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.

Figure 1

Pathogenesis of CBD. A. Beryllium (Be) exposure results in cellular death and the release of DNA and IL-1α into the lung, followed by IL-1R-dependent expression of KC and neutrophil recruitment. Ingestion of Be also results in dendritic cell activation and trafficking to lung-draining lymph nodes. B. Dendritic cells expressing HLA-DP molecules with a glutamic acid at amino acid position 69 of the β-chain present Be (depicted as red star) to CD4⁺ T cells resulting in T cell activation, proliferation, and trafficking to the lung. C. Clonally expanded CD4⁺ T cells in the lung are CD28-independent, express an effector memory T cell phenotype and secrete Th1-type cytokines including IFN-γ, IL-2, and TNF-α. The release of IFN-γ and TNF-α promotes macrophage accumulation, activation, and aggregation, resulting in the development of granulomatous inflammation. Within granulomas, HLA-DP-expressing DCs present the Be-peptide complex to Ag-experienced CD4⁺ T cells.

Figure 2

Beryllium-induced alterations in the structure of the HLA-DP2-mimotope 2 (M2) complex. A. Comparison of the electrostatic surface potential map of the HLA-DP2-M2 complex in the absence (left) and presence (right) of Be is shown (PDB ID code 4P4R)(67). In both cases, the water accessible surfaces surrounding the Be²⁺/Na⁺ binding site of HLA-DP2-M2 complex are shown, viewed looking directly at the areas of contact. The surface is colored by the electrostatic surface potential (red-negative, blue-positive). Gluβ68 underwent most significant change and is circled on the surface map. B. Conformational changes of the residues involved in Be²⁺/Na⁺ coordination are shown. Sidechains of Gluβ26, Gluβ68 and Gluβ69 of the HLA-DP2 β1 helix (magenta) and p4D and p7E of the M2 peptide (yellow) are shown in sticks with CPK coloring. Be²⁺ and Na⁺ are shown as spheres and are colored in green and gold, respectively.