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http://purl.uniprot.org/citations/28801345 | http://www.w3.org/1999/02/22-rdf-syntax-ns#type | http://purl.uniprot.org/core/Journal_Citation |
http://purl.uniprot.org/citations/28801345 | http://www.w3.org/1999/02/22-rdf-syntax-ns#type | http://purl.uniprot.org/core/Journal_Citation |
http://purl.uniprot.org/citations/28801345 | http://www.w3.org/2000/01/rdf-schema#comment | "ObjectiveThe 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.MethodsHLA 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.ResultsACPA+ 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.ConclusionHLA-DRB1*14:02 broadens the capacity for citrullinated and native self-peptide presentation and T cell expansion, increasing risk of ACPA+ RA."xsd:string |
http://purl.uniprot.org/citations/28801345 | http://purl.org/dc/terms/identifier | "doi:10.1136/annrheumdis-2017-211300"xsd:string |
http://purl.uniprot.org/citations/28801345 | http://purl.org/dc/terms/identifier | "doi:10.1136/annrheumdis-2017-211300"xsd:string |
http://purl.uniprot.org/citations/28801345 | http://purl.uniprot.org/core/author | "Meng X."xsd:string |
http://purl.uniprot.org/citations/28801345 | http://purl.uniprot.org/core/author | "Meng X."xsd:string |
http://purl.uniprot.org/citations/28801345 | http://purl.uniprot.org/core/author | "Scally S.W."xsd:string |
http://purl.uniprot.org/citations/28801345 | http://purl.uniprot.org/core/author | "Scally S.W."xsd:string |
http://purl.uniprot.org/citations/28801345 | http://purl.uniprot.org/core/author | "Thomas R."xsd:string |
http://purl.uniprot.org/citations/28801345 | http://purl.uniprot.org/core/author | "Thomas R."xsd:string |
http://purl.uniprot.org/citations/28801345 | http://purl.uniprot.org/core/author | "Rossjohn J."xsd:string |
http://purl.uniprot.org/citations/28801345 | http://purl.uniprot.org/core/author | "Rossjohn J."xsd:string |
http://purl.uniprot.org/citations/28801345 | http://purl.uniprot.org/core/author | "Ting Y.T."xsd:string |
http://purl.uniprot.org/citations/28801345 | http://purl.uniprot.org/core/author | "Ting Y.T."xsd:string |
http://purl.uniprot.org/citations/28801345 | http://purl.uniprot.org/core/author | "Raychaudhuri S."xsd:string |
http://purl.uniprot.org/citations/28801345 | http://purl.uniprot.org/core/author | "Raychaudhuri S."xsd:string |
http://purl.uniprot.org/citations/28801345 | http://purl.uniprot.org/core/author | "Reid H.H."xsd:string |
http://purl.uniprot.org/citations/28801345 | http://purl.uniprot.org/core/author | "Reid H.H."xsd:string |
http://purl.uniprot.org/citations/28801345 | http://purl.uniprot.org/core/author | "Bernstein C.N."xsd:string |
http://purl.uniprot.org/citations/28801345 | http://purl.uniprot.org/core/author | "Bernstein C.N."xsd:string |
http://purl.uniprot.org/citations/28801345 | http://purl.uniprot.org/core/author | "Law S.C."xsd:string |
http://purl.uniprot.org/citations/28801345 | http://purl.uniprot.org/core/author | "Law S.C."xsd:string |
http://purl.uniprot.org/citations/28801345 | http://purl.uniprot.org/core/author | "Toes R.E."xsd:string |
http://purl.uniprot.org/citations/28801345 | http://purl.uniprot.org/core/author | "Toes R.E."xsd:string |