1. ¹Autoimmunity Research Laboratory, Department of Immunology, Allergy and Arthritis, Flinders Medical Centre and Flinders University, Adelaide, South Australia, Australia
2. ²Center for Neuroscience, Department of Human Physiology, Flinders Medical Centre and Flinders University, Adelaide, South Australia, Australia

Correspondence: Dr MW Jackson, Department of Immunology, Allergy and Arthritis, Flinders University, GPO Box 2100, Adelaide, South Australia 5001, Australia. E-mail: michael.jackson@flinders.edu.au

Received 20 May 2009; Revised 24 August 2009; Accepted 26 August 2009; Published online 5 October 2009.

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.