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Ronald L Schnaar - One of the best experts on this subject based on the ideXlab platform.
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anti ganglioside antibody mediated neuronal cytotoxicity and its protection by intravenous immunoglobulin implications for immune neuropathies
Brain, 2004Co-Authors: Ronald L Schnaar, John W. Griffin, Gang Zhang, Pablo H H Lopez, C Y Li, Niraj R Mehta, Kazim A. SheikhAbstract:Antibodies against GD1a, GM1 and related Gangliosides are frequently present in patients with the motor variant of Guillain–Barre syndrome (GBS), and their pathological role in this variant of GBS is now widely accepted. However, two basic issues related to anti‐ganglioside antibody‐mediated neural injury are not completely resolved: (i) some anti‐ganglioside antibodies can cross‐react with glycoproteins and therefore the nature of antigens targeted by these antibodies is not well established; and (ii) although pathological studies suggest that complement activation occurs in GBS, experimental data for the role of complement remain inconclusive. To address these issues, we developed and characterized a simple anti‐ganglioside antibody‐mediated cytotoxicity assay. Our results demonstrate first, that both GBS sera containing anti‐ganglioside antibodies and monoclonal anti‐ganglioside antibodies cause neuronal cell lysis by targeting specific cell surface Gangliosides, and secondly, that this cell lysis is complement dependent. In this assay, the GD1a cell membrane pool appears to be more susceptible to anti‐ganglioside antibody‐mediated injury than the GM1 pool. Further, human intravenous immunoglobulin (IVIg), now a standard treatment for GBS, significantly decreased cytotoxicity in this assay. Our data indicate that the mechanisms of IVIg‐mediated protection in this assay include anti‐idiotypic antibodies and downregulation of complement activation. This simple cytotoxicity assay can potentially be used for screening of (i) pathogenic anti‐ganglioside antibodies in patients with immune‐mediated neuropathies; and (ii) new/experimental therapies to prevent anti‐ganglioside antibody‐mediated neural injury.
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An anti-ganglioside antibody-secreting hybridoma induces neuropathy in mice.
Annals of neurology, 2004Co-Authors: Kazim A. Sheikh, Ronald L Schnaar, Gang Zhang, Yanpin Gong, John W. GriffinAbstract:Immune responses against Gangliosides are strongly implicated in the pathogenesis of some variants of Guillain-Barre syndrome (GBS). For example, IgG antibodies against GM1, GD1a, and related Gangliosides are frequently present in patients with post-Campylobacter acute motor axonal neuropathy (AMAN) variant of GBS, and immunization of rabbits with GM1 has produced a model of AMAN. However, the role of anti-ganglioside antibodies in GBS continues to be debated because of lack of a passive transfer model. We recently have raised several monoclonal IgG anti-ganglioside antibodies. We passively transfer these antibodies by intraperitoneal hybridoma implantation and by systemic administration of purified anti-ganglioside antibodies in mice. Approximately half the animals implanted with an intraperitoneal clone of anti-ganglioside antibody-secreting hybridoma developed a patchy, predominantly axonal neuropathy affecting a small proportion of nerve fibers. In contrast to hybridoma implantation, passive transfer with systemically administered anti-ganglioside antibodies did not cause nerve fiber degeneration despite high titre circulating antibodies. Blood-nerve barrier studies indicate that animals implanted with hybridoma had leaky blood-nerve barrier compared to mice that received systemically administered anti-ganglioside antibodies. Our findings suggest that in addition to circulating antibodies, factors such as antibody accessibility and nerve fiber resistance to antibody-mediated injury play a role in the development of neuropathy.
