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Ann Rheum Dis. 2017 Nov;76(11):1915-1923. doi: 10.1136/annrheumdis-2017-211300. Epub 2017 Aug 11.

Molecular basis for increased susceptibility of Indigenous North Americans to seropositive rheumatoid arthritis.

Author information

1
Department of Biochemistry and Molecular Biology, Infection and Immunity Program, Biomedicine Discovery Institute Monash University, Clayton, Australia.
2
The University of Queensland Diamantina Institute, Translational Research Institute, Princess Alexandra Hospital, Brisbane, Australia.
3
Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands.
4
Department of Medicine/Immunology and Rheumatology, Stanford University, VA Palo Alto Health Care System, Palo Alto, California.
5
Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
6
Department of Microbiology and Immunology, The University of Melbourne, Peter Doherty Institute for Infection and Immunity, Melbourne, Australia.
7
Faculty of Agricultural Technology, Technological Educational Institute of Ionian Islands, Argostoli Kefalonia, Greece.
8
Laboratory of Biochemistry and Biophysics, Faculty of Agricultural Technology, Epirus Institute of Technology, Arta, Greece.
9
Arthritis Centre, University of Manitoba, Winnipeg, Manitoba, Canada.
10
Division of Community Health Services, Alaska Native Tribal Health Consortium, Anchorage, Alaska, USA.
11
Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, USA.
12
Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, USA.
13
Center for Data Sciences, Brigham and Women's Hospital, Boston, Massachusetts, USA.
14
Arthritis Research UK Centre for Genetics and Genomics, University of Manchester, Manchester, UK.
15
Institute of Infection and Immunity, Cardiff University School of Medicine, Heath Park, Cardiff, UK.
16
Australian Research Council Centre of Excellence in Advanced Molecular Imaging, Monash University, Clayton, Australia.

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.

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.

KEYWORDS:

T cells; autoimmunity; rheumatoid arthritis

PMID:
28801345
DOI:
10.1136/annrheumdis-2017-211300
[Indexed for MEDLINE]

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