Pre- and postsynaptic blockade of neuromuscular transmission by Miller-Fisher syndrome IgG at mouse motor nerve terminals.
Miller-Fisher syndrome, a variant of an acute inflammatory neuropathy is often associated with serum antibodies to the ganglioside GQ1b, but the pathogenic role of these antibodies and other serum factors is unclear. We here investigated the effect of highly purified immunoglobulin G (IgG) from patients with typical Miller-Fisher syndrome, recording quantal endplate currents by means of a perfused macro-patch-clamp electrode on hemidiaphragms of adult mice. The GQ1b-positive and the GQ1b-negative Miller-Fisher IgG as well as its monovalent Fab-fragments depressed evoked quantal release in a fast and fully reversible, concentration and voltage dependent manner. The time-course of quantal release was changed with the late releases becoming more frequent. The extent of depression of release followed a Michaelis-Menten kinetic and depended on the extracellular calcium concentration. In addition the amplitude of quanta was reduced postsynaptically. IgG and sera from healthy subjects had no effect. Our results indicate that in Miller-Fisher syndrome, IgG antibodies to an undetermined antigen depress the release process, most likely by interfering with the presynaptic Ca2+ inflow or by interacting with proteins of the exocytotic apparatus, and prevent the activation of postsynaptic channels. Antibodies thus seem to be one pathogenic factor for muscle weakness in Miller-Fisher syndrome and our findings may explain why muscle strength recovers rapidly after therapeutical plasmapheresis.
Buchwald
B
B
Physiologisches Institut der Technischen Universität München, Germany.
Weishaupt
A
A
Toyka
K V
KV
Dudel
J
J
D000818:Animals; D000937:Antigen-Antibody Reactions; D001323:Autoantibodies / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D007140:Immunoglobulin Fab Fragments / Q000494:pharmacology; D007074:Immunoglobulin G / Q000494:pharmacology*; D008564:Membrane Potentials / Q000502:physiology; D051379:Mice; D008807:Mice, Inbred BALB C; D019846:Miller Fisher Syndrome / Q000276:immunology*; D009046:Motor Neurons / Q000502:physiology*; D009469:Neuromuscular Junction / Q000276:immunology* / Q000378:metabolism; D018408:Patch-Clamp Techniques; D017729:Presynaptic Terminals / Q000276:immunology / Q000378:metabolism; D009435:Synaptic Transmission / Q000276:immunology*; D013997:Time Factors
D001323:Autoantibodies; D007140:Immunoglobulin Fab Fragments; D007074:Immunoglobulin G; D002118:Calcium