The purpose of this application is to elucidate the immunopathogenic role of antiglycosphingolipid (GSL) antibodies in peripheral neuropathies and related neurological disorders and to develop effective therapies for these diseases. In recent years, mounting evidence implicates the involvement of anti-GSL antibodies in the pathogenesis of peripheral neuropathies, such as Guillain-Barr? syndrome (GBS). Potential antigens include a variety of acidic GSLs, such as gangliosides and sulfated glycolipids, and neutral GSLs. These GSLs are most abundant in nervous tissues and represent targets of circulating antibodies and cytotoxic immune cells in patients with these neurological disorders. At present, many questions remain regarding the origin of these antibodies and the pathogenic mechanisms of autoantibodies, particularly related to the invasion of antibodies or immune cells from the circulation to the endoneurial space. Our knowledge of the emergence of autoantibodies against neural antigens is still fragmentary, but such knowledge would be prerequisite in developing strategies for preventing and treating these peripheral neurological disorders. Since there is growing awareness that the anti-GSL antibodies arise as the result of antecedent infection, we hypothesize that anti-GSL antibodies may arise from a variety of glycoconjugate antigens through a molecular mimicry mechanism. These glycoconjugates include bacterial lipopolysaccharides (LPSs) that share carbohydrate epitopes similar to those of GSLs.
Three specific aims will be carried out: (1) To test the hypothesis that there is strong correlation between LPSs, anti-GSLs, and the manisfestation of clinical symptoms, we will isolate pure LPSs from several bacteria and studies their structures and antigenicity. (2) We will test the hypothesis that brain microvascular endothelial-cell (BMEC) surface glycoconjugates provide sites for antibody attack and inflammatory leukocyte attachment, leading to permeability changes prior to the onset of neurological symptoms. (3) We will develop rationale and effective therapeutics for immunemediated peripheral neuropathies by "neutralizing" autoantibodies with anti-idiotypes and peptide "mimitopes" that bind to the antibodies. Our ultimate goal is to develop a rational and effective treatment of autoimmune peripheral neuropathies and related neurological disorders. RELATIONSHIP TO PUBLIC HEALTH: Infectious agents can induce severe peripheral neuropathies. Some of these agents can come from food, e.g., chicks. This research is to determine what, why, and how these agents can do it. Based on the knowledge gained, we will test a number of novel strategies for the effective treatment of these disorders.
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