GLYCOLIPIDS AND EXPERIMENTAL NEUROPATHOLOGY

这个项目的总体目标是阐明致病因素 自身免疫性脱髓鞘神经病的机制。特价 人们的注意力将集中在一类新的硫酸盐的作用上 含葡萄糖醛酸糖脂(SGGL)，主要是 定位于外周神经系统(PNS)髓鞘、轴膜和雪旺 疾病过程中的细胞。这些糖脂有一个共同的 具有髓鞘相关糖蛋白(MAG)的碳水化合物表位和一些 神经和免疫系统中的细胞黏附分子。尽管 这些糖结合物参与了这类疾病的发病机制。 周围神经病变仍不清楚，有越来越多的证据 提示糖脂可能是重要的靶抗原。 脱髓鞘神经病患者循环免疫球蛋白的变化 在这个项目中，我们将继续描述额外的免疫反应 糖脂结构并确定它们的细胞和亚细胞 定位，为辨证论治寻求依据 这种疾病的表现。这个实验室之前的研究已经 提示了一种抗体介导的补体依赖细胞毒机制 治疗这种类型的紊乱。我们将进一步定义 实验性动物模型中的致病抗体和补体成分 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液的主要解剖结构- 神经屏障，我们假设循环中的抗体和血液 成分可能通过攻击内皮细胞进入神经- 结合SGGL，导致屏障功能改变。SGGL在植物生长发育过程中的作用 维护血管系统的功能完整性将是 在体内和体外系统中进行研究。最后，也是最重要的 我们将通过以下方式评估一种治疗方法的安全性和有效性 选择性体外清除动物致病免疫球蛋白的实验研究 神经病的模型。我们的长期目标是应用所获得的知识 通过本研究为其他相关自身免疫疾病的有效治疗提供参考。 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.