RT Journal Article
SR Electronic
T1 Molecular basis for increased susceptibility of Indigenous North Americans to seropositive rheumatoid arthritis
JF Annals of the Rheumatic Diseases
JO Ann Rheum Dis
FD BMJ Publishing Group Ltd and European League Against Rheumatism
SP 1915
OP 1923
DO 10.1136/annrheumdis-2017-211300
VO 76
IS 11
A1 Stephen W Scally
A1 Soi-Cheng Law
A1 Yi Tian Ting
A1 Jurgen van Heemst
A1 Jeremy Sokolove
A1 Aaron J Deutsch
A1 E Bridie Clemens
A1 Antonis K Moustakas
A1 George K Papadopoulos
A1 Diane van der Woude
A1 Irene Smolik
A1 Carol A Hitchon
A1 David B Robinson
A1 Elizabeth D Ferucci
A1 Charles N Bernstein
A1 Xiaobo Meng
A1 Vidyanand Anaparti
A1 Tom Huizinga
A1 Katherine Kedzierska
A1 Hugh H Reid
A1 Soumya Raychaudhuri
A1 René E Toes
A1 Jamie Rossjohn
A1 Hani El-Gabalawy
A1 Ranjeny Thomas
YR 2017
UL http://ard.bmj.com/content/76/11/1915.abstract
AB 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.