Published ahead of print on July 15, 2004, doi:10.1165/rcmb.2004-0090OC Am. J. Respir. Cell Mol. Biol., Volume 31, Number 4, October 2004, 470-477 A more recent version of this article appeared on October 1, 2004
Submitted on March 11, 2004 Beryllium-Ferritin: Lymphocyte Proliferation and Macrophage Apoptosis in Chronic Beryllium DiseaseRichard T Sawyer1*,1 Department of Medicine, Robert H. Hollis Laboratory of Environmental and Occupational Health Sciences, National Jewish Medical and Research Center, Denver, CO, USA; Department of Medicine, Division of Pulmonary Science and Critical Care Medicine, University of Colorado Health Sciences Center, Denver, CO, USA, 2 Department of Medicine, Division of Pulmonary Science and Critical Care Medicine, University of Colorado Health Sciences Center, Denver, CO, USA, 3 Department of Pediatrics, National Jewish Medical and Research Center, Denver, CO, USA, 4 Forensic Toxicology, Lawrence Livermore National Laboratory, Livermore, CA, USA, 5 Department of Medicine, Robert H. Hollis Laboratory of Environmental and Occupational Health Sciences, National Jewish Medical and Research Center, Denver, CO, USA; Department of Medicine, Division of Pulmonary Science and Critical Care Medicine, University of Colorado Health Sciences Center, Denver, CO, USA; Department of Preventive Medicine and Biometrics, University of Colorado Health Sciences Center, Denver, CO, USA, 6 Department of Medicine, Robert H. Hollis Laboratory of Environmental and Occupational Health Sciences, National Jewish Medical and Research Center, Denver, CO, USA * To whom correspondence should be addressed. E-mail: sawyerr{at}njc.org.
A beryllium (Be)-ferritin adduct containing 270 picomoles of Be stimulated proliferation of bronchoalveolar lavage (BAL) lymphocytes from chronic beryllium disease (CBD) subjects at concentrations 5-6 logs lower than the amounts of 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 the unstimulated controls) and Be-ferritin (40% ± 2%) whereas only 2% ± 0.2% of BAL lymphocytes underwent activation-induced cell death. Be-ferritin also induced apoptosis in BAL macrophages from subjects with Be-sensitization (BeS = 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 Th1-type cytokine production and potentially explains the chronicity of CBD and its development years after environmental Be exposure has ceased.
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