Nobuhiro Yuki

Sera from patients with Guillain-Barré syndrome (GBS) following Campylobacter jejuni infection have autoantibody to GM1 ganglioside in the acute phase of the illness. There is a strong association between GBS and Penner's serotype 19 (PEN 19) of C. jejuni. The terminal structure of the bacterial lipopolysaccharide is identical to the terminal tetrasaccharide of GM1 ganglioside. Anti-GM1 antibody inhibits motoneuron excitability. Molecular mimicry between infectious agents and nerve tissue components may function in the development of GBS.

There is a strong association between Guillain-Barré syndrome (GBS) and Penner's serotype 19 (PEN 19) of Campylobacter jejuni. Sera from patients with GBS after C. jejuni infection have autoantibodies to GM1 ganglioside in the acute phase of the illness. Our previous work has suggested that GBS results from an immune response to cross-reactive antigen between lipopolysaccharide (LPS) of the Gram-negative bacterium and membrane components of peripheral nerves. To clarify the pathogenesis of GBS, we have investigated whether GM1-oligosaccharide structure is present in the LPS of C. jejuni (PEN 19) that was isolated from a GBS patient. After extraction of the LPS, the LPS showing the binding activity of cholera toxin, that specifically recognizes the GM1-oligosaccharide was purified by a silica bead column chromatography. Gas-liquid chromatography-mass spectrometric analysis has shown that the purified LPS contained Gal, GalNAc, and NeuAc, which are sugar components of GM1 ganglioside. 1H NMR methods [Carr-Purcell-Meiboom-Gill (CPMG), total correlation spectroscopy (TOCSY), and nuclear Overhauser effect spectroscopy (NOESY)] have revealed that the oligosaccharide structure [Gal beta 1-3 GalNAc beta 1-4(NeuAc alpha 2-3)Gal beta] protrude from the LPS core. This terminal structure [Gal beta 1-3GalNAc beta 1-4(NeuAc alpha 2-3)Gal beta] is identical to the terminal tetrasaccharide of the GM1 ganglioside. This is the first study to demonstrate the existence of molecular mimicry between nerve tissue and the infectious agent that elicits GBS.

Molecular mimicry between microbial and self-components is postulated as the mechanism that accounts for the antigen and tissue specificity of immune responses in postinfectious autoimmune diseases. Little direct evidence exists, and research in this area has focused principally on T cell-mediated, antipeptide responses, rather than on humoral responses to carbohydrate structures. Guillain–Barré syndrome, the most frequent cause of acute neuromuscular paralysis, occurs 1–2 wk after various infections, in particular, Campylobacter jejuni enteritis. Carbohydrate mimicry [Galβ1–3GalNAcβ1–4(NeuAcα2–3)Galβ1-] between the bacterial lipooligosaccharide and human GM1 ganglioside is seen as having relevance to the pathogenesis of Guillain–Barré syndrome, and conclusive evidence is reported here. On sensitization with C. jejuni lipooligosaccharide, rabbits developed anti-GM1 IgG antibody and flaccid limb weakness. Paralyzed rabbits had pathological changes in their peripheral nerves identical with those present in Guillain–Barré syndrome. Immunization of mice with the lipooligosaccharide generated a mAb that reacted with GM1 and bound to human peripheral nerves. The mAb and anti-GM1 IgG from patients with Guillain–Barré syndrome did not induce paralysis but blocked muscle action potentials in a muscle–spinal cord coculture, indicating that anti-GM1 antibody can cause muscle weakness. These findings show that carbohydrate mimicry is an important cause of autoimmune neuropathy.

We report 2 patients with Guillain-Barré syndrome (GBS) following Campylobacter jejuni enteritis. Electrophysiologic studies indicated that the predominant process was axonal degeneration of motor nerves, and clinical recovery was poor. Serum testing by thin-layer chromatography and enzyme-linked immunosorbent assay revealed that the sera from both patients contained high titers of IgG antibody against GM1 ganglioside. These cases may represent a subgroup of GBS as acute axonal polyneuropathy following C jejuni enteritis associated with anti-GM1 antibodies.