Binding of conserved islet peptides by human and murine MHC class II molecules associated with susceptibility to type I diabetes.
The major histocompatibility complex (MHC) is the most important susceptibility locus for type I diabetes in humans and NOD mice. NOD mice express a single MHC class II molecule (I-Ag7) which carries a unique beta chain sequence. In humans, DQ alleles that encode DQ8 and DQ2 confer the highest risk for the disease. Soluble DQ8 and I-Ag7 were used to directly compare the binding specificity of these MHC molecules. Peptides from three islet antigens--insulin, GAD 65 and HSP 60--bound to both CQ8 and I-Ag7. These peptides included epitopes that are immunodominant in NOD mice, namely insulin (9-23), GAD (206-220) and HSP 60 (441-460). All of these peptide sequences are highly conserved between the human and murine antigens. The binding specificity of DQ8 and I-Ag7 was similar, but not identical, since two peptides eluted from splenocytes of NOD mice did not bind to DQ8. DQ8 formed long-lived complexes with the majority of these peptides, indicating that DQ8 is not a poor peptide binder. These results demonstrate functional similarities between human and murine MHC class II molecules that confer susceptibility to type I diabetes.
Yu
B
B
Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
Gauthier
L
L
Hausmann
D H
DH
Wucherpfennig
K W
KW
D000595:Amino Acid Sequence; D000818:Animals; D018834:Chaperonin 60 / Q000378:metabolism*; D017124:Conserved Sequence; D003922:Diabetes Mellitus, Type 1 / Q000209:etiology*; D004198:Disease Susceptibility; D005968:Glutamate Decarboxylase / Q000378:metabolism*; D006683:HLA-DQ Antigens / Q000378:metabolism*; D000949:Histocompatibility Antigens Class II / Q000378:metabolism*; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D051379:Mice; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000378:metabolism
D018834:Chaperonin 60; D006683:HLA-DQ Antigens; C109756:HLA-DQ8 antigen; D000949:Histocompatibility Antigens Class II; C407099:I-A g7 antigen; D007328:Insulin; D010446:Peptide Fragments; D005968:Glutamate Decarboxylase