GD1b-specific antibodies may bind to complex of GQ1b and GM1, causing ataxia

Monospecific IgG antibodies to GD1b ganglioside (GD1b-specific antibodies) have been found in patients with acute ataxic neuropathy and Guillain–Barré syndrome, but the association of the GD1b-specific antibodies with specific neurological conditions has yet to be established. We tested sera from more than 10,000 patients with various neurological disorders, and found six sera, which contained IgG antibodies to GD1b, but not to LM1, GM1, GM1b, GD1a, GalNAc-GD1a, GT1a, GT1b and GQ1b. All six patients who carried GD1b-specific antibodies presented with acute onset of ataxia and monophasic course of the illness, of whom five demonstrated cerebellar-like ataxia. Four patients had antecedent symptoms of upper respiratory tract infection. The six patients demonstrated areflexia, and four complained of distal numbness. All the six patients who had the GD1b-specific antibodies carried IgG antibodies to complex of GQ1b/GM1 and GT1a/GM1. GD1b-specific antibodies were significantly absorbed by GQ1b/GM1 and GT1a/GM1 and anti-GQ1b/GM1 and -GT1a/GM1 antibodies were absorbed by GD1b. In conclusion, the GD1b-specific antibodies, which recognizes GQ1b/GM1 or GT1a/GM1 complex, are associated with acute ataxia.     

Anti-ganglioside antibody and neuropathy: review of our research

Some patients developed Guillain-Barré syndrome (GBS) after the administration of bovine gangliosides. Patients with GBS subsequent to Campylobacter jejuni enteritis frequently have IgG antibody to GM1 ganglioside. Fisher's syndrome (FS), a variant of GBS, is associated with IgG antibody to GQ1b ganglioside. We showed the existence of molecular mimicry between GM1 and lipopolysaccharide (LPS) of C. jejuni isolated from a GBS patient, and that between GQ1b and C. jejuni LPSs from FS patients. Several lines of evidence suggest a pathogenic role for anti-ganglioside antibodies. Some patients developed sensorimotor polyneuropathy after anti-GD2 antibody administration. Anti-GM1 antibody can block motor nerve conduction. The molecular mimicry between infectious agents and gangliosides may function in the production of anti-ganglioside antibodies and the development of GBS and FS. Anti-GQ1b IgG antibody is detected also in Bickerstaff's brainstem encephalitis and acute ophthalmoparesis, which suggests that these conditions are categorized as autoimmune diseases related to FS. Since a tryptophan-immobilized column effectively adsorb anti-GQ1b IgG antibody, immunoadsorption with the column should be considered as an alternative form of plasmapheresis for the anti-GQ1b IgG antibody syndrome.     

Spectrum of neurological diseases associated with antibodies to minor gangliosides GM1b and GalNAc-GD1a

The authors reported the neurological disease spectrum associated with autoantibodies against minor gangliosides GM1b and GalNAc-GD1a. IgG and IgM antibody reactivity against gangliosides GM1, GM2, GM1b, GD1a, GalNAc-GD1a and GQ1b was investigated in sera from 7000 consecutive patients who had various neurological conditions. The clinical diagnoses for 456 anti-GM1b-positive patients were Guillain-Barré syndrome (GBS, 71%), atypical GBS with preserved deep tendon reflexes (12%), Fisher syndrome (10%), Bickerstaff's brainstem encephalitis (2%), ataxic GBS (2%) and acute ophthalmoparesis (1%). For 193 anti-GalNAc-GD1a-positive patients, the diagnoses were GBS (70%), atypical GBS (16%), Fisher syndrome (10%) and Bickerstaff's brainstem encephalitis (3%). Of the patients with GBS or atypical GBS, 28% of 381 anti-GM1b-positive and 31% of 166 anti-GalNAc-GD1a-positive patients had neither anti-GM1 nor anti-GD1a antibodies. Of those patients with Fisher syndrome, Bickerstaff's brainstem encephalitis, ataxic GBS or acute ophthalmoparesis, 33% of 67 anti-GM1b-positive, and 52% of 25 anti-GalNAc-GD1a-positive patients had no anti-GQ1b antibodies. Autoantibodies against GM1b and GalNAc-GD1a are associated with GBS, Fisher syndrome and related conditions. These antibodies should provide useful serological markers for identifying patients who have atypical GBS with preserved deep tendon reflexes, ataxic GBS, Bickerstaff's brainstem encephalitis or acute ophthalmoparesis, especially for those who have no antibodies to GM1, GD1a or GQ1b. A method to prepare GM1b was developed.     

