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.     

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.     

Axonal Guillain-Barré syndrome: relation to anti-ganglioside antibodies and Campylobacter jejuni infection in Japan

To clarify the relations of the axonal form of Guillain-Barré syndrome (GBS) to anti-ganglioside antibodies and Campylobacter jejuni infection, 86 consecutive Japanese GBS patients were studied. Electrodiagnostic criteria showed acute inflammatory demyelinating polyneuropathy in 36% of the patients and acute motor axonal neuropathy (AMAN) in 38%. Frequent anti-ganglioside antibodies were of the IgG class and against GM1 (40%), GD1a (30%), GalNAc-GD1a (17%), and GD1b (21%). Identified infections were C. jejuni (23%), cytomegalovirus (10%), Mycoplasma pneumoniae (6%), and Epstein-Barr virus (3%). There was a strong association between AMAN and IgG antibodies against GM1, GD1a, GalNAc-GD1a, or GD1b. Almost all the patients with at least one of these antibodies had the AMAN pattern or rapid resolution of conduction slowing/block possibly because of early-reversible changes on the axolemma. C. jejuni infection was frequently associated with AMAN or anti-ganglioside antibodies, but more than half of the patients with AMAN or anti-ganglioside antibodies were C. jejuni-negative. These findings suggest that the three phenomena "axonal dysfunctions (AMAN or early-reversible conduction failure)," "IgG antibodies against GM1, GD1a, GalNAc-GD1a, or GD1b," and "C. jejuni infection" are closely associated but that microorganisms other than C. jejuni frequently trigger an anti-ganglioside response and elicit axonal 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.     

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.     

A case of Guillain-Barré syndrome following a family outbreak of Campylobacter jejuni enteritis

We describe an outbreak of Campylobacter jejuni enteritis involving three family members of whom one developed Guillain-Barré syndrome (GBS). The patients' serum reacted strongly with several gangliosides and with the lipopolysaccharide (LPS) fractions from the C. jejuni strains isolated from his family members. Only low titer anti-ganglioside antibodies were found in his siblings. HLA-typing did not indicate a locus associated with auto-antibody production. Comparing the immune response in GBS patients and C. jejuni enteritis patients can be of great value in determining the additional factors that lead to post-Campylobacter GBS. Ganglioside mimicry alone is necessary but not sufficient for the induction of anti-ganglioside antibodies. Other susceptibility factors are required to induce an anti-neural immune response.     

Detection of anti-ganglioside antibodies in Guillain-Barré syndrome and its variants by the agglutination assay

Sera from 40 patients with Guillain-Barré syndrome (GBS), including the subtypes acute inflammatory demyelinating polyneuropathy (AIDP), acute motor axonal neuropathy (AMAN), acute motor and sensory axonal neuropathy (AMSAN), and Miller Fisher syndrome (MFS) were examined for the presence of anti-ganglioside antibodies using the ganglioside agglutination assay, and the enzyme-linked immunosorbent assay (ELISA). In the ELISA system, sera were tested for IgM and IgG antibodies to GM1, GM2, GD1a, GD1b, GT1b, and GQ1b gangliosides. Antibodies to gangliosides were detected in 21 (53%) of the GBS patients by agglutination assay and in 17 (43%) of the patients by ELISA. Some of the sera reacted with more than one ganglioside. Antibodies were not found in the control sera that were studied. The agglutination assay may be useful for rapid screening of GBS sera for antibodies to multiple gangliosides.     

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.     

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.     

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.     

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 coli enteritis and Guillain-Barré syndrome: no evidence of molecular mimicry and serological relationship

Campylobacter coli was isolated from two Guillain-Barré syndrome (GBS) patients who had anti-GM1 and anti-GD1 IgG antibodies. Although both this bacteria and Campylobacter jejuni are common causes of diarrheal illness, previous studies have focused only on C. jejuni as the causal agent of GBS. To determine whether C. coli also is a causative agent, we examined the hypothesis that production of anti-ganglioside antibodies is induced by ganglioside-mimics on that bacterial lipo-oligosaccharide (LOS), as in C. jejuni-associated GBS. LOSs of both C. coli isolates had very weak reactivities with anti-GM1 and anti-GD1a IgG monoclonal antibodies, whereas those of some GBS-related C. jejuni isolates had strong reactivities. Anti-GM1 and anti-GD1a IgG antibodies from the two patients were not absorbed as much by the LOSs of their isolates as were those of GBS-related C. jejuni strains. These findings do not support the hypothesis of ganglioside mimicry on C. coli isolates' LOSs. We next made a serological assay of recent C. coli infection in 74 patients with GBS, 26 with Fisher syndrome (FS), 49 with other neurological diseases (OND), and 37 normal controls (NC) using the bacterial outer membrane protein as antigen. Eight (11%) GBS and two (8%) FS patients had two or three classes of IgG, IgM, and IgA anti-C. coli antibodies. Anti-C. jejuni IgG and IgA antibody titers were significantly higher than those of anti-C. coli (respectively, p = 0.03 and 0.01). This suggests that anti-C. coli antibodies cross-react with C. jejuni protein. We concluded that a C. coli infection was not the cause of GBS in our patients. Both isolation of a microorganism from, and the positive infectious serology of, GBS patients do not always indicate the causal agent.     

Ganglioside-induced antiganglioside antibodies from a neuropathy patient cross-react with lipopolysaccharides of Campylobacter jejuni associated with Guillain-Barré syndrome

Antiganglioside serum antibodies from a patient treated with gangliosides were examined for cross-reactivity with lipopolysaccharides (LPSs) of Campylobacter jejuni strains associated with Guillain-Barré syndrome (GBS). The patient had no preceding infection with C. jejuni and developed chronic progressive motor polyneuropathy following parenteral ganglioside treatment. Serum IgG antibodies recognised GM1 and GD1b gangliosides as well as asialo-GM1, and cross-reactivity was observed with LPSs from C. jejuni O:2, O:4, O:19 and O:41. The results give a clear indication that gangliosides and LPSs from C. jejuni serotypes associated with GBS share common epitopes.     

Origin of ganglioside complex antibodies in Guillain-Barré syndrome

The origin of antibodies to ganglioside complexes, as new immunotargets for Guillain-Barré syndrome (GBS), is unknown. This was investigated in 21 GBS patients from which Campylobacter jejuni was isolated. Two of these patients had serum IgG to the GM1/GD1a complex and two other patients had IgG to the GQ1b/GD1a complex. These pairs of patients were clinically distinct. These antibodies all cross-reacted to lipo-oligosaccharides (LOS) from the autologous C. jejuni strain. Previous mass spectrometry studies on these LOS showed the presence of oligosaccharides with a similar structure, further supporting the hypothesis that in these patients LOS induced the ganglioside complex antibodies.