GLYCOLIPIDS AND EXPERIMENTAL NEUROPATHY

这个项目的总体目标是为更好地 了解脱髓鞘的免疫致病机制 伴发伽马失调症的周围神经病和相关的自身免疫 神经退行性疾病。重点将放在一名 一类硫代葡萄糖醛酸基糖脂(SGGL)，主要是 定位于外周神经系统(PNS)髓鞘、轴膜和 雪旺细胞，在疾病过程中。这些糖脂共享一种 髓鞘相关糖蛋白(MAG)的共同碳水化合物表位和 几种具有细胞黏附特性的低分子糖蛋白 在神经和免疫系统中。此外，这些糖偶联物 与人类NK细胞具有共同的免疫反应性(HNK-1表位)， 提示它们可能在慢性粒细胞白血病自身免疫中发挥重要作用 神经系统。我们此前提供的证据表明， 糖脂抗原可作为血吸虫病的重要靶抗原。 脱髓鞘神经病患者循环免疫球蛋白的变化 游戏冷漠。我们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。在此应用程序中， 我们将继续调查临床病理， 动物模型的电生理和免疫学特征 由主动免疫和被动免疫诱导。我们将进一步定义 致病抗体的特异性和致病病毒的性质 在这种疾病的动物模型中以及在髓鞘形成中的补体 大鼠背根神经节/雪旺细胞共培养体系。既然我们 发现SGGL表达于内皮细胞上，内皮细胞构成 血脑屏障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， 导致屏障功能的改变。此外，由于SGGL可以提供 作为L的配体-选择素在白细胞上的表达 被证明受到炎症细胞因子的上调，如IL-1 1β，我们认为它们可能在急性和慢性疾病中发挥重要作用。 慢性炎症性脱髓鞘多神经根神经病以及 多灶性运动神经病。SGGL在维持植物生长发育中的作用 血管系统的功能完整性将在体内进行研究 和体外系统。最后，也是最重要的，我们将评估 选择性体外治疗的安全性和有效性 在神经病动物模型中清除致病免疫球蛋白。 我们的长期目标是应用通过这项研究获得的知识 用于其他相关自身免疫性神经退行性变的有效治疗 精神错乱。

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.