Session Type: ACR Plenary Session
Session Time: 11:00AM-12:30PM
Large-scale genomic studies have identified many genetic associations with autoimmune diseases, but the precise pathogenetic mechanisms by which the associated genes impact disease susceptibility remain unclear in most cases. Furthermore, interpretations may be skewed by the ethnic mix of the samples. RA is linked to particular HLA-DRB1 alleles. In the current understanding, based largely on studies of Caucasians, alleles associated with ACPA-positive RA share a conserved motif at amino acid positions 11, 13, 71 and 74 of DRβ termed the “shared susceptibility epitope (SE)”. His/Phe13β is associated with ACPA-positive RA, while His13βSer polymorphisms are associated with ACPA-negative RA and RA-protection. Indigenous North American (INA) RA patients have a high prevalence of ACPA. In this population, HLA-DRB1*04:04 and 14:02 are implicated as risk factors for RA. While HLA-DRB1*04:04 has a typical SE His/Phe13β, HLA-DRB1*14:02 unexpectedly has a His13βSer polymorphism. Therefore, we aimed to determine the molecular mechanism explaining the association of HLA-DRB1*14:02with ACPA+ RA in INA.
Methods: Competitive HLA-DR binding assays compared citrullinated and native vimentin peptide binding against HA(305-319) indicator peptide. HLA-DRB1*14:02 molecules with their class II-associated invariant peptide (CLIP) were expressed and purified, then loaded with Vimentin-64Arg(59-71) or Vimentin-64Cit(59-71), and the structure was solved using x-ray crystallography. Single CD4+ T cells were sorted from peripheral blood mononuclear cells (PBMC) of 5 HLA-DRB1*1402+ ACPA+ RA patients and 5 of their HLA-DRB1*1402+ ACPA+ non-RA first-degree relatives, based on staining with fluorescent vimentin-64Cit(59-71)-specific and vimentin(59-71)-specific pHLA tetramers. Paired TCRα/β chains were analyzed using multiplex, nested PCR and sequencing.
Results: In binding studies, HLA-DRB1*14:02 displayed no preference for citrulline residues in the P4 pocket. Structures of HLA-DRB1*14:02 complexed with Vimentin-64Arg(59-71) or Vimentin-64Cit(59-71) showed that both citrulline and arginine were accommodated in the P4-pocket of HLA-DRB1*14:02, in contrast to HLA-DRB1*0401/0404 where citrulline but not arginine was accommodated within the electro-positive P4-pocket. When bound to HLA-DRB1*04:01/04 or HLA-DRB1*14:02, citrulline was upright and TCR-exposed. In contrast, arginine was buried in the P4 pocket of HLA-DRB1*14:02. T cell receptor repertoires of citrullinated and native vimentin-sorted CD4+ T cells were distinct among PBMC of HLA-DRB1*14:02+ ACPA+ RA patients and relatives.
Together, these findings based on SE alleles prevalent among Caucasians and INA suggest a new model for the HLA-DRB1 association with ACPA+ RA, in which the SE shapes the molecular orientation of citrulline and thus the autoreactive citrulline-specific TCR repertoire required for the development of ACPA.
To cite this abstract in AMA style:van Heemst J, Scally S, Law SC, van der Woude D, Hitchon C, Robinson DB, Huizinga TWJ, Reid HH, Toes REM, El-Gabalawy H, Rossjohn J, Thomas R. The Shared Rheumatoid Arthritis HLA-DRB1 Susceptibility Epitope Shapes the Molecular Orientation of Citrulline and the Autoreactive T Cell Receptor Repertoire [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10). https://acrabstracts.org/abstract/the-shared-rheumatoid-arthritis-hla-drb1-susceptibility-epitope-shapes-the-molecular-orientation-of-citrulline-and-the-autoreactive-t-cell-receptor-repertoire/. Accessed April 16, 2021.
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