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 Be2+ 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.