g(m1)-ganglioside and Autoimmune-Diseases

Guillain-Barré syndrome (GBS), the most frequent cause of acute flaccid paralysis, can develop after infection by Campylobacter jejuni. The condition is often associated with serum anti-GM1 or anti-GD1a IgG antibodies. Gangliosides contribute to stability of paranodal junctions and ion channel clusters in myelinated nerve fibers. Autoantibodies to GM1 and GD1a disrupt lipid rafts, paranodal or nodal structures, and ion channel clusters in peripheral motor nerves. Molecular mimicry exists between GM1 and GD1a gangliosides and lipo-oligosaccharides of C. jejuni isolates from GBS patients. Sensitization of rabbits with GM1 or C. jejuni lipo-oligosaccharide produces replica of GBS. These findings provide strong evidence for carbohydrate mimicry being a cause of GBS and show the role of gangliosides in peripheral nerves.

Topics: Animals; Autoimmune Diseases; Brain; Campylobacter jejuni; Cattle; Electrophysiology; G(M1) Ganglioside; Gangliosides; Humans; Immunoglobulin G; Lipopolysaccharides; Mice; Polyneuropathies; Rabbits; Sialyltransferases

Glycans are a class of molecules with high structural variability, frequently found in the plasma membrane facing the extracellular space. Because of these characteristics, glycans are often considered as recognition molecules involved in cell social functions, and as targets of pathogenic factors. Induction of anti-glycan antibodies is one of the early events in immunological defense against bacteria that colonize the body. Because of this natural infection, antibodies recognizing a variety of bacterial glycans are found in sera of adult humans and animals. The immune response to glycans is restricted by self-tolerance, and no antibodies to self-glycans should exist in normal subjects. However, antibodies recognizing structures closely related to self-glycans do exist, and can lead to production of harmful anti-self antibodies. Normal human sera contain low-affinity anti-GM1 IgM-antibodies. Similar antibodies with higher affinity or different isotype are found in some neuropathy patients. Two hypotheses have been developed to explain the origin of disease-associated anti-GM1 antibodies. According to the "molecular mimicry" hypothesis, similarity between GM1 and Campylobacter jejuni lipopolysaccharide carrying a GM1-like glycan is the cause of Guillain-Barré syndrome associated with anti-GM1 IgG-antibodies. According to the "binding site drift" hypothesis, IgM-antibodies associated with disease originate through changes in the binding site of normally occurring anti-GM1 antibodies. We now present an "integrated" hypothesis, combining the "mimicry" and "drift" concepts, which satisfactorily explains most of the published data on anti-GM1 antibodies.

Topics: Animals; Antibodies; Autoantigens; Autoimmune Diseases; Autoimmunity; G(M1) Ganglioside; Humans; Polysaccharides

Topics: Acute Disease; Aged; Antibodies, Antinuclear; Antibody Specificity; Autoantibodies; Autoimmune Diseases; Evoked Potentials; Female; France; G(M1) Ganglioside; Gastroenteritis; Guillain-Barre Syndrome; Humans; Immunoglobulin M; Neurologic Examination

Topics: Amyotrophic Lateral Sclerosis; Autoantibodies; Autoimmune Diseases; Diagnosis, Differential; Enzyme-Linked Immunosorbent Assay; G(M1) Ganglioside; Humans; Immunoglobulin M; Motor Neuron Disease; Sensitivity and Specificity

Topics: Antibody Specificity; Autoantibodies; Autoantigens; Autoimmune Diseases; Brain; Carbohydrate Sequence; CD57 Antigens; Chronic Disease; G(M1) Ganglioside; Gangliosides; Globosides; Glycolipids; Guillain-Barre Syndrome; Humans; Immunoglobulin M; Molecular Sequence Data; Motor Neuron Disease; Myelin Sheath; Paraproteinemias; Peripheral Nervous System; Polyradiculoneuropathy; Sulfoglycosphingolipids

Some patients develop 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. Miller Fisher syndrome (MFS), a variant of GBS, is associated with IgG antibody to GQ1b ganglioside. Molecular mimicry between GM1 and lipopolysaccharide of C. jejuni isolated from patients with GBS, and between GQ1b and C. jejuni lipopolysaccharides from patients with MFS have been demonstrated. The molecular mimicry between infectious agents and gangliosides may function in the production of anti-ganglioside antibodies. This sugar mimicry is one possible cause of the Guillain-Barré and Miller Fisher syndromes; however, unidentified host factors may contribute to the development of these syndromes.

Topics: Animals; Antigens, Bacterial; Autoantigens; Autoimmune Diseases; Campylobacter Infections; Campylobacter jejuni; Cattle; Epitopes, B-Lymphocyte; G(M1) Ganglioside; Gangliosides; Guillain-Barre Syndrome; Humans; Lipopolysaccharides; Miller Fisher Syndrome; Molecular Mimicry

Cholera toxin and its close relative, Escherichia coli heat-labile enterotoxin, are potent immunogens and mucosal adjuvants. The recent findings that their B subunits can promote tolerance highlights the complexity of their interactions with the immune system. Here, Neil Williams and colleagues review the mechanisms by which these molecules modulate leukocyte populations and seek to explain the paradox.

