ArticleNature communications2026
Autoantibodies to IL-1Ra and PGRN in severe COVID-19 are associated with inflammation-induced hyperphosphorylated antigen isoforms.
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82 authors.
Lorenz ThurnerJosé Carreras Center for Immuno- and Gene Therapy and Department of Internal Medicine I, Saarland University, Homburg/Saar, Germany. lorenz.thurner@uks.eu.ORCID 0000-0002-8167-2989
Natalie FadleJosé Carreras Center for Immuno- and Gene Therapy and Department of Internal Medicine I, Saarland University, Homburg/Saar, Germany.
Bernhard ThurnerClinic Network Allgäu, Medical Care Center "Die Kindersprechstunde" Mindelheim, Mindelheim, Germany.
Igor Age KosJosé Carreras Center for Immuno- and Gene Therapy and Department of Internal Medicine I, Saarland University, Homburg/Saar, Germany.
Moritz BewarderJosé Carreras Center for Immuno- and Gene Therapy and Department of Internal Medicine I, Saarland University, Homburg/Saar, Germany.
Evi RegitzJosé Carreras Center for Immuno- and Gene Therapy and Department of Internal Medicine I, Saarland University, Homburg/Saar, Germany.
Birgit BetteJosé Carreras Center for Immuno- and Gene Therapy and Department of Internal Medicine I, Saarland University, Homburg/Saar, Germany.
Yvan FischerInstitute of Physiology, Medical Faculty, RWTH Aachen, Aachen, Germany.
Vadim LesanJosé Carreras Center for Immuno- and Gene Therapy and Department of Internal Medicine I, Saarland University, Homburg/Saar, Germany.
Torben RixeckerDepartment of Internal Medicine V - Pulmonology, Allergology and Critical Care Medicine, Saarland University, Homburg, Germany.
Marie-Christin HoffmannJosé Carreras Center for Immuno- and Gene Therapy and Department of Internal Medicine I, Saarland University, Homburg/Saar, Germany.
Klaus-Dieter PreussJosé Carreras Center for Immuno- and Gene Therapy and Department of Internal Medicine I, Saarland University, Homburg/Saar, Germany.
Claudia SchormannJosé Carreras Center for Immuno- and Gene Therapy and Department of Internal Medicine I, Saarland University, Homburg/Saar, Germany.
Dominic Kaddu-MulindwaJosé Carreras Center for Immuno- and Gene Therapy and Department of Internal Medicine I, Saarland University, Homburg/Saar, Germany.
Klaus RoemerJosé Carreras Center for Immuno- and Gene Therapy and Department of Internal Medicine I, Saarland University, Homburg/Saar, Germany.
Onur CetinJosé Carreras Center for Immuno- and Gene Therapy and Department of Internal Medicine I, Saarland University, Homburg/Saar, Germany.ORCID 0009-0007-3441-7743
Sebastian MangDepartment of Internal Medicine V - Pulmonology, Allergology and Critical Care Medicine, Saarland University, Homburg, Germany.
André BeckerDepartment of Internal Medicine V - Pulmonology, Allergology and Critical Care Medicine, Saarland University, Homburg, Germany.
Frederik SeilerDepartment of Internal Medicine V - Pulmonology, Allergology and Critical Care Medicine, Saarland University, Homburg, Germany.
Christian HerrDepartment of Internal Medicine V - Pulmonology, Allergology and Critical Care Medicine, Saarland University, Homburg, Germany.ORCID 0000-0001-9422-6569
Christian LenschDepartment of Internal Medicine V - Pulmonology, Allergology and Critical Care Medicine, Saarland University, Homburg, Germany.
Johannes LehmannDepartment of Medicine II, Saarland University, Homburg, Germany.
Angela Thiel-BodenstaffDepartment of Medicine II, Saarland University, Homburg, Germany.
Andreas LinkDepartment of Internal Medicine III-Cardiology, Saarland University, Homburg, Germany.
Christian WernerDepartment of Internal Medicine III-Cardiology, Saarland University, Homburg, Germany.
Patrick WuchterInstitute of Transfusion Medicine and Immunology, Heidelberg University, Medical Faculty Mannheim, German Red Cross Blood Service of Baden-Württemberg - Hessen gGmbH, Mannheim, Germany.
Sixten KörperInstitute of Clinical Transfusion Medicine and Immunogenetics Ulm, German Red Cross Blood andvTransfusion Service, Baden Wuerttemberg-Hessen, and University Hospital Ulm, Ulm, Germany.
Thorsten PfuhlInstitute of Virology, University of Saarland, Homburg, Germany.