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Gangliosides are functional nerve cell ligands for myelin associated glycoprotein mag an inhibitor of nerve regeneration
Proceedings of the National Academy of Sciences of the United States of America, 2002Co-Authors: Alka A Vyas, Himatkumar V Patel, Susan E Fromholt, Marija Hefferlauc, Kavita A Vyas, Jiyoung M Dang, Melitta Schachner, Ronald L SchnaarAbstract:Myelin-associated glycoprotein (MAG) binds to the nerve cell surface and inhibits nerve regeneration. The nerve cell surface ligand(s) for MAG are not established, although sialic acid-bearing glycans have been implicated. We identify the nerve cell surface Gangliosides GD1a and GT1b as specific functional ligands for MAG-mediated inhibition of neurite outgrowth from primary rat cerebellar granule neurons. MAG-mediated neurite outgrowth inhibition is attenuated by (i) neuraminidase treatment of the neurons; (ii) blocking neuronal ganglioside biosynthesis; (iii) genetically modifying the terminal structures of nerve cell surface Gangliosides; and (iv) adding highly specific IgG-class antiganglioside mAbs. Furthermore, neurite outgrowth inhibition is mimicked by highly multivalent clustering of GD1a or GT1b by using precomplexed antiganglioside Abs. These data implicate the nerve cell surface Gangliosides GD1a and GT1b as functional MAG ligands and suggest that the first step in MAG inhibition is multivalent ganglioside clustering.
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high affinity anti ganglioside igg antibodies raised in complex ganglioside knockout mice reexamination of gd1a immunolocalization
Journal of Neurochemistry, 2001Co-Authors: Michael P Lunn, Alka A Vyas, Susan E Fromholt, Ronald L Schnaar, John W. Griffin, Laurelle A Johnson, Saki Itonori, Jian Huang, James E K HildrethAbstract:Gangliosides, sialic acid-bearing glycosphingolipids, are highly enriched in the vertebrate nervous system. Anti-ganglioside antibodies are associated with various human neuropathies, although the pathogenicity of these antibodies remains unproven. Testing the pathogenic role of anti-ganglioside antibodies will be facilitated by developing high-affinity IgG-class complement-fixing monoclonal anti-bodies against major brain Gangliosides, a goal that has been difficult to achieve. In this study, mice lacking complex Gangliosides were used as immune-naive hosts to raise anti-ganglioside antibodies. Wild-type mice and knockout mice with a disrupted gene for GM2/GD2 synthase (UDP-N-acetyl-D-galactosamine : GM3/GD3 N-acetyl-D-glactosaminyltransferase) were immunized with GD1a conjugated to keyhole limpet hemocyanin. The knockout mice produced a vigorous anti-GD1a IgG response, whereas wildtype littermates failed to do so. Fusion of spleen cells from an immunized knockout mouse with myeloma cells yielded numerous IgG anti-GD1a antibody-producing colonies. Ganglioside binding studies revealed two specificity classes; one colony representing each class was cloned and characterized. High-affinity monoclonal antibody was produced by each hybridoma : an IgG1 that bound nearly exclusively to GD1a and an IgG2b that bound GD1a, GT1b, and GT1aalpha. Both antibodies readily readily detected Gangliosides via ELISA, TLC immune overlay, immunohistochemistry, and immunocytochemistry. In contrast to prior reports using anti-GD1a and anti-GT1b IgM class monoclonal antibodies, the new antibodies bound avidly to granule neurons in brain tissue sections and cell cultures. Mice lacking complex Gangliosides are improved hosts for raising high-affinity, high-titer anti-ganglioside IgG antibodies for probing for the distribution and physiology of Gangliosides and the pathophysiology of anti-ganglioside antibodies.
Elodie Masson - One of the best experts on this subject based on the ideXlab platform.
