Tinkle S S, Kittle L A, Schumacher B A, Newman L S
Department of Medicine, National Jewish Center for Immunology and Respiratory Medicine, Denver, CO 80206, USA.
J Immunol. 1997 Jan 1;158(1):518-26.
Chronic beryllium disease (CBD) provides a model for study of the Ag-stimulated, cell-mediated immune response that, over time, progresses to granulomatous lung disease. Using cells obtained with bronchoalveolar lavage from patients with CBD and normal individuals, we evaluated beryllium salt-stimulated T lymphocyte proliferation and production of proinflammatory cytokines. Our findings demonstrate that beryllium sulfate stimulates production of both IL-2 and IFN-gamma, not IL-4 and IL-7. We observed a brief time course for IL-2 protein (6-48 h after BeSO4 stimulation) and mRNA production (3-6 h) and a protracted time course for IFN-gamma protein (24-168 h) and mRNA (0.25-168 h). Beryllium-stimulated T lymphocyte proliferation and IFN-gamma release were only partially inhibited by neutralization of IL-2. On the basis of these findings, we hypothesized that IFN-gamma and the IL-2/IFN-gamma-inducible alpha subunit of the soluble IL-2 receptor were elevated in serum and bronchoalveolar lavage fluid of individuals with disease and were molecular markers of granulomatous disease. The data demonstrate that levels of the alpha subunit of the soluble IL-2 receptor, but not IFN-gamma, are elevated in the serum (median = 1428 U/ml; interquartile range = 823-2137 U/ml) and bronchoalveolar lavage fluid (median = 1.56 U/ml, interquartile range = 1.04-4.22 U/ml) of patients with CBD and correlate with the degree of pulmonary lymphocytosis and clinical measures of disease severity. We conclude that IL-2 and IFN-gamma are produced in the beryllium-stimulated, cell-mediated immune response with different time courses and that the alpha subunit of the soluble IL-2 receptor may serve as a biomarker of disease progression.
慢性铍病（CBD）为研究银刺激的细胞介导免疫反应提供了一个模型，随着时间的推移，这种免疫反应会发展为肉芽肿性肺病。我们使用从CBD患者和正常个体的支气管肺泡灌洗中获得的细胞，评估了铍盐刺激的T淋巴细胞增殖和促炎细胞因子的产生。我们的研究结果表明，硫酸铍刺激IL-2和IFN-γ的产生，而非IL-4和IL-7。我们观察到IL-2蛋白（硫酸铍刺激后6-48小时）和mRNA产生（3-6小时）的时间进程较短，而IFN-γ蛋白（24-168小时）和mRNA（0.25-168小时）的时间进程较长。IL-2的中和仅部分抑制了铍刺激的T淋巴细胞增殖和IFN-γ释放。基于这些发现，我们假设疾病个体血清和支气管肺泡灌洗液中IFN-γ以及可溶性IL-2受体的IL-2/IFN-γ诱导α亚基升高，并且是肉芽肿性疾病的分子标志物。数据表明，CBD患者血清（中位数=1428 U/ml；四分位间距=823-2137 U/ml）和支气管肺泡灌洗液（中位数=1.56 U/ml，四分位间距=1.04-4.22 U/ml）中可溶性IL-2受体α亚基水平升高，且与肺淋巴细胞增多程度和疾病严重程度的临床指标相关。我们得出结论，IL-2和IFN-γ在铍刺激的细胞介导免疫反应中以不同时间进程产生，并且可溶性IL-2受体α亚基可能作为疾病进展的生物标志物。
