PMID: 24190431

 

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Title : A molecular basis for the association of the HLA-DRB1 loc us , citrullination, and rheumatoid arthritis

Abstract :

1. Rheumatoid arthritis (RA) is strongly associated with the human leukocyte antigen ( HLA )-DRB1 loc us that possesses the shared s us ceptibility epitope (SE) and the citrullination of self-antigens
2. We show how citrullinated aggrecan and vimentin epitopes bind to HLA-DRB1 *04:01/04
3. 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
4. Peptide elution studies revealed P4 arginine-containing peptides from HLA-DRB1 *04:02, but not from HLA-DRB1 *04:01/04
5. Citrullination altered protease susceptibility of vimentin , thereby generating self-epitopes that are presented to T cells in HLA-DRB1 *04:01(+) individuals
6. 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
7. In RA patients, autoreactive T cell numbers correlated with disease activity and were deficient in regulatory T cells relative to healthy individuals
8. These findings reshape our understanding of the association between citrullination, the HLA-DRB1 loc us , and T cell autoreactivity in RA