title: HLA-B*0702 antibody epitopes are affected indirectly by distant antigen residues.
abstract: We examine the effect of mutations in the HLA-B*0702 alpha 1 domain on the binding of several well-characterized monoclonal antibodies. BB7.1 recognizes the alpha-helix, with a special requirement for residue 67. Combined with an established requirement for the alpha 2 alpha-helix, BB7.1 appears to span the B*0702 peptide-binding groove. Alternatively, BB7.1 epitope conformation may be altered by distant B*0702 sites. ME1 and B27M1 recognize connecting loop residues 41 and 43 and alpha 1 alpha-helical residues 67-71. Instead of contacting residue 67-71 side chains directly, however, ME1 appears to recognizes a B*0702 configuration that depends upon the proper interaction of these and other HLA residues. In addition to solvent-accessible residues 41 and 43, the B27M1 epitope depends on solvent-inaccessible residue 32 at the bottom of the peptide-binding groove. MB40.2, known to require residues 169-182 near the alpha 2-alpha 3 junction, also requires the proper combination of distant residues in the alpha 1 beta-strand and alpha-helix. The effect of mutations near the peptide-binding groove suggests that bound peptides may directly or indirectly affect HLA epitopes. These results illustrate that HLA epitope conformation is very sensitive to changes at distant HLA sites and forecast that epitope models based on sequential amino acid residues will often fail to predict HLA epitopes.
authors.affiliation: Department of Pathology, University of Iowa, Iowa City 52242.
authors.forename: J A
authors.initials: JA
authors.lastname: McCutcheon
authors.forename: K D
authors.initials: KD
authors.lastname: Smith
authors.forename: A
authors.initials: A
authors.lastname: Valenzuela
authors.forename: K
authors.initials: K
authors.lastname: Aalbers
authors.forename: C T
authors.initials: CT
authors.lastname: Lutz
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology; D001666:Binding Sites, Antibody / Q000276:immunology; D002460:Cell Line; D000939:Epitopes / Q000276:immunology*; D005434:Flow Cytometry; D005805:Genes, MHC Class I / Q000235:genetics; D015235:HLA-B Antigens / Q000235:genetics / Q000276:immunology*; D006801:Humans; D006825:Hybridomas; D016297:Mutagenesis, Site-Directed; D051381:Rats; D014162:Transfection
chemical_list: D000911:Antibodies, Monoclonal; D000939:Epitopes; D015235:HLA-B Antigens