Abstract

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.

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Acknowledgements

We thank C. Stoll, A. Klej and U. Appelt for technical assistance; Boehringer-Ingelheim for the fully mouse antibody to mouse IL-23p19; MD Bioscience for the collagen-antibody-induced arthritis 'cocktail'; and K. Ralph, D. Souza and G. Nabozny (Boehringer Ingelheim Pharmaceuticals) for technical advice and monoclonal antibody to anti-IL23. Supported by Deutsche Forschungsgemeinschaft (CRC1181 to G.K., G.S., F.N., C.B. and D.D.; SPP1468-IMMUNOBONE to G.K., G.S. and F.N.; and CRC643 to G.S., F.N. and D.D.), the European Union (ERC StG 640087 – SOS to G.K.; MASTERSWITCH project to G.S.; and BTCure to G.S. and C.B.), the Interdisciplinary Centre for Clinical Research, Erlangen (IZKF A55 to G.K.; and A68 to G.K. and F.N.), the Bundesministerium für Bildung und Forschung (METARTHROS to G.K. and G.S.), the Else-Kröner Fresenius Stiftung (2013_A274 to G.K.), the ELAN Fonds of the Universitätsklinikum Erlangen (14-10-17-1 to G.H.), the Strategic Science Foundation (R.H.), the KAWallenberg Fondation (R.H.) and the Bavarian Genome Network (BayGene to D.D.).

Author information

Affiliations

  1. Department of Internal Medicine 3 and Institute for Clinical Immunology, University Hospital Erlangen, Erlangen, Germany.

    • René Pfeifle
    • , Tobias Rothe
    • , Natacha Ipseiz
    • , Stephan Culemann
    • , Ulrike Harre
    • , Jochen A Ackermann
    • , Arnd Kleyer
    • , Stefan Uderhardt
    • , Benjamin Haugg
    • , Axel J Hueber
    • , Iryna Magorivska
    • , Martin Herrmann
    • , Georg Schett
    •  & Gerhard Krönke
  2. Nikolaus-Fiebiger Center for Molecular Medicine, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany.

    • René Pfeifle
    • , Tobias Rothe
    • , Natacha Ipseiz
    • , Stephan Culemann
    • , Jochen A Ackermann
    • , Martina Seefried
    • , Stefan Uderhardt
    • , Benjamin Haugg
    • , Patrick Daum
    • , Wolfgang Schuh
    • , Thomas H Winkler
    •  & Gerhard Krönke
  3. Department of Rheumatology, Leiden University Medical Centre, Leiden, the Netherlands.

    • Hans U Scherer
    • , Yoann Rombouts
    •  & René Toes
  4. Institute of Genetics at the Department of Biology, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany.

    • Martina Seefried
    • , Sybille Böhm
    • , Anja Lux
    • , Thomas H Winkler
    •  & Falk Nimmerjahn
  5. Division of Molecular Immunology, Department of Internal Medicine 3, University Hospital Erlangen, Erlangen, Germany.

    • Patrick Daum
    •  & Wolfgang Schuh
  6. Department of Dermatology, Laboratory of Dendritic Cell Biology, University Hospital Erlangen, Erlangen, Germany.

    • Gordon F Heidkamp
    •  & Diana Dudziak
  7. Medical Inflammation Research, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.

    • Changrong Ge
    • , Kutty S Nandakumar
    • , Erik Lönnblom
    •  & Rikard Holmdahl
  8. Department of Medicine 1, University Hospital Erlangen, Erlangen, Germany.

    • Christoph Becker
  9. Center for Proteomics and Metabolomics, Leiden University Medical Center, Leiden, the Netherlands.

    • Manfred Wuhrer
    • , Yoann Rombouts
    •  & Carolien A Koeleman
  10. Institut de Pharmacologie et de Biologie Structurale, Université de Toulouse, CNRS, UPS, France.

    • Yoann Rombouts
  11. Division of Rheumatology, Internal Medicine 3, Medical University Vienna, Vienna, Austria.

    • Stephan Blüml

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Contributions

R.P. designed the study, performed and interpreted experiments and wrote the manuscript; T.R., N.I., S.C., U.H., J.A.A., M.S., B.H. and P.D. performed experiments and collected and interpreted the data; H.U.S, R.T., T.H.W. and R.H. provided help during the design of the study and wrote the manuscript; A.K., S.U. and A.J.H. designed the study and experiments and interpreted data; G.F.H., C.G., S.Bö., A.L., I.M., K.S.N. and E.L. measured samples and interpreted the data; C.B. was involved in the generation of Il23a−/− mice and provided input; W.S. and D.D. provided expertise and input and wrote the manuscript; M.W., Y.R. and C.A.K. measured and interpreted the glycostructure of IgG; M.H., S Bl., F.N., G.S. and G.K. designed the study and experiments and wrote the manuscript; and all authors read and commented on the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Gerhard Krönke.

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https://doi.org/10.1038/ni.3579

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