Antibodies to GD3, GT3, and O-acetylated species in Guillain-Barré and Fisher's syndromes: their association with cranial nerve dysfunction.

We examined serum antibodies to the four fetal antigens GD3, O-acetyl GD3, GT3, and O-acetyl GT3 ganglioside in patients with Guillain-Barré syndrome (GBS) or its variant Fisher's syndrome (FS). The patients with FS more often had significant IgG antibodies against GD3, GT3, and O-acetyl GT3 than did the healthy controls. Furthermore, anti-GD3 and anti-GT3 IgG antibodies were more often significantly present in the patients with FS than in those with GBS. IgG antibody to GD3, GT3, and O-acetyl GT3 had a significant association with the presence of ophthalmoparesis. These antibodies, however, cross-reacted with GQ1b and we detected no antibodies which specifically reacted with fetal gangliosides. In addition, oculomotor involvement was more closely related to IgG antibodies to GQ1b than to those to fetal gangliosides. No evidence was obtained that the serum antibodies to these fetal gangliosides are associated with specific neurologic signs of cranial nerves.     

Association of antibodies to ganglioside complexes and conduction blocks in axonal Guillain‐Barré syndrome presenting as acute motor conduction block neuropathy

A close relationship between acute motor conduction block neuropathy and antibodies against the complex of GM1 and GalNAc‐GD1a has been reported. This study investigates the hypothesis that conduction block at the early phase of axonal Guillain‐Barré syndrome (GBS) is also associated with such ganglioside complexes. Sera were obtained from seven French patients with initial evidence of isolated conduction blocks that resolved or progressed to acute motor axonal neuropathy. Serum IgG to asialo‐GM1 and gangliosides of LM1, GM1, GM1b, GD1a, GalNAc‐GD1a, GD1b, GT1a, GT1b, and GQ1b as well as their complexes were measured. Five of seven patients progressed within the first month of disease to AMAN. One patient had IgG antibodies against the complex of asialo‐GM1 and each of the other ganglioside antigens. Another patient carried IgG antibodies against GM1 complex with GM1b, GD1a, and GT1a as well as asialo‐GM1 complex with GD1a and GT1a. None had IgG antibodies against GM1/GalNAc‐GD1a complex. Six patients had IgG against single antigens GM1, GD1a, GalNAc‐GD1a, GD1b, and asialo‐GM1. In three patients, a reduced reaction against GM1/GalNAc‐GD1a complex was observed. The presence of conduction block in axonal GBS is not always associated with anti‐GM1/GalNAc‐GD1a complex antibodies.     

Features of sensory ataxic neuropathy associated with anti-GD1b IgM antibody

Some reports have called sensory ataxic neuropathy (SAN) associated with IgM antibody against b-series gangliosides a chronic form of Miller Fisher syndrome (MFS), but this has yet to be established. We examined five patients with SAN and eight patients with IgG anti-GQ1b-positive MFS. Only one patient with SAN complained of diplopia, whose ocular movement was not limited. The other four patients had neither diplopia nor limitation of ocular movement. All the SAN patients had severe deep sense impairment, whereas one patient with MFS showed only mild vibratory sense impairment. All sera from the SAN patients had remarkably high IgM antibody titers to the b-series gangliosides GD3, GD2, GD1b, GT1b, GQ1b, GQ1b alpha, fucosyl-GD1b, and alpha galactosyl [alpha fucosyl] GD1b. An absorption study confirmed that the anti-GQ1b antibodies cross-reacted with GD3, GD2, GD1b, and GT1b. In contrast, only two samples from the MFS patients had IgG antibody to GD3, and no sample reacted with GD2, GD1b, or GT1b. SAN has different clinical or serological features from MFS, and therefore is not a chronic form of it.     

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.     

