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.