Topics: Adjuvants, Immunologic; Animals; Arthritis; Autoantigens; Autoimmune Diseases; Bacterial Toxins; Carbohydrate Sequence; Cholera Toxin; Collagen; Diabetes Mellitus, Type 1; Encephalomyelitis, Autoimmune, Experimental; Enterotoxins; Escherichia coli Proteins; G(M1) Ganglioside; Gene Expression Regulation; Hydrogen Bonding; Immune Tolerance; Interferon-gamma; Mice; Mice, Inbred NOD; Models, Molecular; Molecular Sequence Data; Protein Binding; Protein Conformation; Rats; Structure-Activity Relationship; Th2 Cells

Topics: Autoantibodies; Autoimmune Diseases; G(M1) Ganglioside; Gangliosides; Humans; Nervous System Diseases

Autoantibodies to Gal(beta 1-3)GalNAc epitopes on glycolipids and glycoproteins are associated with motor neuron disease and motor or sensorimotor neuropathy. These epitopes are ubiquitously distributed on cell surfaces. In the nervous system they are present on axons and myelin, specifically also at the nodes of Ranvier. Binding of GM1 antibodies to the nodal area may contribute to disease development in some of these conditions.

Topics: Animals; Antigens, Tumor-Associated, Carbohydrate; Autoantibodies; Autoimmune Diseases; G(M1) Ganglioside; Humans; Motor Neuron Disease; Ranvier's Nodes

Pure motor neuropathy syndromes resemble amyotrophic lateral sclerosis variants with no upper motor neuron signs. Their identification is important, as, in contrast to amyotrophic lateral sclerosis, they are often immune mediated and treatable. Typically the immune-mediated motor neuropathy syndromes are distal and asymmetrical and progress slowly. The clinical features may help alert the clinician to the diagnosis, but other ancillary evidence such as abnormalities on electrophysiological testing and the presence of serum autoantibodies to neural antigens are helpful in making the diagnosis more secure. Electrophysiological abnormalities include not only motor conduction block but also other evidence of a demyelinative process such as prolonged distal latencies or F-wave abnormalities. High-titer anti-GM1 antibodies occur frequently but more specific patterns of reactivity may be especially helpful. Treatment of these motor neuropathy syndromes includes cyclophosphamide, which we use in combination with plasma exchange, and in some patients, human immune globulin. Clinical responses to therapy may occur within the first 2 to 4 months in patients with motor neuropathy syndromes with demyelinative features, but only become obvious 6 months or later after starting treatment in patients with predominantly axonal disorders.

Topics: Adult; Aged; Amyotrophic Lateral Sclerosis; Antibody Specificity; Antigens; Autoantibodies; Autoimmune Diseases; Chronic Disease; Cyclophosphamide; Diagnosis, Differential; Female; G(M1) Ganglioside; Humans; Immunosuppressive Agents; Male; Middle Aged; Neural Conduction; Neuromuscular Diseases

Multifocal motor neuropathy (MMN) is a disorder with a highly characteristic clinical picture and one which is defined by a specific electrodiagnostic abnormality, namely, multifocal conduction block which is confined to motor axons. Sensory axons which traverse segments of severe or even complete motor conduction block conduct normally. A proportion of patients with MMN also have elevated levels of antibodies to GM1 ganglioside. However, about one half of MMN patients lack elevated levels of these antibodies and many others have only modest elevations, to a degree often seen in other neurological and even non-neurological disorders. Furthermore, clinical and electrophysiological improvement of MMN in response to treatment with high dose intravenous immunoglobulin is achieved in the absence of any change in antiglycolipid levels. Injection of serum from patients with MMN and elevated GM1 antibody levels produces demyelination in recipient rat nerves, suggesting a pathogenetic role for these antibodies in demyelination. However, sera of patients with identical antibody titers in other motor system diseases produced no demyelination, suggesting that the demyelinating factor resides in some other serum fraction. At present, there is insufficient evidence to support the contention that these antibodies play a critical pathogenetic role in MMN. Until more evidence is available it is important to define MMN on the basis of a characteristic clinical picture and a unique electrodiagnostic abnormality rather than on a pattern of serum antibodies.

Topics: Animals; Antibodies; Autoimmune Diseases; G(M1) Ganglioside; Glycolipids; Humans; Motor Neuron Disease; Nervous System Diseases; Rats

Increased serum titers of antibodies against the ganglioside GM1 or its carbohydrate epitope Gal(B1-3)GalNAc have been associated with motor neuron disease, motor neuropathies with or without conduction block and sensorimotor neuropathies, whereas low level titers are part of the normal immune repertoire and are present in control groups and in neonatal blood. The target antigens of the antibodies are widely distributed and highly concentrated in the peripheral and central nervous system. The antibodies could damage neural tissue at several anatomic sites. Possible binding sites are the anterior horn cells in the spinal cord and the nodes of Ranvier. Reduction of serum titers with chemotherapy or plasmapheresis can lead to clinical improvement.

