Hernandez-Pando R, Orozco H, Honour J, Silva P, Leyva R, Rook G A
Department of Pathology, Instituto Nacional de la nutrition, Mexico DF, Mexico.
FEMS Immunol Med Microbiol. 1995 Sep;12(1):63-72. doi: 10.1111/j.1574-695X.1995.tb00176.x.
When mice were infected with virulent Mycobacterium tuberculosis H37Rv by the intra-tracheal route, there was an early phase of adrenal hyperplasia, histologically resembling the adrenocorticotropic (ACTH)-driven changes seen in Cushing's disease. This was followed at 3 weeks by progressive atrophy until the weight of the adrenals was approximately 50% of that seen in control uninfected mice, in spite of the fact that the adrenals were not infected. All layers of the adrenal cortex were affected, but the medulla was normal. Electron microscope studies revealed apoptosis. The switch from adrenal hyperplasia to adrenal atrophy corresponded to onset of an IgG1 response recognising a wide range of mycobacterial components in Western blots. Delayed type hypersensitivity (DTH) responses were seen throughout, but differed in their sensitivity to TNF alpha. Thus if TNF alpha was injected at 24 h into DTH sites elicited during the phase of adrenal hyperplasia, there was no increment in swelling at 48 h. However similar injections of TNF alpha resulted in a doubling of the swelling in DTH sites elicited during the phase of adrenal atrophy. This may be relevant to the pathogenesis of cytokine-mediated tissue damage in the human disease. If 2 months before mice received the intratracheal infection, they were pre-immunised with 1 x 1097) autoclaved Mycobacterium vaccae, a stimulus previously shown to induce a Th1 pattern of response, the early increase in adrenal weight was attenuated and delayed, and the subsequent atrophy did not occur. In sharp contrast, pre-immunisation with 1 x 10(9) autoclaved M. vaccae, known to prime a mixed pattern of cytokine release (IFN gamma and IL-4), resulted in adrenal atrophy that began within 4 days of infection, and was complete by day 14. These results suggested that the pattern of cytokine release provoked by the infection, modulated the adrenal changes, perhaps in synergy with products derived from the organisms themselves. Since we have already shown that profound adrenal changes also occur in human tuberculosis, we now propose that a change somewhere in the cytokine-hypothalamo-pituitary-adrenal axis may underlie the T cell dysfunction and immunologically-mediated tissue damage in this disease.
当小鼠经气管内途径感染强毒力结核分枝杆菌H37Rv时，会出现肾上腺增生的早期阶段，组织学上类似于库欣病中促肾上腺皮质激素（ACTH）驱动的变化。3周后，肾上腺逐渐萎缩，直至其重量约为未感染对照小鼠的50%，尽管肾上腺并未被感染。肾上腺皮质的所有层均受到影响，但髓质正常。电子显微镜研究显示存在细胞凋亡。从肾上腺增生到肾上腺萎缩的转变与在蛋白质免疫印迹中识别多种分枝杆菌成分的IgG1反应的开始相对应。整个过程中均可见迟发型超敏反应（DTH），但其对肿瘤坏死因子α（TNFα）的敏感性有所不同。因此，如果在肾上腺增生阶段诱导的DTH部位于24小时注射TNFα，48小时时肿胀并无增加。然而，在肾上腺萎缩阶段诱导的DTH部位进行类似的TNFα注射，会导致肿胀增加一倍。这可能与人类疾病中细胞因子介导的组织损伤的发病机制有关。如果在小鼠接受气管内感染前2个月，用1×10⁹个经高压灭菌的母牛分枝杆菌进行预免疫，此前已证明该刺激可诱导Th1型反应模式，则肾上腺重量的早期增加会减弱并延迟，随后的萎缩也不会发生。与之形成鲜明对比的是，用1×10⁹个经高压灭菌的母牛分枝杆菌进行预免疫，已知其可引发细胞因子释放的混合模式（干扰素γ和白细胞介素-4），会导致感染后4天内开始肾上腺萎缩，并在第14天完成。这些结果表明，感染引发的细胞因子释放模式调节了肾上腺的变化，可能与生物体自身产生的产物协同作用。由于我们已经表明人类结核病中也会发生显著的肾上腺变化，我们现在提出，细胞因子-下丘脑-垂体-肾上腺轴某处的变化可能是该疾病中T细胞功能障碍和免疫介导的组织损伤的基础。
