Aquaporin-4-binding autoantibodies in patients with neuromyelitis optica impair glutamate transport by down-regulating EAAT2.
Aquaporin-4-binding autoantibodies in patients with neuromyelitis optica impair glutamate transport by down-regulating EAAT2.
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神经霉素炎患者Optica患者的Aquaporin-4结合自身抗体通过下调EAAT2损害谷氨酸的转运。
DOI：
10.1084/jem.20081241
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发表时间：
2008-10-27
影响因子：
15.3
通讯作者：
Lennon, Vanda A.
中科院分区：
文献类型：
--
作者：
Hinson, Shannon R.;Roemer, Shanu F.;Lucchinetti, Claudia F.;Fryer, James P.;Kryzer, Thomas J.;Chamberlain, Jayne L.;Howe, Charles L.;Pittock, Sean J.;Lennon, Vanda A.
视神经肌萎缩症（NMO）-免疫球蛋白G（IgG）是一种临床验证的血清生物标志物，可区分与NMO相关的复发性中枢神经系统（CNS）炎性脱髓鞘疾病和多发性硬化症。这种自身抗体靶向星形胶质细胞水通道蛋白-4（AQP 4）水通道。临床、放射学和免疫病理学数据表明，NMO-IgG可能是致病性的。特征性CNS病变表现为AQP 4的选择性耗竭，伴或不伴相关髓鞘丢失; IgG、IgM和补体的局灶性血管中心沉积;显著水肿;和炎症。NMO-IgG对星形胶质细胞的作用尚未研究。在这项研究中，我们证明，暴露于NMO患者血清和活性补体损害CNS源性星形胶质细胞的膜完整性。在没有补体的情况下，星形胶质细胞膜保持完整，但AQP 4被内吞，伴随着Na+依赖性谷氨酸转运的丧失和兴奋性氨基酸转运蛋白2（EAAT 2）的丧失。我们的数据表明，EAAT 2和AQP 4存在于星形胶质细胞膜作为一个大分子复合物。在分化中的星形胶质细胞祖细胞和转基因表达AQP 4的非神经细胞中，具有运输能力的EAAT 2蛋白上调。NMO患者脊髓病变的AQP 4缺陷区域中EAAT 2的显着减少支持了我们的免疫细胞化学和免疫沉淀数据。因此，NMO-IgG与星形胶质细胞AQP 4的结合启动了几种潜在的神经致病机制：补体激活、AQP 4和EAAT 2下调以及谷氨酸稳态的破坏。
Neuromyelitis optica (NMO)-immunoglobulin G (IgG) is a clinically validated serum biomarker that distinguishes relapsing central nervous system (CNS) inflammatory demyelinating disorders related to NMO from multiple sclerosis. This autoantibody targets astrocytic aquaporin-4 (AQP4) water channels. Clinical, radiological, and immunopathological data suggest that NMO-IgG might be pathogenic. Characteristic CNS lesions exhibit selective depletion of AQP4, with and without associated myelin loss; focal vasculocentric deposits of IgG, IgM, and complement; prominent edema; and inflammation. The effect of NMO-IgG on astrocytes has not been studied. In this study, we demonstrate that exposure to NMO patient serum and active complement compromises the membrane integrity of CNS-derived astrocytes. Without complement, astrocytic membranes remain intact, but AQP4 is endocytosed with concomitant loss of Na+-dependent glutamate transport and loss of the excitatory amino acid transporter 2 (EAAT2) . Our data suggest that EAAT2 and AQP4 exist in astrocytic membranes as a macromolecular complex. Transport-competent EAAT2 protein is up-regulated in differentiating astrocyte progenitors and in nonneural cells expressing AQP4 transgenically. Marked reduction of EAAT2 in AQP4-deficient regions of NMO patient spinal cord lesions supports our immunocytochemical and immunoprecipitation data. Thus, binding of NMO-IgG to astrocytic AQP4 initiates several potentially neuropathogenic mechanisms: complement activation, AQP4 and EAAT2 down-regulation, and disruption of glutamate homeostasis.
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影响因子：
64.8
作者：
Lin, CLG;Orlov, I;Rothstein, JD
通讯作者：
Rothstein, JD
影响因子：
6.4
作者：
Newcombe, Jia;Uddin, Alim;Smith, Terence
通讯作者：
Smith, Terence
影响因子：
64.8
作者：
Salter, MG;Fern, R
通讯作者：
Fern, R
影响因子：
3.5
作者：
Zeng, Xiao-Ning;Sun, Xiu-Lan;Hu, Gang
通讯作者：
Hu, Gang
影响因子：
--
作者：
Pittock, Sean J.;Lennon, Vanda A.;Weinshenker, Brian G.
通讯作者：
Weinshenker, Brian G.