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.).
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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.
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Integrated supplementary information
Supplementary Figure 1 Il23a−/− mice develop regular arthritis induced by the transfer of K/BxN serum.
(a) Clinical scoring of arthritis in wild type (WT) and Il23a−/− mice that received serum from arthritic K/BxN mice. Error bars represent SEM *P<0.05; **P<0.01; ***P<0.001; Student’s t test.
Supplementary Figure 2 Humoral immune response in wild-type and Il23a−/− mice during CIA.
(a-d) Analysis of levels of (a) collagen type II (CII)-specific IgG, (b) CII-specific IgG subsets, (c) IgG specifically directed against murine CII (d) and IgG detecting different murine CII epitopes in the sera of WT and Il23a−/− mice at day 50 after induction of collagen-induced arthritis (CIA). (e) KSCN titration assay for the determination of the binding affinity of CII-specific IgG in WT and Il23a−/− mice. (f,g) Analysis of the appearance of (f) germinal centers and the appearance of germinal center (CD19 pre-gated) B cells (g) at day 26 after induction of CIA in WT and Il23a−/− mice. (h) Measurement of the levels of regular and high affinity antibodies in response to a T cell dependent immunization with 4-hydroxy-3-nitrophenylacetyl (NP) coupled to chicken g-globulin (NP-CGG) in WT and Il23a−/− mice. Error bars represent SEM*P<0.05; **P<0.01; ***P<0.001; Student’s t test.
Supplementary Figure 3 Analysis of the glycostructure of CII-specific IgG by mass spectrometry.
Representative mass spectra illustrating IL-23-dependent changes of the glycosylation at Asn-297 of the indicated IgG subclasses of collagen type II-specific IgG isolated from the sera of WT and Il23a−/− mice at day 50 after induction of CIA.
Supplementary Figure 4 Identification of plasma cells and plasmablasts.
(a) Sorting strategy and sorting purity analysis of splenic plasma cells (CD19+CD138+B220-) and plasmablasts (CD19+CD138lowB220+) for mRNA-analysis. (b) Gating strategy for the flow cytometric analysis of St6gal1 protein expression in splenic Ova-specific plasmacells and plasmacells isolated during collagen-induced arthritis. Plasmacells were gated to be B220lowCD138+Taci+ and Ova+, respectively.
Supplementary Figure 5 Characterization of the TH17 response during CIA.
(a) Flow-cytometric analysis of the content of IL-17-expressing CD3+ T cells in spleen, inguinal lymph nodes (LN) and paws of wild-type (WT) DBA mice at indicated time points during the course of collagen-induced arthritis (CIA). (b) Mean percentage and fold change of the numbers as well as (c) total cells/organ of indicated T cell subsets in spleen, LN and paws of WT DBA/1 mice at indicated time points after induction of CIA. CD4+CD3+ T cells were subcategorized into IFNγ-expressing Th1 cells, IL-4-expressing Th2 cells, IL-17-expressing TH17 cells and FoxP3-expressing Treg cells. (d) Frequency of IL-17-positive, IL-22-positive and IL-17/IL-22 double-positive T cells in spleens and lymph nodes of WT mice at the indicated time points after induction of CIA. (e) Identification of CD4+Bcl-6+IL17+ T cells within germinal centers of the spleen 26 days after induction of CIA (f) Proposed model of the IL23/Th17-mediated control of autoantibody activity. (g) Flow cytometry-based quantification of the expression of the IL-22 receptor (IL22Rα1) on CD19+B220+ B cells that were differentiated into plasmablasts by incubation with LPS (5μg/ml). (h) Quantification of IL-22 receptor (IL-22Rα1) surface expression on splenic CD19+B220+ B cells at day 0 and day 26 after induction of CIA. (i) mRNA expression of IL22Ra1 in in vitro differentiating plasmacells. Error bars represent SEM*P < 0.05, **P < 0.01, ***P < 0.001; Student’s t test. Error bars represent SEM*P < 0.05, **P < 0.01, ***P < 0.001; Student’s t test.
Supplementary Figure 6 Evaluation of the specificity of SNA lectin surface staining for determination of cellular St6gal1 activity.
(a) B and T cells of wild-type (WT) and St6gal1−/− mice were stained with a FITC-coupled SNA-lectin to determine the levels of surface sialic acid. (b) Immunofluorescence microscopy of spleens of WT and St6gal1−/− mice determining the levels of sialic acid on B220+ B cells by co-staining with an antibody against B220 (A488, green) and a SNA lectin (QDot705, red). (c) Human CD19+ B cells were stained with FITC-stained SNA-lectin to determine the levels of surface sialic acid. B cells were pre-treated with neuraminidase (100 mU, 1h at 37°C) or iodate (2mM, 1h at 4°C) to remove sialic acid where indicated. Error bars represent SEM*P < 0.05, **P < 0.01, ***P < 0.001; Student’s t test.
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Pfeifle, R., Rothe, T., Ipseiz, N. et al. Regulation of autoantibody activity by the IL-23–TH17 axis determines the onset of autoimmune disease. Nat Immunol 18, 104–113 (2017). https://doi.org/10.1038/ni.3579
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DOI: https://doi.org/10.1038/ni.3579
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