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Immunization with neuronal nicotinic acetylcholine receptor induces neurological autoimmune disease
Vanda A. Lennon, … , Joseph H. Szurszewski, Steven Vernino
Vanda A. Lennon, … , Joseph H. Szurszewski, Steven Vernino
Published March 15, 2003
Citation Information: J Clin Invest. 2003;111(6):907-913. https://doi.org/10.1172/JCI17429.
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Article Autoimmunity

Immunization with neuronal nicotinic acetylcholine receptor induces neurological autoimmune disease

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Abstract

Neuronal nicotinic AChRs (nAChRs) are implicated in the pathogenesis of diverse neurological disorders and in the regulation of small-cell lung carcinoma growth. Twelve subunits have been identified in vertebrates, and mutations of one are recognized in a rare form of human epilepsy. