more severe COVID-19 phenotypes.

Department

Dermatology

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