Department of Microbiology and Immunology, University of Leuven, Leuven 3000, Belgium; and at the VIB Center for Brain and Disease Research, Leuven 3000, Belgium.
Inflammation Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, 3052, Australia; and at the Department of Medical Biology, University of Melbourne, Parkville, Victoria 3010, Australia.
Nat Rev Immunol. 2017 Mar;17(3):208-214. doi: 10.1038/nri.2016.151. Epub 2017 Feb 6.
The innate immune system uses a distinct set of germline-encoded pattern recognition receptors (PRRs) to initiate downstream inflammatory cascades. This recognition system is in stark contrast to the adaptive immune system, which relies on highly variable, randomly generated antigen receptors. A key limitation of the innate immune system's reliance on fixed PRRs is its inflexibility in responding to rapidly evolving pathogens. Recent advances in our understanding of inflammasome activation suggest that the innate immune system also has sophisticated mechanisms for responding to pathogens for which there is no fixed PRR. This includes the recognition of debris from dying cells, known as danger-associated molecular patterns (DAMPs), which can directly activate PRRs in a similar manner to pathogen-associated molecular patterns (PAMPs). Distinct from this, emerging data for the inflammasome components NLRP3 (NOD-, LRR- and pyrin domain-containing 3) and pyrin suggest that they do not directly detect molecular patterns, but instead act as signal integrators that are capable of detecting perturbations in cytoplasmic homeostasis, for example, as initiated by infection. Monitoring these perturbations, which we term 'homeostasis-altering molecular processes' (HAMPs), provides potent flexibility in the capacity of the innate immune system to detect evolutionarily novel infections; however, HAMP sensing may also underlie the sterile inflammation that drives chronic inflammatory diseases.
先天免疫系统利用一组独特的胚系编码模式识别受体 (PRR) 启动下游炎症级联反应。这种识别系统与适应性免疫系统形成鲜明对比，适应性免疫系统依赖于高度可变的、随机产生的抗原受体。先天免疫系统依赖固定的 PRR 的一个关键限制是其对快速进化的病原体的反应缺乏灵活性。最近我们对炎症小体激活的理解的进展表明，先天免疫系统也有复杂的机制来应对没有固定 PRR 的病原体。这包括对死亡细胞碎片的识别，称为危险相关分子模式 (DAMP)，其可以以类似于病原体相关分子模式 (PAMP) 的方式直接激活 PRR。与此不同，炎症小体成分 NLRP3（NOD、LRR 和 pyrin 结构域包含 3）和 pyrin 的新兴数据表明，它们并非直接检测分子模式，而是作为信号整合因子发挥作用，能够检测细胞质内稳态的扰动，例如由感染引发的扰动。监测这些我们称之为“改变内稳态的分子过程”（HAMP）的扰动，为先天免疫系统检测进化上新出现的感染提供了强大的灵活性；然而，HAMP 检测也可能是驱动慢性炎症性疾病的无菌性炎症的基础。
