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; 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

doi:10.1038/s41467-026-73316-5

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

L Lorenz Thurner N Natalie Fadle B Bernhard Thurner I Igor Age Kos M Moritz Bewarder E Evi Regitz B Birgit Bette Y Yvan Fischer V Vadim Lesan T Torben Rixecker M Marie-Christin Hoffmann K Klaus-Dieter Preuss C Claudia Schormann D Dominic Kaddu-Mulindwa K Klaus Roemer O Onur Cetin S Sebastian Mang A André Becker F Frederik Seiler C Christian Herr C Christian Lensch J Johannes Lehmann A Angela Thiel-Bodenstaff A Andreas Link C Christian Werner (Biocenter, Department of Biotechnology and Biophysics, Julius-Maximilians-Universität (JMU) Würzburg, Am Hubland, 97074 Würzburg, Germany) P Patrick Wuchter S Sixten Körper T Thorsten Pfuhl S Stefan Lohse J Jürgen Rissland K Katrin Thieser J Jan Pilch C Cihan Papan S Sophie Roth J J. Janne Vehreschild M Margarete Scherer I Isabel Bröhl P Patricia Wagner M Martin Witzenrath C Charlotte Thibeault I Ira an Haack L Lazar Mitrov S Sina M. Pütz J Jens-Peter Reese M Michael Krawczak E Eckard Hamelmann V Verena Kopfnagel K Karin Fiedler R Ramsia Geisler H Heike Valentin D Dana Stahl S Sabine Hanß S Sabine Ameling (Department of Functional Genomics, Universitätsmedizin Greifswald, Greifswald, Germany) U Uwe Völker (Department of Functional Genomics, Universitätsmedizin Greifswald, Greifswald, Germany) S Stefan Hansch M Marcus Dörr S Sabine Blaschke J Josephine Braunsteiner E Edgar Dahl D Daniel Pape A Astrid Petersmann S Stephan Stilgenbauer (Division of CLL, Department of Internal Medicine III, Ulm University, Ulm, Germany) F Frank Bloos H Hubert Schrezenmeier F Frank Langer G Gereon Gäbelein B Bettina Friesenhahn-Ochs J Jochen Pfeifer M Michael Bauer S Sören Leif Becker F Frank Neumann M Michael Böhm G Gabriele Anton C Carsten Kuenne S Soni Savai Pullamsetti M Mario Looso R Robert Bals S Sigrun Smola P Patrick Meybohm M Marcin Krawczyk P Philipp M. Lepper C Christoph Kessel

Abstract

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.

Download PDF View Original

APA MLA Chicago BibTeX RIS

Article Details

Journal Nature Communications

Volume / Issue Vol. 17, Issue 1

Published May 27, 2026

DOI 10.1038/s41467-026-73316-5

ISSN 2041-1723

Publisher Nature Portfolio

Journal Info

Nature Communications

Nature Portfolio

ISSN: 2041-1723 Open Access Life Sciences

Authors (82)

L

Lorenz Thurner

N

Natalie Fadle

B

Bernhard Thurner

I

Igor Age Kos

M

Moritz Bewarder

E

Evi Regitz

B

Birgit Bette

Y

Yvan Fischer

V

Vadim Lesan

T

Torben Rixecker

M

Marie-Christin Hoffmann

K

Klaus-Dieter Preuss

C

Claudia Schormann

D

Dominic Kaddu-Mulindwa

K

Klaus Roemer

O

Onur Cetin

S

Sebastian Mang

A

André Becker

F

Frederik Seiler

C

Christian Herr

C

Christian Lensch

J

Johannes Lehmann

A

Angela Thiel-Bodenstaff

A

Andreas Link

C

Christian Werner

Biocenter, Department of Biotechnology and Biophysics, Julius-Maximilians-Universität (JMU) Würzburg, Am Hubland, 97074 Würzburg, Germany

P

Patrick Wuchter

S

Sixten Körper

T

Thorsten Pfuhl

S

Stefan Lohse

J

Jürgen Rissland

K

Katrin Thieser

J

Jan Pilch

C

Cihan Papan

S

Sophie Roth

J

J. Janne Vehreschild

M

Margarete Scherer

I

Isabel Bröhl

P

Patricia Wagner

M

Martin Witzenrath

C

Charlotte Thibeault

I

Ira an Haack

L

Lazar Mitrov

S

Sina M. Pütz

J

Jens-Peter Reese

M

Michael Krawczak

E

Eckard Hamelmann

V

Verena Kopfnagel

K

Karin Fiedler

R

Ramsia Geisler

H

Heike Valentin

D

Dana Stahl

S

Sabine Hanß

S

Sabine Ameling

Department of Functional Genomics, Universitätsmedizin Greifswald, Greifswald, Germany

U

Uwe Völker

Department of Functional Genomics, Universitätsmedizin Greifswald, Greifswald, Germany

S

Stefan Hansch

M

Marcus Dörr

S

Sabine Blaschke

J

Josephine Braunsteiner

E

Edgar Dahl

D

Daniel Pape

A

Astrid Petersmann

S

Stephan Stilgenbauer

Division of CLL, Department of Internal Medicine III, Ulm University, Ulm, Germany

F

Frank Bloos

H

Hubert Schrezenmeier

F

Frank Langer

G

Gereon Gäbelein

B

Bettina Friesenhahn-Ochs

J

Jochen Pfeifer

M

Michael Bauer

S

Sören Leif Becker

F

Frank Neumann

M

Michael Böhm

G

Gabriele Anton

C

Carsten Kuenne

S

Soni Savai Pullamsetti

M

Mario Looso

R

Robert Bals

S

Sigrun Smola

P

Patrick Meybohm

M

Marcin Krawczyk

P

Philipp M. Lepper

C

Christoph Kessel

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

Abstract

Article Details

Journal Info

Authors (82)

Related Articles from this Journal

Synthesis of adaptive 15N-nitrosyl-Co7 nanocluster for electrocatalytic C–H functionalization

Pan-Ebolavirus nanoparticle vaccine provides protection in rodents from lethal infection by Zaire and Sudan viruses

Multi-population GWAS meta-analysis identifies bladder cancer susceptibility loci and highlights genetic regulation of smoking-related risk

Genome-wide annotation of human multi-nucleotide variants reveals widespread functional differences from single nucleotide variants

Allele-specific chromatin architecture shapes imprinted domains and coordinates a distal enhancer and antisense transcription at the mouse Mest-Copg2 domain