Association between glycoconjugate antibodies and Campylobacter infection in patients with Guillain-Barré syndrome
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Glycoconjugate
Ganglioside
Lipopolysaccharides (LPS) from Campylobacter jejuni strains isolated from patients with Guillain‐Barre syndrome (GBS) display molecular mimicry with GM1. We immunized rabbits with C. jejuni LPS from GBS‐associated strains containing a GM1‐like epitope. All animals produced high titre anti‐LPS antibodies that were cross‐reactive with GM1. We conclude that C. jejuni strains from GBS patients are able to induce antibodies that cross‐react with gangliosides and LPS. This study further confirms the role of molecular mimicry in the induction of anti‐ganglioside antibodies in GBS patients.
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Miller-Fisher syndrome
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In the Schwann cells and neuronal plasma membranes the gangliosides are organized in clusters forming complexes of gangliosides in the microdomains termed lipid rafts. We investigated frequency, clinical correlates, fine specificity and pro-inflammatory properties of antibodies to ganglioside complexes (GSCs) in a Guillain Barré syndrome (GBS) population. In 63 patients with different GBS variants we performed an ELISA for antibodies to Campylobacter Jejuni ( C. jejuni), gangliosides and GSCs. We studied the fine specificity of antibodies to GSCs by immunoabsorption study and performed a complement activation assay. Twenty-seven percent of patients had antibodies to GSCs and 71% had antibodies either to single gangliosides or to GSCs. Patients with antibodies to GSCs had more frequent involvement of cranial nerves but did not present more frequent antecedent respiratory, gastrointestinal or C. jejuni infection, did not have a preferential demyelinating or primary axonal GBS variant and did not develop greater disability at six months. The absorption study showed in 2 sera that antibodies to the complex GD1a/GD1b did not react with the gangliosides forming the complex or other single gangliosides, suggesting that antibodies to GSCs are targeted to new conformational glycoepitopes different from the ones displayed by the single gangliosides. Antibody anti-GSCs activated the complement more frequently than antibodies to single gangliosides. Complement activation indicates that antibodies to GSCs have high avidity, pro-inflammatory properties and may exert a pathogenic role in GBS.
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Antibodies to ganglioside GM1 have been associated with Guillain-Barré syndrome. To clarify their role we have studied their frequency, fine specificity and relationship to clinical features in a series of patients with this disease. Antibodies to ganglioside GM1 were identified, by both enzyme-linked immunosorbent assay and binding to thin-layer chromatograms of human brain, in 12 (28.6%) of 42 patients with Guillain-Barré syndrome and in only 1 (2.4%) of 41 normal control subjects (p = 0.002). Eight sera contained IgM antibodies and six sera contained IgG antibodies, including 2 sera which contained both. The fine specificity of the sera varied. Only four of the 12 sera also showed reactivity with ganglioside GD1b and gangliotetraosyl-ceramide (asialo-GM1), consistent with reactivity with the terminal Gal beta 1-3GalNAc disaccharide. Two sera had low titre anti-asialo-GM1 antibodies of a different class to the anti-ganglioside GM1 antibodies. The antibodies in these sera therefore react with a variety of epitopes. There was a strong relationship between the presence of anti-ganglioside GM1 antibodies in the acute stage and prolonged disability, especially if IgG antibodies were present. Seven of 12 patients with anti-ganglioside GM1 antibodies had serological evidence of recent Campylobacter jejuni infection, but antigens from a strain of this bacterium not associated with Guillain-Barré syndrome did not absorb the anti-ganglioside GM1 antibodies.
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Guillain–Barré syndrome is often caused by Campylobacter jejuni infection that has induced antibodies to the lipo-oligosaccharide (LOS) that cross-react with gangliosides at peripheral nerves causing polyneuropathy. To examine fine specificities of anti-ganglioside antibodies and develop a more robust platform for diagnosis and disease monitoring, we developed a chemoenzymatic approach that provided an unprecedented panel of oligosaccharides composed of the inner-core of the LOS of C. jejuni extended by various ganglioside mimics. The compounds and corresponding ganglio-oligosaccharides were printed as a microarray to examine binding specificities of lectins, anti-ganglioside antibodies, and serum antibodies of GBS patients. Although lectins and anti-ganglioside antibodies did not differentiate the ganglio-oligosaccharides and mimics, the patient serum samples bound much more strongly to the ganglioside mimics. The data indicate that antibodies have been elicited to a foreign epitope that includes a heptosyl residue unique of bacterial LOS and that these antibodies subsequently cross-react with lower affinity to gangliosides. The microarray detected anti-GM1a antibodies with high sensitivity and will be attractive for diagnosis, disease monitoring, and immunological research.
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The therapeutic effect of plasma exchange in Guillain-Barré syndrome (GBS) is related to the removal of circulating factors. Plasma concentrations of interleukin and other cytokines are elevated in GBS, but because their circulating half-lives are only a few hours, the effect of plasma exchange on their plasma levels would be short term. In contrast, the half-life of IgG is 3 weeks, much longer than that of other plasma proteins. This indicates that IgG is the most important factor in the development of GBS. Results of a large clinical study suggest that 2 exchanges are sufficient for mild cases of GBS, and for all others 4 exchanges are optimal. We showed that a significant IgG decrease was obtained in the first 2 sessions. Our result supports that at least 2 exchanges are needed for treating GBS. In Japan, patients with GBS often receive not only plasma exchange but also double-filtration plasmapheresis or immunoadsorption. We compared their abilities to remove immunoglobulins and anti-ganglioside antibodies. Plasma exchange decreased the IgG concentration much more than double-filtration plasmapheresis. The ability to remove IgG anti-ganglioside antibodies in plasma exchange was significantly superior to that of the other plasmaphereses.
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