Biologic Effects of Anti-Ganglioside Antibodies

描述（由申请人提供）：在几乎根除脊髓灰质炎后，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）是在术语GBS下分组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用，但仍有相当比例的患者留下永久性神经系统后遗症。有神经系统后遗症的患者几乎总是轴突再生和靶神经再支配失败。几项研究表明，特异性抗聚糖抗体与恢复不良相关。我们的小组检查了抗聚糖抗体对周围神经修复的作用，发现这些抗体在临床前模型中抑制损伤轴突的再生。这个翻译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作用的机制，并制定策略，可以防止抗聚糖抗体对神经修复的有害影响。我们的初步结果表明，特异性激活Fc-γ受体（Fc？Rs），特别是在受损神经中募集的巨噬细胞上的表达是Ab介导的神经修复抑制的关键决定因素。此外，糖基化的抗神经节苷脂抗体是至关重要的，在他们的相互作用与Fc？Rs和抗glyca Ab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的唾液酸化部分（sIVIG）（IVIG的次要组分）抑制Ab介导的轴突再生抑制。我们假设，抗聚糖抗体结合神经细胞表面的神经节苷脂，形成免疫复合物的近端损伤轴突和这些反过来结合到特定的激活Fc？邻近胶质细胞表达受体诱导组织炎症影响轴突再生。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（对致病性Ab和IVIG）以改变抗神经节苷脂Ab或IVIG介导的作用。这一更新申请将测试这些假设的以下具体目标：目标1将检查特定的Fc的作用？Rs和神经胶质细胞表达Fc？RS介导神经损伤;目的2将研究N-聚糖结构的作用，进行抗聚糖抗体，在他们的相互作用与Fc？Rs诱导炎症;目的3将检查Fc/IgG唾液酸化作为IVIG功效的决定因素通过所谓的“DC-SIGN-Th 2”抗炎途径的作用。这些转化和“原理证明”研究对轴突再生失败具有病理生物学和治疗意义，特别是在自身免疫性疾病如免疫神经病和多发性硬化症中的免疫损伤/炎症后观察到的轴突再生失败，其中轴突修复失败是疾病严重程度和恢复的核心。

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.