Longitudinal changes of anti-ganglioside antibodies before and after Guillain-Barré syndrome onset subsequent to Campylobacter jejuni enteritis

Anti-ganglioside antibodies frequently are present in sera from patients with Guillain–Barré syndrome (GBS) during the acute phase, but no patients in whom anti-ganglioside antibodies were tested before the onset of the syndrome have been reported. We describe the first case of GBS subsequent to Campylobacter jejuni infection, in which longitudinal changes in anti-ganglioside antibody titers were measured before and after the onset of limb weakness. Serum antibody titers against GM1 (IgM/IgG), GM1b (IgM/IgG), GalNAc-GD1a (IgM/IgG), and GD1b (IgG) were highest on the day of onset, but negative before onset. Anti-C. jejuni IgG and IgA antibody titers paralleled those of the anti-ganglioside antibodies, indicative that C. jejuni infection triggered anti-ganglioside antibody production. Press et al. [J. Neurol. Sci. 190 (2001) 41] reported that anti-ganglioside antibody titers peaked during the recovery phase, but our findings are counter to theirs. We speculate that anti-ganglioside antibodies are the primary effectors of nerve damage in GBS.     

Comparative study of preceding Campylobacter jejuni infection in Guillain-Barré syndrome in Japan and The Netherlands

A comparative study was made in Japan and The Netherlands of the presence of preceding Campylobacter jejuni infections in Guillain-Barré syndrome (GBS). It was conducted in two laboratories using different serological criteria. The Japanese results showed no significant difference in the frequency of C jejuni infection between the Japanese (17/88, 19%) and Dutch (21/132, 16%) patients with GBS. The Dutch investigation showed a higher frequency in Dutch patients (45/132; 34%) than in Japanese patients(20/88; 23%), but the difference did not reach significance. Although the frequencies of preceding C jejuni infection have been reported to be higher in Asian countries than in western countries, the findings of this collaborative study show that the incidence of antecedent C jejuni infection in GBS in Japan is not higher than in The Netherlands and that serological assays vary considerably between laboratories.     

Campylobacter jejuni enteritis and Guillain-Barré syndrome]

Guillain-Barré syndrome (GBS) is the most common cause of acute neuromuscular paralysis. Sera from patients with GBS following Campylobacter jejuni infection frequently have autoantibody to GM 1 ganglioside in the acute phase of the illness. We revealed that the lipopolysaccharide (LPS) of C. jejuni that was isolated from a GBS patient has the oligosaccharide structure [Gal beta 1-3 GalNAc beta 1-4 (NeuAc alpha 2-3) Gal beta 1-], which is identical to the terminal tetrasaccharide of GM 1 ganglioside. (1) Infection by C. jejuni that bears the GM 1-like lipopolysaccharide associated with the serotypic determinant of PEN 19 induces high production of IgG 1 and IgG 3 anti-GM 1 antibodies with help of T cells. (2) IgG anti-GM 1 antibody binds to motor nerve terminal axons, inhibits motoneuron excitability, and produces the development of GBS.     

Hyperreflexia in axonal Guillain-Barré syndrome subsequent to Campylobacter jejuni enteritis

A 66-year-old woman presented with a 3-year history of progressive right-sided hemiparkinsonism manifested by a right-hand resting tremor and right-sided bradykinesia. Magnetic resonance imaging (MRI) of the brain revealed a non-enhanced polycystic mass in the left midbrain. (11)C-methylspiperone ((11)C-NMSP) and (18)F-fluorodopa ((18)F-DOPA) positron emission tomography (PET) revealed a striatal hypometabolism that was restricted to the left side. These findings are consistent with a dysfunction in the left nigrostriatal dopaminergic pathway that is presumably induced by the cystic mass in the left midbrain. This case is significant due to the paucity of reports regarding the occurrence of a relatively pure parkinsonism that is associated with a mesencephalic space-occupying lesion.     

