title: Anti-ganglioside antibodies can bind peripheral nerve nodes of Ranvier and activate the complement cascade without inducing acute conduction block in vitro.
abstract: The neurophysiological effects of nine neuropathy-associated human anti-ganglioside antisera, three monoclonal antibodies to ganglioside GM1 (GM1) and of the cholera toxin B subunit (a GM1 ligand) were studied on mouse sciatic nerve in vitro. GM1 antisera and monoclonal antibodies from patients with chronic motor neuropathies and Guillain-Barre syndrome, and GQ1b/ disialosyl antisera and monoclonal antibodies from patients with chronic ataxic neuropathies and Miller Fisher syndrome were studied. In vitro recording, for up to 6 h, of compound nerve action potentials, latencies, rise times and stimulus thresholds from isolated desheathed sciatic nerve was performed in the presence of antiganglioside antibodies and fresh human serum as an additional source of complement. No changes were observed over this time course, with 4-6 h values for all electrophysiological parameters being within 15% of the starting values for both normal and antibody containing sera and for the cholera toxin B subunit. Parallel experiments on identically prepared desheathed nerves performed with 0.5 nM saxitoxin led to complete conduction block within 10 min of application. Under identical conditions to those used for electrophysiological recordings, quantitative immunohistological evaluation revealed a significant increase in IgM (immunoglobulin M) deposition at nodes of Ranvier from 5.3+/-3.1% to 28.7+/-8.4% (mean+/-SEM) of desheathed nerves exposed to three normal and three antibody containing sera, respectively (P < 0.03). Complement activation was seen at 100% of normal and 79% of disease-associated IgM positive nodes of Ranvier. These data indicate that anti-ganglioside antibodies can diffuse into a desheathed nerve, bind to nodes of Ranvier and fix complement in vitro without resulting in any overt physiological deterioration of the nerve over 4-6 h. This suggests that the node of Ranvier is relatively resistant to acute antiganglioside antibody mediated injury over this time scale and that anti-ganglioside antibodies and the cholera toxin B subunit are unlikely to have major direct pharmacological effects on nodal function, at least in comparison with the effect of saxitoxin. This in vitro sciatic nerve model appears of limited use for analysing electrophysiologically the effects of anti-ganglioside antibodies on nerve function, possibly because its short-term viability and isolation from circulating systemic factors do not permit the evolution of an inflammatory lesion of sufficient magnitude to induce overt electrophysiological abnormalities. In vivo models may be more suitable for identifying the effects of these antibodies on nerve conduction.
authors.affiliation: University Department of Neurology, Institute of Neurological Sciences, Southern General Hospital, Glasgow, Scotland, UK.
authors.forename: K
authors.initials: K
authors.lastname: Paparounas
authors.forename: G M
authors.initials: GM
authors.lastname: O'Hanlon
authors.forename: C P
authors.initials: CP
authors.lastname: O'Leary
authors.forename: E G
authors.initials: EG
authors.lastname: Rowan
authors.forename: H J
authors.initials: HJ
authors.lastname: Willison
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal; D000937:Antigen-Antibody Reactions; D003167:Complement Activation; D005455:Fluorescent Antibody Technique; D005677:G(M1) Ganglioside / Q000276:immunology; D005732:Gangliosides / Q000276:immunology*; D006801:Humans; D007136:Immunoglobulins / Q000097:blood; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009186:Myelin Sheath / Q000187:drug effects / Q000276:immunology; D009407:Nerve Block; D011901:Ranvier's Nodes / Q000276:immunology*; D012530:Saxitoxin / Q000494:pharmacology; D012584:Sciatic Nerve / Q000276:immunology* / Q000648:ultrastructure
chemical_list: D000911:Antibodies, Monoclonal; D005732:Gangliosides; D007136:Immunoglobulins; D012530:Saxitoxin; D005677:G(M1) Ganglioside