6atz
HLA-DRB1*1402 in complex with citrullinated fibrinogen peptide
Structural highlights
DiseaseFIBB_HUMAN Defects in FGB are a cause of congenital afibrinogenemia (CAFBN) [MIM:202400. This rare autosomal recessive disorder is characterized by bleeding that varies from mild to severe and by complete absence or extremely low levels of plasma and platelet fibrinogen. Note=Patients with congenital fibrinogen abnormalities can manifest different clinical pictures. Some cases are clinically silent, some show a tendency toward bleeding and some show a predisposition for thrombosis with or without bleeding. FunctionFIBB_HUMAN Fibrinogen has a double function: yielding monomers that polymerize into fibrin and acting as a cofactor in platelet aggregation. Publication Abstract from PubMedOBJECTIVE: 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/Phe13beta stratifies with ACPA-positive RA, while His13betaSer 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 His13betaSer 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 beta-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, TCRalpha and beta-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 His13betaSer 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. Molecular basis for increased susceptibility of Indigenous North Americans to seropositive rheumatoid arthritis.,Scally SW, Law SC, Ting YT, Heemst JV, Sokolove J, Deutsch AJ, Bridie Clemens E, Moustakas AK, Papadopoulos GK, Woude DV, Smolik I, Hitchon CA, Robinson DB, Ferucci ED, Bernstein CN, Meng X, Anaparti V, Huizinga T, Kedzierska K, Reid HH, Raychaudhuri S, Toes RE, Rossjohn J, El-Gabalawy H, Thomas R Ann Rheum Dis. 2017 Aug 11. pii: annrheumdis-2017-211300. doi:, 10.1136/annrheumdis-2017-211300. PMID:28801345[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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