High beryllium-stimulated TNF-α is associated with the -308 TNF-α promoter polymorphism and with clinical severity in chronic beryllium disease

Beryllium (Be)-antigen stimulates tumor necrosis factor-alpha (TNF-α) from bronchoalveolar lavage (BAL) cells in chronic beryllium disease (CBD). This study tested the hypothesis that high concentrations of Be-stimulated TNF-α are related to polymorphisms in the TNF-α promoter and clinical markers of disease severity in CBD. Demographic and clinical information was obtained from patients with CBD (n = 20). TNF-α concentrations were measured in BAL cell culture supernatant by ELISA. A priori, we categorized CBD subjects as either high or low TNF-α producers using a cutoff of 1,500 pg/ml. The TNF-α promoter sequence, +64 to -1045, was determined by direct sequencing. Human leukocyte-associated antigen (HLA)-DPB1 and -DRB1 genotyping was determined by polymerase chain reaction (PCR). High Be-stimulated TNF-α was associated with TNF2 alleles, Hispanic ethnicity, presence of HLA-DPB1 Glu69, and absence of HLA-DR4. Be-stimulated TNF-α concentrations correlated with markers of disease severity, including chest radiograph, beryllium lymphocyte proliferation, and spirometry. We found no novel TNF-α promoter polymorphisms. These data suggest that the TNF2 A allele at -308 in the TNF-α promoter region is a functional polymorphism, associated with a high level of Be-antigen-stimulated TNF-α and that these high TNF-α levels indicate disease severity in CBD.