g(m1)-ganglioside and Autoimmune-Diseases-of-the-Nervous-System

Multifocal motor neuropathy (MMN) is characterized by asymmetric weakness of limbs and the electrophysiological finding of conduction block in motor nerves. Conduction block is the inability of nerves to propagate action potentials and is probably caused by immune-mediated dysfunction of the axon at the nodes of Ranvier or the myelin sheath. MMN immune pathogenesis has not been elucidated.. In approximately 50% of all patients, IgM antibodies that bind to the glycolipid GM1, which is abundantly expressed in peripheral motor nerves, can be detected. A recent study showed an association with HLA-DRB1*15, and virtually all patients respond to treatment with intravenous immunoglobulin (IVIG) in at least the early stages of the disease.. This review aims at providing a concise overview of what is known about MMN pathogenesis, and how the beneficial effect of IVIG might be explained.

Topics: Adult; Aged; Autoantibodies; Autoantigens; Autoimmune Diseases of the Nervous System; Female; Forecasting; G(M1) Ganglioside; Genetic Predisposition to Disease; HLA-DR Antigens; HLA-DRB1 Chains; Humans; Immunoglobulin M; Immunoglobulins, Intravenous; Male; Middle Aged; Motor Neuron Disease; Neural Conduction; Peripheral Nerves; Young Adult

The association of neuropathy with IgM paraprotein has been known for several years, but only recently the pathogenetic relevance of this association has been clarified. Reactivity of the paraprotein with several neural antigens has been reported even if their pathogenetic relevance is not always clear. IgM binding to the Myelin-associated glycoprotein (MAG) is associated with a homogeneous demyelinating neuropathy, deposits of the paraprotein and complement on nerve myelin, and improvement concomitantly to anti-MAG IgM reduction. In particular, treatment with rituximab durably improved the neuropathy in two thirds of the patients, particularly those with moderately increased anti-MAG titres, which might be more easily reduced by this treatment. Several other IgM reactivities with nerve antigens have been reported in these patients, including several gangliosides and sulfatide even if, with the only exceptions of anti-sulfatide and anti-GQ1b ganglioside reactivities, their possible pathogenetic relevance remains to be established.

Topics: Autoimmune Diseases of the Nervous System; G(M1) Ganglioside; Humans; Immunoglobulin M; Myelin-Associated Glycoprotein; Paraproteins; Sulfoglycosphingolipids

Topics: Adjuvants, Immunologic; Animals; Antigens, Neoplasm; Autoantibodies; Autoantigens; Autoimmune Diseases of the Nervous System; Brain Chemistry; Carbohydrate Sequence; Epitopes; G(M1) Ganglioside; G(M2) Ganglioside; Galactosylceramides; Gangliosides; Globosides; Glycolipids; Glycosphingolipids; Humans; Immune Tolerance; Immunoglobulin G; Immunoglobulin M; Melanoma; Melanoma, Experimental; Mice; Molecular Sequence Data; Molecular Structure; N-Acetylneuraminic Acid; Oligosaccharides; Paraneoplastic Syndromes, Nervous System

Intravenous immunoglobulin (IVIg) therapy is efficacious in some peripheral nervous autoimmune diseases associated with anti-GM1 antibodies. Numerous mechanisms of action have been proposed to account for the immunomodulatory effects of IVIg in immune-mediated diseases. Up to now, the mechanisms of action of IVIg in pathology associated with anti-GM1 antibodies have not been well documented. In the present study, we discovered that IVIg did not inhibit the binding of anti-GM1 antibodies to its antigen and IVIg perfusions did not reduce anti-GM1 antibodies titers. In this observation, we have the result different from the hypothesis of presence of anti-idiotypic antibodies in different IVIg preparations, and show that IVIg inhibits the binding of cholera toxin and galectin-1 to GM1-expressing cells using flow cytometry. Our results suggest that the correct ratio galactosyl/agalactosyl IgG in IVIg interact with macrophages receptors to down-regulate inflammatory function of macrophages and autoimmune diseases in peripheral nerve system.

