Am. J. Respir. Crit. Care Med., Volume 164, Number 7, October 2001, 1192-1199

High Beryllium-stimulated TNF- Is Associated with the 308 TNF- Promoter Polymorphism and with Clinical Severity in Chronic Beryllium Disease

LISA A. MAIER, RICHARD T. SAWYER, ROSLYN A. BAUER, LORI A. KITTLE, PENNY LYMPANY, DEIRDRE MCGRATH, ROLAND DUBOIS, ELAINE DANILOFF, CECILE S. ROSE, and LEE S. NEWMAN

Division of Environmental and Occupational Health Sciences, Department of Medicine, National Jewish Medical and Research Center, Denver, Colorado; Division of Pulmonary Science and Critical Care Medicine, Department of Medicine, and Department of Preventive Medicine and Biometrics, University of Colorado Health Sciences Center, Denver, Colorado; and Interstitial Lung Disease Unit, Department of Occupational and Environmental Medicine, Imperial College of Science, Technology and Medicine, National Heart and Lung Institute, London, United Kingdom

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

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