Arthritogenic peptide binding to DRB1*01 alleles correlates with susceptibility to rheumatoid arthritis.

ABSTRACT

Genetic susceptibility to rheumatoid arthritis (RA) is often defined by the presence of a shared epitope (QKRAA, QRRAA, or RRRAA) at positions 70-74 in HLA-DRß1. However, DRß1*0101 and 0102 contain the same QRRAA epitope, but differ considerably in their susceptibility to RA. The purpose of this study was to determine if this difference could be explained by their ability to bind three arthritogenic peptides that we have previously shown to bind to the archetypal RA-susceptible allele, DRß1*0401, but not to the resistant DRß1*0801 allele. Binding of type II collagen(258-272), citrullinated and native vimentin(66-78), and citrullinated and native α-enolase(11-25) were measured on cell lines expressing either DRß1*0101, *0102 or *0103 in association with DRα1*0101. DRß1*0101 and *0102 both exhibited a 6.5-fold preference for citrullinated vimentin(66-78) compared to native vimentin. However, DRß1*0101 also exhibited a 1.7-fold preference for citrullinated α-enolase(11-25) and bound collagen(258-272), while DRß1*0102 bound neither of these peptides. Consistent with its known resistance to RA, DRß1*0103 preferentially bound native vimentin(66-78) and α-enolase(11-25) over the citrullinated forms of these peptides, and also failed to bind collagen(258-272). Site-directed mutagenesis was performed to determine which amino acid residues were responsible for the differences between these alleles. Mutating position 86 in DRß1*0101 from glycine to the valine residue found in DRß1*0102 eliminated binding of both citrullinated α-enolase(11-25) and collagen(258-272), thereby recapitulating the peptide-binding profile of DRß1*0102. The difference in susceptibility to rheumatoid arthritis between DRß1*0101 and *0102 thus correlates with the effect of position 86 on the binding of these arthritogenic peptides. Consistent with their association with RA resistance, positions I67, D70 and E71 all contributed to the inability of DRß1*0103 to bind these arthritogenic peptides.