Topics: Autoantibodies; Autoantigens; Autoimmune Diseases of the Nervous System; Cell Line; Cell Membrane; Cholera Toxin; G(M1) Ganglioside; Galectin 1; Humans; Immunoglobulins, Intravenous; Protein Binding; Treatment Outcome

Topics: Adult; Anemia, Hemolytic, Autoimmune; Anti-Inflammatory Agents; Ataxia; Autoantibodies; Autoantigens; Autoimmune Diseases of the Nervous System; Diagnosis, Differential; Female; G(M1) Ganglioside; Humans; Ophthalmoplegia; Prednisone

Antibodies to the ganglioside GD1b have been reported in various forms of immune-mediated neuropathy, but their clinical relevance for diagnosis and prognosis is unknown. We investigated the prevalence of anti-GD1b antibodies in acute and chronic immune-mediated neuropathies, and the clinical presentation and outcome in Guillain-Barré syndrome (GBS) and Miller Fisher-GBS overlap syndrome (MF-GBS). Anti-GD1b, anti-GM1 and anti-GQ1b antibodies were tested in serum of patients with GBS (N = 165), Miller Fisher syndrome (N = 10), MF-GBS (N = 28), monoclonal gammopathy of unknown significance neuropathy (MGUS; N = 101), chronic inflammatory demyelinating polyneuropathy (N = 29), paraneoplastic syndrome with anti-Hu-associated neuropathy (PNS; N = 11), other auto-immune diseases (AID; N = 60), and healthy controls (HC; N = 60). All samples were tested by enzyme-linked immunosorbent assay according to the Inflammatory Neuropathy Cause and Treatment protocol. IgM anti-GD1b antibodies were found in GBS (N = 4; 2.4%), MGUS (N = 3; 3.0%), and PNS patients (N = 1; 9.1%). IgG anti-GD1b antibodies were found in GBS (N = 20; 12.1%) and MF-GBS (N = 4; 14.3%) patients, but not in the AID and HC group. In the combined group of MF-GBS and GBS patients ((MF-)GBS), 14/36 (38.9%) patients with IgG anti-GD1b antibodies also had IgG anti-GM1 antibodies, and IgG anti-GD1b and IgG anti-GQ1b antibodies were found in 3/29 (10.3%) patients. Patients with (MF-)GBS and anti-GD1b without anti-GM1 antibodies did not differ regarding sensory disturbances or disease severity but recovered faster regarding the ability to walk independently compared with patients without anti-GD1b antibodies (P = 0.031) and with patients with both anti-GD1b and anti-GM1 antibodies (P = 0.034). In conclusion, testing for anti-GD1b antibodies may identify a specific group of immune-mediated neuropathies and (MF-)GBS patients with only anti-GD1b antibodies tend to recover faster.

Topics: Adult; Aged; Autoantibodies; Autoantigens; Autoimmune Diseases of the Nervous System; G(M1) Ganglioside; Gangliosides; Guillain-Barre Syndrome; Humans; Immunoglobulin G; Immunoglobulin M; Lupus Erythematosus, Systemic; Middle Aged; Miller Fisher Syndrome; Monoclonal Gammopathy of Undetermined Significance; Paraneoplastic Polyneuropathy; Polyradiculoneuropathy, Chronic Inflammatory Demyelinating; Sjogren's Syndrome

Polyethylene glycol-interferon alpha (PEG-IFNalpha) has been used as the standard treatment for hepatitis C virus (HCV) infection. There have been no previous reports of polyradiculoneuropathy with anti-ganglioside antibodies induced by PEG-IFNalpha-2b. We report a 59-year-old man who developed polyradiculoneuropathy during treatment with PEG-IFN alpha-2b for chronic HCV infection. Serum levels of anti-asialo-GM1 (GA1) and anti-GM1 antibodies were elevated. Cessation of therapy with double filtration plasmapheresis resulted in marked improvement in his symptoms accompanied by a reduction in the antibody level. PEG-IFN alpha-2b may induce peripheral neuropathy mediated by anti-GA1 and anti-GM1 antibodies.

