Biologic effects of anti-ganglisiode 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。GBS由一组临床和病理生理学相关的自身免疫性急性单相神经病组成。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，包括无法在没有辅助的情况下行走。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。抗神经节苷脂抗体(Abs)是与GBS相关的最常见的自身免疫标记物。这些抗体的病理生物学效应的光谱还没有完全定义。我们假设具有一定特异性的抗神经节苷脂抗体通过将神经节苷脂交联在再生轴突的生长锥体上作为抑制性引导信号。我们的目标是检测抗神经节苷脂抗体介导的抑制(目标1)的特异性，并表征脂筏和神经节苷脂交联(目标2)以及二级信使(肿瘤坏死因子受体家族成员p75和Troy和Rho GTP酶)在抗体介导的生长锥体水平上对轴突再生的抑制作用(目标3和4)。我们建议使用轴突再生和生长锥行为的体外模型，并在神经移植动物模型中研究实验产生的抗神经节苷脂单抗的病理生物学效应，并将其与来自GBS患者的抗神经节苷脂抗体进行比较。这些动物模型也将被用来研究神经节苷脂交联物、p75和Troy以及RhoA GTPase下游效应因子的作用。这项拟议的研究将为抗神经节苷脂抗体及其靶神经节苷脂可以在再生轴突中诱导抑制信号的原理提供证据，并有可能确定特定治疗的靶点。我们的发现应该为轴突再生失败的生物学提供洞察力，轴突再生失败不仅与周围神经疾病有关，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：这一翻译研究项目旨在研究格林-巴利综合征和其他神经疾病后永久性神经后遗症和不完全恢复的潜在机制，并确定目标，以开发合理的治疗策略来预防这种并发症。

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.