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<p>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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月27日

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  • 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

摘要

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.