In Guillain-Barré syndrome (GBS), both axonal and demyelinating variants can be mediated by complement-fixing anti–GM1 ganglioside autoantibodies that target peripheral nerve axonal and Schwann cell (SC) membranes, respectively. Critically, the extent of axonal degeneration in both variants dictates long-term outcome. The differing pathomechanisms underlying direct axonal injury and the secondary bystander axonal degeneration following SC injury are unresolved. To investigate this, we generated glycosyltransferase-disrupted transgenic mice that express GM1 ganglioside either exclusively in neurons [GalNAcT^–/–-Tg(neuronal)] or glia [GalNAcT^–/–-Tg(glial)], thereby allowing anti-GM1 antibodies to solely target GM1 in either axonal or SC membranes, respectively. Myelinated-axon integrity in distal motor nerves was studied in transgenic mice exposed to anti-GM1 antibody and complement in ex vivo and in vivo injury paradigms. Axonal targeting induced catastrophic acute axonal disruption, as expected. When mice with GM1 in SC membranes were targeted, acute disruption of perisynaptic glia and SC membranes at nodes of Ranvier (NoRs) occurred. Following glial injury, axonal disruption at NoRs also developed subacutely, progressing to secondary axonal degeneration. These models differentiate the distinctly different axonopathic pathways under axonal and glial membrane targeting conditions, and provide insights into primary and secondary axonal injury, currently a major unsolved area in GBS research.

中文翻译：

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雪旺细胞结膜破坏在格林-巴利综合征小鼠模型中引发旁观者轴突变性

在格林-巴利综合征 (GBS) 中，轴突和脱髓鞘变异均可由补体固定抗 GM1 神经节苷脂自身抗体介导，这些自身抗体分别靶向外周神经轴突和雪旺细胞 (SC) 膜。至关重要的是，两种变体的轴突变性程度决定了长期结果。直接轴突损伤和 SC 损伤后继发性旁观者轴突变性的不同病理机制尚未解决。为了研究这一点，我们生成了糖基转移酶破坏的转基因小鼠，这些小鼠仅在神经元 [ GalNAcT ^–/– -Tg(neuronal) ] 或神经胶质 [ GalNAcT ^–/– -Tg(glial)]中表达 GM1 神经节苷脂]，从而允许抗 GM1 抗体分别单独靶向轴突或 SC 膜中的 GM1。在体外和体内损伤范例中暴露于抗 GM1 抗体和补体的转基因小鼠中研究了远端运动神经的有髓轴突完整性。正如预期的那样，轴突靶向诱导了灾难性的急性轴突破坏。当 SC 膜中具有 GM1 的小鼠被靶向时，Ranvier (NoRs) 节点处的突触周围神经胶质细胞和 SC 膜发生急性破坏。神经胶质损伤后，NoR 处的轴突变性也呈亚急性发展，发展为继发性轴突变性。这些模型区分轴突和神经胶质膜靶向条件下明显不同的轴突通路，并提供对原发性和继发性轴突损伤的见解，这是目前 GBS 研究中一个主要未解决的领域。