Gastrointestinal hypomotility with loss of enteric nicotinic acetylcholine receptors: active immunization model in mice.
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 α3 subunits [α3*- nicotinic acetylcholine receptor (nAChR)]. Rabbits immunized with recombinant α3-polypeptide produce α3*-nAChR autoantibodies, and profound AGID ensues. Human and rabbit α3*-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) α3-polypeptide, intradermally or (ii) live α3*-nAChR-expressing xenogeneic cells, intraperitoneally. We measured serum α3*-nAChR-IgG twice monthly, and terminally assessed blue dye gastrointestinal transit, total small intestinal α3*-nAChR content (radiochemically) and myenteric plexus neuron numbers (immunohistochemically, ileal-jejunal whole-mount preparations).


RESULTS
Standard cutaneous inoculation with α3-polypeptide was minimally immunogenic, regardless of dose. Intraperitoneally injected live cells were potently immunogenic. Self-reactive α3*-nAChR-IgG was induced only by rodent immunogen; small intestinal transit slowing and enteric α3*-nAChR loss required high serum levels. Ganglionic neurons were not lost.


CONCLUSIONS
Autoimmune gastrointestinal dysmotility is inducible in mice by active immunization. Accompanying enteric α3*-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.
Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905, USA.
J W
JW
Meeusen
K E
KE
Haselkorn
J P
JP
Fryer
T J
TJ
Kryzer
S J
SJ
Gibbons
Y
Y
Xiao
V A
VA
Lennon
D000818:Animals; D001323:Autoantibodies / Q000097:blood / Q000276:immunology; D001324:Autoantigens / Q000276:immunology; D001327:Autoimmune Diseases / Q000276:immunology* / Q000378:metabolism; D004195:Disease Models, Animal; D005772:Gastrointestinal Transit / Q000276:immunology; D006801:Humans; D007074:Immunoglobulin G; D051379:Mice; D009197:Myenteric Plexus / Q000276:immunology / Q000378:metabolism; D054969:Primary Dysautonomias / Q000276:immunology* / Q000378:metabolism; D011978:Receptors, Nicotinic / Q000276:immunology* / Q000378:metabolism; D014611:Vaccination
D001323:Autoantibodies; D001324:Autoantigens; D007074:Immunoglobulin G; D011978:Receptors, Nicotinic