Stefan LohseInstitute of Virology, University of Saarland, Homburg, Germany.ORCID 0000-0003-2529-1900
Jürgen RisslandInstitute of Virology, University of Saarland, Homburg, Germany.
Katrin ThieserInstitute of Virology, University of Saarland, Homburg, Germany.
Jan PilchInstitute of Clinical Haemostaseology and Transfusion Medicine, Homburg, Germany.
Cihan PapanCenter of Infectious disease, Institute of Medical Microbiology and Hygiene, University of Saarland, Homburg, Germany.
Sophie RothCenter of Infectious disease, Institute of Medical Microbiology and Hygiene, University of Saarland, Homburg, Germany.
J Janne VehreschildInstitute for Digital Medicine and Clinical Data Sciences, Faculty of Medicine, Goethe University, Frankfurt a. M, Germany.ORCID 0000-0002-5446-7170
Margarete SchererInstitute for Digital Medicine and Clinical Data Sciences, Faculty of Medicine, Goethe University, Frankfurt a. M, Germany.
Isabel BröhlInstitute for Digital Medicine and Clinical Data Sciences, Faculty of Medicine, Goethe University, Frankfurt a. M, Germany.ORCID 0009-0000-2471-9456
Patricia WagnerInstitute for Digital Medicine and Clinical Data Sciences, Faculty of Medicine, Goethe University, Frankfurt a. M, Germany.
Martin WitzenrathCharité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu, Berlin, Germany.ORCID 0000-0002-9787-5633
Charlotte ThibeaultCharité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu, Berlin, Germany.
Ira An HaackCharité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu, Berlin, Germany.
Lazar MitrovDepartment I of Internal Medicine, Center for Integrated Oncology (CIO) Aachen Bonn Cologne Duesseldorf, University of Cologne, Medical Faculty and University Hospital Cologne, Cologne, Germany.
Sina M PützDepartment I of Internal Medicine, Center for Integrated Oncology (CIO) Aachen Bonn Cologne Duesseldorf, University of Cologne, Medical Faculty and University Hospital Cologne, Cologne, Germany.
Jens-Peter ReeseInstitute for Clinical Epidemiology and Biometry, University of Würzburg, Würzburg, Germany.
Michael KrawczakInstitute of Medical Informatics and Statistics, University Medical Center Schleswig-Holstein, Kiel University, Kiel, Germany.
Eckard HamelmannDepartment of Pediatrics, Children's Center Bethel, Bielefeld, University Hospital OWL, University of Bielefeld, Bielefeld, Germany.
Verena KopfnagelHannover Unified Biobank, Hannover Medical School, Hannover, Germany.
Karin FiedlerInstitute for Digital Medicine and Clinical Data Sciences, Faculty of Medicine, Goethe University, Frankfurt a. M, Germany.
Ramsia GeislerInstitute for Digital Medicine and Clinical Data Sciences, Faculty of Medicine, Goethe University, Frankfurt a. M, Germany.
Heike ValentinIndependent Trusted Third Party of the University Medicine Greifswald, Greifswald, Germany.
Dana StahlIndependent Trusted Third Party of the University Medicine Greifswald, Greifswald, Germany.
Sabine HanßDepartment of Medical Informatics, University Medical Center Göttingen, Göttingen, Germany.
Sabine AmelingDepartment of Functional Genomics, Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, Germany.ORCID 0000-0002-3095-8362
Uwe VölkerDepartment of Functional Genomics, Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, Germany.ORCID 0000-0002-5689-3448
Stefan HanschDepartment for Infectious Diseases and Infection Control, University Hospital Regensburg, Regensburg, Germany.
Marcus DörrDepartment of Internal Medicine B, University Medicine Greifswald, Greifswald, Germany.
Sabine BlaschkeEmergency Department, University Medical Center, Goettingen, Germany.ORCID 0000-0001-8800-7554
Josephine BraunsteinerCenter for Anesthesiology and Intensive Care Medicine, University Hospital UKE, Hamburg-Eppendorf, Hamburg, Germany.
Edgar DahlRWTH centralized Biomaterial Bank (RWTH cBMB), Institute of Pathology, Medical Faculty, RWTH Aachen University, Aachen, Germany.
Daniel PapeDepartment I of Internal Medicine, University Medical Center Schleswig-Holstein Campus Kiel, Kiel, Germany.
Astrid PetersmannInstitute for Clinical Chemistry and Laboratory Medicine, University Medicine Oldenburg, Oldenburg, Germany.
