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

Beryllium (Be)-antigen stimulates tumor necrosis factor-alpha (TNF-alpha) f rom bronchoalveolar lavage (BAL) cells in chronic beryllium disease (CBD). This study tested the hypothesis that high concentrations of Be-stimulated TNF-alpha are related to polymorphisms in the TNF-alpha promoter and clinic al markers of disease severity in CBD. Demographic and clinical information was obtained from patients with CBD (n = 20). TNF-alpha concentrations wer e measured in BAL cell culture supernatant by ELISA. A prior), we categoriz ed CBD subjects as either high or low TNF-alpha producers using a cutoff of 1,500 pg/ml. The TNF-alpha promoter sequence, +64 to -1045, was determined by direct sequencing. Human leukocyte-associated antigen (HLA)-DPB1 and -D RB1 genotyping was determined by polymerase chain reaction (PCR). High Be-s timulated TNF-alpha was associated with TNF2 alleles, Hispanic ethnicity, p resence of HLA-DPB1 Glu69, and absence of HLA-DR4. Be-stimulated TNF-alpha concentrations correlated with markers of disease severity, including chest radiograph, beryllium lymphocyte proliferation, and spirometry. We found n o novel TNF-alpha promoter polymorphisms. These data suggest that the TNF2 A allele at -308 in the TNF-alpha promoter region is a functional polymorph ism, associated with a high level of Be-antigen-stimulated TNF-alpha and th at these high TNF-alpha levels indicate disease severity in CBD.