title: Structural basis of chronic beryllium disease: linking allergic hypersensitivity and autoimmunity.
abstract: T-cell-mediated hypersensitivity to metal cations is common in humans. How the T cell antigen receptor (TCR) recognizes these cations bound to a major histocompatibility complex (MHC) protein and self-peptide is unknown. Individuals carrying the MHCII allele, HLA-DP2, are at risk for chronic beryllium disease (CBD), a debilitating inflammatory lung condition caused by the reaction of CD4 T cells to inhaled beryllium. Here, we show that the T cell ligand is created when a Be(2+) cation becomes buried in an HLA-DP2/peptide complex, where it is coordinated by both MHC and peptide acidic amino acids. Surprisingly, the TCR does not interact with the Be(2+) itself, but rather with surface changes induced by the firmly bound Be(2+) and an accompanying Na(+) cation. Thus, CBD, by creating a new antigen by indirectly modifying the structure of preexisting self MHC-peptide complex, lies on the border between allergic hypersensitivity and autoimmunity.
authors.affiliation: Howard Hughes Medical Institute, National Jewish Health, Denver, CO 80206, USA; Department of Biomedical Research, National Jewish Health, Denver, CO 80206, USA; Department of Immunology and Microbiology, University of Colorado Denver School of Medicine, Aurora, CO 80045, USA.
authors.forename: Gina M
authors.initials: GM
authors.lastname: Clayton
authors.affiliation: Department of Biomedical Research, National Jewish Health, Denver, CO 80206, USA; Department of Immunology and Microbiology, University of Colorado Denver School of Medicine, Aurora, CO 80045, USA.
authors.forename: Yang
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Howard Hughes Medical Institute, National Jewish Health, Denver, CO 80206, USA; Department of Biomedical Research, National Jewish Health, Denver, CO 80206, USA; Department of Immunology and Microbiology, University of Colorado Denver School of Medicine, Aurora, CO 80045, USA.
authors.forename: Frances
authors.initials: F
authors.lastname: Crawford
authors.affiliation: Department of Biomedical Research, National Jewish Health, Denver, CO 80206, USA; Department of Immunology and Microbiology, University of Colorado Denver School of Medicine, Aurora, CO 80045, USA.
authors.forename: Andrey
authors.initials: A
authors.lastname: Novikov
authors.affiliation: Department of Biochemistry and Molecular Genetics, Howard Hughes Medical Institute, University of Colorado Denver School of Medicine, Aurora, CO 80045, USA; Department of Biochemistry and Molecular Genetics, University of Colorado Denver School of Medicine, Aurora, CO 80045, USA; Program in Structural Biology and Biochemistry, University of Colorado Denver School of Medicine, Aurora, CO 80045, USA.
authors.forename: Brian T
authors.initials: BT
authors.lastname: Wimberly
authors.affiliation: Department of Biochemistry and Molecular Genetics, Howard Hughes Medical Institute, University of Colorado Denver School of Medicine, Aurora, CO 80045, USA; Department of Biochemistry and Molecular Genetics, University of Colorado Denver School of Medicine, Aurora, CO 80045, USA; Program in Structural Biology and Biochemistry, University of Colorado Denver School of Medicine, Aurora, CO 80045, USA.
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Kieft
authors.affiliation: Department of Medicine, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USA.
authors.forename: Michael T
authors.initials: MT
authors.lastname: Falta
authors.affiliation: Department of Medicine, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USA.
authors.forename: Natalie A
authors.initials: NA
authors.lastname: Bowerman
authors.affiliation: Howard Hughes Medical Institute, National Jewish Health, Denver, CO 80206, USA; Department of Biomedical Research, National Jewish Health, Denver, CO 80206, USA; Department of Immunology and Microbiology, University of Colorado Denver School of Medicine, Aurora, CO 80045, USA; Department of Biochemistry and Molecular Genetics, University of Colorado Denver School of Medicine, Aurora, CO 80045, USA.
authors.forename: Philippa
authors.initials: P
authors.lastname: Marrack
authors.affiliation: Department of Biomedical Research, National Jewish Health, Denver, CO 80206, USA; Department of Immunology and Microbiology, University of Colorado Denver School of Medicine, Aurora, CO 80045, USA; Department of Medicine, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USA.
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Fontenot
authors.affiliation: Department of Biomedical Research, National Jewish Health, Denver, CO 80206, USA; Department of Immunology and Microbiology, University of Colorado Denver School of Medicine, Aurora, CO 80045, USA. Electronic address: dais@njhealth.org.
authors.forename: Shaodong
authors.initials: S
authors.lastname: Dai
authors.affiliation: Howard Hughes Medical Institute, National Jewish Health, Denver, CO 80206, USA; Department of Biomedical Research, National Jewish Health, Denver, CO 80206, USA; Department of Immunology and Microbiology, University of Colorado Denver School of Medicine, Aurora, CO 80045, USA; Program in Structural Biology and Biochemistry, University of Colorado Denver School of Medicine, Aurora, CO 80045, USA. Electronic address: kapplerj@njhealth.org.
authors.forename: John W
authors.initials: JW
authors.lastname: Kappler
mesh_terms: D015551:Autoimmunity; D001607:Berylliosis / Q000276:immunology*; D001608:Beryllium / Q000378:metabolism*; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism*; D018360:Crystallography, X-Ray; D059868:HLA-DP beta-Chains / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D006967:Hypersensitivity / Q000276:immunology*; D008168:Lung / Q000473:pathology; D008958:Models, Molecular; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism*; D012964:Sodium / Q000737:chemistry / Q000378:metabolism
chemical_list: D059868:HLA-DP beta-Chains; C083176:HLA-DPw2 antigen; D011948:Receptors, Antigen, T-Cell; D012964:Sodium; D001608:Beryllium