Topics: Antibody Specificity; Antigens, Tumor-Associated, Carbohydrate; Autoantibodies; Autoimmune Diseases; Disaccharides; G(M1) Ganglioside; Humans; Immunosuppressive Agents; Neuromuscular Diseases

Multifocal motor neuropathy (MMN) is an immune-mediated disorder characterized by slowly progressive asymmetrical limb weakness. Treatment with immunoglobulins (IVIg) leads to improvement of muscle strength. Anecdotal evidence suggests that immunosuppressive drugs as adjunctive therapy may be beneficial. Mycophenolate mofetil (MMF) is a potent and safe immunosuppressant. Safety and efficacy of MMF as adjunctive therapy for MMN patients receiving IVIg maintenance treatment were evaluated in a randomized controlled trial. MMN patients responding to IVIg treatment were eligible for randomization. Muscle strength and functional status were assessed at monthly intervals for 1 year. Three months after the start of MMF or placebo treatment, IVIg doses were reduced stepwise, until a deterioration of functioning or decline in muscle strength could be observed. An IVIg dose reduction of 50% during adjunctive treatment was defined as a primary endpoint. Secondary outcome measures were improvement in muscle strength and functional status after 3 months and reduction of anti GM1-IgM titres after 12 months of MMF treatment. Twenty-eight patients were randomized. One patient allocated to MMF reached the primary endpoint of 50% IVIg dose reduction. After 12 months IVIg reduction did not differ significantly between the two treatment groups. Patients did not experience drug toxicity and none of the patients showed significant disease progression after 12 months. Muscle strength and functional scores after 3 months and anti GM1-IgM titres after 12 months did not change. Adjunctive treatment of MMN patients with MMF at a dose of 1 g twice daily is safe but does not alter disease course or allow significant reduction of IVIg doses.

Topics: Adult; Aged; Autoantibodies; Autoimmune Diseases; Chemotherapy, Adjuvant; Disease Progression; Double-Blind Method; Drug Administration Schedule; Female; G(M1) Ganglioside; Humans; Immunoglobulin M; Immunoglobulins, Intravenous; Immunosuppressive Agents; Male; Middle Aged; Motor Neuron Disease; Muscle Strength; Muscle, Skeletal; Mycophenolic Acid; Treatment Outcome

Antiganglioside antibodies are found in various neurological disorders that constitute a continuum from peripheral neuropathy to encephalitis. However, nystagmus has rarely been described in patients with ataxia associated with antiganglioside antibodies.. From January 2008 to July 2009, we identified 3 patients with acute ataxia and nystagmus in 2 University Hospitals of Korea, who were found to have anti-GD1b, anti-GM1, or anti-GQ1b antibodies.. In addition to acute ataxia, all 3 patients showed various combinations of nystagmus, which included central positional nystagmus (n = 3), vertical nystagmus (n = 1), and periodic alternating nystagmus (n = 1). The spontaneous and positional nystagmus were mostly detectable only with the elimination of fixation and magnification of the eyes using video goggles. Two patients also exhibited gaze-evoked nystagmus that was noticeable without the aid of video goggles. Patients had serum IgG antibodies to GD1b, GM1, or GQ1b. Cerebrospinal fluid examination, nerve conduction studies, and brain MRI were normal. In all patients, the symptoms and signs resolved over 3-12 months.. Various forms of nystagmus with acute ataxia may be a sole or predominant manifestation of disorders related to antiganglioside antibodies. The nystagmus indicates a central pathology involving the cerebellum or brainstem in this antibody-associated disorder. Antiganglioside antibodies should be measured in patients with nystagmus and acute ataxia of undetermined etiology.

Topics: Acute Disease; Adolescent; Adult; Ataxia; Autoantibodies; Autoantigens; Autoimmune Diseases; Cerebrospinal Fluid; Dizziness; Enzyme-Linked Immunosorbent Assay; Female; G(M1) Ganglioside; Gangliosides; Humans; Immunoglobulin G; Male; Nystagmus, Pathologic; Postural Balance; Sensation Disorders; Vertigo

Antibodies against hydrophobic antigens are common in several autoimmune diseases. However, detection of such antibodies by standard immune-assays, such as ELISA, is problematic, in part because of the problems with coating hydrophobic molecules onto polystyrene multi-well plates. We describe a novel method of stably associating hydrophobic antigens to ELISA plates. By mixing the antigen with a hydrophobic molecule containing a hydrophilic anchor, we generate mixed lipid aggregates that can attach to ELISA plates, and are resistant to detergent wash. Using the ganglioside GM-1 and phosphatidylethanolamine conjugated to the hapten DNP (dinitrophenyl) as model antigens, we show that hydrophobic antigens incorporated into mixed lipid aggregates expose their antigenic determinants in a correct configuration. The detection limit of both GM-1 and DNP-PE was considerably improved compared to when these antigens were coated on ELISA plates using organic solvents. Furthermore GM-1 incorporated into mixed lipid aggregates can be detected by specific antibodies in patient serum. The method of incorporating hydrophobic antigens into mixed lipid aggregates for stable association to ELISA plates can presumably be applied to a vast array of hydrophobic antigens, and may well be developed into a large scale screening system for serum reactivity towards different hydrophobic antigens.

Topics: Autoantibodies; Autoantigens; Autoimmune Diseases; Dinitrobenzenes; Enzyme-Linked Immunosorbent Assay; G(M1) Ganglioside; Haptens; Humans; Hydrophobic and Hydrophilic Interactions; Liposomes; Phosphatidylethanolamines; Sensitivity and Specificity

Multifocal motor neuropathy (MMN) with conduction block is an acquired, autoimmune-mediated neuropathy that is responsive to treatment. The clinical history is one of slowly, progressive distal weakness, which more commonly involves the upper extremities, and it affects mainly young adults. Physical examination reveals weakness without sensory loss in the distribution of individual nerves. Atrophy may be present, but hyperreflexia and spasticity are not seen. Electrophysiological studies reveal motor conduction blocks at sites not prone to compression with normal sensory responses. Immunoglobulin M anti-GM1 titers may be elevated. Treatment with human immunoglobulin or cyclophosphamide has been shown to improve strength in the majority of patients with MMN in the short term. However, motor strength and function may gradually decline over years in spite of long-term therapy.

