Pathogenesis of Anti-ganglioside Antibody-Mediated Neuropathies

描述(申请人提供)：抗神经节苷脂抗体(抗神经节苷脂抗体)是免疫性神经病中最常见的自身免疫反应，归类于格林-巴利综合征(�综合征)。具有不同特异性的ABS与GBS的轴突变体有最强的相关性。在轴突GBS中，Ranvier结节和轴突首当其冲。抗体介导的兰维尔结节损伤和轴突完整性的发病机制尚不完全清楚。研究抗多糖抗体介导的神经病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完整的纤维损伤。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潜在病理生物学作用机制。我们的初步研究表明，在一种新的漏血-神经屏障(BNB)模型中，被动转移抗神经节苷脂抗体会导致Ranvier结节和轴突连续损伤，类似于轴索性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，Abs对结节和轴突的损伤是通过特定的相应神经节苷脂直接介导的，并且不依赖于补体介导的细胞溶解损伤。值得注意的是，在该模型中，神经损伤依赖于损伤神经中激活的Fc-γ受体(Fc？Rs)的表达。根据这些结果，我们推测抗神经节苷脂抗体与神经细胞表面的神经节苷脂结合在受损神经中形成免疫复合体，这些免疫复合体与邻近神经胶质细胞表达的特异性激活Fc？Rs结合，从而诱导组织炎症，影响结节和轴突的完整性。这次更新将通过以下具体目标来验证这些假说：目的1将表征一种新的被动转移动物模型，该动物模型具有BNB通透性改变和抗多糖抗体介导的神经病；目的2将研究在受损神经中特异激活的Fc？RS的表达是否是诱发神经病变所必需的；目的3将研究表达Fc？RS的特定胶质细胞在介导神经损伤中的作用。这些翻译研究将提供抗体介导的轴突损伤的详细发病机制，并评估免疫复合体诱导的炎症是否是轴突变性的机制。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，在这些疾病中，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.