Biologic Effects of Anti-Ganglioside Antibodies

描述(申请人提供)：在接近消灭脊髓灰质炎后，格林-巴利综合征(GBS)是急性迟缓性麻痹的最常见原因。抗神经节苷脂/葡聚糖抗体(Abs)是在免疫性神经病中最常见的自身免疫反应，被归类为GBS。尽管有两种免疫调节疗法可用，但相当大一部分患者会留下永久性的神经后遗症。有神经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，特定的抗葡聚糖抗体与康复不良有关。我们小组研究了抗糖链抗体对周围神经修复的影响，并在临床前模型中发现这些抗体抑制了受损轴突的再生。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潜在病理生物学效应的机制，并开发能够防止抗多糖抗体对神经修复的有害影响的策略。我们的初步结果表明，特异性激活Fc-γ受体(Fc？Rs)，特别是聚集在受损神经中的巨噬细胞上的Fc？RS是抗体介导的抑制神经修复的关键决定因素。此外，抗神经节苷脂抗体的糖基化在它们与Fc？RS的相互作用中是关键的，而抗GlycA抗体的脱糖基化抑制了它们对神经修复的抑制作用。此外，人静脉注射免疫球蛋白的唾液酸化部分(SIVIG)是IVIG的次要成分，可抑制抗体介导的轴突再生抑制。我们推测，抗糖蛋白抗体与神经细胞表面的神经节苷脂结合，在损伤轴突的近端形成免疫复合体，进而与邻近神经胶质细胞表达的特异性激活的Fc？Rs结合，从而诱导影响轴突再生的组织炎症。此外，Ig G Fc与天然免疫受体的相互作用严重依赖于Ig G的糖基化状态，这种糖基化状态可以被操纵(在致病抗体和IVIG上)来改变抗神经节苷脂抗体或IVIG介导的效应。这一新的应用将通过以下具体目标来检验这些假说：目标1将研究表达Fc？RS的特定Fc？RS和神经胶质细胞在介导神经损伤中的作用；目标2将研究由抗糖链抗体携带的N-糖链结构在它们与Fc？Rs相互作用以诱导炎症中的作用；以及目标3将研究Fc/Ig G唾液酸化作为通过所谓的‘DC-Sign-Th2’抗炎途径作为IVIG疗效决定因素的作用。这些转化性和“原则证据”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(如免疫性神经病和多发性硬化症)的免疫损伤/炎症之后，轴突修复失败是疾病严重程度和康复的核心。

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.