Antiganglioside antibody in patients with Guillain-Barré syndrome who show bulbar palsy as an initial symptom

OBJECTIVES: To identify valuable antiganglioside antibodies that support the diagnosis of Guillain-Barré syndrome (GBS) and its variants in patients showing bulbar palsy as an initial symptom. METHODS: Medical records of 602 patients with GBS or its variants were reviewed. Fifteen patients had bulbar palsy as an initial symptom. Serum antibodies against GM1, GM1b, GD1a, GalNAc-GD1a, GT1a, and GQ1b were examined in 13 of them. RESULTS: Serum antiganglioside antibodies were positive in 11 (85%) patients. IgG anti-GT1a (n=8; 62%) and anti-GM1b (n=7; 54%) antibodies were often present, whereas all the patients had low or no anti-GM1 antibody activity. High anti-GD1a and anti-GQ1b IgG antibody titres were also present in some patients, but most had higher IgG antibody titres to GM1b or GT1a. All five patients with high IgG antibody titre to GM1b or GT1a only had had antecedent diarrhoea. Some patients with pharyngeal-cervical-brachial weakness (PCB) had IgG antibody to GT1a which did not cross react with GQ1b. Other patients with PCB had antibody to GT1a which cross reacted with GQ1b or antibody to GM1b, but anti-GM1b and anti-GT1a antibodies were not associated with the presence of bulbar palsy. All the patients who had no IgG antiganglioside antibodies recovered completely. CONCLUSIONS: Measurement of serum IgG anti-GT1a and anti-GM1b antibodies gives helpful support for the diagnosis of GBS and its variants when there is early involvement of the oropharyngeal function independently of other neurological findings which appear as the illness progresses.     

Ataxic Guillain-Barré syndrome associated with anti-GM1b and anti-GalNAc-GD1a antibodies

Abstract. Ataxic Guillain-Barré syndrome (GBS) associated with anti-GQ1b IgG antibody has been reported. We, however, have had a patient with ataxic GBS who had IgG antibodies to the minor gangliosides GM1b and GalNAc-GD1a, and we therefore retrospectively investigated the clinical features of patients who had antibodies to GM1b or GalNAc-GD1a, but not to GQ1b. Information on patients antecedent illnesses, initial symptoms, neurological signs, and CSF findings was reviewed in those with ataxic GBS or Fisher syndrome (FS) with anti-GM1b or anti-GalNAc-GD1a IgG antibodies. We tested whether the anti-GM1b and anti-GalNAc-GD1a antibodies are cross-reactive and constructed three-dimensional structural models of GM1b and GalNAc-GD1a. Ataxic GBS was diagnosed in 1 of 65 patients who had both anti-GM1b and anti-GalNAc-GD1a antibodies and in 3 of 159 patients who had anti-GM1b antibody without anti-GalNAc-GD1a antibody: FS was diagnosed in 1 of the 159 patients and in 1 of 35 who had anti-GalNAc-GD1a antibody without anti-GM1b antibody. All the patients antibodies to GM1b or GalNAc-GD1a were associated with the IgG isotype. The clinical features of patients with ataxic GBS associated with anti-GM1b or anti-GalNAc-GD1a IgG antibodies did not differ from those of patients who had anti-GQ1b IgG antibody. Absorption study findings for serum from the patient who had both anti-GM1b and anti-GalNAc-GD1a IgG antibodies showed significant absorbance of anti-GM1b IgG antibody by GalNAc-GD1a and of anti-GalNAc-GD1a IgG antibody by GM1b, indicating that these antibodies are cross-reactive. This is the first report of ataxic GBS or FS associated with anti-GM1b or anti-GalNAc-GD1a IgG antibodies. These autoantibodies, as well as anti-GQ1b IgG antibody, may function in the development of some patients with ataxic GBS and FS.     

Ganglioside reactive antibodies in the neuropathy associated with celiac disease

We tested patients with celiac disease (CD) for the presence of serum anti-ganglioside antibodies. Six of twenty-seven patient sera were reactive against brain gangliosides by an agglutination immunoassay. Neurological examination in all six revealed the presence of distal sensory loss, consistent with the diagnosis of peripheral neuropathy. When tested by ELISA for antibodies to isolated GM1, GM2, GD1a, GD1b, GT1b, and GQ1b gangliosides, all six were positive for IgG antibodies to at least one. The neuropathy of celiac disease may be autoimmune and associated with anti-ganglioside antibodies. The presence of IgG reactivity furthermore implicates a T cell-mediated response to ganglioside antigens.     

