title: Concanavalin A inhibits pathophysiological effects of anti-ganglioside GQ1b antibodies at the mouse neuromuscular synapse.
abstract: Anti-GQ1b antibodies are present in the Miller Fisher syndrome (MFS), a monophasic neuropathy characterized by ataxia, areflexia, ophthalmoplegia, and sometimes cranial muscle weakness. We have previously shown, at the mouse neuromuscular junction (NMJ) ex vivo, that anti-GQ1b antibodies, through complement classic pathway activation, block synaptic transmission in a way that resembles the effect of the pore-forming alpha-latrotoxin (alphaLTx). In order to clarify the mechanism of these alphaLTx-like effects, including possible involvement of the alternative and mannose-binding protein complement pathways, we studied the effects of concanavalin A (ConA), a lectin known to block the action of alphaLTx, immunoglobulins, and early complement components. With electrophysiological, immunohistological, and bioassay experiments, we showed that the alphaLTx-like effects of anti-GQ1b antibody and complement were inhibited by pre- and coincubation with ConA. However, ConA was not able to inhibit evolution of alphaLTx-like effects when coincubated upon addition of complement at NMJs that had already bound anti-GQ1b antibody. Our data suggest that the mannose-binding protein pathway is not involved in the alphaLTx-like effect and that the inhibiting effect of ConA principally arises through interference with presynaptic binding of anti-GQ1b antibody. In control experiments, ConA prevented the neuroexocytotic effects of alphaLTx, indicating that alphaLTx receptors were inhibited under these conditions. We conclude that, although the physiological effects at the NMJ of anti-GQ1b antibody and alphaLTx are very similar, the activity of anti-GQ1b antibody is not mediated through activation of alphaLTx receptors, but rather is caused by direct presynaptic membrane damage through classic complement pathway activation.
authors.affiliation: Department of Neurology, Leiden University Medical Centre, Leiden, The Netherlands.
authors.forename: Roland W M
authors.initials: RW
authors.lastname: Bullens
authors.forename: Susan K
authors.initials: SK
authors.lastname: Halstead
authors.forename: Graham M
authors.initials: GM
authors.lastname: O'Hanlon
authors.forename: Jean
authors.initials: J
authors.lastname: Veitch
authors.forename: Peter C
authors.initials: PC
authors.lastname: Molenaar
authors.forename: Hugh J
authors.initials: HJ
authors.lastname: Willison
authors.forename: Jaap J
authors.initials: JJ
authors.lastname: Plomp
mesh_terms: D000818:Animals; D001323:Autoantibodies / Q000276:immunology / Q000633:toxicity*; D001665:Binding Sites / Q000187:drug effects / Q000276:immunology; D001667:Binding, Competitive / Q000187:drug effects / Q000276:immunology; D003165:Complement System Proteins / Q000276:immunology; D003208:Concanavalin A / Q000494:pharmacology*; D004195:Disease Models, Animal; D005732:Gangliosides / Q000276:immunology*; D008297:Male; D051379:Mice; D019846:Miller Fisher Syndrome / Q000276:immunology / Q000503:physiopathology*; D009469:Neuromuscular Junction / Q000187:drug effects / Q000276:immunology / Q000503:physiopathology*; D011485:Protein Binding / Q000187:drug effects / Q000276:immunology; D018000:Receptors, Peptide / Q000187:drug effects / Q000276:immunology; D013111:Spider Venoms / Q000494:pharmacology; D013570:Synaptic Membranes / Q000187:drug effects / Q000276:immunology; D009435:Synaptic Transmission / Q000187:drug effects / Q000276:immunology
chemical_list: D001323:Autoantibodies; D005732:Gangliosides; D018000:Receptors, Peptide; D013111:Spider Venoms; C034800:alpha-latrotoxin receptor; D003208:Concanavalin A; C020763:alpha-latrotoxin; C039129:GQ1b ganglioside; D003165:Complement System Proteins