title: High beryllium-stimulated TNF-alpha is associated with the -308 TNF-alpha promoter polymorphism and with clinical severity in chronic beryllium disease.
abstract: 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.
authors.affiliation: Division of Environmental and Occupational Health Sciences, Department of Medicine, National Jewish Medical and Research Center, Denver, Colorado 80206, USA. MaierL@njc.org
authors.forename: L A
authors.initials: LA
authors.lastname: Maier
authors.forename: R T
authors.initials: RT
authors.lastname: Sawyer
authors.forename: R A
authors.initials: RA
authors.lastname: Bauer
authors.forename: L A
authors.initials: LA
authors.lastname: Kittle
authors.forename: P
authors.initials: P
authors.lastname: Lympany
authors.forename: D
authors.initials: D
authors.lastname: McGrath
authors.forename: R
authors.initials: R
authors.lastname: Dubois
authors.forename: E
authors.initials: E
authors.lastname: Daniloff
authors.forename: C S
authors.initials: CS
authors.lastname: Rose
authors.forename: L S
authors.initials: LS
authors.lastname: Newman
mesh_terms: D000941:Antigens / Q000276:immunology; D001607:Berylliosis / Q000235:genetics* / Q000276:immunology; D001608:Beryllium / Q000008:administration & dosage* / Q000276:immunology; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D002908:Chronic Disease; D015343:DNA Probes, HLA; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D012720:Severity of Illness Index; D014409:Tumor Necrosis Factor-alpha / Q000187:drug effects* / Q000235:genetics*
chemical_list: D000941:Antigens; D015343:DNA Probes, HLA; C439524:TNF protein, human; D014409:Tumor Necrosis Factor-alpha; D001608:Beryllium