g(m1)-ganglioside and Paraproteinemias

Most inflammatory neuropathies, both acute and chronic, probably result from an immune attack against antigens of the peripheral nervous system. Specific antibodies in serum that react with the peripheral nervous system have been described in a number of inflammatory neuropathies. We review the pathophysiological significance of auto-antibodies and discuss their use for the diagnosis of patients with peripheral neuropathy.

Topics: Ataxia; G(M1) Ganglioside; Humans; Immunoassay; Immunoglobulin M; Motor Neurons; Neuritis; Paraproteinemias; Peripheral Nervous System Diseases

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

In peripheral neuropathies with monoclonal gammopathy, mainly IgM, it appears clear from clinical, electrophysiological, and experimental data, that the target glycolipid or glycolipid epitope for the IgM is related to the type of neuropathy--purely sensory, predominantly sensory, or uniquely motor. Investigations have focused on chronic peripheral neuropathies associated with polyclonal IgM reactivity to glycolipids. Although IgM anti-GM1 antibodies are present in normal controls, there is a subgroup of motor neuropathies with high titer anti-GM1 antibodies, mainly multifocal neuropathies with conduction blocks (MMNCB). Another subgroup of MMNCB may include IgM anti-SGPG antibodies that do not cross-react with MAG. The importance of the fine structure of the epitope has to be considered in view of the pathogenicity of the antibody. It may bear consequences on its binding properties on the neuronal surfaces and on its biological implications.

Topics: Autoantibodies; G(M1) Ganglioside; Glycolipids; Humans; Immunoglobulin M; Motor Neurons; Neural Conduction; Neurons, Afferent; Paraproteinemias; Peripheral Nervous System Diseases

Topics: Amyotrophic Lateral Sclerosis; Antibodies; Autoantibodies; Epitopes; G(M1) Ganglioside; Humans; Immunoglobulin A; Incidence; Intermediate Filaments; Motor Neurons; Nerve Tissue Proteins; Neuromuscular Diseases; Paraproteinemias

Antibodies to the ganglioside GM1 are associated with various forms of acute and chronic immune-mediated neuropathy, including Guillain-Barré syndrome (GBS) and multifocal motor neuropathy. In diagnostics and research, these antibodies are usually detected by GM1 preparations derived from bovine brain tissue, which are non-covalently attached to solid carriers such as enzyme-linked immunosorbent assay (ELISA) plates. Such brain-derived GM1 preparations are potentially contaminated with other glycolipids. In the current study, uncontaminated mono- and divalent synthetic analogs of the ganglioside GM1 were successfully attached via covalent bonds onto the surface of ELISA plates. The resulting modified diagnostic tool showed strong affinities and good specificities for binding of monoclonal mouse and human anti-GM1 antibodies and cholera toxin, as well as for the anti-GM1 antibodies in serum samples from neuropathy patients. While these proof-of-principle experiments reveal the potential of synthetic ganglioside mimics in diagnostics, they show the necessity of further studies to overcome certain limitations, specifically the non-specific interactions in the negative control assays with synthetic GM1.

Topics: Antibodies, Monoclonal; G(M1) Ganglioside; Guillain-Barre Syndrome; Humans; Molecular Mimicry; Paraproteinemias; Polyneuropathies

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

The authors report a newborn with motor neuropathy associated with anti-GM1 antibodies from an affected mother. This finding suggests that the disorder was due to transplacental transfer of pathogenic antibodies.

Topics: Adult; Antibody Specificity; Female; G(M1) Ganglioside; Humans; Immunity, Maternally-Acquired; Immunoglobulin G; Infant, Newborn; Isoantibodies; Maternal-Fetal Exchange; Motor Neuron Disease; Neural Conduction; Paraproteinemias; Pregnancy; Pregnancy Complications

Topics: Antibodies; Diaphragm; G(M1) Ganglioside; Humans; Male; Middle Aged; Paraproteinemias; Respiratory Paralysis

