Mycobacterium tuberculosis growth at the cavity surface:: a microenvironment with failed immunity
Mycobacterium tuberculosis growth at the cavity surface:: a microenvironment with failed immunity
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DOI：
10.1128/iai.71.12.7099-7108.2003
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发表时间：
2003-12-01
影响因子：
3.1
通讯作者：
Bekker, LG
中科院分区：
文献类型：
--
作者：
Kaplan, G;Post, FA;Bekker, LG
肺结核病(TB)的保护性免疫的特征是在肺内形成由巨噬细胞和产生肿瘤坏死因子α和γ干扰素的激活的T细胞组成的肉芽肿，两者都是激活吞噬细胞所必需的。在90%的有免疫能力的人中，这种反应可以控制感染。为了了解其他10%的人免疫失败的原因，我们研究了6名因不治之症而接受手术的患者的肺部。不同肺部病变的组织学检查显示抗酸杆菌的形态和分布不均；只有在空洞的表面，即与呼吸道有明显连接的肉芽肿，才有大量的细菌。这些分离株的突变图谱表明，结核分枝杆菌的单个创始菌株可能在治疗过程中经历基因变化，导致在离散的物理地点独立获得额外的耐药性。在空洞表面优先观察到额外的耐药性。细胞因子基因表达显示，未能控制细菌与普遍的细胞免疫抑制无关，因为在所有被测试的病变中，细胞因子mRNA上调。相反，腔内表面有选择性地缺乏CD4(+)和CD8(+)T细胞，阻止了T细胞与巨噬细胞在该部位的直接相互作用，可能允许腔内吞噬细胞保持对细菌生长的容许性。相反，在肉芽肿的坏死区，两种细胞类型共存，细菌数量显著减少，这表明在这个微环境中产生了有效的抑菌或杀菌吞噬细胞群。
Protective immunity against pulmonary tuberculosis (TB) is characterized by the formation in the lungs of granulomas consisting of macrophages and activated T cells producing tumor necrosis factor alpha and gamma interferon, both required for the activation of the phagocytes. In 90% of immunocompetent humans, this response controls the infection. To understand why immunity fails in the other 10%, we studied the lungs of six patients who underwent surgery for incurable TB. Histologic examination of different lung lesions revealed heterogeneous morphology and distribution of acid-fast bacilli; only at the surface of cavities, i.e., in granulomas with a patent connection to the airways, were there numerous bacilli. The mutation profile of the isolates suggested that a single founder strain of Mycobacterium tuberculosis may undergo genetic changes during treatment, leading to acquisition of additional drug resistance independently in discrete physical locales. Additional drug resistance was preferentially observed at the cavity surface. Cytokine gene expression revealed that failure to control the bacilli was not associated with a generalized suppression of cellular immunity, since cytokine mRNA was up regulated in all lesions tested. Rather, a selective absence of CD4(+) and CD8(+) T cells was noted at the luminal surface of the cavity, preventing direct T-cell-macrophage interactions at this site, probably allowing luminal phagocytes to remain permissive for bacillary growth. In contrast, in the perinecrotic zone of the granulomas, the two cell types colocalized and bacillary numbers were substantially lower, suggesting that in this microenvironment an efficient bacteriostatic or bactericidal phagocyte population was generated.