g(m1)-ganglioside and Paralysis

Early in life, commensal bacteria play a major role in immune development, helping to guide the host response toward harmful stimuli while tolerating harmless antigens to prevent autoimmunity. Guillain-Barré syndrome (GBS) is an autoimmune disease caused by errant immune attack of antibody-bound ganglioside receptors on host nerve cells, resulting in paralysis. Lipooligosaccharides enveloping the prevalent enteric pathogen, Campylobacter jejuni, frequently mimic human gangliosides and can trigger GBS by stimulating the autoimmune response. In low- to middle-income countries, young children are consistently exposed to C. jejuni, and it is not known if this impacts GBS susceptibility later in life. Using a macrophage model, we examined the effect of training these cells with low doses of ganglioside-mimicking bacteria prior to challenge with GBS-associated antigens. This training caused decreased production of proinflammatory cytokines, suggesting tolerance induction. We then screened Campylobacter isolates from 154 infant fecal samples for GM1 ganglioside mimicry, finding that 23.4% of strains from both symptomatic and asymptomatic infants displayed GM1-like structures. Training macrophages with one of these asymptomatic carrier isolates also induced tolerance against GBS-associated antigens, supporting that children can be exposed to the tolerizing antigen early in life. RNA interference of Toll-like receptor 2 (TLR2) and TLR4 suggests that these receptors are not involved in tolerance associated with decreases in tumor necrosis factor (TNF), interleukin-6 (IL-6), or IL-1β levels. The results of this study suggest that exposure to ganglioside-mimicking bacteria early in life occurs naturally and impacts host susceptibility to GBS development.

Topics: Bacteria; Campylobacter Infections; Campylobacter jejuni; Child; Child, Preschool; G(M1) Ganglioside; Gangliosides; Guillain-Barre Syndrome; Humans; Lipopolysaccharides; Macrophages; Molecular Mimicry; Paralysis

Acute motor axonal neuropathy (AMAN) in humans is associated with the presence of GM1-specific antibodies. Immunization of rabbits with GM1-containing ganglioside mixtures, purified GM1, or Campylobacter jejuni lipo-oligosaccharide exhibiting a GM1-like structure elicits GM1-specific antibodies, but axonal polyneuropathy only occurs in a subset of animals. This study aimed to dissect the molecular basis for the variable induction of AMAN in rabbits. Therefore, we analyzed the pro-inflammatory characteristics of GM1-specific antibodies in plasma samples from ganglioside-immunized rabbits with and without neurological deficits. GM1-specific plasma samples from all rabbits with AMAN were capable of activating both complement and leukocytes, in contrast to none of the plasma samples from rabbits without paralysis. Furthermore, GM1-specific IgG-mediated activation of leukocytes was detected before the onset of clinical signs. These data suggest that AMAN only occurs in rabbits that develop GM1-specific antibodies with pro-inflammatory properties.

Topics: Acute Disease; Animals; Autoantibodies; Axons; Cell Degranulation; Complement Activation; G(M1) Ganglioside; Immunoglobulin Fab Fragments; Immunoglobulin G; Leukocytes; Motor Neuron Disease; Muscle Hypotonia; Paralysis; Rabbits; Receptors, IgG

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 [Galbeta1-3GalNAcbeta1-4(NeuAcalpha2-3)Galbeta1-] 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.

Topics: Animals; Antibodies, Monoclonal; Autoantibodies; Campylobacter jejuni; Cells, Cultured; G(M1) Ganglioside; Guillain-Barre Syndrome; Humans; Immunization, Passive; Immunoglobulin G; Lipopolysaccharides; Male; Molecular Mimicry; Muscle Fibers, Skeletal; Paralysis; Rabbits; Spinal Cord; Spinal Nerve Roots

Antibody responses to myelin antigens were analysed in 15 patients who developed acute neuroparalytic accidents (ANPA) during post-exposure rabies vaccination using a rabies vaccine prepared on brain tissues and in 30 individuals who were uneventfully vaccinated. High titers (> or = 100) of IgG and IgM antibodies to GM1 or GD1a gangliosides were detected by enzyme linked immunosorbent-assay (ELISA) in plasmas from ANPA patients but not in controls. These data suggest that antibodies to GM1 and GD1a gangliosides may play a pathogenic role in the demyelinating and/or inflammatory processes characteristic of rabies vaccine-induced acute neurologic complications.

Topics: Adult; Antibodies, Viral; Brain Chemistry; Child; Chromatography, High Pressure Liquid; Encephalomyelitis, Acute Disseminated; Enzyme-Linked Immunosorbent Assay; G(M1) Ganglioside; Gangliosides; Humans; Immunoglobulin G; Immunoglobulin M; Male; Middle Aged; Myelin Proteins; Paralysis; Rabies

Serum IgG anti-GM1 antibodies have been reported to occur in a variety of disorders, including Guillain-Barré syndrome and chronic polyneuropathies. Of over 5,000 serums tested in our laboratory, high titers of selective IgG anti-GM1 antibodies (> 1:1,000) and without binding to sulfatide were found in 35 patients. Clinical correlation revealed that almost all patients had axonal, motor neuropathies. One subgroup was comprised of individuals with an acute motor neuropathy, described either as an acute axonal Guillain-Barré-like syndrome that was occasionally associated with a prodrome of Campylobacter jejuni enteritis or as Chinese paralysis syndrome. A second group of patients had chronic asymmetric lower motor neuron (LMN) syndromes with no conduction block or other evidence of demyelination. The presence of selective high-titer IgG anti-GM1 antibody reactivity in serum is uncommon but when present is strongly associated with acute axonal motor neuropathies or chronic asymmetric LMN syndromes.

Topics: Antibodies; Axons; Campylobacter Infections; Demyelinating Diseases; Enteritis; G(M1) Ganglioside; Humans; Immunoglobulin G; Motor Neuron Disease; Paralysis; Polyradiculoneuropathy; Syndrome