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.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.


  1. 1.

    & The pathogenesis of rheumatoid arthritis. N. Engl. J. Med. 365, 2205–2219 (2011).

  2. 2.

    et al. Arthritis critically dependent on innate immune system players. Immunity 16, 157–168 (2002).

  3. 3.

    et al. Essential role for the C5a receptor in regulating the effector phase of synovial infiltration and joint destruction in experimental arthritis. J. Exp. Med. 196, 1461–1471 (2002).

  4. 4.

    , & Induction and suppression of collagen-induced arthritis is dependent on distinct Fcγ receptors. J. Exp. Med. 191, 1611–1616 (2000).

  5. 5.

    , , & B cell-deficient mice do not develop type II collagen-induced arthritis (CIA). Clin. Exp. Immunol. 111, 521–526 (1998).

  6. 6.

    , , & Arthritis provoked by linked T and B cell recognition of a glycolytic enzyme. Science 286, 1732–1735 (1999).

  7. 7.

    , , , & Characterization of the antibody response in mice with type II collagen-induced arthritis, using monoclonal anti-type II collagen antibodies. Arthritis Rheum. 29, 400–410 (1986).

  8. 8.

    , & Anti-CCP antibodies: the past, the present and the future. Nat. Rev. Rheumatol. 7, 391–398 (2011).

  9. 9.

    B cell depletion in early rheumatoid arthritis: a new concept in therapeutics. Ann. NY Acad. Sci. 1173, 729–735 (2009).

  10. 10.

    et al. Antibodies against cyclic citrullinated peptide and IgA rheumatoid factor predict the development of rheumatoid arthritis. Arthritis Rheum. 48, 2741–2749 (2003).

  11. 11.

    et al. A combination of autoantibodies to cyclic citrullinated peptide (CCP) and HLA-DRB1 locus antigens is strongly associated with future onset of rheumatoid arthritis. Arthritis Res. Ther. 6, R303–R308 (2004).

  12. 12.

    et al. Anticitrullinated protein antibody, but not its titer, is a predictor of radiographic progression and disease activity in rheumatoid arthritis. J. Rheumatol. 39, 694–700 (2012).

  13. 13.

    , , , & Levels of anti-citrullinated protein antibodies and IgM rheumatoid factor are not associated with outcome in early arthritis patients: a cohort study. Arthritis Res. Ther. 12, R8 (2010).

  14. 14.

    The IL-23-IL-17 axis in inflammatory arthritis. Nat. Rev. Rheumatol. 11, 425–429 (2015).

  15. 15.

    et al. Role of Th17 cells in human autoimmune arthritis. Arthritis Rheum. 62, 2876–2885 (2010).

  16. 16.

    et al. Divergent pro- and antiinflammatory roles for IL-23 and IL-12 in joint autoimmune inflammation. J. Exp. Med. 198, 1951–1957 (2003).

  17. 17.

    et al. Th1 but not Th17 cells predominate in the joints of patients with rheumatoid arthritis. Ann. Rheum. Dis. 67, 1299–1304 (2008).

  18. 18.

    IL-17 producing T cells in mouse models of multiple sclerosis and rheumatoid arthritis. J. Mol. Med. 90, 613–624 (2012).

  19. 19.

    & Autoantigens and immune pathways in rheumatoid arthritis. Crit. Rev. Immunol. 22, 281–293 (2002).

  20. 20.

    & Antibody-mediated modulation of immune responses. Immunol. Rev. 236, 265–275 (2010).

  21. 21.

    et al. Recapitulation of IVIG anti-inflammatory activity with a recombinant IgG Fc. Science 320, 373–376 (2008).

  22. 22.

    et al. IL-23 dependent and independent stages of experimental arthritis: no clinical effect of therapeutic IL-23p19 inhibition in collagen-induced arthritis. PLoS One 8, e57553 (2013).

  23. 23.

    et al. Proinflammatory T helper type 17 cells are effective B-cell helpers. Proc. Natl. Acad. Sci. USA 107, 14292–14297 (2010).

  24. 24.

    et al. Plasticity of TH17 cells in Peyer's patches is responsible for the induction of T cell-dependent IgA responses. Nat. Immunol. 14, 372–379 (2013).

  25. 25.

    et al. Interleukin 17-producing T helper cells and interleukin 17 orchestrate autoreactive germinal center development in autoimmune BXD2 mice. Nat. Immunol. 9, 166–175 (2008).

  26. 26.

    et al. Gut-residing segmented filamentous bacteria drive autoimmune arthritis via T helper 17 cells. Immunity 32, 815–827 (2010).

