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

Thurner L, Fadle N, Thurner B, Kos IA, Bewarder M, Regitz E, Bette B, Fischer Y, Lesan V, Rixecker T, Hoffmann MC, Preuss KD, Schormann C, Kaddu-Mulindwa D, Roemer K, Cetin O, Mang S, Becker A, Seiler F, Herr C, Lensch C, Lehmann J, Thiel-Bodenstaff A, Link A, Werner C, Wuchter P, Körper S, Pfuhl T, Lohse S, Rissland J, Thieser K, Pilch J, Papan C, Roth S, Vehreschild JJ, Scherer M, Bröhl I, Wagner P, Witzenrath M, Thibeault C, Haack Ia, Mitrov L, Pütz SM, Reese JP, Krawczak M, Hamelmann E, Kopfnagel V, Fiedler K, Geisler R, Valentin H, Stahl D, Hanß S, Ameling S, Völker U, Hansch S, Dörr M, Blaschke S, Braunsteiner J, Dahl E, Pape D, Petersmann A, Stilgenbauer S, Bloos F, Schrezenmeier H, Langer F, Gäbelein G, Friesenhahn-Ochs B, Pfeifer J, Bauer M, Becker SL, Neumann F, Böhm M, Anton G, Kuenne C, Pullamsetti SS, Looso M, Bals R, Smola S, Meybohm P, Krawczyk M, Lepper PM, Kessel C (2026)

Publication Type: Journal article

Publication year: 2026

Journal

Book Volume: 17

Article Number: 4768

Journal Issue: 1

DOI: 10.1038/s41467-026-73316-5

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.

Involved external institutions

Carl von Ossietzky Universität Oldenburg Germany (DE) Universitätsklinikum Ulm Germany (DE) Universitätsklinikum Jena Germany (DE) Universitätsklinikum des Saarlandes (UKS) Germany (DE) Institut für Klinische Transfusionsmedizin und Immungenetik Ulm (IKT) Germany (DE) Universität Bielefeld Germany (DE) Max Planck Institute for Heart and Lung Research / Max-Planck-Institut für Herz- und Lungenforschung Germany (DE) Universitätsklinikum Hamburg-Eppendorf (UKE) Germany (DE) Rheinisch-Westfälische Technische Hochschule (RWTH) Aachen Germany (DE) Universitätsklinikum Schleswig-Holstein (UKSH) Germany (DE) Universitätsklinikum Würzburg Germany (DE) Universität Münster (ehem. Westfälische Wilhelms-Universität (WWU)) Germany (DE) Universitätsklinikum Mannheim / University Medical Centre Mannheim (Universitätsmedizin Mannheim) Germany (DE) Universitätsmedizin Greifswald / Universitätsklinikum Greifswald Germany (DE) Universitätsklinikum Göttingen Germany (DE) Universitätsklinikum Regensburg Germany (DE) Goethe-Universität Frankfurt am Main Germany (DE) Charité - Universitätsmedizin Berlin Germany (DE) Universitätsklinikum Köln Germany (DE) Julius-Maximilians-Universität Würzburg Germany (DE) Medizinische Hochschule Hannover (MHH) / Hannover Medical School Germany (DE) Klinikverbund Allgäu gGmbH - Klinik Ottobeuren Germany (DE) Universitätsklinikum Aachen (UKA) Germany (DE)

How to cite

APA:

Thurner, L., Fadle, N., Thurner, B., Kos, I.A., Bewarder, M., Regitz, E.,... Kessel, C. (2026). Autoantibodies to IL-1Ra and PGRN in severe COVID-19 are associated with inflammation-induced hyperphosphorylated antigen isoforms. Nature Communications, 17(1). https://doi.org/10.1038/s41467-026-73316-5

MLA:

Thurner, Lorenz, et al. "Autoantibodies to IL-1Ra and PGRN in severe COVID-19 are associated with inflammation-induced hyperphosphorylated antigen isoforms." Nature Communications 17.1 (2026).

BibTeX: Download