IgM, IgG, IgA, and IgG subclass anti-GM1, anti-GQ1b, and anti-asialo-GM1 (anti-GA1) antibodies, respectively, were investigated by ELISA in serum from neurological and other patients. Increased anti-GM1 occurred mostly in approximately 15-35% of the cases without statistical differences; high percentages were found in Guillain-Barré syndrome (GBS) preceded by gastrointestinal infection and multifocal motor neuropathy. Roughly, IgM anti-GM1 was most frequent; however, distinct IgG and IgA reactions were found i.a. in GBS. A particular IgM anti-mono- and disialoganglioside pattern occurred in a patient with sensorimotor neuropathy and paraproteinemia. Anti-GQ1b was elevated in all Miller-Fisher patients, with some prevalence of IgG2 among IgG subclasses. Cross-reactivity of anti-GQ1b was demonstrated with Campylobacter jejuni lipopolysaccharides. Increased anti-GM1 and/or anti-GA1 was more frequent in systemic lupus erythematosus with central nervous system involvement than without. Incidence of anti-GM1 and anti-GA1 in X-adrenoleukodystrophy was relatively high. Although anti-GSL antibodies seem to have limited diagnostic value, studies of isotypes, subclass patterns, and cross-reactivities may lead to further insight into the origin of (auto) immune responses and their immunepathogenetic role in disease.

Topics: Autoantibodies; Campylobacter Infections; Campylobacter jejuni; Enzyme-Linked Immunosorbent Assay; G(M1) Ganglioside; Gangliosides; Gastrointestinal Diseases; Humans; Immunoglobulin A; Immunoglobulin G; Immunoglobulin Isotypes; Immunoglobulin M; Lipopolysaccharides; Nervous System Diseases; Paraproteinemias; Polyradiculoneuropathy

We reviewed the clinical and electrophysiologic features of 36 patients with increased titers of IgM anti-GM1 antibodies. Mildly elevated titers of up to 3,200 were not associated with any particular clinical syndrome or disease. Clinically, 14 of 16 patients with highly elevated titers of 6,400 or higher had progressive weakness with lower motor neuron signs; six had active tendon reflexes and eight had absent reflexes, but none had definite upper motor neuron signs. Electrophysiologic studies showed spontaneous activity in all 14 patients, one or more motor conduction blocks in nine, slowed motor conductions in one, and normal conductions in four patients. None had abnormal sensory conductions. These patients presented with a syndrome that has features of, but is distinct from, both motor neuron disease and demyelinating neuropathy.

Topics: Adult; Aged; Antibodies; Electrophysiology; Female; G(M1) Ganglioside; Humans; Immunoglobulin M; Male; Middle Aged; Motor Activity; Motor Neuron Disease; Nervous System Diseases; Neural Conduction; Paraproteinemias; Reflex, Stretch

We tested monoclonal IgM anti-GM1 and asialo-GM1 antibodies from 6 patients with chronic motor neuropathies for binding to lipopolysaccharides (LPS) from three stains of Campylobacter jejuni. Four of the 6 patients showed strong reactivity with LPS from at least one of the three C. jejuni strains tested as shown by enzyme-linked immunosorbent assay or western blot. Preabsorption with GM1 or asialo-GM1, or blocking with cholera toxin, prevented antibody binding to LPS. These studies indicate that human anti-GM1 or anti-asialo-GM1 antibodies cross-react with LPS from certain strains of C. jejuni, and that bacterial LPS might provide antigenic stimuli for the activation of B cells expressing anti-GM1 antibodies.

Topics: Antibodies, Monoclonal; Arachis; Campylobacter jejuni; Cholera Toxin; Cross Reactions; Enzyme-Linked Immunosorbent Assay; G(M1) Ganglioside; Glycolipids; Humans; Immunoglobulin M; Lectins; Lipopolysaccharides; Motor Neuron Disease; Paraproteinemias; Peanut Agglutinin; Plant Lectins; Species Specificity

Six of 110 patients (5.5%) with forms of motor neuron disease had abnormal titers of GM1 antibodies of 1:1,600 or higher. Four others came with previously known high titers. Three patients with upper motor neuron (UMN) signs had titers of 1,600; those with probable or no UMN signs had higher titers. Nine patients had conduction block; six of them had abnormal antibody titers, four with 6,400 or higher. Therefore, patients with motor neuron disease and abnormal anti-GM1 titers may have UMN signs or conduction block.

