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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-64Arg 59-71 , vimentin-64Cit 59-71 and fibrinogen β-74Cit 69-81 were solved using X-ray crystallography. Vimentin-64Cit 59-71 -specific and vimentin 59-71 -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 vimentin 59-71 were observed in patients with HLA-DRB1*14:02 + RA and at-risk ACPA - first-degree relatives. HLA-DRB1*14:02-vimentin 59-71 -specific and HLA-DRB1*14:02-vimentin-64Cit 59-71 -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., Competing Interests: 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., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)