Biologic Effects of Anti-Ganglioside Antibodies

抗神经节苷脂抗体的生物学效应

• 批准号: 8761854
• 负责人: KAZIM A SHEIKH
• 金额: $ 33.25万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-15 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8761854
• 关键词: Acute; Affect; Affinity; Animal Model; Anti-Inflammatory Agents; Anti-inflammatory; Antibodies; Antigen-Antibody Complex; Autoantibodies; Autoimmune Process; Autoimmune Responses; Axon; Binding; CD209 gene; Cell surface; Cell-Mediated Cytolysis; Cells; Complex; Data; Dependency; Development; Disease; Fab Immunoglobulins; Failure; Fc Immunoglobulins; Fc Receptor; Fractionation; Fucose; Gangliosides; Goals; Guillain-Barré Syndrome; Human; IgG Receptors; Immune; Immune system; Immunoglobulin G; Immunologic Receptors; In Vitro; Individual; Inflammation; Injury; Intravenous Immunoglobulins; Lectin; Left; Mass Spectrum Analysis; Mediating; Mediator of activation protein; Microglia; Minor; Modeling; Multiple Sclerosis; Natural regeneration; Nerve; Nerve Crush; Neuroglia; Neurologic; Neurons; Neuropathy; Paralysed; Pathogenicity; Pathway interactions; Patients; Peripheral Nerves; Peripheral Nervous System; Poliomyelitis; Polysaccharides; Population; Pre-Clinical Model; Recombinants; Recovery; Recruitment Activity; Research; Role; Schwann Cells; Severity of illness; Sialic Acids; Site; Specificity; Structure; Surface Plasmon Resonance; Syndrome; Testing; Therapeutic; Tissues; Transgenic Mice; Transplantation; antibody-dependent cell cytotoxicity; axon regeneration; base; comparative efficacy; glycosylation; in vivo; inhibiting antibody; injured; macrophage; nerve injury; parent grant; prevent; public health relevance; reinnervation; repaired; role model; sialylation

DESCRIPTION (provided by applicant): After the near eradication of polio, Guillain-Barre syndrome (GBS) is the commonest cause of acute flaccid paralysis. Anti-ganglioside/glycan antibodies (Abs) are the most frequently recognized autoimmune responses in immune neuropathies grouped under the term GBS. Despite the availability of two immunomodulatory therapies, a significant proportion of patients are left with permanent neurologic sequelae. Patients with neurologic sequelae almost always have failure of axon regeneration and target reinnervation. Several studies indicate that specific anti-glycan Abs associate with poor recovery. Our group examined the effects of anti- glycan Abs on peripheral nerve repair and found these Abs inhibit regeneration of injured axons in preclinical models. The overall goals of this translational project are to study mechanisms underlying pathobiologic effects of anti-ganglioside Abs on axon regeneration and to develop strategies that could prevent the deleterious effects of anti-glycan Abs on nerve repair. Our preliminary results show that specific activating Fc-gamma receptors (Fc?Rs) particularly on macrophages recruited in the injured nerves are key determinants of Ab-mediated inhibition of nerve repair. Further, glycosylation of anti-ganglioside Abs is critical in their interactions with Fc?Rs and deglycosylation of anti-glyca Abs suppresses their inhibitory effects on nerve repair. Further, sialylated- fraction of human intravenous immunoglobulins (sIVIG), a minor component of IVIG, suppresses Ab-mediated inhibition of axon regeneration. We hypothesize that anti-glycan Abs bind to gangliosides on neural cell surfaces to form immune complexes on the proximal tips of injured axons and these in turn bind to specific activating Fc?Rs expressed by adjacent glial cells to induce tissue inflammation affecting axon regeneration. Furthermore, IgG Fc interactions with innate immune receptors are critically dependent on the IgG glycosylation and this glycosylation status can be manipulated (on pathogenic Abs and IVIG) to alter anti- ganglioside Ab- or IVIG-mediated effects. This renewal application will test these hypotheses by the following specific aims: Aim 1 will examine the role of specific Fc?Rs and glial cells expressing Fc?Rs in mediating nerve injury; Aim 2 will examine the role of N-glycan structures, carried by anti-glycan Abs, in their interactions with Fc?Rs to induce inflammation; and Aim 3 will examine the role of Fc/IgG sialylation as determinants of IVIG efficacy via the so-called 'DC-SIGN-Th2' anti-inflammatory pathway. These translational and 'proof of principle' studies have pathobiologic and therapeutic implications for failure of axon regeneration particularly that seen after immune insults/inflammation in autoimmune conditions like immune neuropathies and multiple sclerosis where failure of axonal repair is central to severity of the disease and recovery.

描述（由申请人提供）：在几乎消灭脊髓灰质炎之后，格林-巴利综合征（GBS）是急性弛缓性麻痹的最常见原因。抗神经节苷脂/聚糖抗体 (Abs) 是 GBS 术语下的免疫神经病中最常见的自身免疫反应。尽管有两种免疫调节疗法可供使用，但仍有相当一部分患者留下了永久性的神经系统后遗症。患有神经系统后遗症的患者几乎总是轴突再生和目标神经支配失败。多项研究表明，特定的抗聚糖抗体与恢复不良有关。我们的小组检查了抗聚糖抗体对周围神经修复的影响，发现这些抗体在临床前模型中抑制受损轴突的再生。该转化项目的总体目标是研究抗神经节苷脂抗体对轴突再生的病理生物学影响的机制，并制定可以防止抗聚糖抗体对神经修复产生有害影响的策略。我们的初步结果表明，特别是在受损神经中募集的巨噬细胞上的特异性激活 Fc-γ 受体 (Fc?R) 是 Ab 介导的神经修复抑制的关键决定因素。此外，抗神经节苷脂抗体的糖基化在其与 Fc?R 的相互作用中至关重要，而抗糖基化抗体的去糖基化抑制其对神经修复的抑制作用。此外，人静脉内免疫球蛋白 (sIVIG) 的唾液酸化部分（IVIG 的次要成分）可抑制 Ab 介导的轴突再生抑制。我们假设抗聚糖抗体与神经细胞表面的神经节苷脂结合，在受损轴突的近端形成免疫复合物，这些复合物又与相邻神经胶质细胞表达的特异性激活 Fc?R 结合，诱导影响轴突再生的组织炎症。此外，IgG Fc 与先天免疫受体的相互作用严重依赖于 IgG 糖基化，并且可以操纵这种糖基化状态（针对致病性 Ab 和 IVIG）以改变抗神经节苷脂 Ab 或 IVIG 介导的作用。该更新申请将通过以下具体目标来测试这些假设： 目标 1 将检查特定 Fc?R 和表达 Fc?R 的神经胶质细胞在介导神经损伤中的作用；目标 2 将检查抗聚糖抗体携带的 N-聚糖结构在与 Fc?R 相互作用诱导炎症中的作用；目标 3 将通过所谓的“DC-SIGN-Th2”抗炎途径研究 Fc/IgG 唾液酸化作为 IVIG 功效决定因素的作用。这些转化和“原理证明”研究对于轴突再生失败具有病理生物学和治疗意义，特别是在免疫神经病和多发性硬化症等自身免疫性疾病中的免疫损伤/炎症后观察到的轴突再生失败，其中轴突修复失败对于疾病的严重程度和恢复至关重要。