What does tumour necrosis factor excess do to the immune system long term?
What does tumour necrosis factor excess do to the immune system long term?
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DOI：
10.1136/ard.2005.042523
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发表时间：
2005-11-01
影响因子：
27.4
通讯作者：
Cope, AP
中科院分区：
文献类型：
--
作者：
Clark, J;Vagenas, P;Cope, AP
肿瘤坏死因子（TNF）/TNF受体（TNF-R）超家族成员在多个水平上协调免疫应答。例如，TNF、LT α、LT β和RANKL提供淋巴新生所需的信号，CD 27、OX-40、4-伊布和CD 30递送共刺激信号以增强免疫应答，而促凋亡成员如TNF、CD 95 L和TRAIL可能有助于终止应答。通过对功能获得或基因缺陷突变体的研究，揭示了单个家族成员的生物学特性。最值得注意的是在人TNF-珠蛋白转基因小鼠中自发性炎性多关节炎的发展，由55-kDa TNF-R突变引起的自身炎性综合征，特别是RANKL/RANK轴在破骨细胞生成和骨重建中的强制性作用。越来越多的赞赏信号转导通路的分子基础TNF-R提供了一个框架，更好地了解这个不断扩大的家庭的生物学。虽然NF-κ B和MAPK途径的快速和强烈激活是急性TNF-R参与的典型特征，但持续受体信号传导的分子基础仍然是一个谜，尽管其与慢性炎症和免疫应答相关。本报告以T细胞为重点，描述了持续TNF-R参与的一些分子足迹，并说明了这些分子足迹如何影响免疫功能。一个共同的主题是，随着时间的推移，长期的TNF刺激改变信号阈值。作者提出，长期暴露于TNF的一个主要结果是炎症部位的局部IL-2缺乏状态。这种缺陷的影响进行了讨论。
Members of the tumour necrosis factor (TNF)/TNF-receptor (TNF-R) superfamily coordinate the immune response at multiple levels. For example, TNF, LT alpha, LT beta and RANKL provide signals required for lymphoid neogenesis, CD27, OX-40, 4-IBB and CD30 deliver costimulatory signals to augment immune responses, while pro-apoptotic members such as TNF, CD95L and TRAIL may contribute to the termination of the response. Biological identity of individual family members has been revealed through studies of gain of function or gene deficient mutants. Most notable are the development of spontaneous inflammatory polyarthritis in human TNF-globin transgenic mice, the auto-inflammatory syndromes resulting from mutations in the 55-kDa TNF-R, and, in particular, the obligatory role for the RANKL/RANK axis in osteoclastogenesis and bone remodelling. A growing appreciation of the molecular basis of signalling pathways transduced by TNF-R has provided a framework for better understanding the biology of this expanding family. For while the rapid and robust activation of NF-kappa B and MAPK pathways is typical of acute TNF-R engagement, the molecular basis of sustained receptor signalling remains a mystery, in spite of its relevance to chronic inflammatory and immune responses. Focusing on T cells, this report describes some of the molecular footprints of sustained TNF-R engagement and illustrates how these may influence immune function. A common theme arising is that prolonged TNF stimulation alters signalling thresholds over time. The authors propose that one major outcome of long term exposure to TNF is a state of localised IL-2 deficiency at sites of inflammation. The implications of this deficiency are discussed.