  27. 27.

    et al. Glycan profiling of anti-citrullinated protein antibodies isolated from human serum and synovial fluid. Arthritis Rheum. 62, 1620–1629 (2010).

  28. 28.

    et al. Anti-citrullinated protein antibodies acquire a pro-inflammatory Fc glycosylation phenotype prior to the onset of rheumatoid arthritis. Ann. Rheum. Dis. 74, 234–241 (2015).

  29. 29.

    et al. Tolerance induction with T cell-dependent protein antigens induces regulatory sialylated IgGs. The Journal of allergy and clinical immunology 129, 1647–1655 e1613 (2012).

  30. 30.

    et al. T cell-independent B cell activation induces immunosuppressive sialylated IgG antibodies. J. Clin. Invest. 123, 3788–3796 (2013).

  31. 31.

    et al. Efficacy and safety of secukinumab in patients with rheumatoid arthritis: a phase II, dose-finding, double-blind, randomised, placebo controlled study. Ann. Rheum. Dis. 72, 863–869 (2013).

  32. 32.

    et al. Cutting edge: IL-23 cross-regulates IL-12 production in T cell-dependent experimental colitis. J. Immunol. 177, 2760–2764 (2006).

  33. 33.

    & Efficient promotion of collagen antibody induced arthritis (CAIA) using four monoclonal antibodies specific for the major epitopes recognized in both collagen induced arthritis and rheumatoid arthritis. J. Immunol. Methods 304, 126–136 (2005).

  34. 34.

    et al. Autoantibody profiling in multiple sclerosis using arrays of human protein fragments. Mol. Cell. Proteomics 12, 2657–2672 (2013).

  35. 35.

    et al. Type II collagen antibody response is enriched in the synovial fluid of rheumatoid joints and directed to the same major epitopes as in collagen induced arthritis in primates and mice. Arthritis Res. Ther. 16, R143 (2014).

  36. 36.

    et al. Glycosylation of immunoglobulin G determines osteoclast differentiation and bone loss. Nat. Commun. 6, 6651 (2015).

  37. 37.

    et al. Extensive glycosylation of ACPAs-IgG variable domains modulates binding to citrullinated antigens in rheumatoid arthritis. Ann. Rheum. Dis. 75, 578–585 (2015).

  38. 38.

    et al. Fc specific IgG glycosylation profiling by robust nano-reverse phase HPLC-MS using a sheath-flow ESI sprayer interface. J. Proteomics 75, 1318–1329 (2012).

  39. 39.

    , & Mechanisms of tolerance induction in major histocompatibility complex class II-restricted T cells specific for a blood-borne self-antigen. J. Exp. Med. 180, 2089–2099 (1994).

  40. 40.

    et al. An advanced culture method for generating large quantities of highly pure dendritic cells from mouse bone marrow. J. Immunol. Methods 223, 77–92 (1999).

  41. 41.

    et al. Oxidized phospholipids induce expression of human heme oxygenase-1 involving activation of cAMP-responsive element-binding protein. J. Biol. Chem. 278, 51006–51014 (2003).

Download references


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


  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


  1. Search for René Pfeifle in:

  2. Search for Tobias Rothe in:

  3. Search for Natacha Ipseiz in:

  4. Search for Hans U Scherer in:

  5. Search for Stephan Culemann in:

  6. Search for Ulrike Harre in:

  7. Search for Jochen A Ackermann in:

  8. Search for Martina Seefried in:

  9. Search for Arnd Kleyer in:

  10. Search for Stefan Uderhardt in:

  11. Search for Benjamin Haugg in:

  12. Search for Axel J Hueber in:

  13. Search for Patrick Daum in:

  14. Search for Gordon F Heidkamp in:

  15. Search for Changrong Ge in:

  16. Search for Sybille Böhm in:

  17. Search for Anja Lux in:

  18. Search for Wolfgang Schuh in:

  19. Search for Iryna Magorivska in:

  20. Search for Kutty S Nandakumar in:

  21. Search for Erik Lönnblom in:

  22. Search for Christoph Becker in:

  23. Search for Diana Dudziak in:

  24. Search for Manfred Wuhrer in:

  25. Search for Yoann Rombouts in:

  26. Search for Carolien A Koeleman in:

  27. Search for René Toes in:

  28. Search for Thomas H Winkler in:

  29. Search for Rikard Holmdahl in:

  30. Search for Martin Herrmann in:

  31. Search for Stephan Blüml in:

  32. Search for Falk Nimmerjahn in:

  33. Search for Georg Schett in:

  34. Search for Gerhard Krönke in:


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.

Integrated supplementary information

Supplementary information

PDF files

  1. 1.

    Supplementary Text and Figures

    Supplementary Figures 1–6

About this article

Publication history






Further reading