Immunity and Immunopathology in the Tuberculous Granuloma
Immunity and Immunopathology in the Tuberculous Granuloma
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DOI：
10.1101/cshperspect.a018499
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发表时间：
2015-09-01
影响因子：
5.4
通讯作者：
Ramakrishnan, Lalita
中科院分区：
文献类型：
--
作者：
Pagan, Antonio J.;Ramakrishnan, Lalita
肉芽肿是免疫细胞的有组织聚集体，是结核病（TB）的一个定义特征。肉芽肿的形成与多种炎症性疾病的发病机制有关。然而，结核性肉芽肿被认为是一种宿主保护结构，可以“隔离”分枝杆菌。在过去十年中进行的工作提供了一个更微妙的观点，其在发病机制中的作用。一方面，致病性分枝杆菌通过操纵宿主免疫应答以使白细胞募集和细胞死亡途径转向有利于它们的方向来加速和利用肉芽肿形成以用于它们的扩张和传播。另一方面，肉芽肿巨噬细胞可以通过发挥杀微生物免疫应答来保持肉芽肿的完整性，从而防止细胞外环境中感染的更加猖獗的扩张。即使是维持细胞内细菌所需的这种宿主有益的免疫应答也必须得到调节，因为过度强烈的免疫应答也会导致肉芽肿破裂，从而直接支持细菌在细胞外生长。本文将讨论分枝杆菌如何操纵炎症反应，驱动肉芽肿的形成，并将考虑肉芽肿的发病机制和保护性免疫的作用，从结核病在人类和动物模型，啮齿动物，斑马鱼和非人灵长类动物的临床研究。更深入地了解结核病的发病机制和免疫的肉芽肿可能会建议治疗方法，以消除主机有害方面的肉芽肿形成，将其转化为主机的有益结构，它一直被认为是近世纪。
Granulomas, organized aggregates of immune cells, are a defining feature of tuberculosis (TB). Granuloma formation is implicated in the pathogenesis of a variety of inflammatory disorders. However, the tuberculous granuloma has been assigned the role of a host protective structure which "walls-off" mycobacteria. Work conducted over the past decade has provided a more nuanced view of its role in pathogenesis. On the one hand, pathogenic mycobacteria accelerate and exploit granuloma formation for their expansion and dissemination by manipulating host immune responses to turn leukocyte recruitment and cell death pathways in their favor. On the other hand, granuloma macrophages can preserve granuloma integrity by exerting a microbicidal immune response, thus preventing an even more rampant expansion of infection in the extracellular milieu. Even this host-beneficial immune response required to maintain the bacteria intracellular must be tempered, as an overly vigorous immune response can also cause granuloma breakdown, thereby directly supporting bacterial growth extracellularly. This review will discuss how mycobacteria manipulate inflammatory responses to drive granuloma formation and will consider the roles of the granuloma in pathogenesis and protective immunity, drawing from clinical studies of TB in humans and from animal models-rodents, zebrafish, and nonhuman primates. A deeper understanding of TB pathogenesis and immunity in the granuloma could suggest therapeutic approaches to abrogate the host-detrimental aspects of granuloma formation to convert it into the host-beneficial structure that it has been thought to be for nearly a century.