Beryllium-Induced Hypersensitivity: Genetic Susceptibility and Neoantigen Generation.

Andrew P Fontenot, Michael T Falta, John W Kappler, Shaodong Dai, Amy S McKee

Journal: Journal of immunology (Baltimore, Md. : 1950) 2016;196(1):22-7

PMID: 26685315

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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.

Address: 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; [email protected].; 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; Howard Hughes Medical Institute, National Jewish Health, Denver, CO 80206; and Department of Biomedical Research, National Jewish Health, Denver, CO 80206.; Department of Immunology and Microbiology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045; Department of Biomedical Research, National Jewish Health, Denver, CO 80206.

DOI: 10.4049/jimmunol.1502011