Studies of T-cell activation in chronic inflammation.
Studies of T-cell activation in chronic inflammation.
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DOI：
10.1186/ar557
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发表时间：
2002
期刊：
影响因子：
--
通讯作者：
Cope AP
中科院分区：
文献类型：
--
作者：
Cope AP
MHC II类区域内编码的特定等位基因与类风湿性关节炎（RA）的发展之间的强关联提供了迄今为止CD 4 + T细胞在这种慢性炎性疾病的发病机制中发挥作用的最佳证据。然而，滑膜T细胞的不寻常表型，包括其对TCR连接的显著增殖性低反应性，挑战了T细胞效应器反应由发炎滑膜关节中的同源软骨抗原驱动的概念。从外周血到发炎关节的T细胞功能障碍的层次表明，这些缺陷是通过长期暴露于促炎细胞因子如肿瘤坏死因子（TNF）-α而获得的。事实上，现在有令人信服的数据表明，慢性细胞因子激活可能会大大有助于滑膜T细胞的表型和效应功能。研究表明，T细胞长期暴露于TNF通过损害TCR/CD 3复合物在细胞表面的组装和稳定性来解偶联TCR信号转导途径。尽管有这种膜近端效应，TNF选择性地解偶联下游信号传导途径，如钙信号传导反应的显著抑制所示，而Ras/ERK活化则幸免。在这些数据的基础上，有人提出，T细胞的生存和效应反应是由抗原独立的，依赖于精氨酸的机制，并寻求恢复T细胞稳态，而不是进一步抑制T细胞功能的治疗策略，应在未来探索。
The strong association between specific alleles encoded within the MHC class II region and the development of rheumatoid arthritis (RA) has provided the best evidence to date that CD4+ T cells play a role in the pathogenesis of this chronic inflammatory disease. However, the unusual phenotype of synovial T cells, including their profound proliferative hyporesponsiveness to TCR ligation, has challenged the notion that T-cell effector responses are driven by cognate cartilage antigens in inflamed synovial joints. The hierarchy of T-cell dysfunction from peripheral blood to inflamed joint suggests that these defects are acquired through prolonged exposure to proinflammatory cytokines such as tumour necrosis factor (TNF)-α. Indeed, there are now compelling data to suggest that chronic cytokine activation may contribute substantially to the phenotype and effector function of synovial T cells. Studies reveal that chronic exposure of T cells to TNF uncouples TCR signal transduction pathways by impairing the assembly and stability of the TCR/CD3 complex at the cell surface. Despite this membrane-proximal effect, TNF selectively uncouples downstream signalling pathways, as is shown by the dramatic suppression of calcium signalling responses, while Ras/ERK activation is spared. On the basis of these data, it is proposed that T-cell survival and effector responses are driven by antigen-independent, cytokine-dependent mechanisms, and that therapeutic strategies that seek to restore T-cell homeostasis rather than further depress T-cell function should be explored in the future.
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DOI：
10.1084/jem.185.9.1573
发表时间：
1997-05-05
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Cope AP;Liblau RS;Yang XD;Congia M;Laudanna C;Schreiber RD;Probert L;Kollias G;McDevitt HO
通讯作者：
McDevitt HO
影响因子：
--
作者：
CHU, CQ;FIELD, M;MAINI, RN
通讯作者：
MAINI, RN
影响因子：
15.9
作者：
COPE, AP;LONDEI, M;FELDMANN, M
通讯作者：
FELDMANN, M
影响因子：
5.4
作者：
BRENNAN, FM;GIBBONS, DL;FELDMANN, M
通讯作者：
FELDMANN, M
影响因子：
27.4
作者：
Collantes, E;Blázquez, MV;Muñoz, E
通讯作者：
Muñoz, E