Beryllium-ferritin: lymphocyte proliferation and macrophage apoptosis in chronic beryllium disease.

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 (BeSO 4 ) needed to induce proliferation. We observed increased apoptotic CBD BAL macrophages after exposure to both BeSO 4 (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.