Possible association of non-binding of HSP70 to HLA-DRB1 peptide sequences and protection from rheumatoid arthritis.
The beta-chains of HLA-DR molecules associated with susceptibility to rheumatoid arthritis (RA) share a common amino acid sequence in their third hypervariable region at position 70-74. This shared epitope could either contribute to preferential binding of a given disease-associated peptide, be involved in disease-induction by molecular mimicry or, by binding to heat shock proteins, influence antigen presentation. It is known that the Escherichia coli M(r)70,000 heat shock protein DnaK can bind peptides from the shared epitope. Using a highly sensitive method, we show that peptides covering the third hypervariable region of associated, but also most of the non-associated HLA-DR alleles, bind to DnaK. Similar binding specificities could be found for the constitutively expressed mammalian M(r)70,000 heat shock protein Hsc73 and the inducible mammalian Hsp72. However, peptides containing the amino acid sequence DERAA, found in HLA-DR alleles and strongly associated with protection from RA, did not bind any HSP70. Thus, our results suggest a possible association of non-binding of HSP70 to HLA-DR molecules or its 70-74 fragments and protection from RA.
Maier
Jan T
JT
Department of Hematology and Oncology, Children's Hospital, University of Tübingen, Hoppe-Seyler-Strasse 1, 72076 Tübingen, Germany.
Haug
Markus
M
Föll
Jürgen L
JL
Beck
Hermann
H
Kalbacher
Hubert
H
Rammensee
Hans-Georg
HG
Dannecker
Günther E
GE
D000483:Alleles; D000595:Amino Acid Sequence; D024342:Amino Acids, Acidic / Q000737:chemistry; D001172:Arthritis, Rheumatoid / Q000235:genetics / Q000517:prevention & control; D001665:Binding Sites; D029968:Escherichia coli Proteins; D006684:HLA-DR Antigens / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D059811:HLA-DRB1 Chains; D018840:HSP70 Heat-Shock Proteins / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry / Q000378:metabolism; D017434:Protein Structure, Tertiary
D024342:Amino Acids, Acidic; D029968:Escherichia coli Proteins; D006684:HLA-DR Antigens; D059811:HLA-DRB1 Chains; D018840:HSP70 Heat-Shock Proteins; D010455:Peptides; C063842:dnaK protein, E coli