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ganglioside profiling of the human retina comparison with other ocular structures brain and plasma reveals tissue specificities
PLOS ONE, 2016Co-Authors: Estelle Sibille, Olivier Berdeaux, Lucy Martine, Alain M Bron, C Creuzotgarcher, G Thuret, Lionel Bretillon, Elodie MassonAbstract:Gangliosides make a wide family of glycosphingolipids, highly heterogeneous in both the ceramide moiety and the oligosaccharide chain. While ubiquitously expressed in mammalian tissues, they are particularly abundant in the brain and the peripheral nervous system. Gangliosides are known to play a crucial role in the development, maintenance and functional integrity of the nervous system. However, the expression and roles of Gangliosides in the retina, although often considered as a window on the brain, has been far less studied. We performed an in-depth analysis of Gangliosides of the human retina, especially using powerful LC/MS methods. We compared the pattern of ganglioside classes and ceramide molecular species of this tissue with other ocular structures and with brain and plasma in elderly human individuals. About a hundred of ganglioside molecular species among 15 distinct classes were detected illustrating the huge structural diversity of these compounds. The retina exhibited a very diverse ganglioside profile and shared several common features with the brain (prominence of tetraosylGangliosides, abundance of d20:1 long chain base and 18:0 fatty acid…). However, the retina stood out with the specific expression of GD3, GT3 and AcGT3, which further presented a peculiar molecular species distribution. The unique ganglioside pattern we observed in the human retina suggests that these ganglioside species play a specific role in the structure and function of this tissue. This lipidomic study, by highlighting retina specific ganglioside species, opens up novel research directions for a better understanding of the biological role of Gangliosides in the retina.
Toshio Ariga - One of the best experts on this subject based on the ideXlab platform.
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the pathogenic role of ganglioside metabolism in alzheimer s disease cholinergic neuron specific Gangliosides and neurogenesis
Molecular Neurobiology, 2017Co-Authors: Toshio ArigaAbstract:Alzheimer's disease (AD) is the most common type of dementia with clinical symptoms that include deficits in memory, judgment, thinking, and behavior. Gangliosides are present on the outer surface of plasma membranes and are especially abundant in the nervous tissues of vertebrates. Ganglioside metabolism, especially the cholinergic neuron-specific Gangliosides, GQ1bα and GT1aα, is altered in mouse model of AD and patients with AD. Thus, alterations in ganglioside metabolism may participate in several events related to the pathogenesis of AD. Increased expressions of GT1aα may reflect cholinergic neurogenesis. Most changes in ganglioside metabolism occur in the specific brain areas and their lipid rafts. Targeting ganglioside metabolism in lipid rafts may represent an underexploited opportunity to design novel therapeutic strategies for AD.
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characterization of blood group abo h active Gangliosides in type ab erythrocytes and structural analysis of type a active ganglioside variants in type a human erythrocytes
Biochimica et Biophysica Acta, 2001Co-Authors: Yasunori Kushi, Shinobu Watarai, Toshio Ariga, Motomasa Shimizu, Kiyohiro Watanabe, Takeshi Kasama, Shizuo HandaAbstract:Abstract Several monosialoGangliosides containing the type A-active epitope have been detected in type A erythrocytes on immunological analysis with a monoclonal antibody, and three of them were purified by repeated silica bead column chromatography and by scraping from the TLC plate. Two of these A-active Gangliosides were characterized by methylation analysis by GC/MS, negative SIMS, MALDI-TOF/MS, proton nuclear magnetic resonance spectroscopy, and immunological assays, and their structures were concluded to be as follows. A-active ganglioside I: Download : Download full-size image A-active ganglioside II: Download : Download full-size image The reactivity of the purified Gangliosides to the anti-A monoclonal antibodies (mAbs) exhibited enhancement after removal of the sialic acid. Therefore, the sialic residue has been shown to inhibit the binding to the terminal A-active epitope through the formation of an immune complex. To confirm the presence of A- (including S-A-I, -II and -III) and B-active Gangliosides, the reactivity of anti-A and -B mAbs were investigated using total Gangliosides from type A, -B and -AB erythrocytes on TLC plate. The results were that the Gangliosides from types A and AB showed positive reaction to anti-A mAbs, whereas in the anti-B mAbs binding the Gangliosides from types B and AB were positive. Thus, it revealed that A-active Gangliosides were present in type A and -AB, and B-active Gangliosides in types B and AB. As there was no difference in respective Gangliosides on type AB erythrocytes of 22 individuals, both A- and B-active Gangliosides are equally present in type AB erythrocytes. The biological significance of these A- and B-active ganglioside variants remains vague at present. As these molecules exhibit different reactivities to the anti-A mAbs, it is very likely that they can regulate the antigenicity of the A-epitope on the cell surface.
