Autoantibodies to IL-1Ra and PGRN in severe COVID-19 are associated with inflammation-induced hyperphosphorylated antigen isoforms

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.

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Nature Communications
Published
2026-05-27
DOI
https://doi.org/10.1038/s41467-026-73316-5
Primary Topic
Long-Term Effects of COVID-19
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article
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article

Autoantibodies to IL-1Ra and PGRN in severe COVID-19 are associated with inflammation-induced hyperphosphorylated antigen isoforms

Jürgen Rissland, Igor Age Kos, Andreas Link, Thorsten Pfuhl et al.
Nature Communications
Long-Term Effects of COVID-19
article

Autoantibodies to IL-1Ra and PGRN in severe COVID-19 are associated with inflammation-induced hyperphosphorylated antigen isoforms

Jürgen Rissland, Igor Age Kos, Andreas Link, Thorsten Pfuhl, Johannes Lehmann, Angela Thiel-Bodenstaff, Astrid Petersmann, Margarete Scherer, Stephan Stilgenbauer, Frederik Seiler, Evi Regitz, Patrick Wuchter, Birgit Bette, Patricia Wagner, Gereon Gäbelein, Sigrun Smola, Sixten Körper, Lazar Mitrov, Frank Langer, Jochen Pfeifer, Onur Cetin, Dominic Kaddu‐Mulindwa, Yvan Fischer, Soni Savai Pullamsetti, Sebastian Mang, Cihan Papan, Vadim Lesan, Verena Kopfnagel, Claudia Schormann, Christoph Kessel, Ján Pilch, Josephine Braunsteiner, Lorenz Thurner, Sören L. Becker, Hubert Schrezenmeier, Natalie Fadle, Moritz Bewarder, Charlotte Thibeault, Katrin Thieser, Heike Valentin, Stefan Lohse, Klaus‐Dieter Preuss, Dana Stahl, Ira an Haack, Uwe Völker, Bettina Friesenhahn‐Ochs, Sophie Roth, Frank Neumann, Bernhard Thurner, Isabel Bröhl, K Fiedler, Marie-Christin Hoffmann, Michael Böhm, Klaus Roemer, Stefan Hansch, Sina M. Pütz, Carsten Kuenne, Eckard Hamelmann, Torben Rixecker, Philipp M. Lepper, Ramsia Geisler, Marcin Krawczyk, Sabine Ameling, Michael Krawczak, Christian Herr, Christian Werner, Sabine Blaschke, Daniel Pape, Frank Bloos, Jens-Peter Reese, Michael Bauer, Sabine Hanß, André Becker, Christian Lensch, Edgar Dahl, J. Janne Vehreschild, Gabriele Anton, Mario Looso, Robert Bals, Martin Witzenrath, Patrick Meybohm, Marcus Dörr
article en

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.

Nature CommunicationsVol. 17(1)
Goethe University Frankfurt (DE), Witten/Herdecke University (DE), Universität Hamburg (DE), Centre Hospitalier de Luxembourg (LU), University of Cologne (DE), Universität Ulm (DE), Bielefeld University (DE), Hochschule Bielefeld (DE), Heidelberg University (DE), University of Münster (DE), University of Würzburg (DE), Medical University of Warsaw (PL), Universitätsmedizin Greifswald (DE), German Red Cross (DE), University Hospital Heidelberg (DE), University Hospital Regensburg (DE), Hochschule für Angewandte Wissenschaften Kiel (DE), Medizinische Hochschule Hannover (DE), Humboldt-Universität zu Berlin (DE), Institute for Transfusion Medicine (US), Universitätsklinikum Erlangen (DE), Cardiovascular Center Bethanien (DE), Düsseldorf University Hospital (DE), Max Planck Institute for Heart and Lung Research (DE), University Hospital Münster (DE), Evangelisches Krankenhaus Bielefeld (DE), University Medical Center Hamburg-Eppendorf (DE), University Hospital Schleswig-Holstein (DE), Universitätsmedizin Göttingen (DE), Universitätsklinikum Würzburg (DE), Klinikum Bielefeld (DE), Jena University Hospital (DE), Institute of Medical Microbiology and Hygiene (DE), University Hospital Cologne (DE), University Hospital Ulm (DE), Heinrich Heine University Düsseldorf (DE), Technische Hochschule Mittelhessen (DE), University of Duisburg-Essen (DE), University of Göttingen (DE), RWTH Aachen University (DE), Saarland University (DE), University of Lübeck (DE)
Westfälische Wilhelms-Universität Münster, Universität des Saarlandes, South East Physics Network
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Long-Term Effects of COVID-19
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