T-cell and B-cell signaling biomarkers and treatment targets in lupus.
T-cell and B-cell signaling biomarkers and treatment targets in lupus.
复制标题
狼疮中的 T 细胞和 B 细胞信号传导生物标志物和治疗靶点。
DOI：
10.1097/bor.0b013e32832e977c
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发表时间：
2009-09
影响因子：
5.1
通讯作者：
Phillips PE
中科院分区：
文献类型：
--
作者：
Perl A;Fernandez DR;Telarico T;Doherty E;Francis L;Phillips PE
系统性红斑狼疮的特征是产生抗核自身抗体以及T细胞、B细胞和树突状细胞功能障碍。在这里，我们回顾了新发现的遗传因素和机制，这些因素和机制是系统性红斑狼疮免疫系统内异常细胞内信号处理和细胞间通讯的基础。哺乳动物雷帕霉素靶点的激活在系统性红斑狼疮的T、B细胞异常激活中起着关键作用。在T细胞中，一氧化氮的产生增加和线粒体超极化被认为是哺乳动物雷帕霉素激活靶点上游的代谢检查点。哺乳动物靶标雷帕霉素通过增加内体循环调节因子HRES-1/Rab4基因的表达，调控T细胞受体相关信号蛋白ζ的表达，促进T细胞和B细胞中钙离子的流动和酪氨酸激酶的表达，阻断Foxp3的表达和调节性T细胞的扩张。线粒体超极化和由此产生的ATP耗竭使T细胞易于坏死，从而促进树突状细胞的激活、抗核自身抗体的产生和炎症。线粒体超极化、哺乳动物雷帕霉素和Syk激酶活性增强、受体循环增强和钙离子通量增加已成为系统性红斑狼疮常见的T和B细胞生物标志物和治疗靶点。
Systemic lupus erythematosus is characterized by the production of antinuclear autoantibodies and dysfunction of T-cells, B-cells, and dendritic cells. Here, we review newly recognized genetic factors and mechanisms that underlie abnormal intracellular signal processing and intercellular communication within the immune system in systemic lupus erythematosus. Activation of the mammalian target of rapamycin plays a pivotal role in abnormal activation of T and B-cells in systemic lupus erythematosus. In T-cells, increased production of nitric oxide and mitochondrial hyperpolarization were identified as metabolic checkpoints upstream of mammalian target of rapamycin activation. Mammalian target of rapamycin controls the expression T-cell receptor-associated signaling proteins CD4 and CD3ζ through increased expression of the endosome recycling regulator HRES-1/Rab4 gene, mediates enhanced Ca2+ fluxing and skews the expression of tyrosine kinases both in T and B-cells, and blocks the expression of Foxp3 and the expansion of regulatory T-cells. Mitochondrial hyperpolarization and the resultant ATP depletion predispose T-cells to necrosis, thus promoting the dendritic cell activation, antinuclear autoantibody production, and inflammation. Mitochondrial hyperpolarization, increased activity of mammalian target of rapamycin and Syk kinases, enhanced receptor recycling and Ca2+ flux have emerged as common T and B-cell biomarkers and targets for treatment in systemic lupus erythematosus.