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 alleles 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 alpha 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 Lys71<-->Arg interchange (0401<-->0408), which scarcely affects epitope binding, rather than from any other associated polymorphism. Furthermore, we proved our recombinant polypeptides to contain the Escherichia 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 alleles to disease predisposition.
Roth
Sabine
S
Clinical Research Unit for Rheumatology, Albert Ludwigs University, Freiburg, Germany.
Willcox
Nicholas
N
Rzepka
Rita
R
Mayer
Matthias P
MP
Melchers
Inga
I
D019943:Amino Acid Substitution / Q000235:genetics*; D000818:Animals; D017951:Antigen Presentation / Q000235:genetics*; D001120:Arginine / Q000235:genetics; D001172:Arthritis, Rheumatoid / Q000235:genetics* / Q000276:immunology*; D002999:Clone Cells; D018984:Epitopes, T-Lymphocyte / Q000276:immunology / Q000378:metabolism; D029968:Escherichia coli Proteins; D020022:Genetic Predisposition to Disease; D006684:HLA-DR Antigens / Q000235:genetics* / Q000378:metabolism; D018840:HSP70 Heat-Shock Proteins / Q000032:analysis / Q000378:metabolism*; D006801:Humans; D006825:Hybridomas; D007941:Leukemia P388; D008239:Lysine / Q000235:genetics; D051379:Mice; D021122:Protein Subunits; D011950:Receptors, Cholinergic / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D011994:Recombinant Proteins / Q000032:analysis / Q000276:immunology / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D014162:Transfection; D014407:Tumor Cells, Cultured
D018984:Epitopes, T-Lymphocyte; D029968:Escherichia coli Proteins; D006684:HLA-DR Antigens; D018840:HSP70 Heat-Shock Proteins; D021122:Protein Subunits; D011950:Receptors, Cholinergic; D011994:Recombinant Proteins; D001120:Arginine; C063842:dnaK protein, E coli; D008239:Lysine