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.
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