Range of cross reactivity of anti-GM1 IgG antibody in Guillain-Barré syndrome

The cross reactivity of anti-GM1 IgG antibody with various gangliosides and asialo-GM1 in serum samples from 27 patients with Guillain-Barré syndrome was investigated. An enzyme linked immunosorbent assay (ELISA) absorption study showed that anti-GM1 IgG antibody cross reacted with asialo-GM1 in 52% of the patients, GM1b in 41%, GD1b in 22%, and GalNAc-GD1a in 19%, and that it did not cross react with GM2, GT1b, or GQ1b. The antibody that cross reacted with GD1b was associated with a high frequency of cranial nerve involvement and negative Campylobacter jejuni serology. Anti-GM1 IgG antibody has a broad range of cross reactivity which may contribute to various clinical variations of Guillain-Barré syndrome.     

Antibodies to GD1alpha and to GQ1beta in Guillain-Barré syndrome and the related disorders.

Certain species of anti-ganglioside antibodies are associated with specific clinical features in various neurologic diseases. Serum autoantibodies to these minor gangliosides were investigated in a number of neurological diseases in order to examine the biological functions of GD1alpha and GQ1beta. Eleven patients with Guillain-Barré syndrome had remarkably high IgG anti-GD1alpha antibody titers, but no GD1alpha was detected in human peripheral nerve. An absorption study showed that IgG anti-GD1alpha antibodies from eight of the 11 patients were significantly absorbed by GD1a and GM1b, indicative that the IgG anti-GD1alpha antibodies cross-react with GD1a and GM1b. Both GD1a and GM1b have been reported to be target molecules for serum antibodies in certain patients with Guillain-Barré syndrome. GD1alpha may induce the production of IgG anti-GD1alpha antibody which cross-reacts with GD1a or GM1b, and subsequently functions in the development of Guillain-Barré syndrome. The IgGs from six patients with Fisher's syndrome who had the anti-GQ1beta antibody had anti-GQ1b activity as well. All the patients had external ophthalmoplegia, but no GQ1beta was detected in the human oculomotor nerve, further evidence that GQ1b, not GQ1beta, is the molecule targeted by the autoantibody in Fisher's syndrome.     

Antiganglioside antibodies in polyneuropathy associated with monoclonal gammopathy.

Antibody reactivity to GA1, GM1, GM2, GD1a, GD1b, and GQ1b gangliosides was measured in 87 patients with polyneuropathy associated with monoclonal gammopathy (60 IgM, 25 IgG, 2 IgA) and 42 control patients with monoclonal gammopathy without polyneuropathy (21 IgM, 21 IgG). Of these 87 patients, 30% had anti-myelin-associated glycoprotein antibodies and 15% had antiganglioside antibodies. Antiganglioside antibodies were significantly associated with demyelinating neuropathy and with IgM monoclonal gammopathy. Anti-GD1b and anti-GQ1b antibodies were significantly associated with predominantly sensory ataxic neuropathy.     

Anti-GQ1b IgG-negative case of overlapping Fisher's and Gullain-Barré syndromes after Campylobacter jejuni (PEN 19) enteritis]

We described a 70-year-old woman with overlapping Fisher's syndrome (FS) and Guillain-Barré syndrome (GBS), from whom Campylobacter jejuni had been isolated. In typical FS as well as GBS with ophthalmoplegia and acute ophthalmoparesis without ataxia, serum anti-GQ1b IgG antibody often is detected and ophthalmoplegia is characterized by the predominant abducens palsy. This patient, however, showed marked oculomotor nerve disturbance. Serum anti-GQ1b IgG antibody was negative and IgG antibodies against GM1, GM1b, and GD1a were strongly positive. Although FS and overlap of FS/GBS have been reported to be associated with PEN2 of C. jejuni, the isolate from our case belonged to PEN 19. C. jejuni serotype may be associated with clinical manifestations and anti-ganglioside antibody species.     

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.     

Bickerstaff's brainstem encephalitis associated with IgM antibodies to GM1b and GalNAc-GD1a

This is the first report of a case of Bickerstaff's brainstem encephalitis (BBE) associated with IgM antibodies to GM1b and GalNAc-GD1a. Subsequent to Campylobacter jejuni enteritis, the patient rapidly developed consciousness disturbance and hyperreflexia in addition to external ophthalmoplegia and cerebellar-like ataxia. EEG showed transient 7 Hz monorhythmic theta activities, predominantly in the front-central area. He received high doses of immunoglobulin intravenously and had completely recovered 3 months later. High anti-GM1b and anti-GalNAc-GD1a IgM antibody titers present during the acute phase decreased with his clinical improvement. An absorption study showed the anti-GM1b and anti-GalNAc-GD1a IgM antibodies to be cross-reactive. Anti-GM1b and anti-GalNAc-GD1a antibodies have been detected in some patients who developed Guillain-Barré syndrome after C. jejuni enteritis, whereas the anti-GQ1b IgG antibody is associated with BBE. Infection by C. jejuni bearing a GM1b-like or GalNAc-GD1a-like lipooligosaccharide may trigger the production of anti-GalNAc-GD1a and anti-GM1b IgM antibodies. It is not clear why our patient developed BBE rather than Guillain-Barré syndrome. These antibodies may, however, prove useful serological markers for identifying BBE patients who do not have the anti-GQ1b IgG antibody.     

