Fulton S A, Martin T D, Redline R W, Henry Boom W
Division of Infectious Diseases and the Institute of Pathology, Case Western Reserve University and University Hospitals of Cleveland, Cleveland, Ohio 44106-4984, USA.
Am J Respir Cell Mol Biol. 2000 Mar;22(3):333-43. doi: 10.1165/ajrcmb.22.3.3776.
Mechanisms of protective immunity to mycobacterial infection in the lung remain poorly defined. In this study, T-cell subset expansion and cytokine expression in bronchoalveolar spaces, lung parenchyma, and mediastinal lymph nodes of mice infected intratracheally with Mycobacterium bovis-Calmette-Guerin bacillus (BCG) were analyzed in parallel with histopathology and bacterial burden. M. bovis-BCG was cleared rapidly from bronchoalveolar spaces without evidence for persistence. In lung parenchyma bacteria grew during the first 4 wk followed by gradual clearance with less than 0.1% of the original inoculum persisting for more than 8 mo. Clearance of M. bovis-BCG from bronchoalveolar lavage was associated with recruitment of both neutrophils and lymphocytes. Lung CD4(+), CD8(+), and gammadelta T-cell receptor-positive T cells expanded maximally by Week 4, and declined by Week 8 to control values despite bacterial persistence. Both CD4(+) and CD8(+) lung T cells produced interferon (IFN)-gamma in response to M. bovis-BCG. Four distinct pathologic states of lung parenchymal infection were noted. Early focal sub-bronchial inflammation with transmigration of cells into airways was followed by diffuse peribronchitis, perivasculitis, and alveolitis with activated macrophages, lymphoblasts, and occasional giant cells. The latter stage corresponded to maximal M. bovis-BCG growth. Resolving infection consisted of small lymphocytes and foamy macrophages, which coincided with decreasing M. bovis-BCG colony-forming units, T-cell infiltration, and IFN-gamma expression. A final quiescent phase consisted of residual lymphoid aggregates and perivasculitis associated with persistent spontaneous IFN-gamma production. Bacterial dissemination to lymph node and spleen occurred by Week 4 and declined in parallel to lung. In contrast to lung, IFN-gamma secretion was detected only late despite early expansion of CD4(+) and CD8(+) T cells. By reverse transcriptase/polymerase chain reaction, IFN-gamma and interleukin (IL)-12 p40 messenger RNA (mRNA) in lung paralleled IFN-gamma protein production. Tumor necrosis factor-alpha, IL-4 and IL-10 mRNA expression was not increased during M. bovis-BCG lung infection. Thus, protective immunity to M. bovis-BCG in the lung evolved differently in air space, lung, and lymph node.
肺部针对分枝杆菌感染的保护性免疫机制仍未完全明确。在本研究中，我们同时分析了经气管内接种卡介苗（BCG）的小鼠支气管肺泡腔、肺实质和纵隔淋巴结中的T细胞亚群扩增及细胞因子表达情况，并结合组织病理学和细菌负荷进行研究。卡介苗能迅速从支气管肺泡腔清除，无持续存在的迹象。在肺实质中，细菌在最初4周内生长，随后逐渐清除，8个月后仅有不到0.1%的初始接种菌持续存在。卡介苗从支气管肺泡灌洗中的清除与中性粒细胞和淋巴细胞的募集有关。肺中的CD4(+)、CD8(+)和γδT细胞受体阳性T细胞在第4周时扩增至最大，尽管细菌持续存在，但到第8周时降至对照值。肺中的CD4(+)和CD8(+) T细胞均能对卡介苗产生干扰素（IFN）-γ。观察到肺实质感染有四种不同的病理状态。早期为局灶性支气管周围炎，细胞迁移至气道，随后发展为弥漫性细支气管炎、血管周围炎和肺泡炎，伴有活化的巨噬细胞、成淋巴细胞和偶尔的巨细胞。后一阶段与卡介苗的最大生长相对应。感染消退期由小淋巴细胞和泡沫状巨噬细胞组成，这与卡介苗菌落形成单位减少、T细胞浸润和IFN-γ表达降低相一致。最后一个静止期由残留的淋巴样聚集物和血管周围炎组成，伴有持续性自发IFN-γ产生。细菌在第4周时扩散至淋巴结和脾脏，并与肺部细菌负荷平行下降。与肺部不同，尽管CD4(+)和CD8(+) T细胞早期扩增，但仅在后期检测到IFN-γ分泌。通过逆转录酶/聚合酶链反应，肺中的IFN-γ和白细胞介素（IL）-12 p40信使核糖核酸（mRNA）与IFN-γ蛋白产生情况平行。在卡介苗肺部感染期间，肿瘤坏死因子-α、IL-4和IL-10 mRNA表达未增加。因此，肺部针对卡介苗的保护性免疫在气道、肺和淋巴结中的演变方式不同。
