Feferman T, Maiti PK, Berrih-Aknin S, Bismuth J, Bidault J, Fuchs S, Souroujon MC.
Myasthenia gravis (MG) and its animal model, experimental autoimmune MG (EAMG), are autoimmune disorders in which the acetylcholine receptor (AChR) is the major autoantigen. Microarray technology was used to identify new potential drug targets for treatment of myasthenia that would reduce the need for the currently used nonspecific immunosuppression. The chemokine IFN-gamma-inducible protein 10 (IP-10; CXCL10), a CXC chemokine, and its receptor, CXCR3, were found to be overexpressed in lymph node cells of EAMG rats. Quantitative real-time PCR confirmed these findings and revealed up-regulated mRNA levels of another chemoattractant that activates CXCR3, monokine induced by IFN-gamma (Mig; CXCL9). TNF-alpha and IL-1beta, which act synergistically with IFN-gamma to induce IP-10, were also up-regulated. These up-regulations were observed in immune response effector cells, namely, lymph node cells, and in the target organ of the autoimmune attack, the muscle of myasthenic rats, and were significantly reduced after suppression of EAMG by mucosal tolerance induction with an AChR fragment. The relevance of IP-10/CXCR3 signaling in myasthenia was validated by similar observations in MG patients. A significant increase in IP-10 and CXCR3 mRNA levels in both thymus and muscle was observed in myasthenic patients compared with age-matched controls. CXCR3 expression in PBMC of MG patients was markedly increased in CD4(+), but not in CD8(+), T cells or in CD19(+) B cells. Our results demonstrate a positive association of IP-10/CXCR3 signaling with the pathogenesis of EAMG in rats as well as in human MG patients.
IFN-gamma诱导蛋白10是一种CXC趋化因子（IP-10; CXCL10），与其受体CXCR3在重症肌无力小鼠模型的淋巴结中有过度表达。实时定量PCR也证实这一发现，并且发现活化CXCR3的因子CXCL9的mRNA水平表达增高，CXCL9是由IFN-gamma诱导的单核因子。TNF-alpha和IL-1beta与IFN-gamma协同作用诱导IP-10，其水平也见增高。这些因子的上调见于免疫效应细胞（淋巴结细胞）和免疫攻击的靶器官（肌无力小鼠的肌肉），但在乙酰胆碱受体片段粘膜耐受的EAMG小鼠中却表达下降。这一关联在重症肌无力病人中也可寻见证据，病人胸腺和肌肉中的IP-10和CXCR3 mRNA表达高于经年龄匹配的对照组。CXCR3 在MG病人外周血单核细胞中的表达在CD4+T细胞中明显增高，而CD8+T细胞、CD19+B细胞中不见增高。研究表明IP-10/CXCR3在EAMG以及MG病人的发病机制中有一定作用。
J Immunol. 2005 May 1;174(9):5324-31.
