Autoantibodies to IL-1Ra and PGRN in severe COVID-19 are associated with inflammation-induced hyperphosphorylated antigen isoforms
- 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
2026-05-27
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.