title: Beryllium-Induced Hypersensitivity: Genetic Susceptibility and Neoantigen Generation.
abstract: Chronic beryllium (Be) disease is a granulomatous lung disorder that results from Be exposure in a genetically susceptible host. The disease is characterized by the accumulation of Be-responsive CD4(+) T cells in the lung, and genetic susceptibility is primarily linked to HLA-DPB1 alleles possessing a glutamic acid at position 69 of the β-chain. Recent structural analysis of a Be-specific TCR interacting with a Be-loaded HLA-DP2-peptide complex revealed that Be is coordinated by amino acid residues derived from the HLA-DP2 β-chain and peptide and showed that the TCR does not directly interact with the Be(2+) cation. Rather, the TCR recognizes a modified HLA-DP2-peptide complex with charge and conformational changes. Collectively, these findings provide a structural basis for the development of this occupational lung disease through the ability of Be to induce posttranslational modifications in preexisting HLA-DP2-peptide complexes, resulting in the creation of neoantigens.
authors.affiliation: Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045; Department of Immunology and Microbiology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045; andrew.fontenot@ucdenver.edu.
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Fontenot
authors.affiliation: Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045;
authors.forename: Michael T
authors.identifier: http://orcid.org/0000-0002-0835-6904
authors.initials: MT
authors.lastname: Falta
authors.affiliation: Department of Immunology and Microbiology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045; Howard Hughes Medical Institute, National Jewish Health, Denver, CO 80206; and Department of Biomedical Research, National Jewish Health, Denver, CO 80206.
authors.forename: John W
authors.initials: JW
authors.lastname: Kappler
authors.affiliation: Department of Immunology and Microbiology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045; Department of Biomedical Research, National Jewish Health, Denver, CO 80206.
authors.forename: Shaodong
authors.identifier: http://orcid.org/0000-0003-4760-2773
authors.initials: S
authors.lastname: Dai
authors.affiliation: Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045;
authors.forename: Amy S
authors.initials: AS
authors.lastname: McKee
mesh_terms: D001607:Berylliosis / Q000235:genetics* / Q000276:immunology*; D001608:Beryllium / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D020022:Genetic Predisposition to Disease; D059868:HLA-DP beta-Chains / Q000235:genetics / Q000276:immunology*; D006801:Humans; D006967:Hypersensitivity / Q000235:genetics / Q000276:immunology; D008168:Lung / Q000276:immunology / Q000473:pathology; D011499:Protein Processing, Post-Translational / Q000235:genetics; D011948:Receptors, Antigen, T-Cell / Q000276:immunology
chemical_list: D059868:HLA-DP beta-Chains; C071170:HLA-DPB1 antigen; C083176:HLA-DPw2 antigen; D011948:Receptors, Antigen, T-Cell; D001608:Beryllium