Topics: Adult; Atrophy; Autoimmune Diseases; Cyclophosphamide; Diagnosis, Differential; Electrophysiology; G(M1) Ganglioside; Humans; Immunoglobulins, Intravenous; Immunosuppressive Agents; Male; Motor Neuron Disease; Neural Conduction; Peripheral Nervous System Diseases; Prognosis

A 36-year-old woman presented acute polyradiculoneuropathy following Chlamydia pneumoniae infection. Although electrophysiologic studies were normal, clinical features were typical of Guillain-Barré syndrome (GBS). Anti-ganglioside GM1 antibodies were positive. Two other cases of GBS following Chlamydia pneumoniae infection have been reported, but no specific feature emerges. Outcome was good in our patient after intravenous globulin then antibiotic therapy. Our case supports the notion that Chlamydia pneumoniae infection can induce GBS. The association is probably underestimated.

Topics: Adult; Antibodies, Bacterial; Autoantibodies; Autoimmune Diseases; Chlamydophila Infections; Chlamydophila pneumoniae; Female; G(M1) Ganglioside; Guillain-Barre Syndrome; Humans; Immunoglobulin G; Immunoglobulin M; Immunoglobulins, Intravenous; Mycoplasma pneumoniae; Pneumonia, Bacterial; Tetracyclines

Myelin basic protein (MBP) is considered to be essential for the maintenance of stability of the myelin sheath. Reduction in cationicity of MBP, especially due to conversion of positively charged arginine residues to uncharged citrulline (Cit), has been found to be associated with multiple sclerosis (MS). Here, the interactions of an anionic phosphatidylserine/monosialoganglioside-G(M1) (4:1, w:w) lipid monolayer with 18.5-kDa MBP preparations from age-matched adult humans without MS (no Cit residues), with chronic MS (6 Cit), and with acute Marburg-type MS (18 Cit) were studied by transmission and ultralow dose scanning transmission electron microscopy under cryogenic conditions. Immunogold labeling and single particle electron crystallography were used to define the nature of the complexes visualized. These electron microscopical analyses showed that the three different MBP charge isomers all formed uniformly sized and regularly shaped protein-lipid complexes with G(M1), probably as hexamers, but exhibited differential association with and organization of the lipid. The least cationic Marburg MBP-Cit(18) formed the most open protein-lipid complex. The data show a disturbance in lipid-MBP interactions at the ultrastructural level that is related to degree of citrullination, and which may be involved in myelin degeneration in multiple sclerosis.

Topics: Adult; Arginine; Autoimmune Diseases; Citrulline; Cryoelectron Microscopy; G(M1) Ganglioside; Humans; Image Processing, Computer-Assisted; Immunohistochemistry; Macromolecular Substances; Microscopy, Electron, Scanning; Multiple Sclerosis; Myelin Basic Protein; Phosphatidylserines; Protein Isoforms; Protein Processing, Post-Translational

Topics: Autoantigens; Autoimmune Diseases; Evoked Potentials; Female; G(M1) Ganglioside; Humans; Immunoglobulins, Intravenous; Middle Aged; Movement Disorders; Neural Conduction; Peripheral Nervous System Diseases; Radial Nerve

The relationship between preceding infections and antibodies to glycolipids was investigated in 205 Japanese patients with Guillain-Barré syndrome (GBS). Serological evidence of recent Campylobacter jejuni (C. jejuni) infection was found in 45% of the patients, compared with 1% in healthy controls. In contrast, recent infection of cytomegalovirus (CMV), Mycoplasma pneumoniae (M. pneumoniae) and Epstein-Barr virus (EBV) was detected in only 5%, 2% and none of the patients, respectively. C. jejuni-associated GBS was more frequent in early spring than in other seasons. All stool specimens positive for C. jejuni isolation were obtained within 10 days after the onset of GBS symptoms. Of 13 C. jejuni isolates from GBS patients, 10 (77%) belonged to Penner serotype 19 (heat-stable, HS-19). Elevated titers of anti-GM1 antibody were found in 8 (80%) of 10 GBS patients whose C. jejuni isolates belonged to HS-19 and in none of those infected with non-HS-19 C. jejuni (P = 0.04), and in 49% of 92 patients with C. jejuni infection and 25% of patients without infection of C. jejuni, CMV, EBV, or M. pneumoniae (P = 0.0007). The frequencies of elevated antibody titers to GD1a, GD1b and GQ1b were also significantly higher in GBS patients associated with C. jejuni than those not associated with C. jejuni, CMV, EBV, and M. pneumoniae. GBS in Japan seems to be associated more frequently with C. jejuni and less frequently with CMV than in Europe and North America.

