title: HLA class I-associated diseases with a suspected autoimmune etiology: HLA-B27 subtypes as a model system.
abstract: Although most autoimmune diseases are connected to major histocompatibility complex (MHC) class II alleles, a small number of these disorders exhibit a variable degree of association with selected MHC class I genes, like certain human HLA-A and HLA-B alleles. The basis for these associations, however, has so far remained elusive. An understanding might be obtained by comparing functional, biochemical, and biophysical properties of alleles that are minimally distinct from each other, but are nevertheless differentially associated to a given disease, like the HLA-B*27:05 and HLA-B*27:09 antigens, which differ only by a single amino acid residue (Asp116His) that is deeply buried within the binding groove. We have employed a number of approaches, including X-ray crystallography and isotope-edited infrared spectroscopy, to investigate biophysical characteristics of the two HLA-B27 subtypes complexed with up to ten different peptides. Our findings demonstrate that the binding of these peptides as well as the conformational flexibility of the subtypes is greatly influenced by interactions of the C-terminal peptide residue. In particular, a basic C-terminal peptide residue is favoured by the disease-associated subtype HLA-B*27:05, but not by HLA-B*27:09. This property appears also as the only common denominator of distinct HLA class I alleles, among them HLA-B*27:05, HLA-A*03:01 or HLA-A*11:01, that are associated with diseases suspected to have an autoimmune etiology. We postulate here that the products of these alleles, due to their unusual ability to bind with high affinity to a particular peptide set during positive T cell selection in the thymus, are involved in shaping an abnormal T cell repertoire which predisposes to the acquisition of autoimmune diseases.
authors.affiliation: Institut für Immungenetik, Charité - Universitätmedizin Berlin, Campus Benjamin Franklin, Freie Universität Berlin, Thielallee 73, 14195 Berlin, Germany. barbara.uchanska-ziegler@charite.de
authors.forename: Barbara
authors.initials: B
authors.lastname: Uchanska-Ziegler
authors.forename: Bernhard
authors.initials: B
authors.lastname: Loll
authors.forename: Heinz
authors.initials: H
authors.lastname: Fabian
authors.forename: Chee Seng
authors.initials: CS
authors.lastname: Hee
authors.forename: Wolfram
authors.initials: W
authors.lastname: Saenger
authors.forename: Andreas
authors.initials: A
authors.lastname: Ziegler
mesh_terms: D001327:Autoimmune Diseases / Q000209:etiology* / Q000235:genetics / Q000276:immunology*; D015235:HLA-B Antigens / Q000737:chemistry* / Q000235:genetics / Q000276:immunology*; D015796:HLA-B27 Antigen / Q000737:chemistry* / Q000235:genetics / Q000276:immunology*; D006801:Humans; D018448:Models, Immunological; D017434:Protein Structure, Tertiary / Q000235:genetics; D016176:T-Lymphocyte Subsets / Q000737:chemistry / Q000276:immunology / Q000473:pathology
chemical_list: D015235:HLA-B Antigens; D015796:HLA-B27 Antigen