g(m1)-ganglioside and Multiple-Sclerosis

The favorable response to treatment with IV immunoglobulins and the presence of IgM antibodies to the glycolipid GM1 are indications that inflammation underlies multifocal motor neuropathy (MMN) pathogenesis. We investigated the association of MMN with human leukocyte antigen (HLA) class I and II antigens.. HLA class I and II antigens of 74 Dutch patients with MMN and 700 controls were determined in a case-control study. Associations of HLA types with MMN disease characteristics were investigated.. Compared with controls, patients with MMN had higher frequencies of HLA-DRB1*15 (41 vs 24%, p = 0.0017). Disease characteristics were not associated with specific HLA types.. Similar associations were found in patients with multiple sclerosis and women with chronic immune-mediated demyelinating neuropathy, which may suggest that these demyelinating disorders share pathogenic mechanisms.

Topics: Adult; Age Factors; Aged; Brachial Plexus; Case-Control Studies; Chi-Square Distribution; Female; G(M1) Ganglioside; HLA-DQ Antigens; HLA-DQ beta-Chains; HLA-DR Antigens; HLA-DRB1 Chains; Humans; Immunoglobulin M; Magnetic Resonance Imaging; Male; Membrane Glycoproteins; Middle Aged; Multiple Sclerosis; Neural Conduction; Polyradiculoneuropathy, Chronic Inflammatory Demyelinating; Retrospective Studies

In order to obtain more information concerning the pathogenic significance of ganglioside GM1 in multiple sclerosis serum polyclonal IgG and IgM antibodies to GM1 were evaluated in multiple sclerosis patients with relapsing-remitting and secondary progressive forms of the disease.. The evaluated sera were from 55 patients with clinically definite multiple sclerosis and from 20 healthy subjects. Forty-two of patients were with relapsing-remitting and 13 with secondary progressive multiple sclerosis. Antibodies to GM1 were measured using a modification of the enzyme-linked immunosorbent assay technique of Mizutamari et al (1994).. A statistically significant difference of serum IgG antibody titres to GM1 was found between the healthy subjects and the multiple sclerosis patients with relapsing-remitting form of the disease (p = 0.04), as well as of serum IgG antibody titres to GM1 between the patients with relapsing-remitting multiple sclerosis in relapse and in remission (p = 0.01).. Bearing in mind the heterogeneity of multiple sclerosis, the pathogenic significance of serum antibodies to GM1 should be interpreted concerning the precise clinical form of the disease and not the whole group of MS patients. The findings in this study argue for the possible involvement of ganglioside GM1 in the pathogenesis of demyelination in relapsing-remitting multiple sclerosis.

Topics: Adult; Aged; Case-Control Studies; Enzyme-Linked Immunosorbent Assay; Female; G(M1) Ganglioside; Humans; Immunoglobulin G; Immunoglobulin M; Male; Middle Aged; Multiple Sclerosis; Multiple Sclerosis, Chronic Progressive; Multiple Sclerosis, Relapsing-Remitting

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

It has been reported recently that Haemophilus influenzae can elicit an axonal form of Guillain-Barré syndrome. To investigate the incidence and features of H. influenzae-related Guillain-Barré syndrome, anti-H. influenzae antibody titres were measured by enzyme-linked immunosorbent assay (ELISA) in 46 consecutive Japanese patients with Guillain-Barré syndrome, 49 normal controls, 24 patients with multiple sclerosis and 27 patients with amyotrophic lateral sclerosis (ALS). Whole bacteria of non-encapsulated (non-typable) H. influenzae isolated from one of the Guillain-Barré syndrome patients was the antigen used. Elevated anti-H. influenzae antibodies for two or three classes of IgG, IgM and IgA were found in six (13%) Guillain-Barré syndrome patients, but not in the normal controls and patients with multiple sclerosis or ALS. The incidence was significantly higher in patients with Guillain-Barré syndrome than in the normal controls (P = 0.01) and patients with multiple sclerosis or ALS (P = 0.009). Western blot analysis confirmed that the H. influenzae-positive patients' IgG recognized the lipopolysaccharides of H. influenzae. Guillain-Barré syndrome patients with anti-H. influenzae antibodies showed relatively uniform clinical and laboratory features: prodromal respiratory infection, less frequent cranial and sensory nerve involvement, pure motor axonal degeneration on electrophysiology, and positivity for IgG anti-GM1 antibodies. Although the features were similar to those in Guillain-Barré syndrome patients infected by Campylobacter jejuni, the recoveries seemed to be better in patients with H. influenzae-related Guillain-Barré syndrome. It is concluded that a form of Guillain-Barré syndrome occurs after respiratory infection by H. influenzae in the Japanese population. A particular strain of non-typable H. influenzae has a ganglioside GM1-like structure and elicits axonal Guillain-Barré syndrome similar to C. jejuni-related Guillain-Barré syndrome.

