The voltage-gated potassium channel Kv1.3 is highly expressed on inflammatory infiltrates in multiple sclerosis brain
The voltage-gated potassium channel Kv1.3 is highly expressed on inflammatory infiltrates in multiple sclerosis brain
复制标题
DOI：
10.1073/pnas.0501770102
复制
发表时间：
2005-08-02
影响因子：
11.1
通讯作者：
Calabresi, PA
中科院分区：
文献类型：
--
作者：
Rus, H;Pardo, CA;Calabresi, PA
多发性硬化（MS）的特征在于由活化的T细胞和巨噬细胞组成的中枢神经系统小静脉周围和实质单核细胞浸润。我们最近表明，电压门控钾通道，Kv1.3，是激活效应记忆T（T-EM）细胞在实验性过敏性脑脊髓炎和髓鞘特异性T细胞来源于MS患者的外周血中的功能标志物的表达升高。在此，我们表明，Kv1.3是高度表达在死后MS脑炎性浸润。表达模式显示Kv1.3（+）T细胞不仅在微静脉周围浸润中，而且在脱髓鞘MS病变的实质中以及正常外观的灰色和白色物质中也有高表达。这些细胞均为趋化因子受体7阴性（CCR 7（-）），与效应记忆表型一致。使用双标记免疫组织化学和共聚焦显微镜，我们证明了共定位的Kv1.3与CD 3，CD 4，CD 8，和一些CD 68细胞。表达模式反映了体外实验，显示Kv1.3的极化免疫突触。Kv1.3在来自脑脊液的CCR 7（+）中央记忆T细胞上以低至中等水平表达，但是，当这些细胞在体外受到刺激时，它们迅速变成Kv1.3（高）/CCR 7-T-EM，这表明脑脊液细胞的一个亚群以准备成为TEM的致敏状态存在。这些研究为在MS中使用特异性Kv1.3拮抗剂提供了进一步的依据。
Multiple Sclerosis (MS) is characterized by central nervous system perivenular and parenchymal mononuclear cell infiltrates consisting of activated T cells and macrophages. We recently demonstrated that elevated expression of the voltage-gated potassium channel, Kv1.3, is a functional marker of activated effector memory T (T-EM) cells in experimental allergic encephalomyelitis and in myelin-specific T cells derived from the peripheral blood of patients with MS. Herein, we show that Kv1.3 is highly expressed in postmortem MS brain inflammatory infiltrates. The expression pattern revealed not only Kv1.3(+) T cells in the perivenular infiltrate but also high expression in the parenchyma of demyelinated MS lesions and both normal appearing gray and white matter. These cells were uniformly chemokine receptor 7 negative (CCR7(-)), consistent with an effector memory phenotype. Using double-labeling immunohistochemistry and confocal microscopy, we demonstrated colocalization of Kv1.3 with CD3, CD4, CD8, and some CD68 cells. The expression patterns mirrored in vitro experiments showing polarization of Kv1.3 to the immunological synapse. Kv1.3 was expressed in low to moderate levels on CCR7(+) central memory T cells from cerebrospinal fluid, but, when these cells were stimulated in vitro, they rapidly became Kv1.3(high)/CCR7-T-EM, suggesting that a subset of cerebrospinal fluid cells existed in a primed state ready to become TEM. These studies provide further rationale for the use of specific Kv1.3 antagonists in MS.