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  • Pathogenic antibody response to glucose-6-phosphate isomerase targets a modified epitope uniquely exposed on joint cartilage

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Rheumatoid arthritis
Pathogenic antibody response to glucose-6-phosphate isomerase targets a modified epitope uniquely exposed on joint cartilage
  1. Taotao Li1,
  2. Changrong Ge1,
  3. Alexander Krämer1,
  4. Outi Sareila1,2,
  5. Monica Leu Agelii2,
  6. Linda Johansson3,
  7. Kristina Forslind4,5,
  8. Erik Lönnblom1,
  9. Min Yang1,
  10. Bingze Xu1,
  11. Qixing Li6,
  12. Lei Cheng1,
  13. Göran Bergström7,
  14. Gonzalo Fernandez1,
  15. Alf Kastbom8,
  16. Solbritt Rantapää-Dahlqvist3,
  17. Inger Gjertsson2,9,
  18. Rikard Holmdahl1
  1. 1 Section of Medical Inflammation Research, Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden
  2. 2 Department of Rheumatology and Inflammation Research, University of Gothenburg Sahlgrenska Academy, Göteborg, Sweden
  3. 3 Department of Public Health and Clinical Medicine/Rheumatology, Umeå Universitet, Umeå, Sweden
  4. 4 Department of Clinical Sciences, Section of Rheumatology, Faculty of Medicine, Lund University, Lund, Sweden
  5. 5 Spenshult Research and Development Center, Halmstad, Sweden
  6. 6 Center for Medical Immunopharmacology Research, Southern Medical University, Guangzhou, China
  7. 7 Department of Clinical Physiology, Sahlgrenska University Hospital, Göteborg, Sweden
  8. 8 Department of Rheumatology and Department of Biochemical and Clinical Sciences, Linköping University, Linköping, Sweden
  9. 9 Rheumatology, Sahlgrenska University Hospital, Göteborg, Sweden
  1. Correspondence to Professor Rikard Holmdahl, Medical Inflammation Research, Karolinska Institute, Stockholm 171 77, Sweden; rikard.holmdahl{at}ki.se

Abstract

Objectives To identify the arthritogenic B cell epitopes of glucose-6-phosphate isomerase (GPI) and their association with rheumatoid arthritis (RA).

Methods IgG response towards a library of GPI peptides in patients with early RA, pre-symptomatic individuals and population controls, as well as in mice, were tested by bead-based multiplex immunoassays and ELISA. Monoclonal IgG were generated, and the binding specificity and affinity were determined by ELISA, gel size exclusion chromatography, surface plasma resonance and X-ray crystallography. Arthritogenicity was investigated by passive transfer experiments. Antigen-specific B cells were identified by peptide tetramer staining.

Results Peptide GPI293-307 was the dominant B cell epitope in K/BxN and GPI-immunised mice. We could detect B cells and low levels of IgM antibodies binding the GPI293-307 epitopes, and high affinity anti-GPI293-307 IgG antibodies already 7 days after GPI immunisation, immediately before arthritis onset. Transfer of anti-GPI293-307 IgG antibodies induced arthritis in mice. Moreover, anti-GPI293-307 IgG antibodies were more frequent in individuals prior to RA onset (19%) than in controls (7.5%). GPI293-307-specific antibodies were associated with radiographic joint damage. Crystal structures of the Fab–peptide complex revealed that this epitope is not exposed in native GPI but requires conformational change of the protein in inflamed joint for effective recognition by anti-GPI293-307 antibodies.

Conclusions We have identified the major pathogenic B cell epitope of the RA-associated autoantigen GPI, at position 293–307, exposed only on structurally modified GPI on the cartilage surface. B cells to this neo-epitope escape tolerance and could potentially play a role in the pathogenesis of RA.

  • arthritis, experimental
  • arthritis, rheumatoid
  • autoimmunity
  • autoantibodies
  • inflammation

Data availability statement

All data relevant to the mouse study are included in the article or uploaded as supplementary information. Data from several clinical studies (BARFOT, TIRA-2, Umeå, TIRA-1 and WINGA,) cannot be made publicly available due to ethical restrictions. The crystallographic coordinates and structure factors elucidated in this study have been deposited in the Protein Data Bank with the accession code 8BBH.

http://dx.doi.org/10.1136/ard-2022-223633

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    Data availability statement

    All data relevant to the mouse study are included in the article or uploaded as supplementary information. Data from several clinical studies (BARFOT, TIRA-2, Umeå, TIRA-1 and WINGA,) cannot be made publicly available due to ethical restrictions. The crystallographic coordinates and structure factors elucidated in this study have been deposited in the Protein Data Bank with the accession code 8BBH.

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    Footnotes

    • Handling editor Josef S Smolen

    • Twitter @taoli

    • Contributors TL, CG, RH contributed to the study design. TL, CG, AKr, KF, EL, AKa, SR-D, IG contributed to the data acquisition, data analysis and data interpretation. OS, MLA, LJ, MY contributed to the data analysis and data interpretation. TL, RH, OS, CG, AKr, MLA, LJ, KF, SR-D contributed to draft the work. BX, QL, LC, GB, GF contributed to the data acquisition. All authors revised the draft critically for intellectual content and approved the final version of the manuscript. RH has full responsibility for the work and conduct of the study, has access to the data and controlled the decision to publish.

    • Funding RH was supported by grants from the Knut and Alice Wallenberg Foundation (KAW 2019.0059), the Swedish Association against Rheumatism (R-757331) and the Swedish Research Council (2019-01209). KF was supported by grants from the Swedish Association against Rheumatism (R-931878) and the Foundation for Assistance to Disabled People in Skåne, Sweden. GB was supported by Heart and Lung foundation (20210383), the Swedish Research Council (2019-01140) and LUA/ALF: ALFGBG-718851.

    • Competing interests RH is the founder, Outi Sareila is an employee and Erik Lönnblom is a consultant of Vacara AB.

    • Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.