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Molecular basis for increased susceptibility of Indigenous North Americans to seropositive rheumatoid arthritis.
- Source :
-
Annals of the rheumatic diseases [Ann Rheum Dis] 2017 Nov; Vol. 76 (11), pp. 1915-1923. Date of Electronic Publication: 2017 Aug 11. - Publication Year :
- 2017
-
Abstract
- 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.<br />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 <subscript>59-71</subscript> , vimentin-64Cit <subscript>59-71</subscript> and fibrinogen β-74Cit <subscript>69-81</subscript> were solved using X-ray crystallography. Vimentin-64Cit <subscript>59-71</subscript> -specific and vimentin <subscript>59-71</subscript> -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.<br />Results: ACPA <superscript>+</superscript> 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 <subscript>59-71</subscript> were observed in patients with HLA-DRB1*14:02 <superscript>+</superscript> RA and at-risk ACPA <superscript>-</superscript> first-degree relatives. HLA-DRB1*14:02-vimentin <subscript>59-71</subscript> -specific and HLA-DRB1*14:02-vimentin-64Cit <subscript>59-71</subscript> -specific CD4+ memory T cells were phenotypically distinct populations.<br />Conclusion: HLA-DRB1*14:02 broadens the capacity for citrullinated and native self-peptide presentation and T cell expansion, increasing risk of ACPA+ RA.<br />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.<br /> (© 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.)
- Subjects :
- Alaska ethnology
Alleles
Arginine genetics
Arginine immunology
Autoantibodies blood
Autoantibodies immunology
CD4-Positive T-Lymphocytes immunology
Canada ethnology
Case-Control Studies
Citrulline genetics
Citrulline immunology
Female
Flow Cytometry
Genotype
Humans
Male
Peptides, Cyclic immunology
Polymorphism, Genetic
Risk Factors
Vimentin genetics
Alaska Natives genetics
Arthritis, Rheumatoid ethnology
Arthritis, Rheumatoid genetics
Genetic Predisposition to Disease ethnology
HLA-DRB1 Chains genetics
Indians, North American genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1468-2060
- Volume :
- 76
- Issue :
- 11
- Database :
- MEDLINE
- Journal :
- Annals of the rheumatic diseases
- Publication Type :
- Academic Journal
- Accession number :
- 28801345
- Full Text :
- https://doi.org/10.1136/annrheumdis-2017-211300