Pathogenesis of Anti-ganglioside Antibody-Mediated Neuropathies

描述（由申请人提供）：抗神经节苷脂抗体（Abs）是在格林-巴综合征（GBS）下的免疫神经病变中最常见的自身免疫反应。不同特异性的抗体与GBS轴突变异的相关性最强。在轴突性GBS中，Ranvier节点和轴突节点首当其冲受到损伤。抗体介导的Ranvier节点和轴突完整性损伤的发病机制尚不完全清楚。研究抗聚糖抗体介导的神经病变的一个基本限制是缺乏可靠的被动转移模型来诱导实验动物损伤完整的纤维。我们的总体目标是研究抗神经节苷脂抗体对完整神经纤维的病理作用机制。我们的初步研究表明，在一种新的漏血神经屏障（BNB）模型中，抗神经节苷类抗体的被动转移诱导了Ranvier节点和轴突的连续损伤，模拟了轴突性GBS患者的病理。在神经节苷脂或补体（C5）表达改变的突变小鼠中，抗体的节和轴突损伤直接通过特异性的相应神经节苷脂介导，不依赖于补体介导的细胞溶解损伤。值得注意的是，该模型中的神经损伤依赖于激活Fc- γ受体的表达(Fc？Rs)损伤的神经。根据这些结果，我们假设抗神经节苷类抗体与神经细胞表面的神经节苷类结合，在受损神经中形成免疫复合物，这些免疫复合物参与特异性激活Fc？Rs由邻近的胶质细胞表达，诱导组织炎症，影响节和轴突的完整性。这项更新将通过以下具体目的来验证这些假设：目的1将表征BNB通透性改变和抗聚糖ab介导的神经病变的新被动转移动物模型；目的2将检测特异性激活Fc？损伤神经中的Rs是诱发神经病变所必需的；和Aim 3将研究表达Fc？r在调节神经损伤中起作用。这些转化研究将提供抗体介导的轴突损伤的详细发病机制，并评估免疫复合物诱导的炎症是否是轴突变性的一种机制。这些研究将有助于开发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，其中轴突损伤是疾病严重程度和康复的核心。

DESCRIPTION (provided by applicant): Anti-ganglioside antibodies (Abs) are the most frequently recognized autoimmune responses in immune neuropathies grouped under the term Guillain-Barr� syndrome (GBS). Abs with different specificities have strongest association with axonal variants of GBS. Nodes of Ranvier and axons bear the brunt of damage in axonal GBS. The pathogenesis of Ab-mediated damage to nodes of Ranvier and axonal integrity is not completely understood. A fundamental limitation in studying anti-glycan Ab-mediated neuropathy is lack of reliable passive transfer models to induce injury to the intact fibers in experimental animals. Our overall goal is to study mechanisms underlying pathobiologic effects of anti-ganglioside Abs on intact nerve fibers. Our preliminary studies show that passive transfer with anti-ganglioside Abs in a new model of leaky blood-nerve barrier (BNB) induces sequential injury to nodes of Ranvier and axons mimicking pathology seen in patients with axonal GBS. In mutant mice with altered ganglioside or complement (C5) expression nodal and axonal injury by Abs is mediated directly through specific corresponding ganglioside and is independent of complement-mediated cytolytic injury. Notably, neural injury in this model is dependent on expression of activating Fc-gamma receptors (Fc?Rs) in injured nerves. From these results we hypothesize that anti- ganglioside Abs bind to gangliosides on neural cell surfaces to form immune complexes in the injured nerves and these immune complexes engage specific activating Fc?Rs expressed by adjacent glial cells to induce tissue inflammation that affects nodal and axonal integrity. This renewal will test these hypotheses by the following specific aims: Aim 1 will characterize a new passive transfer animal model of altered BNB permeability and anti-glycan Ab-mediated neuropathy; Aim 2 will examine whether expression of specific activating Fc?Rs in injured nerves is necessary to induce neuropathy; and Aim 3 will examine the role of specific glial cells expressing Fc?Rs in mediating nerve injury. These translational studies will provide detailed pathogenesis of Ab-mediated axon injury and evaluate whether immune complex-induced inflammation is a mechanism of axonal degeneration. These studies will help in developing therapies for autoimmune conditions like immune neuropathies and multiple sclerosis where axonal damage is central to severity of the disease and recovery.