GLYCOLIPIDS AND EXPERIMENTAL NEUROPATHY

该项目的总体目标是促进更好的 了解脱髓鞘的免疫病理机制 周围神经病伴γ病和相关自身免疫性 神经退行性疾病 重点将放在一个 一类硫酸化葡萄糖醛酸糖脂（SGGL），主要是 局限于周围神经系统（PNS）髓鞘，轴膜，和 施万细胞，在疾病过程中。 这些糖脂共享一个 与髓鞘相关糖蛋白（MAG）共同的碳水化合物表位， 几种具有细胞粘附特性的低分子量糖蛋白 在神经和免疫系统中。 此外，这些糖缀合物 与人NK细胞（HNK-1表位）具有共同的免疫反应性， 这表明它们可能在自身免疫中发挥重要作用， 神经系统 我们以前提供的证据表明， 糖脂抗原可以作为重要的靶抗原， 脱髓鞘性神经病患者的循环免疫球蛋白， 伽玛射线病 我们已经提出了一种抗体介导的，补体依赖的 这类疾病的细胞毒性机制。 在本申请中， 我们将继续研究临床病理学， 动物模型的电生理和免疫学特性 通过主动和被动免疫诱导。 我们将进一步定义 病原性抗体的特异性和抗体的性质 在这种疾病的动物模型中以及在髓鞘形成中， 大鼠背根神经节/雪旺细胞共培养系统。 既然我们 发现SGGL在内皮细胞上表达， 血脑和血神经屏障的主要解剖结构， 我们假设循环抗体和血液成分可能 通过攻击内皮细胞结合的SGGL进入神经， 引起屏障功能的改变。 此外，由于SGGL可以用于 作为白细胞上L-选择素的配体， 被证明是上调的 炎症细胞因子如IL- 1 β，我们建议，他们可能发挥重要作用，在急性和 慢性炎性脱髓鞘性多发性神经根神经病以及 多灶性运动神经病 SGGLs在维持细胞增殖中的作用 将在体内研究血管系统的功能完整性 和体外系统。 最后，也是最重要的，我们将评估 选择性体外循环治疗方法的安全性和有效性 去除神经病动物模型中的致病性免疫球蛋白。 我们的长期目标是应用通过这项研究获得的知识 用于有效治疗其他相关的自身免疫性神经退行性疾病 紊乱

The overall goal of this project is to contribute to a better understanding of the immunopathogenic mechanisms underlying demyelinating peripheral neuropathy with gammapathy and related autoimmune neurodegenerative disorders. Emphasis will be paid to the role of a class of sulfated glucuronosyl glycolipids (SGGLs), which are primarily localized in peripheral nervous system (PNS) myelin, axolemma, and Schwann cells, in the disease processes. These glycolipids share a common carbohydrate epitope with myelin-associated glycoprotein (MAG) and several low molecular weight glycoproteins with cell adhesion properties in the nervous and immune systems. Additionally, these glycoconjugates share common immunoreactivity with human NK cells (the HNK-1 epitope), suggesting that they may play an important role in the autoimmunity of the nervous system. We have previously provided evidence that the glycolipid antigens may serve as important target antigens for the circulating immunoglobulins in patients with demyelinating neuropathy and gammapathy. We have proposed an antibody-mediated, complement-dependent cytotoxicity mechanism for this type of disorder. In this application, we will continue to investigate the clinicopathological, electrophysiological, and immunological characteristics of animals models induced by active and passive immunization. We will further define the specificity of the pathogenic antibodies and the nature of the complements in animal models of this disease as well as in a myelinating rat dorsal root ganglion/Schwann cell co-culture system. Since we discovered that SGGLs are expressed on endothelial cells which constitute the major anatomical structure of blood-brain and blood-nerve barriers, we hypothesize that the circulating antibodies and blood components may gain entrance to the nerve by attacking endothelial cell-bound SGGLs, causing changes in barrier function. Additionally, since SGGLs can serve as a ligand for L-selectin on leukocytes and their expression has been demonstrated to be up-regulated by inflammatory cytokines such as IL- 1Beta, we propose that they may play an important role in acute and chronic inflammatory demyelinating polyradiculoneuropathies as well as multifocal motor neuropathy. The role of SGGLs in the maintenance of the functional integrity of the vascular system will be investigated in vivo and in vitro systems. Finally and most importantly, we will evaluate the safety and efficacy of a therapeutic approach by selective extracorporeal removal of pathogenic immunoglobulins in an animal model of neuropathy. Our long term goal is to apply the knowledge gained through this study for the effective treatment of other related autoimmune neurodegenerative disorders.