Pagán Antonio J, Ramakrishnan Lalita
Department of Microbiology, University of Washington, Seattle, Washington 98195.
Department of Microbiology, University of Washington, Seattle, Washington 98195 Department of Medicine, University of Washington, Seattle, Washington 98195 Department of Immunology, University of Washington, Seattle, Washington 98195.
Cold Spring Harb Perspect Med. 2014 Nov 6;5(9):a018499. doi: 10.1101/cshperspect.a018499.
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.
肉芽肿是免疫细胞的有组织聚集体，是结核病（TB）的一个决定性特征。肉芽肿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性结构，可“隔离”分枝杆菌。过去十年的研究对其在发病机制中的作用提供了更细致入微的观点。一方面，致病性分枝杆菌通过操纵宿主免疫反应，加速并利用肉芽肿形成来实现自身的扩张和传播，使白细胞募集和细胞死亡途径朝着有利于它们的方向发展。另一方面，肉芽肿巨噬细胞可通过发挥杀菌免疫反应来维持肉芽肿的完整性，从而防止感染在细胞外环境中更为猖獗地扩散。即使是维持细菌在细胞内所需的这种对宿主有益的免疫反应也必须加以调节，因为过度强烈的免疫反应也会导致肉芽肿破裂，从而直接支持细菌在细胞外生长。本综述将讨论分枝杆菌如何操纵炎症反应以驱动肉芽肿形成，并将借鉴人类结核病的临床研究以及啮齿动物、斑马鱼和非人灵长类动物模型，探讨肉芽肿在发病机制和保护性免疫中的作用。对肉芽肿中结核病发病机制和免疫的更深入理解可能会提示一些治疗方法，以消除肉芽肿形成对宿主有害的方面，将其转化为近一个世纪以来一直被认为的对宿主有益的结构。
