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-巴利综合征（GBS）下归类的免疫性神经病中最常见的自身免疫反应。具有不同特异性的Ab与GBS的轴突变体具有最强的关联。在轴突GBS中，郎维尔节和轴突首当其冲。Ab介导的朗氏结和轴突完整性损伤的发病机制尚未完全了解。研究抗聚糖Ab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中完整纤维的损伤。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生物学作用的机制。我们的初步研究表明，被动转移与抗神经节苷脂抗体在一个新的模型漏血神经屏障（BNB）诱导的顺序损伤节点的朗维尔和轴突模仿病理学中看到的轴突GBS患者。在具有改变的神经节苷脂或补体（C5）表达的突变小鼠中，Abs直接通过特定的相应神经节苷脂介导结和轴突损伤，并且不依赖于补体介导的细胞溶解性损伤。值得注意的是，该模型中的神经损伤依赖于活化Fc-γ受体（Fc？在受伤的神经。从这些结果中，我们推测，抗神经节苷脂抗体结合神经细胞表面的神经节苷脂，在损伤的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？受体由邻近的神经胶质细胞表达，诱导组织炎症，影响淋巴结和轴突的完整性。本次更新将通过以下具体目标来检验这些假设：目标1将描述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;目标2将检查特异性活化Fc的表达是否？Rs在受伤的神经是必要的，以诱导神经病变，目的3将检查特定的神经胶质细胞表达Fc？RS介导神经损伤。这些翻译研究将提供详细的发病机制抗体介导的轴突损伤，并评估是否免疫复合物诱导的炎症是轴突变性的机制。这些研究将有助于开发治疗自身免疫性疾病的方法，如免疫性神经病和多发性硬化症，其中轴突损伤是疾病严重程度和恢复的核心。

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.