Topics: Antiviral Agents; Autoantibodies; Autoantigens; Autoimmune Diseases of the Nervous System; Drug Carriers; Drug Therapy, Combination; G(M1) Ganglioside; Gait Disorders, Neurologic; Hepatitis C, Chronic; Humans; Interferon alpha-2; Interferon-alpha; Male; Middle Aged; Muscle Weakness; Plasmapheresis; Polyethylene Glycols; Polyradiculoneuropathy; Recombinant Proteins; Ribavirin

Antibodies against several neural antigens have been associated with different chronic immune-mediated neuropathies but their practical clinical relevance remains unclear. To determine the possible diagnostic usefulness of these antibodies we reviewed the clinical correlate of IgM antibodies to the myelin-associated glycoprotein (MAG), sulfatide, the gangliosides GM1, GM2, GD1a and GD1b in 539 consecutive patients examined for neuropathy or related diseases in our Neuropathy Clinics and tested for these antibodies in our laboratory since 1985. 302 patients (56%) had an established diagnosis of definite or possible chronic immune-mediated neuropathy while 237 had a neuropathy of non-immune-mediated origin or of unknown aetiology or a closely related disease. Antibodies to one or more antigen were more frequent (chi(2)=63.32; p<0.00001) in patients with chronic immune-mediated neuropathy (37.7%) than with other neuropathy or related diseases (7.2%) and their presence was associated in 87% of the patients with an immune-mediated neuropathy, incrementing by 31% the probability of having this form. Testing for MAG permitted to identify 24.8% of patients with an immune-mediated neuropathy, GM1 an additional 9.9%, while GM2, GD1b, GD1a and sulfatide altogether an additional 3% of the patients. Concerning clinical correlations, all 75 patients with anti-MAG IgM had neuropathy and IgM monoclonal gammopathy (PN+IgM) with a positive predictive value for this neuropathy of 100%. A similarly high predictive value for neuropathy (91.4%) was observed among 269 patients with IgM monoclonal gammopathy including 103 patients without neuropathy. Anti-sulfatide IgM, though rare, were also significantly and constantly associated with PN+IgM and permitted to identify few patients not bearing anti-MAG IgM. Anti-GM1 IgM were significantly associated with multifocal motor neuropathy (MMN) (29.2%) but where also found in a few patients with other immune or non-immune neuropathies or related diseases with a positive predictive value for MMN of 25.5%. Anti-GM2 IgM were also significantly associated with MMN and increased the sensitivity (36.2%) for MMN obtained with anti-GM1 IgM only, without affecting its specificity and positive predictive value. Anti-GD1a, GD1b, though not significantly more frequent in patients with immune-mediated neuropathy, were associated in 80 to 100% of patients with these neuropathies. In conclusion anti-neural IgM antibodies may help in identifying patie

Topics: Antibody Specificity; Autoimmune Diseases of the Nervous System; Enzyme-Linked Immunosorbent Assay; G(M1) Ganglioside; G(M2) Ganglioside; Gangliosides; Humans; Immunoblotting; Immunoglobulin M; Myelin-Associated Glycoprotein; Paraproteinemias; Retrospective Studies; Sulfoglycosphingolipids

Autoimmune neuropathies including Guillain-Barré syndrome are frequently associated with anti-GM1 ganglioside antibodies. These are believed to play a pathogenic role and their clearance from the circulation would be predicted to produce therapeutic benefit. This study examines the conditions required for effective immunoadsorption of anti-GM1 antibodies using glycan-conjugated Sepharose as a matrix. In solution inhibition studies using a range of GM1-like saccharides in conjunction with mouse and human anti-GM1 antibodies, the whole GM1 pentasaccharide beta-Gal-(1-3)-beta-GalNAc-(1-4)-[alpha-Neu5Ac-(2-3)]-beta-Gal-(1-4)-beta-Glc was the favored ligand for maximal inhibiton of antibody-GM1 interactions in comparison with monosaccharides, Gal-(1-3)-beta-GalNAc-betaOMe, and synthetic GM1 mimetics. Immunoadsorption studies comparing binding of mouse monoclonal anti-GM1 antibodies to GM1-Sepharose and beta-Gal-(1-3)-beta-GalNAc-Sepharose confirmed the preference seen in solution inhibition studies. GM1-Sepharose columns were then used to adsorb anti-GM1 immunoglobulin G and immunoglobulin M antibodies from human neuropathy sera. Anti-GM1 antibodies subsequently eluted from the columns often showed a striking monoclonal or oligoclonal pattern, indicating that the immune response to GM1 is restricted to a limited number of B-cell clones, even in the absence of a detectable serum paraprotein. These data support the view that immunoadsorption plasmapheresis could potentially be developed for the acute depletion of serum anti-GM1 antibodies in patients with neuropathic disease, and also provide purified human anti-GM1 antibodies for analytical studies.

