Department of Medicine and Physiology, University of California, 1246 Health Sciences East Tower, San Francisco, CA 94143-0521, USA.
J Neuroinflammation. 2014 Jan 27;11:16. doi: 10.1186/1742-2094-11-16.
Although optic neuritis (ON) is a defining feature of neuromyelitis optica (NMO), appropriate animal models of NMO ON are lacking. Most NMO patients are seropositive for immunoglobulin G autoantibodies (NMO-IgG) against the astrocyte water channel aquaporin-4 (AQP4).
Several approaches were tested to develop a robust, passive-transfer mouse model of NMO ON, including NMO-IgG and complement delivery by: (i) retrobulbar infusion; (ii) intravitreal injection; (iii) a single intracranial injection near the optic chiasm; and (iv) 3-days continuous intracranial infusion near the optic chiasm.
Little ON or retinal pathology was seen using approaches (i) to (iii). Using approach (iv), however, optic nerves showed characteristic NMO pathology, with loss of AQP4 and glial fibrillary acidic protein immunoreactivity, granulocyte and macrophage infiltration, deposition of activated complement, demyelination and axonal injury. Even more extensive pathology was created in mice lacking complement inhibitor protein CD59, or using a genetically modified NMO-IgG with enhanced complement effector function, including significant loss of retinal ganglion cells. In control studies, optic nerve pathology was absent in treated AQP4-deficient mice, or in wild-type mice receiving control (non-NMO) IgG and complement.
Passive transfer of NMO-IgG and complement by continuous infusion near the optic chiasm in mice is sufficient to produce ON with characteristic NMO pathology. The mouse model of NMO ON should be useful in further studies of NMO pathogenesis mechanisms and therapeutics.
尽管视神经炎（ON）是视神经脊髓炎（NMO）的一个特征性表现，但缺乏合适的 NMO 视神经炎动物模型。大多数 NMO 患者的血清中存在针对星形胶质细胞水通道 aquaporin-4（AQP4）的免疫球蛋白 G 自身抗体（NMO-IgG）。
为了开发一种可靠的、被动转移的 NMO 视神经炎小鼠模型，我们测试了几种方法，包括通过以下方式输送 NMO-IgG 和补体：（i）球后注射；（ii）玻璃体内注射；（iii）视神经交叉附近单次颅内注射；和（iv）视神经交叉附近连续 3 天颅内输注。
使用方法（i）至（iii）时，视神经炎或视网膜病理学变化很小。然而，使用方法（iv）时，视神经显示出典型的 NMO 病理学特征，表现为 AQP4 和神经胶质纤维酸性蛋白免疫反应性丧失、粒细胞和巨噬细胞浸润、激活补体沉积、脱髓鞘和轴突损伤。在缺乏补体抑制剂蛋白 CD59 的小鼠或使用具有增强补体效应功能的基因修饰 NMO-IgG 的小鼠中，视神经炎病理学更为广泛，包括视网膜神经节细胞的显著丧失。在对照研究中，在接受治疗的 AQP4 缺陷型小鼠或接受对照（非 NMO）IgG 和补体的野生型小鼠中，视神经病变不存在。
通过视神经交叉附近的连续输注，在小鼠中被动转移 NMO-IgG 和补体足以产生具有典型 NMO 病理学特征的视神经炎。这种 NMO 视神经炎的小鼠模型应有助于进一步研究 NMO 发病机制和治疗方法。
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