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

Am J Respir Crit Care Med. 2001 Oct 1;164(7):1192-9. doi: 10.1164/ajrccm.164.7.2012123.


Beryllium (Be)-antigen stimulates tumor necrosis factor-alpha (TNF-alpha) from 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 clinical markers of disease severity in CBD. Demographic and clinical information was obtained from patients with CBD (n = 20). TNF-alpha concentrations were measured in BAL cell culture supernatant by ELISA. A priori, we categorized 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 -DRB1 genotyping was determined by polymerase chain reaction (PCR). High Be-stimulated TNF-alpha was associated with TNF2 alleles, Hispanic ethnicity, presence 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 no novel TNF-alpha promoter polymorphisms. These data suggest that the TNF2 A allele at -308 in the TNF-alpha promoter region is a functional polymorphism, associated with a high level of Be-antigen-stimulated TNF-alpha and that these high TNF-alpha levels indicate disease severity in CBD.

Publication types

  • Comparative Study
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Antigens / immunology
  • Berylliosis / genetics*
  • Berylliosis / immunology
  • Beryllium / administration & dosage*
  • Beryllium / immunology
  • Bronchoalveolar Lavage Fluid / cytology
  • Chronic Disease
  • DNA Probes, HLA
  • Female
  • Genotype
  • Humans
  • Male
  • Middle Aged
  • Polymorphism, Genetic
  • Severity of Illness Index
  • Tumor Necrosis Factor-alpha / drug effects*
  • Tumor Necrosis Factor-alpha / genetics*


  • Antigens
  • DNA Probes, HLA
  • TNF protein, human
  • Tumor Necrosis Factor-alpha
  • Beryllium