Topics: Animals; Antibodies, Monoclonal; Autoantibodies; Autoimmune Diseases of the Nervous System; G(M1) Ganglioside; Humans; Mice; Mice, Knockout; Oligosaccharides; Plasmapheresis; Sorption Detoxification

Multifocal motor neuropathy (MMN) was first distinguished from other motor neuropathies in 1986. It is characterised by slowly progressive predominantly distal and asymmetric limb weakness and wasting that predominates in the arms, with muscle cramps and fasciculations, within an anatomical distribution of individual motor nerves. Sensory involvement is minimal or absent. The electrodiagnostic hallmark is focal motor conduction block (CB), persisting for years at atypical sites. The most typical laboratory finding is increased serum IgM autoantibody titers to the ganglioside GM1. High-dose intravenous immunoglobulin (IVIg) is currently the gold-standard treatment for MMN. To document short-term and long-term responses to IVIg, we conducted a retrospective study of 40 patients with MMN defined using ENMC Workshop criteria and treated with periodic IVIg infusions (Tégéline) between 1995 and 2003. For the short-term analysis we compared the 22 patients who had never previously received IVIg with the 18 IVIg-experienced patients. For the long-term evaluation (> 6 months), the patients were classified into four groups according to their dependence on periodic IVIg. The MRC score improved significantly in 14 (70% ; 95% CI 0.46 to 0.88) of the 20 assessable treatment-naive patients (data were missing for two patients). This rate was significantly higher than at six months in a historical group of placebo-treated patients (20%; p < 0.0001). No criteria predictive of the response were identified. At the end of follow-up (mean 2.2 +/- 2.0 years) only 8 patients (22%) in the cohort remained in remission after a good initial response to IVIg, while 25 patients (68%) were dependent on periodic IVIg infusions. This study confirms the good short-term response of MMN to IVIg but indicates that the longer-term results are variable. New therapeutic strategies are required to increase the short-term and long-term efficacy of IVIg, and to reduce reliance on this treatment.

Topics: Adult; Aged; Autoantibodies; Autoimmune Diseases of the Nervous System; Drug Evaluation; Female; G(M1) Ganglioside; Humans; Immunoglobulin M; Immunoglobulins, Intravenous; Male; Middle Aged; Motor Neuron Disease; Motor Neurons; Neural Conduction; Retrospective Studies; Severity of Illness Index; Treatment Outcome

Anti-ganglioside antibodies have been described in celiac disease or gluten sensitivity, in conjunction with the presence of central and peripheral nervous system deficits. The observed antibody reactivity to gangliosides is postulated to be related to the anti-gliadin immune response, either through antigenic mimicry, or by formation of gliadin-ganglioside complexes and haptenization. We examined the possibility of the presence of ganglioside-like epitopes in gliadin, as well as the potential for complex formation between gliadin and GM1 ganglioside. Low levels of glycosylation were present in gliadin, but ganglioside-like carbohydrate epitopes were not detected. However, gliadin was found to bind to GM1 ganglioside and to the GM1-rich intestinal brush border membrane. The described complex formation and possible haptenization of GM1 by gliadin may be responsible for driving the anti-ganglioside antibody response in some patients with gluten sensitivity. Furthermore, binding of gliadin to GM1 on the intestinal epithelium might have a role in the anti-gliadin immune response and contribute to the intestinal inflammatory reaction in celiac disease.

