Genetic factors modify the risk of developing beryllium disease

Chronic beryllium disease (CBD) is a debilitating, granulomatous lung disease that occurs in 1 to 5% of exposed workers. Beryllium stimulates a major histocompatibility Class II-restricted, TH1, CD4+ T cell-mediated immune response. The immunological component of the illness, coupled with the small subset of beryllium workers who develop disease, led researchers to hypothesize that genetic factors modify risk of disease. Analysis of human leukocyte antigen (HLA) genes, the T cell receptor, and tumor necrosis factor (TNF)-alpha focused on three critical steps in the development of beryllium specific immunity. Molecular epidemiological analysis of the association of HLA-DP, -DR, and -DQ has implicated HLA-DPB1E69 allelic variants in disease; however, its role in sensitization is unclear. A single report suggested association between HLA-DQB1G86 and progression from sensitization to disease. A beryllium-specific binding motif was identified in CBD-derived T cell clones. Beryllium-stimulated proliferation using HLA-DPB1*0201 and TCRAV22S1/TCRBVb3 T cell receptors (TCRs) confirmed beryllium specificity of these molecules. The G/A transition at -308 in the TNF-alpha promoter was associated with high concentrations of TNF-alpha in bronchoalveolar lavage and to disease severity. Although these studies are continuing, the data confirm the role of genetic factors in the cellular response to beryllium.