Passive transfer of autoimmune autonomic neuropathy to mice.
Autoimmune autonomic neuropathy (AAN) is an acquired, often severe, form of dysautonomia. Many patients with AAN have serum antibodies specific for the neuronal ganglionic nicotinic acetylcholine receptor (AChR). Rabbits immunized with a fusion protein corresponding to the N-terminal extracellular domain of the ganglionic AChR alpha3 subunit produce ganglionic AChR antibodies and develop signs of experimental AAN (EAAN) that recapitulate the cardinal autonomic features of AAN in man. We now demonstrate that EAAN is an antibody-mediated disorder by documenting sympathetic, parasympathetic, and enteric autonomic dysfunction in mice injected with rabbit IgG containing ganglionic AChR antibodies. Recipient mice develop transient gastrointestinal dysmotility, urinary retention, dilated pupils, reduced heart rate variability, and impaired catecholamine response to stress. The autonomic signs are associated with a reversible failure of nicotinic cholinergic synaptic transmission in superior mesenteric ganglia. Mice injected with IgG from two patients with AAN (of three tested) demonstrated a milder phenotype with evidence of urinary retention and gastrointestinal dysmotility. The demonstration that ganglionic AChR-specific IgG causes impaired autonomic synaptic transmission and autonomic failure in mice implicates an antibody-mediated pathogenesis for AAN. The antibody effect is potentially reversible, justifying early use of immunomodulatory therapy directed at lowering IgG levels and abrogating IgG production in patients with AAN.
Department of Neurology, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA. verns@mayo.edu
Steven
S
Vernino
Leonid G
LG
Ermilov
Lei
L
Sha
Joseph H
JH
Szurszewski
Phillip A
PA
Low
Vanda A
VA
Lennon
D000818:Animals; D001323:Autoantibodies / Q000276:immunology*; D001342:Autonomic Nervous System Diseases / Q000276:immunology*; D002395:Catecholamines / Q000097:blood; D004195:Disease Models, Animal; D005725:Ganglia, Autonomic / Q000503:physiopathology; D005769:Gastrointestinal Motility; D006339:Heart Rate; D006801:Humans; D007116:Immunization, Passive; D007074:Immunoglobulin G / Q000276:immunology; D066298:In Vitro Techniques; D008297:Male; D008643:Mesentery / Q000294:innervation; D051379:Mice; D008807:Mice, Inbred BALB C; D015877:Miosis / Q000503:physiopathology; D009444:Neuritis, Autoimmune, Experimental / Q000276:immunology* / Q000503:physiopathology; D011817:Rabbits; D011978:Receptors, Nicotinic / Q000235:genetics / Q000276:immunology; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000276:immunology; D009435:Synaptic Transmission; D016055:Urinary Retention / Q000276:immunology
D001323:Autoantibodies; D002395:Catecholamines; D007074:Immunoglobulin G; D011978:Receptors, Nicotinic; D011993:Recombinant Fusion Proteins