Ana Rodriguez - One of the best experts on this subject based on the ideXlab platform.
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Anti-ganglioside antibodies in patients with Zika virus infection-associated Guillain-Barré Syndrome in Brazil
PLoS neglected tropical diseases, 2019Co-Authors: Juan Rivera-correa, Isadora Cristina De Siqueira, Sabrina G. R. Mota, Mateus Santana Do Rosário, Pedro Antônio Pereira De Jesus, Luiz Carlos Junior Alcantara, Joel D. Ernst, Ana RodriguezAbstract:Zika virus infection is associated with the development of Guillain-Barre syndrome (GBS), a neurological autoimmune disorder caused by immune recognition of Gangliosides and other components at nerve membranes. Using a high-throughput ELISA, we have analyzed the anti-glycolipid antibody profile, including Gangliosides, of plasma samples from patients with Zika infections associated or not with GBS in Salvador, Brazil. We have observed that Zika patients that develop GBS present higher levels of anti-ganglioside antibodies when compared to Zika patients without GBS. We also observed that a broad repertoire of Gangliosides was targeted by both IgM and IgG anti-self antibodies in these patients. Since Zika virus infects neurons, which contain membrane Gangliosides, antigen presentation of these infected cells may trigger the observed autoimmune anti-ganglioside antibodies suggesting direct infection-induced autoantibodies as a cause leading to GBS development. Collectively, our results establish a link between anti-ganglioside antibodies and Zika-associated GBS in patients.
Norman Latov - One of the best experts on this subject based on the ideXlab platform.
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ganglioside reactive antibodies in the neuropathy associated with celiac disease
Journal of Neuroimmunology, 2002Co-Authors: Armin Alaedini, Peter H R Green, Howard W Sander, Arthur P Hays, Eugenia T Gamboa, Alessio Fasano, Michelle Sonnenberg, Linda D Lewis, Norman LatovAbstract:We tested patients with celiac disease (CD) for the presence of serum anti-ganglioside antibodies. Six of twenty-seven patient sera were reactive against brain Gangliosides by an agglutination immunoassay. Neurological examination in all six revealed the presence of distal sensory loss, consistent with the diagnosis of peripheral neuropathy. When tested by ELISA for antibodies to isolated GM1, GM2, GD1a, GD1b, GT1b, and GQ1b Gangliosides, all six were positive for IgG antibodies to at least one. The neuropathy of celiac disease may be autoimmune and associated with anti-ganglioside antibodies. The presence of IgG reactivity furthermore implicates a T cell-mediated response to ganglioside antigens.
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Detection of anti-ganglioside antibodies in Guillain-Barré syndrome and its variants by the agglutination assay.
Journal of the neurological sciences, 2002Co-Authors: Armin Alaedini, Chiara Briani, Itzhak Wirguin, Gabriele Siciliano, Carla D'avino, Norman LatovAbstract:Sera from 40 patients with Guillain-Barré syndrome (GBS), including the subtypes acute inflammatory demyelinating polyneuropathy (AIDP), acute motor axonal neuropathy (AMAN), acute motor and sensory axonal neuropathy (AMSAN), and Miller Fisher syndrome (MFS) were examined for the presence of anti-ganglioside antibodies using the ganglioside agglutination assay, and the enzyme-linked immunosorbent assay (ELISA). In the ELISA system, sera were tested for IgM and IgG antibodies to GM1, GM2, GD1a, GD1b, GT1b, and GQ1b Gangliosides. Antibodies to Gangliosides were detected in 21 (53%) of the GBS patients by agglutination assay and in 17 (43%) of the patients by ELISA. Some of the sera reacted with more than one ganglioside. Antibodies were not found in the control sera that were studied. The agglutination assay may be useful for rapid screening of GBS sera for antibodies to multiple Gangliosides.