Topics: Adult; Aged; Aged, 80 and over; Amyotrophic Lateral Sclerosis; Antibodies, Bacterial; Autoantibodies; Axons; Case-Control Studies; Enzyme-Linked Immunosorbent Assay; Female; G(M1) Ganglioside; Guillain-Barre Syndrome; Haemophilus Infections; Haemophilus influenzae; Humans; Immunoglobulin A; Immunoglobulin G; Immunoglobulin M; Male; Multiple Sclerosis; Retrospective Studies

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system characterized by discrete areas of demyelination. An autoimmune response against components of myelin is thought to contribute to disease pathogenesis. Here we identify glycolipids as new targets recognized by T cells in multiple sclerosis patients. Circulating T cells reactive with glycolipids are more frequent in MS patients than in control donors as shown by enzyme-linked immunospot assay. They specifically recognize different types of glycolipids, such as gangliosides, sulfatide and galactosylceramide and release IFN-gamma and TNF-alpha. T cells specific for gangliosides were found to be CD8+, TCR alphabeta+, restricted by the MHC-like CD1b molecule and specific for epitopes residing in the carbohydrate moiety of gangliosides. Our findings suggest that in addition to self proteins, self glycolipids may represent potential source of autoantigens recognized by T cells in autoimmune diseases.

Topics: Adult; Animals; Antigen Presentation; Antigens, CD1; Autoantigens; Carbohydrate Sequence; Cattle; Cell Line; Female; G(M1) Ganglioside; Gangliosides; Glycolipids; Humans; Middle Aged; Molecular Sequence Data; Multiple Sclerosis; Receptor-CD3 Complex, Antigen, T-Cell; T-Lymphocytes

The occurrence and role of autoantibodies to gangliosides and other lipid-containing components of the central nervous system in Multiple Sclerosis (MS) are unsettled. Using sensitive ELISAs, we measured IgG and IgM antibody titers and absorbances to the three major gangliosides GD1a, GD1b and GM1, and to sulfatides, cardiolipin and myelin proteins in paired serum and cerebrospinal fluid (CSF) from patients with untreated MS, optic neuritis (ON), acute aseptic meningo-encephalitis (AM) and other neurological diseases (OND). Twenty-three per cent of 30 MS (P<0.04) and 18% of 32 ON patients (P<0.05) presented elevated IgG antibody titers to GD1a in serum compared to 9% of patients with OND. Six (40%) of the patients with malignant MS had elevated serum IgG antibody titers to GD1a compared to one (6%) of the patients with benign MS (P<0.04). In CSF, elevated IgG antibody titers to GD1a were measured in 13% of MS and 20% of ON patients compared to 4% of patients with OND (P<0. 03 and P<0.02, respectively). The augmented IgG response to GD1a in serum also separated MS from Guillain-Barré syndrome. Compared to OND increased IgM absorbances to sulfatides and cardiolipin were observed in CSF of patients with MS, but also in AM. Elevated IgG antibody titers to myelin proteins were found more often in MS patients' serum and MS, ON and AM patients' CSF compared to OND. The data implicate that among the multitude of enhanced B-cell responses occurring in MS and ON, that directed to GD1a is common and more discriminative, and should be evaluated in future MS treatment studies.

Topics: Adult; Antibodies, Anticardiolipin; Autoantibodies; B-Lymphocytes; Cerebrovascular Disorders; Female; G(M1) Ganglioside; Gangliosides; Humans; Immunoglobulin G; Immunoglobulin M; Male; Meningoencephalitis; Middle Aged; Multiple Sclerosis; Myelin Basic Protein; Nervous System Diseases; Optic Neuritis; Recurrence; Sulfoglycosphingolipids

We report an ELISA-type titertray assay for autoantibodies against the ganglioside GM1. Trays were coated with ganglioside GM1 and reacted with patients' sera; bound IgM was detected with rabbit antibody to human IgM. High-titer serum from a patient was used as calibrator, another patient's serum as the positive control, and the GM1-specific cholera toxin as the control for GM1 coating. Regression curves of serum titers obtained from different patients were linear and parallel. Intra- and interassay CVs were 4.0-7.8% and 5.5-16%, respectively. We detected antibodies at a titer of 1:250 in normal subjects. Analytical specificity of the calibrator serum against GM1 was demonstrated by immune thin-layer chromatography. Anti-GM1 antibodies were increased in patients with chronic inflammatory demyelinating polyradiculoneuropathy (P < 0.002) or multiple sclerosis (P < 0.01). In Guillain-Barré syndrome, preliminary longitudinal studies showed a decrease in anti-GM1 titer that was related to clinical recovery.

