PEPTIDE BINDING-SPECIFICITY OF HLA-DR4 MOLECULES - CORRELATION WITH RHEUMATOID-ARTHRITIS ASSOCIATION

We have investigated whether sequence 67 to 74 shared by beta chains o f rheumatoid arthritis (RA)-associated HLA DR molecules imparts a spec ific pattern of peptide binding. The peptide binding specificity of th e RA associated molecules, DRB10401, DRB1*0404, and the closely relat ed, RA nonassociated DRB10402 was, therefore, determined using design er peptide libraries. The effect of single key residues was tested wit h site-directed mutants of DRB10401. The results have demonstrated st riking differences between RA-linked and unlinked DR allotypes in sele cting the portion of peptides that interacts with the 67-74 area. Most differences were associated with a single amino acid exchange at posi tion 71 of the DR beta chain, and affected the charge of residues pote ntially contacting position 71. The observed binding patterns permitte d an accurate prediction of natural protein derived peptide sequences that bind selectively to RA-associated DR molecules. Thus, the 67-74 r egion, in particular position 71, induces changes of binding specifici ty that correlate with the genetic linkage of RA susceptibility. These findings should facilitate the identification of autoantigenic peptid es involved in the pathogenesis of RA.