The intrinsic pathogenic role of autoantibodies to aquaporin 4 mediating spinal cord disease in a rat passive-transfer model.
The intrinsic pathogenic role of autoantibodies to aquaporin 4 mediating spinal cord disease in a rat passive-transfer model.
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DOI：
10.1016/j.expneurol.2014.12.015
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发表时间：
2015-03
影响因子：
5.3
通讯作者：
Toyka, Klaus V.
中科院分区：
文献类型：
--
作者：
Geis, Christian;Ritter, Christian;Ruschil, Christoph;Weishaupt, Andreas;Gruenewald, Benedikt;Stoll, Guido;Holmoy, Trygve;Misu, Tatsuro;Fujihara, Kazuo;Hemmer, Bernhard;Stadelmann, Christine;Bennett, Jeffrey L.;Sommer, Claudia;Toyka, Klaus V.
视神经肌萎缩症（NMO）与针对水通道蛋白4（AQP 4）的自身抗体（AB）存在因果关系。在这里，我们专注于致病作用专门介导的人类AB的AQP 4在体内。我们进行了无细胞鞘内（i.th.）使用纯化的患者NMO免疫球蛋白G（IgG）和各种重组人抗AQP 4 IgG-AB通过植入i.t.导尿管重复应用患者NMO IgG组分和重组人抗AQP 4 AB诱导脊髓疾病体征。磁共振成像（MRI）显示在抗AQP 4 IgG应用部位的纵向脊髓病变。在有症状的动物中，体感诱发电位振幅降低，证实了观察到的功能障碍。脊髓组织学显示，在受影响区域的灰色和白色物质中存在特异性IgG沉积。在免疫球蛋白沉积的脊髓区域，我们没有发现炎性细胞浸润或补体激活。此外，破坏性病变显示轴突或髓鞘损伤和损失的星形胶质细胞和少突胶质细胞都没有。AQP 4和兴奋性氨基酸转运蛋白2（EAAT 2）的免疫反应性显着降低，而星形胶质细胞标记物胶质细胞酸性蛋白（GFAP）的免疫反应性被保留。NMDA受体NR 1亚单位的表达下调IgG沉积可能引起持续的amatergic过度兴奋的领域。疾病体征和组织病理学在停止注射后数周内可逆。我们的结论是，在体内应用针对AQP 4的AB可以诱导受体大鼠的可逆性脊髓疾病，诱导不同的组织病理学异常。这些发现可能是最近报道的NMO患者邻近效应器介导的组织损伤的“半影样”病变的实验相关性。
Neuromyelitis optica (NMO) is causally linked to autoantibodies (ABs) against aquaporin 4 (AQP4). Here, we focused on the pathogenic effects exclusively mediated by human ABs to AQP4 in vivo. We performed cell-free intrathecal (i.th.) passive transfer experiments in Lewis rats using purified patient NMO immunoglobulin G (IgG) and various recombinant human anti-AQP4 IgG-ABs via implanted i.th. catheters. Repetitive application of patient NMO IgG fractions and of recombinant human anti-AQP4 ABs induced signs of spinal cord disease. Magnetic resonance imaging (MRI) revealed longitudinal spinal cord lesions at the site of application of anti-AQP4 IgG. Somatosensory evoked potential amplitudes were reduced in symptomatic animals corroborating the observed functional impairment. Spinal cord histology showed specific IgG deposition in the grey and white matter in the affected areas. We did not find inflammatory cell infiltration nor activation of complement in spinal cord areas of immunoglobulin deposition. Moreover, destructive lesions showing axon or myelin damage and loss of astrocytes and oligodendrocytes were all absent. Immunoreactivity to AQP4 and to the excitatory amino acid transporter 2 (EAAT2) was markedly reduced whereas immunoreactivity to the astrocytic marker glial fibrillary acid protein (GFAP) was preserved. The expression of the NMDA-receptor NR1 subunit was down-regulated in areas of IgG deposition possibly induced by sustained glutamatergic overexcitation. Disease signs and histopathology were reversible within weeks after stopping injections. We conclude that in vivo application of ABs directed at AQP 4 can induce a reversible spinal cord disease in recipient rats by inducing distinct histopathological abnormalities. These findings may be the experimental correlate of “penumbra-like” lesions recently reported in NMO patients adjacent to effector-mediated tissue damage.
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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：
7.1
作者：
Jones MV;Huang H;Calabresi PA;Levy M
通讯作者：
Levy M
影响因子：
3.3
作者：
Geis, Christian;Gruenewald, Benedikt;Sommer, Claudia
通讯作者：
Sommer, Claudia
影响因子：
82.9
作者：
Linker, RA;Mäurer, M;Gold, R
通讯作者：
Gold, R