Biologic effects of anti-ganglisiode antibodies

描述（由申请人提供）：在几乎根除脊髓灰质炎之后，格林-巴利综合征（GBS）是急性弛缓性麻痹的最常见原因。GBS包括一组临床和病理生理相关的自身免疫性急性单相神经性疾病。尽管有两种免疫调节疗法，但很大一部分患者留下了永久性的神经系统后遗症，包括无法独立行走。神经系统后遗症患者几乎都有轴突再生和靶神经再生失败。抗神经节苷脂抗体（Abs）是与GBS相关的最常见的自身免疫标志物。这些抗体的病理作用谱尚未完全确定。我们假设具有一定特异性的抗神经节苷脂抗体通过在再生轴突的生长锥上交联神经节苷脂作为抑制性指导线索。我们的目标是研究抗神经节苷脂介导的抑制（Aim 1）的特异性，并表征脂质载体和神经节苷脂交联（Aim 2）的作用，以及次级信使（TNF受体家族成员p75、TROY和Rho GTPases）在生长锥水平上参与这种Ab介导的轴突再生抑制（Aim 3和4）。我们建议利用体外轴突再生和生长锥行为模型，以及神经移植动物模型来研究实验生成的单克隆抗神经节苷脂抗体的病理生物学作用，并将其与GBS患者的抗神经节苷脂抗体进行比较。这些动物模型也将用于研究神经节苷交联、p75和TROY以及RhoA GTPase的下游效应物的作用。这些研究将为抗神经节苷脂抗体及其靶神经节苷脂在再生轴突中诱导抑制信号提供原理证明，并可能为开发特异性治疗方法确定靶点。我们的发现应该为轴突再生失败的生物学提供见解，这不仅与周围神经病变有关，而且与脊髓损伤和多发性硬化症等CMS疾病有关。公共信息声明：本转化研究项目旨在研究吉兰-巴利综合征和其他神经系统疾病后永久性神经系统后遗症和不完全恢复的潜在机制，并确定目标，制定合理的治疗策略，以预防这种并发症。

DESCRIPTION (provided by applicant): After the near eradication of polio, Guillain-Barre syndrome (GBS) is the commonest cause of acute flaccid paralysis. GBS comprises a group of clinically and pathophysiologically related, acute monophasic neuropathic disorders of autoimmune origin. Despite the availability of two immunomodulatory therapies, a significant proportion of patients are left with permanent neurologic sequelae, including inability to walk unaided. Patients with neurologic sequelae almost always have failure of axon regeneration and target reinnervation. Anti-ganglioside antibodies (Abs) are the single most common autoimmune marker associated with GBS. The spectrum of pathobiologic effects of these Abs is not completely defined. We hypothesize that anti-ganglioside Abs with certain specificities act as inhibitory guidance cues by cross-linking gangliosides on growth cones of regenerating axons. Our goals are to examine the specificity of anti-ganglioside Ab- mediated inhibition (Aim 1), and to characterize the role of lipid rafts and ganglioside cross-linking (Aim 2), and secondary messengers (TNF receptor family members p75 and TROY and Rho GTPases) involved in this Ab-mediated inhibition of axon regeneration at the level of growth cones (Aims 3 and 4). We propose to use in vitro models of axon regeneration and growth cone behavior, and in a nerve graft animal model to study the pathobiologic effects of experimentally generated monoclonal anti-ganglioside Abs and compare them to anti-ganglioside Abs derived from GBS patients. These animal models will also be used to examine the role of ganglioside cross-linking, p75, and TROY and a downstream effector of RhoA GTPase. The proposed studies will provide proof of principle that anti-ganglioside Abs and their target gangliosides can induce inhibitory signals in regenerating axons and potentially identify targets for development of specific therapies. Our findings should provide insight into biology of failure of axon regeneration, which is relevant not only to peripheral neuropathies but also to CMS disorders like spinal cord injury and multiple sclerosis. Public information statement: This translational research project seeks to examine the potential mechanisms underlying permanent neurologic sequelae and incomplete recovery after Guillain-Barre syndrome and other neurologic disorders and to identify targets to develop rational therapeutic strategies to prevent this complication.