Published ahead of print on July 15, 2004, doi:10.1165/rcmb.2004-0090OC
© 2004 American Thoracic Society DOI: 10.1165/rcmb.2004-0090OC Beryllium-FerritinLymphocyte Proliferation and Macrophage Apoptosis in Chronic Beryllium DiseaseDepartment of Medicine, Robert H. Hollis Laboratory of Environmental and Occupational Health Sciences, and Department of Pediatrics, National Jewish Medical and Research Center, Denver; Department of Medicine, Division of Pulmonary Science and Critical Care Medicine, and Department of Preventive Medicine and Biometrics, University of Colorado Health Sciences Center, Denver, Colorado; Lawrence Livermore National Laboratory, Livermore, California Address correspondence to: Dr. R. T. Sawyer, Division of Environmental and Occupational Health Sciences, Hollis Laboratory of Environmental and Occupational Health, National Jewish Medical and Research Center, 1400 Jackson Street, Denver, CO 80206. E-mail: sawyerr{at}njc.org A beryllium (Be)-ferritin adduct containing 270 pm of Be stimulated proliferation of bronchoalveolar lavage (BAL) lymphocytes from subjects with chronic beryllium disease (CBD) at concentrations 5–6 logs lower than the amounts of beryllium sulfate (BeSO4) needed to induce proliferation. We observed increased apoptotic CBD BAL macrophages after exposure to both BeSO4 (50 ± 6%, mean ± SEM, P < 0.05 versus unstimulated controls) and Be-ferritin (40 ± 2%), whereas only 2.0 ± 0.2% of BAL lymphocytes underwent activation-induced cell death. Be-ferritin also induced apoptosis in BAL macrophages from subjects with Be sensitization (25 ± 3%) and in the H36.12j hybrid macrophage cell line (15 ± 2%). Be-ferritin induced lung macrophage CD95 (Fas) expression and the activation of intracellular caspase-3, -8 and -9. Thus, lung macrophages take up Be-ferritin, delivering physiologically relevant levels of Be that promote Be antigen presentation and macrophage apoptosis. Be-ferritin thereby serves as a "Trojan Horse," triggering proliferation of Be-ferritin–specific CBD BAL T cells. We hypothesize that Be-ferritin exposure may result in persistent antigen exposure inducing Be-specific T cell clonal expansion and T cell helper type 1–type cytokine production and potentially explains the chronicity of CBD and its development years after environmental Be exposure has ceased.
Abbreviations: analysis of variance, ANOVA • antigen presenting cells, APC • bronchoalveolar lavage, BAL • beryllium, Be • Be lymphocyte proliferation test, BeLPT • Be sensitization, BeS • chronic Be disease, CBD • counts per minute, cpm • phagocytic index, PI • stimulation index, SI • tumor necrosis factor, TNF • triphosphate (dUTP) nick end labeling, TUNEL This article has been cited by other articles:
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