Pathogenesis of anti-ganglioside antibody-mediated neuropathies

描述（由申请方提供）：抗神经节苷脂抗体（Abs）是称为格林-巴利综合征（GBS）的免疫神经病中最常见的自身免疫反应。具有GM 1和GD 1a特异性的Ab与GBS的运动轴突变体以及该疾病的轴突和脱髓鞘形式的恢复差相关。一个令人困惑的临床发现是，具有相同特异性的抗神经节苷脂抗体的患者在临床表型和结果方面存在差异。我们的总体目标是研究抗神经节苷脂抗体对完整和受损神经纤维的病理生物学作用的机制。我们的初步研究表明：a）抗神经节苷脂Ab在神经的特定区域、朗维尔结和运动神经末梢处诱导功能障碍; B）抗神经节苷脂Ab抑制动物模型中受损神经纤维的再生;和C）具有高亲和力的单克隆Ab在两种动物模型中对完整和受损神经纤维具有病理生物学作用。根据这些结果，我们假设抗神经节苷脂Ab：1）通过改变郎维氏结和运动神经末梢处的离子通道和/或胞吐机制的蛋白质来诱导可逆的神经功能障碍; 2）抑制神经再生，这是具有抗神经节苷脂Ab的GBS患者中恢复不良的一种机制;以及3）Ab亲和力决定神经损伤的程度和类型以及临床表型。本次更新将通过以下具体目标来检验这些假设：目标1将在神经内注射模型中检查抗神经节苷脂Ab对完整Ranvier节点的影响;目标2将通过宏观膜片钳研究来研究这些Ab如何影响神经肌肉传递;目标3将在坐骨神经挤压和神经移植模型中研究这些Ab对神经再生的影响;目的4将通过关联Ab亲和力（如在固相测定中测定的）和神经损伤的动物和组织培养模型中的致病性来评估Ab亲和力在神经性损伤中的作用。这些研究将提供Ab介导的轴突损伤的详细发病机制，这将有助于开发针对自身免疫性疾病的治疗方法，如免疫神经病和多发性硬化症，其中轴突损伤是恢复不良的核心。公共信息声明：该转化研究项目旨在研究GBS中轴突损伤的机制。这些研究将有助于开发治疗策略，以防止轴突变性和增强轴突再生的自身免疫性神经病。

DESCRIPTION (provided by applicant): Anti-ganglioside antibodies (Abs) are the most frequently recognized autoimmune responses in immune neuropathies termed Guillain-Barre syndrome (GBS). Abs with GM1 and GD1a specificity are associated with the motor axonal variant of GBS and poor recovery in both axonal and demyelinating forms of the disease. A puzzling clinical finding is that patients with anti-ganglioside Abs of same specificities have variations in clinical phenotype and outcome. Our overall goal is to study mechanisms underlying pathobiologic effects of anti-ganglioside Abs on intact and injured nerve fibers. Our preliminary studies show that: a) anti-ganglioside Abs induce dysfunction at specialized regions of the nerves, nodes of Ranvier and motor nerve terminals; b) an anti-ganglioside Ab inhibits regeneration of injured nerve fibers in an animal model; and C) a monoclonal Ab with high affinity has pathobiologic effects on intact and injured nerve fibers in two animal models. From these results we hypothesize that anti-ganglioside Abs: 1) induce reversible nerve dysfunction by altering ion channels and/or proteins of exocytic machinery at nodes of Ranvier and motor nerve terminals; 2) inhibit nerve regeneration, which is one mechanism of poor recovery in GBS patients with anti-ganglioside Abs; and 3) Ab affinity determines extent and type of nerve injury and clinical phenotype. This renewal will test these hypotheses by the following specific aims: Aim 1 will examine the effects of anti-ganglioside Abs on intact nodes of Ranvier in an intraneural injection model; how these Abs affect neuromuscular transmission will be investigated by macro-patch-clamp studies in Aim 2; in Aim 3, effects of these Abs on nerve regeneration will be studied in sciatic nerve crush and nerve transplant models; and Aim 4 will evaluate the role of Ab affinity in neuropathic injury by correlating Ab affinity (as determined in solid phase assays) and pathogenicity in animal and tissue culture models of nerve injury. These studies will provide detailed pathogenesis of Ab-mediated axon injury, which will help in developing therapies for autoimmune conditions like immune neuropathies and multiple sclerosis where axonal damage is central to poor recovery. Public information statement: This translational research project seeks to examine mechanisms of axonal injury in GBS. These studies will help develop treatment strategies to prevent axonal degeneration and enhance axonal regeneration in autoimmune neuropathies.