title: Potentiation of a functional autoantibody in narcolepsy by a cholinesterase inhibitor.
abstract: We have recently reported the presence of an immunoglobulin G (IgG) autoantibody (Ab) in patients with narcolepsy with cataplexy that abolishes spontaneous colonic migrating motor complexes (CMMCs) and increases smooth muscle tension and atropine-sensitive phasic contractions in a physiological assay of an isolated colon. In this study, we used the cholinesterase inhibitor, neostigmine, to explore the mechanism of the narcoleptic IgG-mediated disruption of enteric motor function in four patients with narcolepsy with cataplexy and to identify a pharmacological mimic of the Ab. Neostigmine potentiated the narcoleptic IgG-mediated increase in smooth muscle resting tension and phasic smooth muscle contractions by an atropine-sensitive mechanism but exerted no effect on resting tension in the presence of control IgG. Decreased frequency of CMMCs mediated by IgG with anti-M3R activity was reversed by neostigmine. Therefore, a challenge with a cholinesterase inhibitor improves the specificity of the CMMC assay for narcoleptic IgG. Tetrodotoxin (TTX), a neuronal sodium channel blocker, also abolished CMMCs and increased resting tone, and a similar potentiation was observed with neostigmine; thus, TTX is a mimic of the functional effects of the narcoleptic IgG in this bioassay. These findings provide a link to pharmacological studies of canine narcolepsy and are consistent with a functional blockade of both excitatory and inhibitory motor neurons by the narcoleptic Ab, similar to the TTX mimic, presumably by binding to an autoantigenic target expressed in both populations of neurons.
authors.affiliation: Department of Immunology, Allergy and Arthritis, Flinders Medical Centre and Flinders University, Adelaide, South Australia, Australia. michael.jackson@flinders.edu.au
authors.forename: Michael W
authors.initials: MW
authors.lastname: Jackson
authors.forename: Nicolas J
authors.initials: NJ
authors.lastname: Spencer
authors.forename: Joanne H
authors.initials: JH
authors.lastname: Reed
authors.forename: Anthony J F
authors.initials: AJ
authors.lastname: Smith
authors.forename: Tom P
authors.initials: TP
authors.lastname: Gordon
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D001285:Atropine; D001323:Autoantibodies / Q000502:physiology*; D016022:Case-Control Studies; D002800:Cholinesterase Inhibitors / Q000494:pharmacology*; D003106:Colon / Q000503:physiopathology; D017615:Enteric Nervous System / Q000503:physiopathology*; D005260:Female; D006801:Humans; D007074:Immunoglobulin G / Q000502:physiology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008875:Middle Aged; D018727:Muscarinic Antagonists; D009129:Muscle Tonus; D009130:Muscle, Smooth / Q000503:physiopathology; D016065:Myoelectric Complex, Migrating; D009290:Narcolepsy / Q000276:immunology / Q000503:physiopathology*; D009388:Neostigmine / Q000494:pharmacology*; D026941:Sodium Channel Blockers; D009435:Synaptic Transmission; D013779:Tetrodotoxin / Q000494:pharmacology; D055815:Young Adult
chemical_list: D001323:Autoantibodies; D002800:Cholinesterase Inhibitors; D007074:Immunoglobulin G; D018727:Muscarinic Antagonists; D026941:Sodium Channel Blockers; D009388:Neostigmine; D013779:Tetrodotoxin; D001285:Atropine