Topics: Adolescent; Adult; Aged; Antibodies, Bacterial; Antibodies, Viral; Antibody Specificity; Antigens, Bacterial; Autoantibodies; Autoimmune Diseases; Campylobacter Infections; Campylobacter jejuni; Child; Child, Preschool; Comorbidity; Cytomegalovirus Infections; Enteritis; Europe; Feces; Female; G(M1) Ganglioside; Galactosylceramides; Gangliosides; Herpesviridae Infections; Herpesvirus 4, Human; Humans; Japan; Male; Middle Aged; Molecular Mimicry; Mycoplasma pneumoniae; Pneumonia, Mycoplasma; Polyradiculoneuropathy; United States

IgA has an important function in the gastrointestinal immune system. We investigated IgA anti-ganglioside antibodies in Guillain-Barré syndrome (GBS) and Fisher's syndrome (FS) subsequent to Campylobacter jejuni enteritis. In previous studies, serological diagnosis of C. jejuni infection was based on the detection of IgG, IgA, and IgM anti-C. jejuni antibodies. Our study, however, showed that the detection of IgG anti-C. jejuni antibody alone was sufficient for the serological diagnosis of antecedent C. jejuni enteritis in GBS and FS, when the cut-off level was defined for results of sera from C. jejuni-isolated patients. Serological evidence of C. jejuni infection was found in 62 (31%) of 201 GBS patients and 12 (18%) of 65 FS patients. IgA anti-GMI antibody was detected in sera from 33 (16%) of the GBS patients, 1 (2%) of the FS patients, and none of the 46 normal control subjects. IgA anti-GM1 antibody titers were significantly higher in the GBS patients with positive C. jejuni serology than in those with negative serology (P < 0.0001) or the FS patients with positive C. jejuni serology (P = 0.007). IgA anti-GQ1b antibody was detected in sera from 18 (28%) of the FS patients, 9 (4%) of the GBS patients, and none of the normal control subjects. FS patients with positive C. jejuni serology had significantly higher titers of IgA anti-GQ1b antibody than those with negative serology (P = 0.01) or the GBS patients with positive C. jejuni serology (P < 0.0001). We conclude that anti-GM1 and anti-GQ1b IgA antibodies are closely associated with antecedent C. jejuni enteritis in GBS and FS, respectively.

Topics: Antibodies, Bacterial; Antibody Specificity; Autoantibodies; Autoimmune Diseases; Campylobacter Infections; Campylobacter jejuni; Enteritis; G(M1) Ganglioside; Gangliosides; Humans; Immunoglobulin A; Miller Fisher Syndrome; Nervous System Diseases; Polyradiculoneuropathy

A series of monoclonal IgM anti-GM1 ganglioside antibodies has been cloned from peripheral blood lymphocytes of patients with multifocal motor neuropathy and Guillain-Barré syndrome. In solid-phase immunoassay, the antibodies react with GMI, and also in differing degrees to the structurally related glycolipids asialo-GM1 (GA1) and GD1b. Here we describe the binding patterns of six human anti-GM I antibodies to epitopes within the human nervous system. Antibodies were observed to bind to motor neurons and spinal grey matter, dorsal and ventral spinal roots, dorsal root ganglion neurons, nodes of Ranvier, neuromuscular junctions and skeletal muscle. The distribution of immunoreactive epitopes, which included sensory structures, extended beyond those sites conventionally regarded as pathologically affected in anti-GM1 antibody-associated motor nerve syndromes. This undermines a model of disease pathogenesis based solely on antigen distribution. Factors other than the presence or absence of antigen, such as the local ganglioside topography, antibody penetration into, and pathophysiological vulnerability of a particular site may also influence the clinicopathological outcome of anti-GM1 antibody-mediated autoimmune attack.

Topics: Antibodies, Monoclonal; Autoimmune Diseases; Diaphragm; Epitopes; Femoral Nerve; G(M1) Ganglioside; Ganglia, Spinal; Gangliosides; Humans; Immunoglobulin M; Motor Neuron Disease; Nerve Tissue Proteins; Organ Specificity; Peripheral Nerves; Polyradiculoneuropathy; Spinal Cord; Spinal Nerve Roots

We demonstrate that the receptor binding moiety of Escherichia coli heat-labile enterotoxin (EtxB) can completely prevent autoimmune disease in a murine model of arthritis. Injection of male DBA/1 mice at the base of the tail with type II collagen in the presence of complete Freund's adjuvant normally leads to arthritis, as evidenced by inflammatory infiltration and swelling of the joints. A separate injection of EtxB at the same time as collagen challenge prevented leukocyte infiltration, synovial hyperplasia, and degeneration of the articular cartilage and reduced clinical symptoms of disease by 82%. The principle biological property of EtxB is its ability to bind to the ubiquitous cell surface receptor GM1 ganglioside, and to other galactose-containing glycolipids and galactoproteins. The importance of receptor interaction in mediating protection from arthritis was demonstrated by the failure of a non-receptor-binding mutant of EtxB to elicit any protective effect. Analysis of T cell responses to collagen, in cultures of draining lymph node cells, revealed that protection was associated with a marked increase in interleukin 4 production concomitant with a reduction in interferon gamma levels. Furthermore, in protected mice there was a significant reduction in anti-collagen antibody levels as well as an increase in the IgG1/IgG2a ratio. These observations show that protection is associated with a shift in the Th1/Th2 balance as well as a general reduction in the extent of the anti-type II collagen immune response. This suggests that EtxB-receptor-mediated modulation of lymphocyte responses provides a means of preventing autoimmune disease.

