The role of susceptible HLA shared epitopes in rheumatoid arthritis: a proclivity for citrullinated and self peptides (BA7P.158)

Abstract

Abstract Rheumatoid Arthritis (RA) is an autoimmune disorder most strongly linked to the HLA-DRB1 gene locus and associated with antibodies to joint proteins, of which many are citrullinated. Polymorphic positions in the peptide-binding groove of HLA-DRB1 correlate with RA susceptibility, suggesting that these residues mediate binding of arthritogenic peptides. We measured binding of type II collagen259-273 and native and citrullinated forms of vimentin66-78 and α-enolase11-25 to 88 HLA Class II alleles including susceptible and resistant DRB1 alleles. The most susceptible allele, DRB1*04:01, has a strong preference for citrullinated forms of vimentin66-78 and α-enolase11-25. Resistant alleles DRB1*04:02 and *08:01 had either no preference or preferred the native form of these peptides. Mutations at positions 67, 70, 71, 74 or 86 in DRB1*04:01 to the corresponding residues in DRB1*04:02 or *08:01 reduced citrullinated peptide specificity, by increased binding of the native form or decreased binding of the citrullinated. Using DRB1*04:01 restricted collagen259-273 specific T cell hybridomas, we tested the effect of the mutations on T cell response. A good correlation exists between collagen binding and the T cell response, with reduced binding also showing a reduced T cell response. However, while mutation at position 70 from a positively charged amino acid to negative still bound collagen259-273, the T cell response was eliminated.