In the post-polio era the Guillain-Barre syndromes (GBS) are the most frequent causes of acute flaccid paralysis worldwide and remain important causes of mortality and disability. Recent advances in GBS have been propelled by the recognition that Campylobacter jejuni infection is an important antecedent, and that many individuals with GBS have anti- glycoconjugate antibodies. An ongoing project involving the Second Teaching Hospital, Shijiazhuang, China, the University of Pennsylvania, and the Johns Hopkins University has shown that a high proportion of hue extraordinary numbers of GBS seen in Hebel Province follow C. jejuni infection. This project has provided confirmation of the heterogeneity of GBS as clinically defined, and identified both predominantly axonal and predominantly demyelinating patterns of nerve injury. The forms differ in the type of nerve fibers affected and the sites on individual nerve fibers that are targeted by immune attack. Preliminary data show that both forms have evidence of complement binding and activation on nerve fibers. Complement is present on the outer (abaxonal) Schwann cell plasmalemma in the demyelinating cases, and on the nodal axolemma and periaxonal space in the axonal patterns. This project will test the hypothesis that specific glycoconjugates on the lipopolysaccharide of Campylobacter strains lead to an antibody response against shared epitopes with very specific localizations in the peripheral nerves, so that antibody specificity dictates the type of nerve fibers involved and th type of pathologic lesion. A four-pronged attack will provide correlative, clinical, electrophysiologic, bacteriological, and serologic assessment of individual patients; define the immunopathology in autopsied cases; passively transfer the disorder to mice using well-defined sera; and establish animal models of post-Campylobacter disease. To accomplish these goals, we will: 1) ask if there are consistent anti- glycoconjugate antibody patterns that distinguish the patterns of disease; 2) determine if the relevant glycoconjugates are present in C. jejuni isolated from individual with the specific patterns; 3) determine if the physiologic and pathologic features of each patient's disease can be transferred passively by serum to murine nerves in vivo and in vitro; 4) establish animal models of the different forms by feeding the specific Campylobacter strains and by immunization with lipopolysaccharide. The results of these studies should provide general insights into the mechanisms of GBS, and may suggest avenues for development of new therapeutic approaches.
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