Topics: Animals; Antibody Formation; Arthritis, Experimental; Autoimmune Diseases; Bacterial Toxins; Collagen; Enterotoxins; Escherichia coli; Escherichia coli Proteins; G(M1) Ganglioside; Interferon-gamma; Interleukin-4; Lymphocyte Activation; Male; Mice; Mice, Inbred DBA; Protein Binding; Receptors, Cell Surface; T-Lymphocytes

Unlike CNS myelin, human peripheral nerve myelin has the acidic glycosphingolipids sialosyl paragloboside (SPG), sialosyl lactosaminyl paragloboside (SLPG), and sulfated glucuronyl paragloboside (SGPG). To elucidate the pathogenesis of Guillain-Barré syndrome (GBS) and chronic inflammatory demyelinating neuropathy (CIDP), we investigated the autoantibodies to peripheral nerve molecules in patients with these diseases and compared the frequency of the autoantibodies with that of autoantibody to GM1 which is present in both the CNS and PNS. The report of Sheikh et al. (Ann. Neurol. 1995; 38: 350) that Campylobacter jejuni bears the SGPG epitope led us to study whether sera from patients with GBS subsequent to C. jejuni enteritis have anti-SGPG antibody; but, high anti-SGPG antibody titers were not found in the GBS patients from whom C. jejuni was isolated. Although the frequency of the anti-SPG, anti-SLPG and anti-SGPG antibodies were lower than that of the anti-GM1 antibody in GBS, 5 patients with demyelinating GBS had high IgG anti-SPG antibody titers. IgG anti-SPG antibody may function in the development of demyelinating GBS. We found that 6 CIDP patients had elevated IgM anti-SGPG antibody titers. Immunoelectrophoresis failed to detect IgM M-protein in 3 of the patients. IgM anti-SGPG antibody could be a diagnostic marker for a subgroup of CIDP with or without paraprotein.

Topics: Aged; Antibody Specificity; Antigens, Bacterial; Autoantibodies; Autoantigens; Autoimmune Diseases; Biomarkers; Campylobacter jejuni; Carbohydrate Sequence; Chronic Disease; Cross Reactions; Demyelinating Diseases; Epitopes; Female; G(M1) Ganglioside; Globosides; Humans; Immunoelectrophoresis; Immunoglobulin G; Immunoglobulin M; Inflammation; Lipopolysaccharides; Male; Middle Aged; Molecular Mimicry; Molecular Sequence Data; Peripheral Nerves; Polyradiculoneuropathy

Experimental allergic neuritis (EAN) is a T cell mediated disease associated with inflammation and demyelination of peripheral nerves. EAN is an experimental model of Guillain-Barré syndrome. The peripheral nerve myelin components P2 and P0 represent major neuritogens, but the diversity and quantity of B cell responses in EAN are unknown. Lewis rats were immunized with bovine peripheral nerve myelin (BPM), and levels of B cells secreting IgM and IgG antibodies to BPM, P2 and P0, the glycolipid GM1 and five peptides of myelin-associated glycoprotein (MAG) were determined. Already on day 7 post-immunization (p.i.), i.e. before the onset of clinical EAN, lymph nodes contained elevated levels of cells secreting IgM antibodies of all specificities examined. Maximum numbers of IgG antibodies secreting cells were generally reached at the height of clinical disease. The numbers of cells secreting IgG antibodies to BPM, P2, P0, GM1 and MAG peptides were also elevated before disease onset, but they were mostly higher than those of IgM antibodies and they reached their maximum only after recovery. The results imply that EAN is associated with strong B cell responses to all myelin antigens under study without restriction to any immunodominant myelin component or MAG peptides.

Topics: Amino Acid Sequence; Animals; Autoantibodies; Autoimmune Diseases; B-Lymphocytes; Cattle; Disease Models, Animal; G(M1) Ganglioside; Immunization; Immunoglobulin G; Immunoglobulin M; Lymph Nodes; Male; Molecular Sequence Data; Myelin Basic Protein; Myelin P0 Protein; Myelin P2 Protein; Myelin Proteins; Myelin Sheath; Myelin-Associated Glycoprotein; Neuritis, Autoimmune, Experimental; Peptide Fragments; Polyradiculoneuropathy; Rats; Rats, Inbred Lew; Spleen

To compare the titre of anti-ganglioside antibodies (AGA) to GM1 ganglioside in patients with central and peripheral neurological disease and pure motor and sensorimotor neuropathy, in patients with classic autoimmune diseases, and controls.. AGA to GM1 were measured using an enzyme linked immunosorbent assay (ELISA) technique, highly purified bovine GM1 ganglioside, and sequential dilution of control and test sera. Antibody titre was calculated using the optical density readings of three consecutive serum dilutions multiplied by the dilution factor.. A considerable overlap was evident in the titre of AGA to GM1 in control and test sera. High antibody titres were most frequent in patients with multifocal motor neuropathy with conduction block (MMNCB). Low AGA titre were observed in several patient groups. Compared with the controls, the median titre of AGA to GM1 was significantly higher in patients with multiple sclerosis, rheumatoid arthritis, primary Sjögren's syndrome and systemic lupus erythematosus. In contrast, the median titre in patients with diabetic peripheral neuropathy, motor neurone disease, sensorimotor neuropathy and chronic inflammatory demyelinating polyneuropathy was no different from that in normal control subjects.. Estimation of AGA to GM1 may be helpful in the diagnosis of MMNCB in patients with a pure motor neuropathy but in few other conditions. Low titre AGA to GM1 are evident in several autoimmune conditions. The pathogenetic importance of AGA to GM1 in patients with neuropathy is not clear.