Topics: Animals; Autoantibodies; Autoimmune Diseases of the Nervous System; Autonomic Nervous System Diseases; Celiac Disease; Electrophoresis, Polyacrylamide Gel; Enteric Nervous System; Epitopes; G(M1) Ganglioside; Gliadin; Glycosylation; Immunohistochemistry; Intestinal Mucosa; Macromolecular Substances; Mice; Microvilli; Molecular Mimicry; Peripheral Nervous System Diseases; Protein Binding; Transglutaminases

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.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Autoantibodies; Autoimmune Diseases of the Nervous System; Biomarkers; Child; Child, Preschool; Encephalomyelitis, Acute Disseminated; Female; G(M1) Ganglioside; Gangliosides; Guillain-Barre Syndrome; Humans; Immunoglobulin G; Immunoglobulin M; Male; Middle Aged; Miller Fisher Syndrome; Nervous System; Predictive Value of Tests; Retrospective Studies

Topics: Acute Disease; Adult; Antibody Specificity; Autoantibodies; Autoantigens; Autoimmune Diseases of the Nervous System; Axons; Brain; Female; G(M1) Ganglioside; Gait Disorders, Neurologic; Humans; Magnetic Resonance Imaging; Motor Neurons; Plasma Exchange; Polyneuropathies; Reflex, Abnormal; Respiratory Tract Infections

Elevated levels of serum autoantibodies directed against gangliosides are closely associated with acute and chronic autoimmune neuropathies. An agglutination immunoassay using polystyrene microparticles coated with a total extract of brain gangliosides was used to test patient sera for the presence of anti-ganglioside antibodies. Results were compared with those obtained by ELISA for anti-GM1 and anti-GQ1b ganglioside antibodies. Eight of the twelve sera from patients with multifocal motor neuropathy and seven of the thirteen sera from patients with Guillain-Barré syndrome were positive for the presence of anti-ganglioside antibodies by the ganglioside agglutination immunoassay. The assay compared favorably with the ELISA system in sensitivity and specificity, while requiring a fraction of the time and cost to perform. The new assay can serve as a rapid and effective method for detecting or screening for anti-ganglioside antibodies in patients with acute or chronic immune-mediated neuropathies. It would be particularly useful for detecting antibodies that react with multiple gangliosides, or with minor or as yet uncharacterized gangliosides.

Topics: Agglutination; Autoantibodies; Autoimmune Diseases of the Nervous System; Enzyme-Linked Immunosorbent Assay; G(M1) Ganglioside; Gangliosides; Humans; Immunoassay; Nerve Growth Factors

Topics: Autoantibodies; Autoimmune Diseases of the Nervous System; Enzyme-Linked Immunosorbent Assay; G(M1) Ganglioside; Humans; Motor Neuron Disease; Predictive Value of Tests

To investigate the presence of anti-GalNAc-GD1a antibodies in patients with Guillain-Barré syndrome (GBS) and to determine the relation of anti-ganglioside antibodies with clinical features.. The GBS is heterogeneous with regard to clinical manifestations, antecedent infections, and the presence and specificity of anti-ganglioside antibodies. Recently, antibodies to minor gangliosides have been identified in serum from GBS patients.. The authors used ELISA to detect anti-ganglioside antibodies in 132 GBS patients and then correlated results with a database containing information on antecedent infections and clinical parameters.. Anti-GalNAc-GD1a antibodies could be detected in 19 (14%) GBS patients. The presence of anti-GalNAc-GD1a antibodies was related to antecedent Campylobacter jejuni infection (p<0.001). GBS patients with anti-GalNAc-GD1a antibodies had a rapidly progressive, more severe, and predominantly distal weakness. Furthermore, they had less sensory loss, paresthesia, and cranial nerve involvement. In most patients, this reactivity was independent of reactivity to GM1. Dividing patients into separate groups based on their reactivity to GalNAc-GD1a and GM1 enabled the authors to delineate more homogeneous subgroups with regard to clinical features.. This study provides further evidence for the hypothesis that antecedent infections and the specificity of subsequent anti-neural antibody responses determine the clinical manifestations in GBS patients.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Autoantibodies; Autoimmune Diseases of the Nervous System; Campylobacter Infections; Campylobacter jejuni; Child; Child, Preschool; Enzyme-Linked Immunosorbent Assay; Female; G(M1) Ganglioside; Gangliosides; Guillain-Barre Syndrome; Humans; Male; Middle Aged; Neurologic Examination