An autoantibody in narcolepsy disrupts colonic migrating motor complexes.
Despite strong circumstantial evidence for the autoimmune hypothesis of narcolepsy, conventional immunological methods have failed to detect an autoantibody. This study investigated the real-time effects of narcoleptic immunoglobulins on a spontaneous colonic migrating motor complex (CMMC) preparation. IgG from patients with narcolepsy with cataplexy or healthy controls was added directly to isolated mouse colons undergoing CMMC activity to test for autoantibodies that disrupt colonic motility. The effect of immunoglobulins prepared for clinical intravenous treatment (IVIg) on autoantibody-mediated colonic disruption was also assessed. Narcoleptic IgGs markedly reduced the frequency of CMMCs or irreversibly abolished them. Abrogation of CMMCs was followed by an increase in the resting tension of the colon preparation and appearance of atropine-sensitive phasic smooth muscle contractions. IVIg partially neutralized the inhibitory effect of narcoleptic IgG on the CMMCs. The dramatic effect of narcoleptic IgG on CMMC generation is consistent with an autoantibody-mediated disruption of enteric neural pathways. The ex vivo whole-organ approach allows real-time examination of the physiological effects of the narcoleptic autoantibody and offers a new avenue for exploring the autoimmune basis of narcolepsy. The neutralizing effect of IVIg on the autoantibody provides a rationale for the reported clinical improvement in cataplexy when IVIg are given at disease onset.
Jackson
Michael W
MW
Department of Immunology, Autoimmunity Research Laboratory, Flinders Medical Centre and Flinders University, Adelaide, South Australia, Australia. michael.jackson@flinders.edu.au
Reed
Joanne H
JH
Smith
Anthony J F
AJ
Gordon
Tom P
TP
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D001285:Atropine / Q000494:pharmacology; D001323:Autoantibodies / Q000276:immunology* / Q000633:toxicity; D003106:Colon / Q000187:drug effects / Q000276:immunology* / Q000503:physiopathology*; D004347:Drug Interactions / Q000276:immunology; D017615:Enteric Nervous System / Q000187:drug effects / Q000276:immunology / Q000503:physiopathology; D005260:Female; D006801:Humans; D007136:Immunoglobulins / Q000276:immunology / Q000633:toxicity; D016756:Immunoglobulins, Intravenous / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008875:Middle Aged; D018727:Muscarinic Antagonists / Q000494:pharmacology; D009119:Muscle Contraction / Q000187:drug effects / Q000276:immunology; D009130:Muscle, Smooth / Q000187:drug effects / Q000276:immunology / Q000503:physiopathology; D009290:Narcolepsy / Q000188:drug therapy / Q000276:immunology* / Q000503:physiopathology; D009469:Neuromuscular Junction / Q000187:drug effects / Q000276:immunology / Q000503:physiopathology; D010528:Peristalsis / Q000187:drug effects / Q000276:immunology*; D055815:Young Adult
D001323:Autoantibodies; D007136:Immunoglobulins; D016756:Immunoglobulins, Intravenous; D018727:Muscarinic Antagonists; D001285:Atropine