Topics: Arthritis, Rheumatoid; Autoimmune Diseases; G(M1) Ganglioside; Humans; Immunoglobulin M; Motor Neuron Disease; Multiple Sclerosis; Peripheral Nervous System Diseases; Sjogren's Syndrome

Several gangliosides of human nervous tissues have been reported to be potential target antigens in autoimmune neuropathies. To explain the diversity of clinical symptoms in patients with antiganglioside antibodies, we have searched for ganglioside antigens that are specific to individual nervous tissues such as motoneurons, peripheral motor nerves, and sensory nerves. Although the major ganglioside compositions were not different among human peripheral motor and sensory nerves, fucosyl-GM1 was found to be expressed in sensory nervous tissue but not in spinal cord, motor nerve, and sympathetic ganglia. Sera from several patients with sensory nerve involvement also reacted with fucosyl-GM1 as well as GM1. Thus, fucosyl-GM1 may be a responsible target antigen for developing sensory symptoms in some patients with autoimmune neuropathies.

Topics: Animals; Autoantigens; Autoimmune Diseases; G(M1) Ganglioside; Humans; Nervous System Diseases; PC12 Cells; Peripheral Nerves; Rats; Sense Organs

Topics: Adult; Aged; Autoantibodies; Autoimmune Diseases; Chlorambucil; Female; G(M1) Ganglioside; Humans; Male; Middle Aged; Motor Neuron Disease; Neurologic Examination; Synaptic Transmission

Although changes in surface carbohydrate expression of abnormally expanded MRL/Mp-lpr/lpr (MRL/lpr) lymph node (LN) cells have previously been described, the composition and function of glycolipids present on these cells as well as the spectrum of specificity of anti-carbohydrate antibodies reactive with these cells remains obscure. Analysis of antibodies to a panel of 22 carbohydrate structures using a liposome immune lysis assay (LILA) showed that, except for anti-asialo GM2 (GA2) antibodies, marked reduction of antiglycolipid antibody levels was observed in sera from 4-mo-old MRL/lpr mice compared with these from MRL/Mp(-)+/+ (MRL/+) mice. Absorption experiments revealed that both anti-asialo GM1 (GA1) and globoside antibodies had binding capacity to MRL/lpr LN cells. To elucidate the glycolipid profiles of MRL/lpr LN cells, glycolipids were extracted from LN cells of both MRL/lpr and MRL/+ mice and analysed. A 30-fold elevation of GM1 was found in MRL/lpr LN cells compared with MRL/+ LN cells. From the results of LILA using GA1/GM1 mixed liposomes, aberrantly expressed GM1 inhibited the classical complement pathway but did not interfere with the binding of anti-GA1 antibodies to liposomal GA1. These findings suggest that a drastic GM1 increase on MRL/lpr LN cells would inhibit the action of anti-GA1 antibodies and complement on the cell surface. This may explain the escape of these cells from an activated self directed immune response.

Topics: Animals; Antibody Specificity; Autoantibodies; Autoimmune Diseases; Carbohydrate Sequence; Complement System Proteins; G(M1) Ganglioside; Glycolipids; Liposomes; Lymph Nodes; Lymphoproliferative Disorders; Mice; Mice, Inbred Strains; Mice, Mutant Strains; Molecular Sequence Data

Serum IgG in a patient with chronic polyneuropathy after Mycoplasma pneumoniae infection reacted with ganglioside GM1, GD1b and asialo-GM1 on thin-layer chromatograms using an immunostaining technique as well as an enzyme-linked immunosorbent assay, suggesting that the galactosyl (beta 1-3)N-acetylgalactosaminyl moiety could be a target antigen in this patient. Serum IgG reacting with these glycolipids may be involved in the pathogenesis of both motor and sensory neuropathies in this patient.

Topics: Adolescent; Adult; Aged; Autoantibodies; Autoimmune Diseases; Child; Chronic Disease; Enzyme-Linked Immunosorbent Assay; Female; G(M1) Ganglioside; Gangliosides; Humans; Immunoglobulin G; Male; Middle Aged; Neurologic Examination; Pneumonia, Mycoplasma; Polyradiculoneuropathy

Antibodies to GM1 or Gal(beta 1-3)GalNAc are associated with motor or sensorimotor neuropathy and with motor neuron disease. To investigate the role of these antibodies in the neurological disorder, rabbits were immunized with GM1 or with Gal(beta 1-3)GalNAc-BSA, and studied serologically, electrophysiologically and pathologically. Development of antibodies to the immunizing antigens was associated with a fall in the ratio of the amplitudes of the compound muscle action potential evoked by proximal versus distal stimulation of the sciatic nerve. Pathological studies revealed mild axonal degeneration and immunoglobulin deposits at the nodes of Ranvier in peripheral nerve, resembling those reported in a patient with motor neuropathy, motor conduction block and anti-GM1 antibodies. These studies provide evidence that anti-GM1 or anti-Gal(beta 1-3)GalNAc antibodies cause conduction abnormalities and indicate that the antibodies may exert their effect, in part, by binding at the nodes of Ranvier in peripheral nerve.

