Patients with autoimmune autonomic neuropathy (AAN) classically have rapid onset of complete autonomic failure. Less severe forms of AAN occur frequently but are currently under recognized. To prove that AAN is an antibody-mediated disorder of neuronal synaptic transmission, we have developed a robust animal model, experimental autoimmune autonomic neuropathy (EAAN), by inducing autoimmunity against the neuronal ganglionic acetylcholine receptor in rabbits. The animal model develops predictably within two months and recapitulates the phenotype of the human disease. EAAN is the first disease-relevant chronic model of an antibody-mediated disorder of neuronal synaptic transmission. The objective of this project is to test the hypothesis that EAAN begins as a reversible autonomic ganglionopathy followed by a gradual, selective loss of postganglionic autonomic neurons. ? ? The specific aims are to 1) define the temporal pathophysiological profile of EAAN, 2) identify physiological features of EAAN that could be useful diagnostically in humans, and 3) evaluate hypothesis based treatment strategies through controlled treatment trials in the animal model. The first part of the project is a detailed physiological and pharmacological characterization of EAAN correlated with histological changes as they evolve over time. Quantitative pupillometry and telemetry recording of blood pressure and heart rate will be used to evaluate autonomic function and to pharmacologically dissect autonomic deficits. Histological studies of sympathetic and parasympathetic ganglia will include immunohistochemistry and electron microscopy to define the structure of the ganglionic synapse. The goal is an accurate definition of the pathophysiological evolution of this disorder and a correlation of physiology with histopathology. These translational studies will provide insight into disease mechanisms, identify characteristic features to improve clinical diagnosis, and provide rationale for new treatment strategies. In the final year of the project, controlled therapeutic trials that would be impractical in patients will be performed in EAAN rabbits. ? ? In additional to its clinical significance, this project is relevant to understanding ganglionic synaptic transmission, neurological autoimmunity, pathophysiology of acquired dysautonomia, the recuperative and adaptive capabilities of ganglionic transmission and the vulnerability of neurons to autoimmune attack. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
1R01NS048077-01
Application #
6754332
Study Section
Special Emphasis Panel (ZRG1-CNBT (01))
Program Officer
Utz, Ursula
Project Start
2004-02-01
Project End
2004-08-31
Budget Start
2004-02-01
Budget End
2004-08-31
Support Year
1
Fiscal Year
2004
Total Cost
$27,258
Indirect Cost
Name
Mayo Clinic, Rochester
Department
Type
DUNS #
006471700
City
Rochester
State
MN
Country
United States
Zip Code
55905
Tajzoy, Emil; Mukherjee, Shalini; Vernino, Steven (2011) Autonomic ganglia neuronal density and synaptic structure in chronic experimental autoimmune autonomic ganglionopathy. Arch Neurol 68:540-1
Vernino, Steven; Hopkins, Steve; Wang, Zhengbei (2009) Autonomic ganglia, acetylcholine receptor antibodies, and autoimmune ganglionopathy. Auton Neurosci 146:3-7
Vernino, Steven; Lindstrom, Jon; Hopkins, Steve et al. (2008) Characterization of ganglionic acetylcholine receptor autoantibodies. J Neuroimmunol 197:63-9
Vernino, Steven (2008) Neuronal acetylcholine receptor autoimmunity. Ann N Y Acad Sci 1132:124-8
Vernino, Steven; Sandroni, Paola; Singer, Wolfgang et al. (2008) Invited Article: Autonomic ganglia: target and novel therapeutic tool. Neurology 70:1926-32
Mukherjee, Shalini; Vernino, Steven (2007) Dysfunction of the pupillary light reflex in experimental autoimmune autonomic ganglionopathy. Auton Neurosci 137:19-26
Wang, Z; Low, P A; Jordan, J et al. (2007) Autoimmune autonomic ganglionopathy: IgG effects on ganglionic acetylcholine receptor current. Neurology 68:1917-21
Vernino, Steven (2007) Autoimmune and paraneoplastic channelopathies. Neurotherapeutics 4:305-14
Vernino, Steven; Ermilov, Leonid G; Sha, Lei et al. (2004) Passive transfer of autoimmune autonomic neuropathy to mice. J Neurosci 24:7037-42