Experimental models of Acute Motor Axonal Neuropathy (AM

描述（由申请人提供）：格林-巴利综合征（GBS）是一种自身免疫性感染后神经病变，是自根除脊髓灰质炎以来导致急性弛缓性麻痹的最常见原因。目前，人们普遍认为该疾病有两种主要形式，急性炎症性脱髓鞘性多神经根神经病（AIDP）和急性运动轴索神经病（AMAN）。分子模仿被认为是AMAN的致病机制，因为它主要跟随空肠弯曲杆菌感染，AMAN相关的空肠C. LPS含有神经节苷样部分，AMAN患者具有特异性的IgG抗神经节苷类抗体，包括针对GD1a的抗体，病理研究表明IgG和补体在运动轴突上沉积和特异性运动纤维损伤。然而，抗神经节苷脂抗体与神经纤维损伤之间的直接关系尚未建立。此外，还没有抗体介导的运动轴索损伤的体外或动物模型。这在很大程度上反映了产生高亲和力的IgG补体固定抗神经节苷脂抗体的困难，类似于在AMAN中看到的抗体。我们建议使用缺乏复杂神经节苷脂的小鼠，这些小鼠对复杂神经节苷脂具有免疫幼稚性，以产生所需的单克隆（mAb）抗神经节苷脂抗体。这些单克隆抗体将用于在被动转移动物模型和体外脊髓培养系统中复制运动轴索损伤。单克隆抗体也将用于定位和生化研究，以探索AMAN中出现的优先运动轴突损伤的基础。抗神经节苷脂抗体靶向抗原的神经节苷脂性质将通过体外和动物模型中神经节苷脂表达的遗传和或药理学操作来确定。体外系统也将用于研究补体级联参与抗体介导的轴突变性的组成部分。最后，来自AMAN患者的亲和纯化抗神经节苷脂抗体将被平行使用，以建立人抗体与运动轴突变性之间的因果关系。这些研究将证明分子拟态是AMAN发病机制的潜在机制。

DESCRIPTION (provided by applicant): Guillain-Barre syndrome (GBS), an autoimmune post-infectious neuropathy, is the most frequent cause of acute flaccid paralysis since the eradication of polio. It is now widely accepted that there are two major forms of the disease, acute inflammatory demyelinating polyradiculoneuropathy (AIDP) and acute motor axonal neuropathy (AMAN). Molecular mimicry has been proposed as a pathogenic mechanism for AMAN because it mostly follows Campylobacter jejuni infection, the LPS of AMAN associated C. jejuni contain ganglioside-like moieties, patients with AMAN have specific IgG anti-ganglioside antibodies including those against GD1a, and pathological studies demonstrate deposition of IgG and complement on motor axons and specific motor fiber injury. However, a direct relationship between anti-ganglioside antibodies and nerve fiber injury has not been established. Further, in vitro or animal models of antibody mediated motor axonal injury are not available. This largely reflects difficulties in generating high affinity IgG complement fixing anti-ganglioside antibodies similar to those seen in AMAN. We propose to use mice lacking complex gangliosides, which are immune naive to complex gangliosides, to generate the desired monoclonal (mAb) anti-ganglioside antibodies. These mAbs will be used to reproduce motor axonal injury in passive transfer animal models and in an in vitro spinal cord culture system. mAbs will also be used for localization and biochemical studies to probe the basis of the preferential motor axonal damage seen in AMAN. The ganglioside nature of antigens targeted by anti-ganglioside antibodies will be established by genetic and or pharmacologic manipulation of ganglioside expression in in vitro and animal models. An in vitro system will also be used to investigate the components of complement cascade involved in antibody-mediated axonal degeneration. Finally, affinity purified anti-ganglioside antibodies from patients with AMAN will be used in parallel to establish the causal relationship between the human antibodies and motor axonal degeneration. These studies will prove the hypothesis of molecular mimicry as an underlying mechanism for the pathogenesis of AMAN.