title: HLA-DR1 (DRB1*0101) and DR4 (DRB1*0401) use the same anchor residues for binding an immunodominant peptide derived from human type II collagen.
abstract: Rheumatoid arthritis is an autoimmune disease in which susceptibility is strongly associated with the expression of specific HLA-DR haplotypes, including DR1 (DRB1*0101) and DR4 (DRB1*0401). As transgenes, both of these class II molecules mediate susceptibility to an autoimmune arthritis induced by immunization with human type II collagen (hCII). The dominant T cell response of both the DR1 and DR4 transgenic mice to hCII is focused on the same determinant core, CII(263-270). Peptide binding studies revealed that the affinity of DR1 and DR4 for CII(263-270) was at least 10 times less than that of the model Ag HA(307-319), and that the affinity of DR4 for the CII peptide is 3-fold less than that of DR1. As predicted based on the crystal structures, the majority of the CII-peptide binding affinity for DR1 and DR4 is controlled by the Phe(263); however, unexpectedly the adjacent Lys(264) also contributed significantly to the binding affinity of the peptide. Only these two CII amino acids were found to provide binding anchors. Amino acid substitutions at the remaining positions had either no effect or significantly increased the affinity of the hCII peptide. Affinity-enhancing substitutions frequently involved replacement of a negative charge, or Gly or Pro, hallmark amino acids of CII structure. These data indicate that DR1 and DR4 bind this CII peptide in a nearly identical manner and that the primary structure of CII may dictate a different binding motif for DR1 and DR4 than has been described for other peptides that bind to these alleles.
authors.affiliation: Veterans Affairs Medical Center, Research Service (151), 1030 Jefferson Avenue, Memphis, TN 38104, USA. erosloniec@utmem.edu
authors.forename: Edward F
authors.initials: EF
authors.lastname: Rosloniec
authors.forename: Karen B
authors.initials: KB
authors.lastname: Whittington
authors.forename: Dennis M
authors.initials: DM
authors.lastname: Zaller
authors.forename: Andrew H
authors.initials: AH
authors.lastname: Kang
mesh_terms: D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D001665:Binding Sites; D001667:Binding, Competitive; D002478:Cells, Cultured; D024043:Collagen Type II / Q000276:immunology*; D006684:HLA-DR Antigens / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015798:HLA-DR1 Antigen / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D015804:HLA-DR4 Antigen / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D059811:HLA-DRB1 Chains; D006801:Humans; D006825:Hybridomas; D016056:Immunodominant Epitopes / Q000276:immunology; D008213:Lymphocyte Activation; D051379:Mice; D008969:Molecular Sequence Data; D010455:Peptides / Q000276:immunology; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D017386:Sequence Homology, Amino Acid; D013601:T-Lymphocytes / Q000276:immunology
chemical_list: D024043:Collagen Type II; D006684:HLA-DR Antigens; D015798:HLA-DR1 Antigen; D015804:HLA-DR4 Antigen; D059811:HLA-DRB1 Chains; C553505:HLA-DRB1*04:01 antigen; D016056:Immunodominant Epitopes; D010455:Peptides; D011948:Receptors, Antigen, T-Cell