GLYCOLIPIDS AND EXPERIMENTAL NEUROPATHOLOGY

该项目的总体目标是阐明致病性 自身免疫性脱髓鞘性神经病的潜在机制。 特别 注意力将集中在一类新的硫酸盐的作用， 含有葡萄糖醛酸的糖脂（SGGL），其主要是 局限于周围神经系统（PNS）髓鞘、轴膜和许旺氏神经元 疾病过程中的细胞。 这些糖脂有一个共同的 糖表位与髓鞘相关糖蛋白（MAG）和一些 神经和免疫系统中的细胞粘附分子。 虽然 这些糖缀合物参与这种类型的发病机制， 周围神经病变仍然是模糊的，有越来越多的证据表明， 暗示糖脂可能作为重要的靶抗原， 脱髓鞘性神经病患者的循环免疫球蛋白。 在这个项目中，我们将继续表征额外的免疫反应性， 糖脂结构和定义其细胞和亚细胞 为临床辨证施治寻求依据 这种疾病的表现。 该实验室以前的研究表明， 提出了抗体介导的补体依赖性细胞毒性机制 治疗这种疾病 我们将进一步定义 实验模型中的致病性抗体和补体成分 这种疾病。 由于SGGL明显表达于内皮细胞， 它们构成了血脑和血的主要解剖结构， 神经屏障，我们假设循环抗体和血液 成分可能通过攻击内皮细胞进入神经， 结合SGGL，引起屏障功能的变化。 SGGL在 维持血管系统的功能完整性将是 在体内和体外系统中研究。 最后也是最重要的 我们将通过以下方式评估治疗方法的安全性和有效性： 选择性体外去除动物体内的致病性免疫球蛋白 神经病变模型。 我们的长期目标是应用所获得的知识 通过这项研究，有效治疗其他相关的自身免疫性疾病， 神经退行性疾病

The overall objective of this project is to elucidate the pathogenic mechanisms underlying autoimmune demyelinative neuropathy. Special attention will be directed at the role of a new class of sulfated glucuronic acid containing 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 a number of cell adhesion molecules in the nervous and immune systems. Although the involvement of these glycoconjugates in the pathogenesis of this type of peripheral neuropathy is still obscure, there is increasing evidence implicating that the glycolipids may serve as important target antigens for the circulating immunoglobulins in patients with demyelinating neuropathy. In this project, we will continue to characterize additional immunoreactive glycolipid structures and define their cellular and subcellular localization in order to seek the basis for the differential clinical manifestations in this disease. Previous studies from this laboratory have suggested an antibody-mediated complement-dependent cytotoxicity mechanism for this type of disorder. We will further define the specificity of the pathogenic antibodies and the complement components in experimental models of this disease. Since SGGLs are apparently expressed in 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. The role of SGGLs in the maintenance of the functional integrity of the vascular system will be investigated in 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.