Regulation of autoantibody activity by the IL-23-TH17 axis determines the onset of autoimmune disease.
The checkpoints and mechanisms that contribute to autoantibody-driven disease are as yet incompletely understood. Here we identified the axis of interleukin 23 (IL-23) and the TH17 subset of helper T cells as a decisive factor that controlled the intrinsic inflammatory activity of autoantibodies and triggered the clinical onset of autoimmune arthritis. By instructing B cells in an IL-22- and IL-21-dependent manner, TH17 cells regulated the expression of β-galactoside α2,6-sialyltransferase 1 in newly differentiating antibody-producing cells and determined the glycosylation profile and activity of immunoglobulin G (IgG) produced by the plasma cells that subsequently emerged. Asymptomatic humans with rheumatoid arthritis (RA)-specific autoantibodies showed identical changes in the activity and glycosylation of autoreactive IgG antibodies before shifting to the inflammatory phase of RA; thus, our results identify an IL-23-TH17 cell-dependent pathway that controls autoantibody activity and unmasks a preexisting breach in immunotolerance.
Department of Internal Medicine 3 and Institute for Clinical Immunology, University Hospital Erlangen, Erlangen, Germany.|Nikolaus-Fiebiger Center for Molecular Medicine, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany.
René
R
Pfeifle
Department of Internal Medicine 3 and Institute for Clinical Immunology, University Hospital Erlangen, Erlangen, Germany.|Nikolaus-Fiebiger Center for Molecular Medicine, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany.
Tobias
T
Rothe
Department of Internal Medicine 3 and Institute for Clinical Immunology, University Hospital Erlangen, Erlangen, Germany.|Nikolaus-Fiebiger Center for Molecular Medicine, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany.
Natacha
N
Ipseiz
Department of Rheumatology, Leiden University Medical Centre, Leiden, the Netherlands.
Hans U
HU
Scherer
Department of Internal Medicine 3 and Institute for Clinical Immunology, University Hospital Erlangen, Erlangen, Germany.|Nikolaus-Fiebiger Center for Molecular Medicine, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany.
Stephan
S
Culemann
Department of Internal Medicine 3 and Institute for Clinical Immunology, University Hospital Erlangen, Erlangen, Germany.
Ulrike
U
Harre
Department of Internal Medicine 3 and Institute for Clinical Immunology, University Hospital Erlangen, Erlangen, Germany.|Nikolaus-Fiebiger Center for Molecular Medicine, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany.
Jochen A
JA
Ackermann
Nikolaus-Fiebiger Center for Molecular Medicine, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany.|Institute of Genetics at the Department of Biology, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany.
Martina
M
Seefried
Department of Internal Medicine 3 and Institute for Clinical Immunology, University Hospital Erlangen, Erlangen, Germany.
Arnd
A
Kleyer
Department of Internal Medicine 3 and Institute for Clinical Immunology, University Hospital Erlangen, Erlangen, Germany.|Nikolaus-Fiebiger Center for Molecular Medicine, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany.
Stefan
S
Uderhardt
Department of Internal Medicine 3 and Institute for Clinical Immunology, University Hospital Erlangen, Erlangen, Germany.|Nikolaus-Fiebiger Center for Molecular Medicine, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany.
Benjamin
B
Haugg
Department of Internal Medicine 3 and Institute for Clinical Immunology, University Hospital Erlangen, Erlangen, Germany.
Axel J
AJ
Hueber
Nikolaus-Fiebiger Center for Molecular Medicine, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany.|Division of Molecular Immunology, Department of Internal Medicine 3, University Hospital Erlangen, Erlangen, Germany.
Patrick
0000-0002-7577-070X
P
Daum
Department of Dermatology, Laboratory of Dendritic Cell Biology, University Hospital Erlangen, Erlangen, Germany.
Gordon F
GF
Heidkamp
Medical Inflammation Research, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
Changrong
C
Ge
Institute of Genetics at the Department of Biology, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany.
