Pathogenesis of Anti-ganglioside Antibody-Mediated Neuropathies

抗神经节苷脂抗体介导的神经病的发病机制

• 批准号: 8675292
• 负责人: KAZIM A SHEIKH
• 金额: $ 32.92万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-07-03 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8675292
• 关键词: Acute; Affect; Animal Model; Animals; Antibodies; Antigen-Antibody Complex; Autoantibodies; Autoimmune Process; Autoimmune Responses; Autopsy; Axon; Binding; Blood-Nerve Barrier; Bone Marrow; Cell Culture Techniques; Cell surface; Cell-Mediated Cytolysis; Cells; Chung model; Complement; Complement component C5; Complex; Data; Development; Disease; Electrophysiology (science); Failure; Fc Receptor; Fiber; Gangliosides; Glycosphingolipids; Goals; IgG Receptors; Immune; Inflammation; Injury; Mediating; Mediator of activation protein; Microglia; Modeling; Molecular Profiling; Morphology; Motor; Multiple Sclerosis; Mus; Mutant Strains Mice; Nerve; Nerve Fibers; Neuraxis; Neuroglia; Neurons; Neuropathy; Nodal; Paralysed; Pathogenesis; Pathology; Patients; Peripheral; Peripheral Nerves; Permeability; Polysaccharides; Ranvier' s Nodes; Recovery; Recruitment Activity; Research; Resistance; Role; Schwann Cells; Sensory; Severity of illness; Sialic Acids; Specificity; Spinal nerve structure; Syndrome; Testing; Tissues; Transgenic Mice; Up-Regulation; Variant; antibody-dependent cell cytotoxicity; axonal degeneration; base; complement system; immunocytochemistry; injured; macrophage; mutant; nerve injury; parent grant; receptor expression; sciatic nerve; therapy development; translational study

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.

描述（由申请人提供）：抗神经节苷脂抗体（Abs）是在术语格林-巴尔综合征（GBS）下分组的免疫神经病中最常见的自身免疫反应。具有不同特异性的 Abs 与 GBS 的轴突变体具有最强的关联性。 Ranvier 结点和轴突结点在轴突 GBS 中首当其冲。 Ab 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病理生物学作用的潜在机制。我们的初步研究表明，在一种新的渗漏血神经屏障（BNB）模型中使用抗神经节苷脂抗体进行被动转移会引起 Ranvier 节点和轴突的连续损伤，类似于轴突 GBS 患者的病理学。在神经节苷脂或补体 (C5) 表达改变的突变小鼠中，Abs 引起的节点和轴突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，该模型中的神经损伤取决于受损神经中激活的 Fc-γ 受体 (Fc?R) 的表达。根据这些结果，我们假设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物，并且这些免疫复合物与邻近神经胶质细胞表达的特异性激活Fc?R结合，诱导影响节点和轴突完整性的组织炎症。此次更新将通过以下具体目标来测试这些假设：目标 1 将描述一种新的被动转移动物模型，该模型具有 BNB 通透性改变和抗聚糖抗体介导的神经病变；目标 2 将检查受损神经中特异性激活 Fc?R 的表达是否是诱发神经病变所必需的；目标 3 将研究表达 Fc?R 的特定神经胶质细胞在介导神经损伤中的作用。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机制。这些研究将有助于开发针对免疫神经病和多发性硬化症等自身免疫性疾病的治疗方法，其中轴突损伤对于疾病的严重程度和恢复至关重要。