Temporal profile of anti-ganglioside antibodies and their relation to clinical parameters and treatment in Guillain-Barré syndrome

Elevated anti-ganglioside antibody levels mainly of anti-GM1 and anti-GD1a specificities have been reported in THE serum of patients with Guillain–Barré syndrome (GBS). The relevance of anti-ganglioside antibodies other than anti-GM1 and anti-GD1a IgG antibodies and the temporal profile of anti-ganglioside antibodies in GBS is less clear. We studied serum antibodies to GM1, GD1a, GD1b, GQ1b, sulfatide and cardiolipin of the IgM, IgG and IgA classes over the course of GBS in patients who were untreated or treated with highdose intravenous immunoglobulin (IvIg). Antibodies to GD1b, GQ1b, sulfatide and cardiolipin were not detected in the sera of the GBS patients examined in this study. Anti-GM1 IgG titers peaked around 40 days and anti-GD1a IgM around 90 days after GBS onset. Titers of anti-GM1 IgG antibodies decreased following IvIg treatment. Patients with antibody peaks, defined as fivefold or higher increase in antibody titer compared to the lowest antibody titer over the course of GBS, had higher disability scores during the first two weeks of GBS and a worse clinical outcome (anti-GM1 IgG and anti-GD1a IgM antibody peaks) and axonal damage (anti-GD1a IgM antibody peaks), compared to patients without peak antibody titers. Anti-GM1 IgG and anti-GD1a IgM antibodies are thus strongly associated with more severe- and predominantly axonal cases of GBS. The appearance of anti-GM1 IgG and anti-GD1a antibody peaks in the serum after the termination of the acute phase of GBS suggests that these antibodies are produced secondary to nerve damage in GBS. The data does not exclude the possibility that secondarily secreted anti-GM1 IgG and anti-GD1a IgM antibodies may themselves be biologically active and play a role in disease propagation and/or recovery from disease in some patients with GBS.     

Subclass distribution and the secretory component of serum IgA anti-ganglioside antibodies in Guillain-Barré syndrome after Campylobacter jejuni enteritis.

Previously, we reported that IgA anti-GM1 antibody is more closely associated with preceding Campylobacter jejuni enteritis in Guillain-Barré syndrome (GBS) than are IgG and IgM antibodies. However, the mechanism of the induction of IgA anti-ganglioside antibodies is not clear. In this study, serum IgA antibodies against GM1, GM1b, and GD1a, and GalNAc-GD1a were examined in 152 GBS patients. In GBS, antecedent C. jejuni infection is closely associated with IgA antibodies, other than GM1, against GM1b. The IgA subclass distribution is completely restricted to IgA1, no secretory IgA anti-ganglioside antibody being detected. This result does not support the hypothesis that the serum IgA antibodies present in GBS after C. jejuni enteritis originate at mucosal sites, such as the gut mucosal immune system. Seventeen (85%) of 20 patients with IgA anti-ganglioside antibodies had serological evidence of C. jejuni infection and/or a history of antecedent diarrhea. Moreover, a motor nerve conduction study showed that patients with IgA antibodies frequently had axonal neuropathy, whereas none had demyelinating neuropathy. This may support the previous report that IgA isotype anti-GM1 antibodies are more closely associated with poor outcome than are the IgG or IgM isotypes. The induction mechanism of IgA anti-ganglioside antibodies must be clarified by determining whether concentrations of cytokines, which increase the IgA class switch, are elevated in patients with GBS after C. jejuni enteritis.     

A case of Guillain-Barré syndrome after Campylobacter jejuni enterocolitis: anti-ganglioside antibody levels with or without Guillain-Barré syndrome]

A 38-year old man developed enterocolitis one day after he had ingested raw chicken. Nine days later, his grip strength weakened. Eleven days later, he was admitted to our hospital with weakness of four limbs, dysphagia and dysarthria. Serum anti-Campylobacter jejuni antibody and anti-ganglioside antibodies (GM1, GD1a, GD1b, GalNAc-GD1a) were positive, and motor action potentials were not evoked at all extremities. He was diagnosed as having Guillain-Barré syndrome. After receiving immune absorption therapy and plasma exchange therapy, the patient improved. Another person who had also consumed the same raw chicken developed colitis only. Five weeks later, the anti-GalNAc-GD1a-IgG antibody titers (O.D. 490 nm) of the patient and the other man who developed colitis were 0.324 and 0.118, respectively. It was suggested that the pathogenesis of Guillain-Barré syndrome after Campylobacter jejuni enterocolitis may be related to the type and titer of anti-ganglioside antibodies and also to the sensitivity of the individual.     

Clinical presentation and outcome of Guillain-Barré and related syndromes in relation to anti-ganglioside antibodies.

