GLYCOLIPIDS AND EXPERIMENTAL NEUROPATHY

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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.