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Extended report
Molecular basis for increased susceptibility of Indigenous North Americans to seropositive rheumatoid arthritis
  1. Stephen W Scally1,
  2. Soi-Cheng Law2,
  3. Yi Tian Ting1,
  4. Jurgen van Heemst3,
  5. Jeremy Sokolove4,
  6. Aaron J Deutsch5,
  7. E Bridie Clemens6,
  8. Antonis K Moustakas7,
  9. George K Papadopoulos8,
  10. Diane van der Woude3,
  11. Irene Smolik9,
  12. Carol A Hitchon9,
  13. David B Robinson9,
  14. Elizabeth D Ferucci10,
  15. Charles N Bernstein9,
  16. Xiaobo Meng9,
  17. Vidyanand Anaparti9,
  18. Tom Huizinga3,
  19. Katherine Kedzierska6,
  20. Hugh H Reid1,
  21. Soumya Raychaudhuri11,12,13,14,
  22. René E Toes3,
  23. Jamie Rossjohn1,15,16,
  24. Hani El-Gabalawy9,
  25. Ranjeny Thomas2
  1. 1Department of Biochemistry and Molecular Biology, Infection and Immunity Program, Biomedicine Discovery Institute Monash University, Clayton, Australia
  2. 2The University of Queensland Diamantina Institute, Translational Research Institute, Princess Alexandra Hospital, Brisbane, Australia
  3. 3Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands
  4. 4Department of Medicine/Immunology and Rheumatology, Stanford University, VA Palo Alto Health Care System, Palo Alto, California
  5. 5Division of Genetics, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA
  6. 6Department of Microbiology and Immunology, The University of Melbourne, Peter Doherty Institute for Infection and Immunity, Melbourne, Australia
  7. 7Faculty of Agricultural Technology, Technological Educational Institute of Ionian Islands, Argostoli Kefalonia, Greece
  8. 8Laboratory of Biochemistry and Biophysics, Faculty of Agricultural Technology, Epirus Institute of Technology, Arta, Greece
  9. 9Arthritis Centre, University of Manitoba, Winnipeg, Manitoba, Canada
  10. 10Division of Community Health Services, Alaska Native Tribal Health Consortium, Anchorage, Alaska, USA
  11. 11Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, USA
  12. 12Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, USA
  13. 13Center for Data Sciences, Brigham and Women’s Hospital, Boston, Massachusetts, USA
  14. 14Arthritis Research UK Centre for Genetics and Genomics, University of Manchester, Manchester, UK
  15. 15Institute of Infection and Immunity, Cardiff University School of Medicine, Heath Park, Cardiff, UK
  16. 16Australian Research Council Centre of Excellence in Advanced Molecular Imaging, Monash University, Clayton, Australia
  1. Correspondence to Professor Ranjeny Thomas, University of Queensland Diamantina Institute, Level 4, R Wing, Princess Alexandra Hospital, Ipswich Road, Woolloongabba 4102, Queensland, Australia; ranjeny.thomas{at}


Objective The pathogenetic mechanisms by which HLA-DRB1 alleles are associated with anticitrullinated peptide antibody (ACPA)-positive rheumatoid arthritis (RA) are incompletely understood. RA high-risk HLA-DRB1 alleles are known to share a common motif, the ‘shared susceptibility epitope (SE)’. Here, the electropositive P4 pocket of HLA-DRB1 accommodates self-peptide residues containing citrulline but not arginine. HLA-DRB1 His/Phe13β stratifies with ACPA-positive RA, while His13βSer polymorphisms stratify with ACPA-negative RA and RA protection. Indigenous North American (INA) populations have high risk of early-onset ACPA-positive RA, whereby HLA-DRB1*04:04 and HLA-DRB1*14:02 are implicated as risk factors for RA in INA. However, HLA-DRB1*14:02 has a His13βSer polymorphism. Therefore, we aimed to verify this association and determine its molecular mechanism.

Methods HLA genotype was compared in 344 INA patients with RA and 352 controls. Structures of HLA-DRB1*1402-class II loaded with vimentin-64Arg59-71, vimentin-64Cit59-71 and fibrinogen β−74Cit69-81 were solved using X-ray crystallography. Vimentin-64Cit59-71-specific and vimentin59-71-specific CD4+ T cells were characterised by flow cytometry using peptide-histocompatibility leukocyte antigen (pHLA) tetramers. After sorting of antigen-specific T cells, TCRα and β-chains were analysed using multiplex, nested PCR and sequencing.

Results ACPA+ RA in INA was independently associated with HLA-DRB1*14:02. Consequent to the His13βSer polymorphism and altered P4 pocket of HLA-DRB1*14:02, both citrulline and arginine were accommodated in opposite orientations. Oligoclonal autoreactive CD4+ effector T cells reactive with both citrulline and arginine forms of vimentin59-71 were observed in patients with HLA-DRB1*14:02+ RA and at-risk ACPA- first-degree relatives. HLA-DRB1*14:02-vimentin59-71-specific and HLA-DRB1*14:02-vimentin-64Cit59-71-specific CD4+ memory T cells were phenotypically distinct populations.

Conclusion HLA-DRB1*14:02 broadens the capacity for citrullinated and native self-peptide presentation and T cell expansion, increasing risk of ACPA+ RA.

  • rheumatoid arthritis
  • T cells
  • autoimmunity

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  • Contributors Concept and design of the study: RT, HE-G, JR, RET, SWS, S-CL. Data collection, data analysis and interpretation: SWS, S-CL, YTT, JvH, JS, AJD, EBC, AKM, GKP, DvdW, IS, CAH, DBR, EDF, CNB, XM, VA, TH, KK, HHR, SR. Manuscript preparation: SWS, S-CL, JvH, RT, JR, RET, HE-G. All authors revised and approved the manuscript to be published.

  • Funding This work was supported by the Australian National Health and Medical Research Council (NHMRC), Australian Research Council (ARC) and Canadian Institutes of Health Research (CIHR: MOP77700) funding. JR is an ARC Australian Laureate Fellow and RT an NHMRC Fellow.

  • Competing interests There was no commercial support for this work. However we wish to declare that RT is a director of a spin-off company that is commercialising antigen-specific immunotherapy for rheumatoid arthritis.

  • Ethics approval University of Manitoba, Alaska Area Institutional Review Board, Metro South HREC, University of Queensland HREC.

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

  • Data sharing statement No additional data are available.