Neuromyelitis optica IgG does not alter aquaporin-4 water permeability, plasma membrane M1/M23 isoform content, or supramolecular assembly.
Neuromyelitis optica IgG does not alter aquaporin-4 water permeability, plasma membrane M1/M23 isoform content, or supramolecular assembly.
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DOI：
10.1002/glia.22417
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发表时间：
2012-12
期刊：
影响因子：
6.2
通讯作者：
Verkman, A. S.
中科院分区：
文献类型：
--
作者：
Rossi, Andrea;Ratelade, Julien;Papadopoulos, Marios C.;Bennett, Jeffrey L.;Verkman, A. S.
视神经肌萎缩症（NMO）被认为是由针对星形胶质细胞水通道水通道蛋白4（AQP 4）的免疫球蛋白G自身抗体（NMO-IgG）引起的。最近的一项研究（Proc Natl Acad Sci USA 109：1245- 1250）报告称，NMO-IgG直接抑制AQP 4的透水性，并导致AQP 4的M1亚型（而不是M23亚型）的快速细胞内化，导致AQP 4聚集、增强的补体依赖性细胞毒性和组织肿胀。在这里，我们报告的证据挑战这一拟议的NMO-IgG介导的病理机制。我们测定了渗透性水渗透性的停流光散射质膜囊泡分离的AQP 4表达CHO细胞，一种方法，可以检测到水渗透性的变化小至5%，是不混淆的内化效应。我们发现M1-AQP 4四聚体和M23-AQP 4簇（颗粒正交阵列，OAP）的单分子水渗透性相似。AQP 4暴露于来自6名血清阳性NMO患者的高浓度NMOIgG和高亲和力重组单克隆NMO抗体，并没有降低AQP 4的水渗透性。此外，NMO-IgG没有降低水通道蛋白4重建的蛋白脂质体的水渗透性。在单独表达M1-或M23-AQP 4的转染细胞中，NMO-IgG引起M23-比M1-AQP 4更快的内化。在共表达两种亚型的细胞中，M1-和M23-AQP 4在OAP中混合，OAP在对NMO-IgG的应答中内化在一起。超分辨率成像和天然凝胶电泳显示，NMO血清或重组NMO抗体不会改变AQP 4 OAP的大小。我们得出结论，NMO-IgG不：（i）抑制AQP 4水渗透性，（ii）导致M1-AQP 4的优先内化，或（iii）导致膜内AQP 4聚集。
Neuromyelitis optica (NMO) is thought to be caused by immunoglobulin G autoantibodies (NMO-IgG) against astrocyte water channel aquaporin-4 (AQP4). A recent study ( Proc Natl Acad Sci USA 109:1245- 1250) reported that NMO-IgG inhibits AQP4 water permeability directly and causes rapid cellular internalization of the M1 but not M23 isoform of AQP4, resulting in AQP4 clustering, enhanced complement-dependent cytotoxicity, and tissue swelling. Here, we report evidence challenging this proposed mechanism of NMO-IgG-mediated pathology. We measured osmotic water permeability by stopped-flow light scattering on plasma membrane vesicles isolated from AQP4-expressing CHO cells, an approach that can detect changes in water permeability as small as 5% and is not confounded by internalization effects. We found similar single- molecule water permeability for M1-AQP4 tetramers and M23-AQP4 clusters (orthogonal arrays of particles, OAPs). Exposure of AQP4 to high concentrations of NMOIgG from six seropositive NMO patients, and to high-affinity recombinant monoclonal NMO antibodies, did not reduce AQP4 water permeability. Also, NMO-IgG did not reduce water permeability in AQP4-reconstituted proteoliposomes. In transfected cells expressing M1- or M23-AQP4 individually, NMO-IgG caused more rapid internalization of M23- than M1-AQP4. In cells coexpressing both isoforms, M1- and M23-AQP4 comingled in OAPs that were internalized together in response to NMO-IgG. Super-resolution imaging and native gel electrophoresis showed that the size of AQP4 OAPs was not altered by NMO sera or recombinant NMO antibodies. We conclude that NMO-IgG does not: (i) inhibit AQP4 water permeability, (ii) cause preferential internalization of M1-AQP4, or (iii) cause intramembrane AQP4 clustering.
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影响因子：
11.2
作者：
Bennett, Jeffrey L.;Lam, Chiwah;Kalluri, Sudhakar Reddy;Saikali, Philippe;Bautista, Katherine;Dupree, Cecily;Glogowska, Magdalena;Case, David;Antel, Jack P.;Owens, Gregory P.;Gilden, Don;Nessler, Stefan;Stadelmann, Christine;Hemmer, Bernhard
通讯作者：
Hemmer, Bernhard
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。
影响因子：
15.3
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.
通讯作者：
Lennon, Vanda A.
影响因子：
82.9
作者：
Manley, GT;Fujimura, M;Verkman, AS
通讯作者：
Verkman, AS
影响因子：
4.8
作者：
Li, Lihua;Zhang, Hua;Verkman, A. S.
通讯作者：
Verkman, A. S.
DOI：
10.1073/pnas.0902725106
发表时间：
2009-05-05
影响因子：
11.1
作者：
Ho, Joseph D.;Yeh, Ronald;Stroud, Robert M.
通讯作者：
Stroud, Robert M.