Topics: Adult; Aged; Amyotrophic Lateral Sclerosis; Autoantibodies; Female; G(M1) Ganglioside; Humans; Male; Middle Aged; Motor Neuron Disease; Paraproteinemias

Analysis of monoclonal human Ig that occur in association with lymphoproliferative diseases has provided valuable information about antibody structure and idiotypes. We analyzed 940 human sera that contained monoclonal IgM proteins for their ability to bind to four carbohydrate epitopes. Ten sera bound asialo-GM1, five of these sera also bound GM1, 10 bound to 3-fucosyllactosamine (3-FL), and one each bound to levan and galactan. Although the antibody activity in each serum was associated with a single L chain isotype, both kappa and lambda isotypes were represented among the proteins that bound to asialo-GM1 and to 3-FL. Some antibodies against asialo-GM1 were highly specific for this compound, whereas others cross-reacted with the structurally related gangliosides GM1 and GD1b. The antibodies to asialo-GM1 also varied considerably in their ability to lyse liposomes that contain asialo GM1. An association of IgM mAb against gangliosides with peripheral neuropathies has been reported recently, but only one of five patients whose antibodies reacted with GM1 ganglioside had a neuropathy. The antibodies that bound 3-FL exhibited narrower specificity, and less than 10% cross reactivity was noted with structurally related carbohydrates. The frequency of monoclonal proteins that bound 3-FL and asialo-GM1, approximately 1:100 sera for each specificity, was surprisingly high in view of the fact that both of these epitopes are expressed in human tissues. We suggest that these antibodies may be poly-specific and/or that the subset of B lymphocytes that synthesizes these anti-carbohydrate antibodies undergoes malignant transformation more frequently than other B lymphocytes.

Topics: Antibodies, Monoclonal; Antibody Specificity; G(M1) Ganglioside; Glycolipids; Glycosphingolipids; Immunoglobulin M; Lewis X Antigen; Lymphoproliferative Disorders; Oligosaccharides; Paraproteinemias

It was previously reported that monoclonal IgM from two patients with gammopathy and neuropathy showed similar specificity by reacting with the same group of unidentified minor components in the ganglioside fractions of human nervous tissues (Ilyas, A. A., Quarles, R. H., Dalakas, M. C., and Brady, R. O. (1985) Proc. Natl. Acad. Sci. U. S. A. 82, 6697-6700). Enzymatic degradation, ion-exchange chromatography, and immunostaining of purified ganglioside standards on thin-layer chromatograms have now revealed that the antigenic glycolipids recognized by the IgM from these patients are gangliosides GalNAc beta 1-4Gal(3-2 alpha NeuAc)beta 1-4Glc beta 1-1Cer(GM2), GalNAc beta 1-4Gal(3-2 alpha NeuAc)beta 1-3GalNAc beta 1-4Gal beta 1-4Glc beta 1-1Cer (IV4GalNAcGM1b), and GalNAc beta 1-4Gal(3-2 alpha NeuAc)beta 1-3GalNAc beta 1-4 beta Gal(3-2 alpha NeuAc)beta 1-4Glc beta 1-1-Cer (IV4GalNAcGD1a). The monoclonal IgM appears to be reacting with the terminal [GalNAc beta 1-4Gal(3-2 alpha NeuAc)beta 1-] moiety shared by these three gangliosides and is a useful probe for detecting small amounts of GM2, IV4GalNAcGM1b, IV4GalNAcGD1a, and other gangliosides with the same terminal sugar configuration in tissues. Species distribution studies using the antibody revealed that GM2 is present in the brains and nerves of all species examined, while IV4GalNAcGM1b and IV4GalNAcGD1a exhibit some striking species specificity. GM2, but not IV4GalNAcGD1a, is enriched in purified myelin from human brain.

Topics: Animals; Antibodies, Monoclonal; beta-N-Acetylhexosaminidases; Brain Chemistry; Cats; Cattle; Chickens; Electrophoresis, Polyacrylamide Gel; Epitopes; G(M1) Ganglioside; G(M2) Ganglioside; Gangliosides; Guinea Pigs; Humans; Immunoglobulin M; Paraproteinemias; Peripheral Nervous System Diseases; Rabbits; Species Specificity; Subcellular Fractions

Topics: Animals; Antibody Specificity; Autoantibodies; Epitopes; G(M1) Ganglioside; Gangliosides; Humans; Immunoglobulin M; Mice; Mice, Inbred Strains; Motor Neurons; Neuromuscular Diseases; Paraproteinemias