Meeusen_2013_Neurogastroenterol.Motil_25_84

BACKGROUND: Autoimmune gastrointestinal dysmotility (AGID) is a limited form of dysautonomia. The only proven effector to date is IgG specific for ganglionic nicotinic-acetylcholine receptors containing alpha3 subunits [alpha3*- nicotinic acetylcholine receptor (nAChR)]. Rabbits immunized with recombinant alpha3-polypeptide produce alpha3*-nAChR autoantibodies, and profound AGID ensues. Human and rabbit alpha3*-nAChR-specific-IgGs induce transient hypomotility when injected into mice. Here, we describe success and problems encountered inducing gastrointestinal hypomotility in mice by active immunization.
METHODS: We repeatedly injected young adult mice of seven different strains susceptible to autoimmunity (spontaneous diabetes or neural antigen immunization-induced myasthenia gravis or encephalomyelitis) with: (i) alpha3-polypeptide, intradermally or (ii) live alpha3*-nAChR-expressing xenogeneic cells, intraperitoneally. We measured serum alpha3*-nAChR-IgG twice monthly, and terminally assessed blue dye gastrointestinal transit, total small intestinal alpha3*-nAChR content (radiochemically) and myenteric plexus neuron numbers (immunohistochemically, ileal-jejunal whole-mount preparations). KEY
RESULTS: Standard cutaneous inoculation with alpha3-polypeptide was minimally immunogenic, regardless of dose. Intraperitoneally injected live cells were potently immunogenic. Self-reactive alpha3*-nAChR-IgG was induced only by rodent immunogen; small intestinal transit slowing and enteric alpha3*-nAChR loss required high serum levels. Ganglionic neurons were not lost. CONCLUSIONS & INFERENCES: Autoimmune gastrointestinal dysmotility is inducible in mice by active immunization. Accompanying enteric alpha3*-nAChR reduction without neuronal death is consistent with an IgG-mediated rather than T cell-mediated pathogenesis, as is improvement of symptoms in patients receiving antibody-depleting therapies.