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

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/Phe13? stratifies with ACPA-positive RA, while His13?Ser 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 His13?Ser 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 ?-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, TCR? and ?-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 His13?Ser 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.

SUBMITTER: Scally SW

PROVIDER: S-EPMC6724216 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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

Scally Stephen W SW Law Soi-Cheng SC Ting Yi Tian YT Heemst Jurgen van JV Sokolove Jeremy J Deutsch Aaron J AJ Bridie Clemens E E Moustakas Antonis K AK Papadopoulos George K GK van der Woude Diane D Smolik Irene I Hitchon Carol A CA Robinson David B DB Ferucci Elizabeth D ED Bernstein Charles N CN Meng Xiaobo X Anaparti Vidyanand V Huizinga Tom T Kedzierska Katherine K Reid Hugh H HH Raychaudhuri Soumya S Toes René E RE Rossjohn Jamie J El-Gabalawy Hani H Thomas Ranjeny R

Annals of the rheumatic diseases 20170811 11

<h4>Objective</h4>The pathogenetic mechanisms by which <i>HLA-DRB1</i> alleles are associated with anticitrullinated peptide antibody (ACPA)-positive rheumatoid arthritis (RA) are incompletely understood. RA high-risk <i>HLA-DRB1</i> 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, whil ...[more]

PMID: 28801345

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Project description:ObjectiveRheumatoid arthritis (RA) is characterized by the presence of autoantibodies, including seropositivity for rheumatoid factor (RF) and anti-citrullinated protein antibodies (ACPAs). In addition, antibodies to carbamylated proteins (anti-CarP) are present in patients with RA and are associated with joint damage. This study was undertaken to assess the presence of anti-CarP antibodies in indigenous North Americans (First Nations [FN] populations) with RA compared to their at-risk first-degree relatives (FDRs) and healthy controls.MethodsAnti-CarP IgG and ACPAs (specifically, anti-cyclic citrullinated peptide [anti-CCP] antibodies) were measured by enzyme-linked immunosorbent assay in the sera of FN patients with RA (n = 95), their unaffected FDRs (n = 109), and healthy FN controls (n = 85). Antibodies to additional citrullinated peptides were measured using a multiplex ACPA array, and the number of peptides recognized was reported as an ACPA score. Groups were compared using the chi-square test and Mann-Whitney U test. Associations between RA and seropositivity for RF, ACPAs, and anti-CarP antibodies were determined by logistic regression.ResultsAnti-CarP antibodies were more frequent in FN patients with RA (44.3%) compared to FDRs (18.3%) and FN controls (4.7%) (both P < 0.0001 versus RA). Moreover, anti-CarP antibodies were more frequent in FDRs than in FN controls (P = 0.008). The ACPA score was higher in anti-CCP-positive FN patients with RA than in anti-CCP-positive FN FDRs (median score 7 [interquartile range (IQR) 7] versus median score 1 [IQR 4]; P = 0.04). The association with RA was strongest when all 3 autoantibodies (RF, anti-CCP, and anti-CarP) were present in the patients' serum (odds ratio 194, 95% confidence interval 23-1,609, P < 0.0001).ConclusionAnti-CarP antibodies are prevalent in FN patients with RA and also more common in their at-risk FDRs compared to healthy controls. The results indicate an association of RF, ACPAs, and anti-CarP with RA that is strongest when all 3 autoantibodies are present. These findings may provide new insights into the evolution of autoimmunity in preclinical RA.

Dataset Information

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

Publications

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

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