A molecular basis for the association of the HLA-DRB1 locus, citrullination, and rheumatoid arthritis Academic Article uri icon

abstract

  • Rheumatoid arthritis (RA) is strongly associated with the human leukocyte antigen (HLA)-DRB1 locus that possesses the shared susceptibility epitope (SE) and the citrullination of self-antigens. We show how citrullinated aggrecan and vimentin epitopes bind to HLA-DRB1*04:01/04. Citrulline was accommodated within the electropositive P4 pocket of HLA-DRB1*04:01/04, whereas the electronegative P4 pocket of the RA-resistant HLA-DRB1*04:02 allomorph interacted with arginine or citrulline-containing epitopes. Peptide elution studies revealed P4 arginine-containing peptides from HLA-DRB1*04:02, but not from HLA-DRB1*04:01/04. Citrullination altered protease susceptibility of vimentin, thereby generating self-epitopes that are presented to T cells in HLA-DRB1*04:01(+) individuals. Using HLA-II tetramers, we observed citrullinated vimentin- and aggrecan-specific CD4(+) T cells in the peripheral blood of HLA-DRB1*04:01(+) RA-affected and healthy individuals. In RA patients, autoreactive T cell numbers correlated with disease activity and were deficient in regulatory T cells relative to healthy individuals. These findings reshape our understanding of the association between citrullination, the HLA-DRB1 locus, and T cell autoreactivity in RA.

authors

  • Scally, SW
  • Petersen, J
  • Law, SC
  • Dudek, NL
  • Nel, HJ
  • Loh, KL
  • Wijeyewickrema, LC
  • Eckle, SBG
  • van Heemst, J
  • Pike, RN
  • McCluskey, J
  • Toes, RE
  • La Gruta, NL
  • Purcell, AW
  • Reid, HH
  • Thomas, R
  • Rossjohn, J

publication date

  • 2013

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