Stephan StilgenbauerComprehensive Cancer Center Ulm and Division of CLL-Internal Medicine III, Ulm University, Ulm, Germany.ORCID 0000-0002-6830-9296
Frank BloosDepartment of Anesthesiology and Intensive Care Medicine, Jena University Hospital, Jena, Germany.ORCID 0000-0002-0767-7941
Hubert SchrezenmeierInstitute of Clinical Transfusion Medicine and Immunogenetics Ulm, German Red Cross Blood andvTransfusion Service, Baden Wuerttemberg-Hessen, and University Hospital Ulm, Ulm, Germany.
Frank LangerDepartment of Thoracic Surgery, Saarland University Medical Center, Homburg/Saar, Germany.
Gereon GäbeleinDepartment of General, Visceral, Vascular and Pediatric Surgery, University of Saarland, Homburg, Germany.
Bettina Friesenhahn-OchsDepartment of Medicine II, Saarland University, Homburg, Germany.
Jochen PfeiferDepartment of Pediatric Cardiology, University of Saarland, Homburg, Germany.ORCID 0000-0003-1673-6285
Michael BauerDepartment of Anesthesiology and Intensive Care Medicine, Jena University Hospital, Jena, Germany.ORCID 0000-0002-1521-3514
Sören Leif BeckerCenter of Infectious disease, Institute of Medical Microbiology and Hygiene, University of Saarland, Homburg, Germany.ORCID 0000-0003-3634-8802
Frank NeumannJosé Carreras Center for Immuno- and Gene Therapy and Department of Internal Medicine I, Saarland University, Homburg/Saar, Germany.
Michael BöhmDepartment of Internal Medicine III-Cardiology, Saarland University, Homburg, Germany.ORCID 0000-0002-2976-2514
Gabriele AntonMedical School East Westphalia-Lippe, Bielefeld University, Bielefeld, Germany.ORCID 0000-0003-0483-892X
Carsten KuenneMax-Planck Institute for Heart and Lung Research, Bad Nauheim, Germany.
Soni Savai PullamsettiMax-Planck Institute for Heart and Lung Research, Bad Nauheim, Germany.
Mario LoosoMax-Planck Institute for Heart and Lung Research, Bad Nauheim, Germany.ORCID 0000-0003-1495-9530
Robert BalsDepartment of Internal Medicine V - Pulmonology, Allergology and Critical Care Medicine, Saarland University, Homburg, Germany.
Sigrun SmolaInstitute of Virology, University of Saarland, Homburg, Germany.ORCID 0000-0003-3289-6545
Patrick MeybohmDepartment of Anesthesiology, Intensive Care, Emergency and Pain Medicine, University Hospital Würzburg, Würzburg, Germany.
Marcin Krawczyk *Department of Medicine II, Saarland University, Homburg, Germany.ORCID 0000-0002-0113-0777
Philipp M Lepper *Department of Internal Medicine V - Pulmonology, Allergology and Critical Care Medicine, Saarland University, Homburg, Germany.
Christoph Kessel *Department of Pediatric Rheumatology and Immunology, University of Münster, Münster, Germany.ORCID 0000-0002-0638-2949
Funding
No grant is acknowledged in the PubMed record.
Abstract
SARS-CoV-2 infection affects multiple immune mechanisms and leads to severe COVID-19 and death, in part related to infection-induced or pre-existing autoantibodies. Here, we describe severe COVID-19 to associate with autoantibodies against interleukin-1 receptor antagonist (IL-1Ra) and progranulin (PGRN), endogenous antagonists of IL-1 and TNF signaling, respectively. These autoantibodies coincide with hyperphosphorylation of IL-1Ra (Thr111) or PGRN (Ser81), form immune complexes independent of phosphorylation, reduce antigen plasma levels, and permit enhanced IL-1 and TNF signaling. Using phage-display selected Fabs specific for hyperphosphorylated isoforms, we track phospho-antigens and autoantibodies in a German national pandemic network cohort. Most seropositive patients show both autoantibodies. Levels peak at baseline and decline over 12 months, with phospho-antigens decreasing before autoantibodies. Seropositivity associates with hyperinflammation and cytokine profiles. Importantly, signaling by key inflammatory cytokines induce IL-1Ra and PGRN hyperphosphorylation in healthy monocytes, but require up to 1000-fold higher doses than in monocytes from previously seropositive severe COVID-19 survivors.
Indexed as
AutoantibodiesCOVID-19Interleukin 1 Receptor Antagonist ProteinProgranulinsAdultAgedFemaleHumansInflammationInterleukin-1MaleMiddle AgedMonocytesPhosphorylationProtein IsoformsSARS-CoV-2AutoantibodiesGRN protein, humanIL1RN protein, humanInterleukin-1Interleukin 1 Receptor Antagonist ProteinProgranulinsProtein IsoformsTumor Necrosis Factor-alpha
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