title: Beryllium-ferritin: lymphocyte proliferation and macrophage apoptosis in chronic beryllium disease.
abstract: 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.
authors.affiliation: Department of Medicine, Robert H. Hollis Laboratory of Environmental and Occupational Health Sciences, National Jewish Medical and Research Center, 1400 Jackson Street, Denver, CO 80206, USA. sawyerr@njc.org
authors.forename: Richard T
authors.initials: RT
authors.lastname: Sawyer
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Day
authors.forename: Valerie A
authors.initials: VA
authors.lastname: Fadok
authors.forename: Marina
authors.initials: M
authors.lastname: Chiarappa-Zucca
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Maier
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Fontenot
authors.forename: Lori
authors.initials: L
authors.lastname: Silveira
authors.forename: Lee S
authors.initials: LS
authors.lastname: Newman
mesh_terms: D000328:Adult; D000368:Aged; D017951:Antigen Presentation; D017209:Apoptosis / Q000187:drug effects*; D001607:Berylliosis / Q000097:blood / Q000209:etiology* / Q000473:pathology; D001608:Beryllium / Q000009:adverse effects / Q000494:pharmacology*; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D002908:Chronic Disease; D004305:Dose-Response Relationship, Drug; D005260:Female; D005293:Ferritins / Q000009:adverse effects / Q000494:pharmacology*; D006801:Humans; D008168:Lung / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects; D008214:Lymphocytes / Q000166:cytology / Q000187:drug effects* / Q000276:immunology; D016676:Macrophages, Alveolar / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D016273:Occupational Exposure / Q000009:adverse effects; D010586:Phagocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D011868:Radioisotopes; D012907:Smoking / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D019014:fas Receptor / Q000378:metabolism
chemical_list: D011868:Radioisotopes; D019014:fas Receptor; D005293:Ferritins; D001608:Beryllium