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DOI 10.1038/s41467-026-73316-5

Медицинская библиотека · Nature communications · 2026

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

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

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Аннотация

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.

Для цитирования: Thurner Lorenz, Fadle Natalie, Thurner Bernhard, Kos Igor Age, Bewarder Moritz, Regitz Evi, Bette Birgit, Fischer Yvan, Lesan Vadim, Rixecker Torben, Hoffmann Marie-Christin, Preuss Klaus-Dieter, Schormann Claudia, Kaddu-Mulindwa Dominic, Roemer Klaus, Cetin Onur, Mang Sebastian, Becker André, Seiler Frederik, Herr Christian, Lensch Christian, Lehmann Johannes, Thiel-Bodenstaff Angela, Link Andreas, Werner Christian, Wuchter Patrick, Körper Sixten, Pfuhl Thorsten, Lohse Stefan, Rissland Jürgen, Thieser Katrin, Pilch Jan, Papan Cihan, Roth Sophie, Vehreschild J Janne, Scherer Margarete, Bröhl Isabel, Wagner Patricia, Witzenrath Martin, Thibeault Charlotte, Haack Ira An, Mitrov Lazar, Pütz Sina M, Reese Jens-Peter, Krawczak Michael, Hamelmann Eckard, Kopfnagel Verena, Fiedler Karin, Geisler Ramsia, Valentin Heike, Stahl Dana, Hanß Sabine, Ameling Sabine, Völker Uwe, Hansch Stefan, Dörr Marcus, Blaschke Sabine, Braunsteiner Josephine, Dahl Edgar, Pape Daniel, Petersmann Astrid, Stilgenbauer Stephan, Bloos Frank, Schrezenmeier Hubert, Langer Frank, Gäbelein Gereon, Friesenhahn-Ochs Bettina, Pfeifer Jochen, Bauer Michael, Becker Sören Leif, Neumann Frank, Böhm Michael, Anton Gabriele, Kuenne Carsten, Pullamsetti Soni Savai, Looso Mario, Bals Robert, Smola Sigrun, Meybohm Patrick, Krawczyk Marcin, Lepper Philipp M, Kessel Christoph. Autoantibodies to IL-1Ra and PGRN in severe COVID-19 are associated with inflammation-induced hyperphosphorylated antigen isoforms.. Nature communications. 2026. DOI: 10.1038/s41467-026-73316-5.

Предметные рубрики MeSH

HumansCOVID-19PhosphorylationInterleukin 1 Receptor Antagonist ProteinAutoantibodiesSARS-CoV-2FemaleInflammationProgranulinsMaleProtein IsoformsInterleukin-1Middle AgedSignal TransductionAgedTumor Necrosis Factor-alphaMonocytesAdult
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