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The Journal of Neuroscience, August 11, 2004, 24(32):7037-7042; doi:10.1523/JNEUROSCI.1485-04.2004

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Neurobiology of Disease
Passive Transfer of Autoimmune Autonomic Neuropathy to Mice

Steven Vernino,¹ Leonid G. Ermilov,² Lei Sha,² Joseph H. Szurszewski,² Phillip A. Low,¹ and Vanda A. Lennon^1,3,4

Departments of ¹Neurology, ²Physiology and Biomedical Engineering, ³Immunology, and ⁴Laboratory Medicine and Pathology, Mayo Clinic College of Medicine, Rochester, Minnesota 55905

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 3 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.

Key words: neuronal nicotinic acetylcholine receptor; sympathetic; parasympathetic; gastrointestinal dysmotility; electrophysiology; pupil

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Received March 16, 2004; revised June 23, 2004; accepted June 23, 2004.

This article has been cited by other articles:

				C. H. Gibbons, S. A. Vernino, and R. Freeman Combined Immunomodulatory Therapy in Autoimmune Autonomic Ganglionopathy Arch Neurol, February 1, 2008; 65(2): 213 - 217. [Abstract] [Full Text] [PDF]

				Z. Wang, P. A. Low, J. Jordan, R. Freeman, C. H. Gibbons, C. Schroeder, P. Sandroni, and S. Vernino Autoimmune autonomic ganglionopathy: IgG effects on ganglionic acetylcholine receptor current Neurology, May 29, 2007; 68(22): 1917 - 1921. [Abstract] [Full Text] [PDF]

				A. McCampbell, D. Truong, D. C. Broom, A. Allchorne, K. Gable, R. G. Cutler, M. P. Mattson, C. J. Woolf, M. P. Frosch, J. M. Harmon, et al. Mutant SPTLC1 dominantly inhibits serine palmitoyltransferase activity in vivo and confers an age-dependent neuropathy Hum. Mol. Genet., November 15, 2005; 14(22): 3507 - 3521. [Abstract] [Full Text] [PDF]

				C. Schroeder, S. Vernino, A. L. Birkenfeld, J. Tank, K. Heusser, A. Lipp, T. Benter, C. Lindschau, R. Kettritz, F. C. Luft, et al. Plasma exchange for primary autoimmune autonomic failure. N. Engl. J. Med., October 13, 2005; 353(15): 1585 - 1590. [Abstract] [Full Text] [PDF]

				V. A. Lennon, T. J. Kryzer, S. J. Pittock, A.S. Verkman, and S. R. Hinson IgG marker of optic-spinal multiple sclerosis binds to the aquaporin-4 water channel J. Exp. Med., August 15, 2005; 202(4): 473 - 477. [Abstract] [Full Text] [PDF]

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