Fine specificities of anti-LM1 IgG antibodies in Guillain-Barré syndrome

We investigated the prevalence of anti-LM1 IgG antibody and its fine specificity in Guillain-Barré syndrome (GBS). Anti-LM1 IgG and IgM antibodies from sera of 47 patients with GBS--19 with acute inflammatory demyelinating polyneuropathy (AIDP), 27 with acute motor axonal neuropathy (AMAN), and 1 with acute motor-sensory axonal neuropathy (AMSAN)--were tested. Anti-LM1 IgG antibody was detected in only one patient with AIDP, whereas it was present in seven with AMAN and in one with AMSAN. Sera from the eight IgG anti-LM1-positive patients with AMAN/AMSAN also had IgG activity against the gangliosides GM1, GM1b, GD1a, GalNAc-GD1a, GD1b, or GQ1b. Anti-LM1 IgG antibodies from the AMAN/AMSAN patients cross-reacted with other gangliosides, whereas IgG antibody from the AIDP patient was monospecific against LM1. Anti-LM1 IgG antibody therefore, cannot be a marker of AIDP. In addition, whether monospecific anti-LM1 IgG antibody is associated with AIDP remains to be concluded. Larger studies are needed to verify whether monospecific anti-LM1 IgG antibody could be a marker of AIDP.     

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.     

Ganglioside antibodies: a lack of diagnostic specificity and clinical utility?

Summary Serum IgG and IgM antibodies to gangliosides GM1, GM2, GM3, AGM1, GD1a, GD1b and GT1b were determined in 210 patients with different degenerative and inflammatory disorders including motor neuron diseases, peripheral radiculopathies and neuropathies, multiple sclerosis and neuroborreliosis. No single disorder was associated specifically with ganglioside antibodies. No characteristic patterns of ganglioside antibodies were observed in any disease category. However, 32% of all patients had pathological antibody titres to at least one ganglioside. Four patients had pathological IgG and IgM titres for all gangliosides evaluated. They suffered from systemic lupus erythematosus [2], neuroborreliosis and schizophrenia, respectively. The results of this study indicate that the introduction of ganglioside antibody determination as a differential diagnostic test in clinical neurology is only helpful in a few patients with typical lower motor neuron syndromes.     

Bacterial infections in Guillain-Barré and Fisher syndromes

PURPOSE OF REVIEW: Progress has been made in our understanding of Guillain-Barré syndrome, especially in identifying the Campylobacter jejuni genes responsible for the development of clinical features. RECENT FINDINGS: C. jejuni is grouped into several classes based on the organization of lipo-oligosaccharide biosynthesis genes. A specific class carrying a sialyltransferase gene (cst-II) is associated with the development of Guillain-Barré syndrome, which is essential for the biosynthesis of ganglioside-like lipo-oligosaccharides. The class of C. jejuni expressed both GM1-like and GD1a-like lipo-oligosaccharides, which could induce the production of autoantibodies to GM1, to GD1a or to the GM1/GD1a complex, possibly increasing the risk of development. C. jejuni sialyltransferase (Cst-II) consists of 291 amino acids, and the 51st amino acid determines its enzymatic activity. Strains with cst-II (Thr51) expressed GM1-like or GD1a-like lipo-oligosaccharide whereas strains with cst-II (Asn51) expressed GT1a-like or GD1c-like lipo-oligosaccharide. Patients infected with the cst-II (Thr51) strains had anti-GM1 or anti-GD1a IgG antibodies, and showed limb weakness. Patients infected with the cst-II (Asn51) strains had anti-GQ1b IgG antibodies, and showed ophthalmoplegia and ataxia. SUMMARY: The cst-II gene is responsible for the development of Guillain-Barré and Fisher syndromes, and the polymorphism (Thr/Asn51) determines which syndrome develops after C. jejuni enteritis.