Autoantibodies to IL-1Ra and PGRN in severe COVID-19 are associated with inflammation-induced hyperphosphorylated antigen isoforms
Year: 2026
Type: article
Study design: Observational Study
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.
Source: Nature Communications
Authors: Lorenz Thurner, Natalie Fadle, Bernhard Thurner, Igor Age Kos, Moritz Bewarder, Evi Regitz, Birgit Bette, Yvan Fischer, Vadim Lesan, Torben Rixecker, Marie-Christin Hoffmann, Klaus-Dieter Preuss, Claudia Schormann, Dominic Kaddu-Mulindwa, Klaus Roemer, Onur Cetin, Sebastian Mang, André Becker, Frederik Seiler, Christian Herr, Christian Lensch, Johannes Lehmann, Angela Thiel-Bodenstaff, Andreas Link, Christian Werner, Patrick Wuchter, Sixten Körper, Thorsten Pfuhl, Stefan Lohse, Jürgen Rissland, Katrin Thieser, Jan Pilch, Cihan Papan, Sophie Roth, J. Janne Vehreschild, Margarete Scherer, Isabel Bröhl, Patricia Wagner, Martin Witzenrath, Charlotte Thibeault, Ira an Haack, Lazar Mitrov, Sina M. Pütz, Jens-Peter Reese, Michael Krawczak, Eckard Hamelmann, Verena Kopfnagel, Karin Fiedler, Ramsia Geisler, Heike Valentin, Dana Stahl, Sabine Hanß, Sabine Ameling, Uwe Völker, Stefan Hansch, Marcus Dörr, Sabine Blaschke, Josephine Braunsteiner, Edgar Dahl, Daniel Pape, Astrid Petersmann, Stephan Stilgenbauer, Frank Bloos, Hubert Schrezenmeier, Frank Langer, Gereon Gäbelein, Bettina Friesenhahn-Ochs, Jochen Pfeifer, Michael Bauer, Sören Leif Becker, Frank Neumann, Michael Böhm, Gabriele Anton, Carsten Kuenne, Soni Savai Pullamsetti, Mario Looso, Robert Bals, Sigrun Smola, Patrick Meybohm, Marcin Krawczyk, Philipp M. Lepper, Christoph Kessel
Institutions: Saarland University, RWTH Aachen University, Universitätsklinikum Erlangen, University Medical Center Hamburg-Eppendorf, German Red Cross, Medizinische Fakultät Mannheim, University Hospital Ulm, Universitätsklinikum des Saarlandes, Goethe University Frankfurt, Humboldt-Universität zu Berlin, Charité - Universitätsmedizin Berlin, University of Cologne, University Hospital Cologne, University of Würzburg, Technische Hochschule Mittelhessen, Christian-Albrechts-Universität zu Kiel, University Hospital Schleswig-Holstein, Bielefeld University, Medizinische Hochschule Hannover, Universitätsmedizin Greifswald, Universität Greifswald, Universitätsmedizin Göttingen, University Hospital Regensburg, Carl von Ossietzky Universität Oldenburg, Universität Ulm, Jena University Hospital, Max Planck Institute for Heart and Lung Research, Universitätsklinikum Würzburg, Medical University of Warsaw, University of Duisburg-Essen, University of Münster
Language: English
Subfield: Infectious Diseases
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $6,990
OpenAlex ID: W7162512646