Increased titers of anti-GM1 or asialo-GM1 (GA1) antibodies are implicated in the pathogenesis of motor neuropathy. The disease sometimes follows infection with stains of Campylobacter jejuni (Cj) that have lipopolysaccharides (LPS) with GM1 and GA1-like oligosaccharides. The mechanism by which Cj infection induces the autoantibodies is complex, but preliminary studies suggest that Cj-LPS activates antigen-specific 'memory' B-cells, generated by prior exposure to a cross reactive oligosaccharide antigen.
The specific aims of the project are to: 1) investigate the generation of GM1 or GA1-specific ~memory~ B-cell, 2) elucidate the mechanism by which the B-cells are activated by Cj-LPS, 3) determine whether Cj-LPS increases permeability of the blood nerve or blood-brain barrier and whether the antibodies cause neuropathy, and 5) investigate the specific mechanisms by which Cj infection can induce the production of anti-GM1 or GA1 antibodies and cause autoimmune disease. These studies will be carried out in normal and GM1-antibody transgenic mice expressing variable regions of human anti-GM1 antibodies. SCID mice and LPS-resistant mice will be used for lymphocyte reconstitution experiments and as control, respectively. B-cells from patients with neuropathy and high auto-antibody titers will also be investigated. Antibody responses will be measured by ELISA and antigen specific plaque assays. The proposed studies are important as they will help elucidate the role of anti-GM1 or GA1 antibodies in the pathogenesis of motor neuropathy, reveal the mechanisms by which bacterial infection of LPS can lead to the development of anti-glycoconjugate antibodies and autoimmune neurological disease, and provide an experimental model to study the disease mechanisms and test the efficacy of potential new therapies.

Project Start
1999-12-01
Project End
2000-11-30
Budget Start
1998-10-01
Budget End
1999-09-30
Support Year
25
Fiscal Year
2000
Total Cost
$262,030
Indirect Cost
Name
Columbia University (N.Y.)
Department
Type
DUNS #
167204994
City
New York
State
NY
Country
United States
Zip Code
10032
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