Topics: Animals; Antibodies; Antibody Formation; Autoimmune Diseases; Electrophysiology; Fluorescent Antibody Technique; G(M1) Ganglioside; Immunoglobulins; Nervous System Diseases; Rabbits; Ranvier's Nodes

We describe a 52-year-old man who had an acute-onset purely motor neuropathy fulfilling the diagnostic criteria for the Guillain-Barré syndrome, in whom virtually complete spontaneous recovery occurred by 1 year, and in whom high titres of polyclonal serum antibody to GM1, GD1b, asialo-GM1 and lacto-N-tetraose were detected. The titre of IgM antibody to GM1 fell during the course of the disease with a concomitant rise in the IgG titre. This case adds to the widening spectrum of disease associated with anti-GM1 antibodies and provides further evidence for a relationship between anti-GM1 antibodies and motor system disease.

Topics: Acute Disease; Animals; Autoantibodies; Autoimmune Diseases; G(M1) Ganglioside; Humans; Immunoglobulin G; Immunoglobulin M; Male; Middle Aged; Polyradiculoneuropathy; Ranvier's Nodes; Rats

We report 2 patients with a treatable, immune-mediated motor polyneuropathy associated with antibodies to defined neural antigens. In these patients asymmetrical weakness developed in one arm and progressed over 2 to 3 years to involve the other arm, legs, and trunk. Both patients were initially diagnosed as having lower motor neuron forms of amyotrophic lateral sclerosis. However, repeated electrophysiological testing eventually showed multifocal conduction blocks in motor but not sensory fibers compatible with patchy selective demyelination. Serum testing by thin-layer chromatography and enzyme-linked immunosorbent assay revealed that both patients had high titers of antibody directed against GM1 and other gangliosides. Initial therapeutic trials of prednisone (100 mg daily for 4 to 6 months) and plasmapheresis were unsuccessful. Treatment with cyclophosphamide, however, was followed by marked improvement in strength in both patients.

Topics: Adult; Autoantibodies; Autoimmune Diseases; Cyclophosphamide; Female; G(M1) Ganglioside; Humans; Infusions, Intravenous; Male; Middle Aged; Motor Neurons; Neuromuscular Diseases; Synaptic Transmission

BB rats exhibit a syndrome of spontaneous diabetes that has clinical and pathological characteristics analogous to those found in human insulin-dependent diabetes mellitus (IDDM). Islet tissue transplanted into spontaneously diabetic BB rats is uniformly destroyed by a recurrence of the autoimmune response that destroyed the diabetic subject's native islets. To examine recurrent autoimmune destruction of transplanted islets, it is necessary to exclude islet damage that might result from allograft rejection. We utilized neonatal tolerance induction to prevent rejection of Wistar-Furth (WF) (RT1u) islet allografts by spontaneously diabetic BB recipients. We determined that islet-recipient treatment with anti-asialo-GM1 (anti-AGM1) antibody prevents recurrent autoimmune diabetes that would otherwise destroy transplanted WF islet grafts. Anti-AGM1 therapy significantly decreased peripheral blood natural killer (NK) cell activity. These data suggest a role for NK cells in the pathogenesis of recurrent diabetes in neonatally tolerant BB rats.

Topics: Animals; Autoimmune Diseases; Diabetes Mellitus, Experimental; G(M1) Ganglioside; Glycosphingolipids; Immune Sera; Immune Tolerance; Islets of Langerhans; Islets of Langerhans Transplantation; Killer Cells, Natural; Rats; Rats, Inbred BB; Rats, Inbred WF; Recurrence

To study the demyelinative effects of antibodies to glycolipids, well-myelinated cultures of mouse spinal cord tissue were exposed to antisera against galactocerebroside and two gangliosides (GM1 and GM4), as well as to anti-white matter antiserum. The demyelinative process was evaluated by morphologic and biochemical techniques. Cultures exposed to anti-white matter and anti-galactocerebroside antisera showed the most marked changes. These consisted of a decrease in the number of oligodendroglial cells and dissolution and phagocytosis of myelin. Concomitantly, the activity of 2',3'-cyclic nucleotide-3'-phosphohydrolase (CNPase) was decreased by 60-70%. This occurred within 24 h of exposure to a relatively low concentration of serum (10%). Cultures exposed to anti-GM1 and anti-GM4 antisera showed similar changes but to a lesser degree. The CNPase activity was decreased about 30% within 48 h of exposure to a 25% concentration of these antisera. This diminution represents about a 20% loss of myelin, an observation corroborated by electron microscopy where myelin but not oligodendroglial cell loss was observed. Therefore, in addition to anti-galactocerebroside activity, which was previously found to be the major antibody responsible for the demyelinating activity induced by anti-whole CNS tissue antiserum, these data suggest that antibodies to gangliosides like GM1 and GM4 might also play a role in immune-mediated demyelination, including perhaps, the human demyelinating diseases.

Topics: Animals; Autoimmune Diseases; Culture Techniques; Demyelinating Diseases; G(M1) Ganglioside; Galactosylceramides; Gangliosides; Glycolipids; Immune Sera; Mice; Microscopy, Electron; Spinal Cord

Topics: Animals; Autoantibodies; Autoimmune Diseases; Brain Neoplasms; Cell Line; Cytotoxicity Tests, Immunologic; G(M1) Ganglioside; Glycosphingolipids; Guinea Pigs; Humans; Lupus Erythematosus, Systemic; Mice; Nervous System Diseases; Rabbits