Major differences in antigen-processing correlate with a single Arg71⇆Lys substitution in HLA-DR molecules predisposing to rheumatoid arthritis and with their selective interactions with 70-kDa heat shock protein chaperones

Several HLA-DR allelles are genetically associated with rheumatoid arthritis. DRB1*0401 predominates in Northern Europe and has a characteristic (70)QKRAA motif. This sequence contacts bound peptides and the TCR. Further interactions have been suggested with additional proteins during Ag loading. We explored the much stronger processing/presentation of full-length recombinant human acetylcholine receptor a subunit to a specific T cell clone by APC from DRB1*0401(+) than *0408(+) donors. Using DR*04 transfectants, we show that this difference results largely from the single Lys(71)<---->Arg interchange (0401<---->0408), which scarcely affects epitope binding, rather than from any other associated pollymorphism. Furthermore, we proved our recombinant polypeptides to contain the Eschetichia coli 70-kDa heat shock protein molecule Dnak and its requirement for efficient processing and presentation of the epitope by DRB1*0401(+) cells. According to a recent report, 70-kDa heat shock protein chaperones preferentially bind to the QKRAA, rather than the QRRAA, motif. Variations between the shared epitope motifs QKRAA and QRRAA are emphasized by underlining. We propose that such interactions enhance the intracellular epitope loading of *0401 molecules. They may thus broaden immune responses to pathogens and at least partially explain the distinct contributions of DRB1*0401 and other allelles to disease predisposition.