PDF(Pubmed)
Abstract：
Tuberculous meningitis (TBM), the most severe form of tuberculosis, causes death in approximately 25% cases despite antibiotic therapy, and half of survivors are left with neurological disability. Mortality and morbidity are contributed to by a dysregulated immune response, and adjunctive host-directed therapies are required to modulate this response and improve outcomes. Developing such therapies relies on improved understanding of the host immune response to TBM. The historical challenges in TBM research of limited in vivo and in vitro models have been partially overcome by recent developments in proteomics, transcriptomics, and metabolomics, and the use of these technologies in nested substudies of large clinical trials. We review the current understanding of the human immune response in TBM. We begin with M. tuberculosis entry into the central nervous system (CNS), microglial infection and blood-brain and other CNS barrier dysfunction. We then outline the innate response, including the early cytokine response, role of canonical and non-canonical inflammasomes, eicosanoids and specialised pro-resolving mediators. Next, we review the adaptive response including T cells, microRNAs and B cells, followed by the role of the glutamate-GABA neurotransmitter cycle and the tryptophan pathway. We discuss host genetic immune factors, differences between adults and children, paradoxical reaction, and the impact of HIV-1 co-infection including immune reconstitution inflammatory syndrome. Promising immunomodulatory therapies, research gaps, ongoing challenges and future paths are discussed.
摘要：
结核性脑膜炎(TBM),最严重的结核病，尽管抗生素治疗，仍导致约25%的病例死亡，一半的幸存者患有神经残疾。死亡率和发病率是由失调的免疫反应造成的。和辅助宿主导向疗法需要调节这种反应和改善结果。开发此类疗法依赖于对宿主对TBM的免疫应答的改进理解。有限的体内和体外模型的TBM研究的历史挑战已经部分克服了蛋白质组学的最新进展。转录组学，和代谢组学，以及这些技术在大型临床试验的嵌套子研究中的应用。我们回顾了当前对TBM中人类免疫反应的理解。我们从结核分枝杆菌进入中枢神经系统（CNS）开始，小胶质细胞感染和血脑和其他中枢神经屏障功能障碍。然后我们勾勒出与生俱来的反应，包括早期细胞因子反应，规范和非规范炎性体的作用，类花生酸和专门的促分辨介体。接下来,我们回顾了包括T细胞在内的适应性反应，microRNAs和B细胞,其次是谷氨酸-GABA神经递质循环和色氨酸途径的作用。我们讨论宿主遗传免疫因素，成人和儿童之间的差异，矛盾的反应，以及HIV-1共感染的影响，包括免疫重建炎症综合征。有前途的免疫调节疗法，研究空白,讨论了当前的挑战和未来的道路。
