HLA-DR4 AND HLA-DR10 MOTIFS THAT CARRY SUSCEPTIBILITY TO RHEUMATOID-ARTHRITIS BIND 70-KD HEAT-SHOCK PROTEINS

Most patients with rheumatoid arthritis express particular HLA-DR alle les. The DR beta 1 chains of these alleles share a highly homologous a mino acid motif, in their third hypervariable (HV3) region, and this m otif seems to help the development of rheumatoid arthritis via unknown mechanisms. In an attempt to identify a ligand of this motif, we scre ened bacterial proteins. HV3 peptides from HLA-DRB1 alleles containing a QKRAA or RRRAA motif bound the 70-kD heat shock protein (HSP) from Escherichia coli, dnaK. In lymphoblastoid cells homozygous for these s ame HLA-DRB1 alleles the constitutive 70-kD HSP, HSP73, that targets s elected proteins to lysosomes coprecipitated with HLA-DR. Thus, the QK RAA and RRRAA amino acid motifs of HLA-DR mediate binding of HLA-DR to HSP73. This property may influence the intracellular route, processin g or peptide associations of the HLA-DR beta 1 chain in these two rheu matoid arthritis-associated alleles.