We correlated the clinical features of 78 patients with Guillain-Barré syndrome (GBS) or related variants, with the presence of serum antibodies to the gangliosides GM1, GM2, GD1a, GD1b and GQ1b in order to determine whether these antibodies may influence the clinical presentation or outcome of GBS. Sixty-three patients had typical GBS (81%), nine a pure motor form (11%), three a paraparetic form (4%), and three had Miller Fisher syndrome (MFS). IgG or IgM (or both) anti-ganglioside antibodies were found by ELISA in 37% of patients, including 36% with typical, 33% with pure motor and 100% with MFS. Beside the constant occurrence of anti-GQ1b antibodies in patients with MFS (P<0.00001), the other clinical forms were not associated with a specific anti-ganglioside reactivity. Anti-GM1 and anti-GD1a antibodies tended to be associated with a worse disability at 6 month than other or no reactivity and, similarly to anti-GM2 antibodies, with a more frequent respiratory impairment. Anti-GM2 and anti-GD1b antibodies were always associated with typical GBS and, in all but one patient, with a complete recovery; still they were found in only 13 and 3%, respectively, of the patients with this presentation. Anti-GQ1b antibodies, though always associated with ophthalmoplegia and ataxia in both MFS and GBS, were found in only 36 and 26%, respectively, of patients with these symptoms. Even if different anti-ganglioside antibodies tend to be associated with some clinical features possibly suggesting that they may influence the clinical presentation or outcome, with the exception of anti-GQ1b antibodies for ophthalmoplegia and ataxia, they do not permit to predict the clinical presentation or outcome in individual patients.     

Campylobacter jejuni lipopolysaccharides from Guillain-Barré syndrome patients induce IgG anti-GM1 antibodies in rabbits

Lipopolysaccharides (LPS) from Campylobacter jejuni strains isolated from patients with Guillain-Barré 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.     

The relation of clinical symptoms and anti-ganglioside antibodies to MEPPs frequency increase in 8 cases of variant type Guillain-Barré syndrome

Many patients with variant forms of Guillain-Barré syndrome (vGBS) associated with anti-ganglioside antibodies, including Miller Fisher syndrome (MFS), sometimes exhibit miniature endplate potential (MEPP) frequency increases (MFI, described as alpha-latrotoxin-like effects in a previous report) and the factor to produce this effect is present in their sera. MFI-positive sera increase the frequency of MEPPs, then block neuromuscular transmission at the mouse neuromuscular junction. A connection between this effect at the neuromuscular junction and some vGBS symptoms is suspected. We measured MFI directly at several points during the clinical course of 8 vGBS patients who had various symptoms and courses. Six patients had confirmed MFI and this activity decreased with convalescence. In 3 clinically mild cases, we were able to elicit MFI using normal serum to supply complement after exposure to the patient's serum. The anti-GQ1b/GT1a IgG titer, the extent of ophthalmoplegia and the extent of MFI were significantly correlated. They did not correlate with the severity of limb weakness or the occurrence of respiratory failure. These results support the hypothesis that MFI caused by anti-ganglioside antibodies is the pathogenic mechanism responsible for ophthalmoplegia in vGBS; different mechanisms or antibodies may explain limb weakness and respiratory failure. Furthermore, MFI may be an important indicator of how serum injures the nerve terminals. The symptoms of vGBS may result from multiple pathogenic factors.     

Axonal Guillain-Barré syndrome: carbohydrate mimicry and pathophysiology

Abstract   Acute motor axonal neuropathy (AMAN), an axonal subtype of Guillain-Barré syndrome (GBS), is characterized by pure motor involvement, frequent antecedent infection by Campylobacter jejuni , association with anti-GM1 or anti-GD1a immunoglobulin G (IgG) antibodies, and the electrophysiological features of axonal degeneration and reversible conduction block. Molecular mimicry exists between GM1 and GD1a gangliosides and lipooligosaccharides (LOSs) of C. jejuni isolates from AMAN. Sensitization of rabbits with GM1 or C. jejuni LOS induces anti-GM1 IgG antibodies and subsequent flaccid paralysis. Pathological changes seen in rabbit model peripheral nerves are identical to those in human AMAN. Immunohistochemistry of AMAN rabbits shows disruption of nodal sodium channel clusters and detachment of paranodal myelin terminal loops, similar to paranodal demyelination, which would significantly reduce the safety factor for impulse transmission and might be responsible for the rapidly reversible conduction block frequently present in human AMAN. C. jejuni sialyltransferase (Cst-II), which functions in the biosynthesis of ganglioside-like LOSs, determines the transferase activity. Strains with cst-II (Thr51) express GM1 and GD1a epitopes, whereas GBS patients infected with cst-II (Thr51) strains have anti-GM1 or anti-GD1a IgG antibodies. The cst-II gene is responsible for the development of GBS. Immunological, pathological, electrophysiological, and bacteriological studies have provided strong evidence of carbohydrate mimicry being a cause of AMAN and clarified the mechanisms of nerve conduction failure in AMAN.