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.

Anti-Tribbles Homolog 2 (TRIB2) Autoantibodies in Narcolepsy are Associated with Recent Onset of Cataplexy

“…27 Although narcolepsy is associated with HLA and TCRA polymorphisms, autoantibodies specific to HCRT cells have been difficult to detect reliably using immunocytochemistry, western blots and other assays. 16,28,29 Jackson et al 30 suggested the presence of autoantibodies interfering with colonic migrating contractions and bladder contractile responses using functional assays in animals, but this work awaits replication. The fact anti-TRIB2 antibodies are primarily found in recent onset cases, suggests the need for searching new autoimmune markers in this population.…”

Autoantibodies and Sjogren’s Syndrome: A Physiologist’s Perspective

“…Anti-M3R are not exclusive to Sjögren's syndrome, but also occur in Sceleroderma [67], dermatomyositis [105] and Narcolepsy [106][107][108]. The putative anti-M3R in the IgG fraction in these conditions appear functionally indistinguishable from those seen in Sjögren's syndrome.…”