Membrane TNF and lymphotoxin control of chemokine induction and inflammation in tuberculosis

结核病(TB)仍然是一个世界性的巨大问题。大多数结核病不是由感染时的疾病引起的，而是在从未完全根除这些微生物的人身上重新激活了潜伏的疾病。含有休眠结核微生物的巨噬细胞位于称为肉芽肿的病变中。肉芽肿由结核感染的巨噬细胞组成，周围环绕着积极控制感染的T淋巴细胞。T淋巴细胞可以防止巨噬细胞中结核微生物的生长，从而防止在宿主中引起疾病的广泛感染。识别受结核感染的巨噬细胞的活化T淋巴细胞在血液中循环，从毛细血管招募到肺内，在组织中迁移并与受感染的巨噬细胞共存。已知的可溶性分子(细胞因子和趋化因子)提供指导细胞迁移和激活事件的信号。这项研究将详细调查涉及的细胞因子和趋化因子，然后产生的细胞以及这些细胞在肺中的位置。我们最近发现，肿瘤坏死因子及其相关的细胞因子淋巴毒素(LT)是淋巴细胞在肺内迁移所必需的。它们属于相关分子家族，通过同一组受体发出信号，调节趋化因子的表达和炎症。在这项研究中，我们将使用缺乏肿瘤坏死因子的基因操纵的小鼠。LT或其他家族成员或仅表达膜结合的肿瘤坏死因子，以研究每个成员如何影响不同趋化因子、趋化因子受体和其他分子的产生。由于至少有50种已知的趋化因子和17种趋化因子受体，我们将使用微阵列技术同时筛选数千个基因的表达变化，并使用激光显微解剖来研究感染肺中不同位置的细胞。了解引导T细胞进入肉芽肿所需的信号可能有助于预防结核病再激活疾病的新疗法。

Tuberculosis (TB) remains an enormous problem worldwide. Most TB is not due to disease at the time of infection, but is a reactivation of dormant disease in people who have never completely eradicated the organisms. Macrophages containing dormant TB organisms are located in lesions called granulomas. Granulomas consist of TB-infected macrophages surrounded by T lymphocytes that actively contain the infection. T lymphocytes prevent the growth of TB organisms in the macrophages and so prevent widespread infection that would cause illness in the host. Activated T lymphocytes that recognise TB-infected macrophages circulate in blood, are recruited from blood capillaries into the lung, migrate through the tissue and co-localise with infected macrophages. Soluble molecules (cytokines and chemokines) are known to provide the signals that direct cell migration and activation events. This study will investigate in detail cytokines and chemokines that are involved, the cells that produce then and where these cells are located in the lung. We recently showed that tumour necrosis factor (TNF), and the related cytokine lymphotoxin (LT), are essential for lymphocyte migration through the lung. These belong to a family of related molecules that signal through the same panel of receptors and regulate chemokine expression and inflammation. In this study we will use genetically manipulated mice that lack TNF. LT or other family members or that express only membrane-bound TNF to study how each affects production of different chemokines, chemokine receptors and other molecules. Since there are at least 50 known chemokines and 17 chemokine receptors we will use microarray technology to simultaneously screen changes in expression of several thousand genes and laser microdissection to study cells from different location in infected lungs. Understanding signals necessary to direct T cells into granulomas may facilitate new treatments to prevent TB reactivation disease.