Topics: Autoantibodies; Carcinoma, Small Cell; Drug Stability; Enzyme-Linked Immunosorbent Assay; Ethanol; G(M1) Ganglioside; HIV Seropositivity; Humans; Immunoglobulin M; Lung Neoplasms; Motor Neuron Disease; Multiple Sclerosis; Polyradiculoneuropathy; Sensitivity and Specificity; Solvents

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

Topics: Adult; Cerebrosides; Female; G(M1) Ganglioside; Humans; Immunoglobulins; In Vitro Techniques; Lymphocytes; Male; Middle Aged; Multiple Sclerosis; Myelin Basic Protein

Antibody titers against myelin constituents in sera and CSF of patients with multiple sclerosis (MS) were examined by a solid-phase radioimmunoassay. Anti-GM4 and anti-galactocerebroside antibody titers were significantly elevated in the CSF of MS patients, but not anti-GM1 and anti-myelin basic protein antibodies. In sera of MS patients, the titers of antibodies against these myelin constituents were not elevated. Total IgG level was also significantly elevated in the CSF, but not in the sera of MS patients. Immune complexes from the CSF of MS patients were dissociated by acid-ultrafiltration and assayed for antibodies to GM4, GM1, and galactocerebroside. Anti-GM4 and antigalactocerebroside antibody titers were significantly enhanced after acid dissociation and ultrafiltration. These data suggest that antibodies of the IgG class against GM4 and galactocerebroside are present in CSF of MS patients, and a significant number of them exist as immune complexes with their corresponding glycolipid antigens.

Topics: Antibody Specificity; Autoantibodies; Brain; G(M1) Ganglioside; Galactosylceramides; Gangliosides; Glycolipids; Humans; Immune Complex Diseases; Immunoglobulin G; Multiple Sclerosis; Myelin Basic Protein; Myelin Proteins; Myelin Sheath; Radioimmunoassay

A spin-membrane immunoassay has been employed to examine the immune reactivity of whole serum from patients with chronic-progressive multiple sclerosis (CPMS) against liposomes containing ganglioside GM1. Exposure to serum resulted in complement-mediated lysis of the GM1-liposomes. No lysis occurred with liposomes devoid of ganglioside. The mean (+/- S.E.M.) lysis values were 52.6 (+/- 9.8)% for fifteen CPMS patients and 32.9 (+/- 7.2)% for nine controls. The difference between the means was highly significant (student's t-test, P less than 0.0001), indicating increased anti-ganglioside immunity in patients with CPMS.

Topics: Cytotoxicity, Immunologic; Dose-Response Relationship, Drug; Electron Spin Resonance Spectroscopy; G(M1) Ganglioside; Gangliosides; Humans; Immunoassay; Liposomes; Multiple Sclerosis; Spin Labels

We used a liposome lysis assay to measure antibodies against a panel of glycolipids. Antibodies to one or more compounds were detected in 34 of 46 patients with multiple sclerosis, 19 of 31 patients with systemic lupus erythematosus (SLE), and in the majority of patients with cranial trauma or cerebrovascular accidents. Antibodies against ganglioside GM1 and asialo GM1 were found most commonly, and they were frequently present in the same sera. The specificity of the antibodies was tested in four sera that contained antibodies to both glycolipids. The anti-GM1 antibodies cross-reacted with asialo GM1, but the converse was not true. Among patients whose sera contained antibodies to glycolipids, anti-asialo GM1 alone was more common in patients with SLE (7 of 17) than in multiple sclerosis (2 of 34; p = 0.004). Anti-GM1 alone was found in 9 of 34 patients with multiple sclerosis and 1 of 17 patients with SLE, a difference that was not statistically significant (0.135). No correlation was observed between the presence of anti-glycolipid antibodies and symptoms related to the nervous system in patients with SLE. Because of our inability to detect these antibodies by a solid phase immunoassay (ELISA), a comparison was made of the titers obtained with three monoclonal anti-glycolipid antibodies in the liposome lysis assay and ELISA. The ELISA was less sensitive in all instances, requiring from four to 1000 times as much antibody as the liposome lysis assay to give a positive test. We conclude that antibodies to glycolipids occur frequently in patients with multiple sclerosis, SLE, major cranial trauma, and cerebrovascular accidents. Their role in the initiation or perpetuation of inflammatory disease of the central nervous system has yet to be determined.

Topics: Antibodies; Antibody Specificity; Binding Sites, Antibody; Enzyme-Linked Immunosorbent Assay; G(M1) Ganglioside; Glycosphingolipids; Humans; Lupus Erythematosus, Systemic; Multiple Sclerosis

Topics: Antibodies; Antigen-Antibody Complex; G(M1) Ganglioside; Gangliosides; Glycosphingolipids; Humans; Kinetics; Liposomes; Lupus Erythematosus, Systemic; Multiple Sclerosis

Multiple sclerosis serum contains a factor or factors capable of releasing sequestered [14C]glucose from liposomes containing GM1, the major ganglioside present in human central nervous system myelin. Although some control sera can also release large quantities of liposomal glucose, multiple sclerosis and control sera differ in the mechanism of this release. Liposomal damage by multiple sclerosis serum does not appear to be complement mediated, but shares certain releasing characteristics of cholera toxin.

Topics: Adult; G(M1) Ganglioside; Gangliosides; Humans; Immune Sera; Liposomes; Middle Aged; Multiple Sclerosis