Raymond Tracy, Schaller Matthew, Hogaboam Cory M, Lukacs Nicholas W, Rochford Rosemary, Kunkel Steven L
Immunology Program and Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan 48109-2200, USA.
Proc Am Thorac Soc. 2007 Dec;4(8):635-41. doi: 10.1513/pats.200706-067TH.
Current dogma supports the concept that the expression of a disease-inducing signature cytokine phenotype is important to the maintenance stage of chronic lung disorders. This cytokine phenotype has been characterized as a polarization toward type 2 cytokines, which are profibrotic and immunoregulatory. The biology of this latter activity could mechanistically explain pathogen-induced exacerbation of chronic lung inflammation, as a skewed cytokine profile in the lung alters dendritic cell function, activates fibroblasts, and facilitates a subsequent "second hit" by an infectious pathogen. In this setting, cytokine biology is also linked to Toll-like receptors (TLRs) in the maintenance of lung immunity, as the activity of this receptor-ligand system by both leukocytes and stromal cells is likely an important component of disease chronicity. The participation of dendritic cells via TLRs in chronic lung disease could facilitate communication circuits established between antigen-presenting cells and lymphocytes. Data suggest that TLR activation via myeloid differentiation factor 88 adaptor protein leads to the induction of a Notch ligand known as Delta-like-4 on dendritic cells that activate the Notch receptor on T cells, promoting a helper T-cell type 1 cytokine response. It is likely that the evolution of host defense signals designed to recognize patterns emitted from a hostile microbial environment may now be superimposed on adaptive immunity and provide the underpinning to support the maintenance of chronic lung disease.
当前的教条支持这样一种概念，即疾病诱导性标志性细胞因子表型的表达对于慢性肺部疾病的维持阶段很重要。这种细胞因子表型已被表征为向2型细胞因子极化，2型细胞因子具有促纤维化和免疫调节作用。后一种活性的生物学机制可以从机械角度解释病原体诱导的慢性肺部炎症的加重，因为肺部细胞因子谱的失衡会改变树突状细胞功能、激活成纤维细胞，并促进感染性病原体随后的“二次打击”。在这种情况下，细胞因子生物学在维持肺部免疫方面也与Toll样受体（TLR）相关，因为白细胞和基质细胞的这种受体-配体系统的活性可能是疾病慢性化的一个重要组成部分。树突状细胞通过TLR参与慢性肺部疾病可能会促进抗原呈递细胞和淋巴细胞之间建立的通信回路。数据表明，通过髓样分化因子88衔接蛋白激活TLR会导致树突状细胞上诱导一种名为Delta样-4的Notch配体，该配体激活T细胞上的Notch受体，促进辅助性T细胞1型细胞因子反应。旨在识别来自敌对微生物环境发出的模式的宿主防御信号的演变现在可能叠加在适应性免疫上，并为支持慢性肺部疾病的维持提供基础。