Sybille
S
Böhm
Institute of Genetics at the Department of Biology, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany.
Anja
A
Lux
Nikolaus-Fiebiger Center for Molecular Medicine, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany.|Division of Molecular Immunology, Department of Internal Medicine 3, University Hospital Erlangen, Erlangen, Germany.
Wolfgang
W
Schuh
Department of Internal Medicine 3 and Institute for Clinical Immunology, University Hospital Erlangen, Erlangen, Germany.
Iryna
I
Magorivska
Medical Inflammation Research, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
Kutty S
0000-0001-7790-8197
KS
Nandakumar
Medical Inflammation Research, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
Erik
E
Lönnblom
Department of Medicine 1, University Hospital Erlangen, Erlangen, Germany.
Christoph
C
Becker
Department of Dermatology, Laboratory of Dendritic Cell Biology, University Hospital Erlangen, Erlangen, Germany.
Diana
D
Dudziak
Center for Proteomics and Metabolomics, Leiden University Medical Center, Leiden, the Netherlands.
Manfred
M
Wuhrer
Department of Rheumatology, Leiden University Medical Centre, Leiden, the Netherlands.|Center for Proteomics and Metabolomics, Leiden University Medical Center, Leiden, the Netherlands.|Institut de Pharmacologie et de Biologie Structurale, Université de Toulouse, CNRS, UPS, France.
Yoann
0000-0003-4482-2199
Y
Rombouts
Center for Proteomics and Metabolomics, Leiden University Medical Center, Leiden, the Netherlands.
Carolien A
CA
Koeleman
Department of Rheumatology, Leiden University Medical Centre, Leiden, the Netherlands.
René
R
Toes
Nikolaus-Fiebiger Center for Molecular Medicine, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany.|Institute of Genetics at the Department of Biology, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany.
Thomas H
TH
Winkler
Medical Inflammation Research, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
Rikard
0000-0002-4969-2576
R
Holmdahl
Department of Internal Medicine 3 and Institute for Clinical Immunology, University Hospital Erlangen, Erlangen, Germany.
Martin
0000-0002-0258-2484
M
Herrmann
Division of Rheumatology, Internal Medicine 3, Medical University Vienna, Vienna, Austria.
Stephan
0000-0002-2758-4400
S
Blüml
Institute of Genetics at the Department of Biology, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany.
Falk
F
Nimmerjahn
Department of Internal Medicine 3 and Institute for Clinical Immunology, University Hospital Erlangen, Erlangen, Germany.
Georg
G
Schett
Department of Internal Medicine 3 and Institute for Clinical Immunology, University Hospital Erlangen, Erlangen, Germany.|Nikolaus-Fiebiger Center for Molecular Medicine, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany.
Gerhard
G
Krönke
D000818:Animals; D001172:Arthritis, Rheumatoid / Q000276:immunology*; D001323:Autoantibodies / Q000378:metabolism*; D001402:B-Lymphocytes / Q000276:immunology*; D002454:Cell Differentiation; D002478:Cells, Cultured; D004195:Disease Models, Animal; D006031:Glycosylation; D006801:Humans; D007108:Immune Tolerance; D007074:Immunoglobulin G / Q000378:metabolism*; D053759:Interleukin-23 / Q000378:metabolism*; D007378:Interleukins / Q000378:metabolism; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D012799:Sialyltransferases / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D058504:Th17 Cells / Q000276:immunology*; D000094802:beta-D-Galactoside alpha 2-6-Sialyltransferase; D000097043:Interleukin-22; D000098546:Interleukin-21
D001323:Autoantibodies; D007074:Immunoglobulin G; D053759:Interleukin-23; D007378:Interleukins; D012799:Sialyltransferases; D000094802:beta-D-Galactoside alpha 2-6-Sialyltransferase; D000097043:Interleukin-22; D000098546:Interleukin-21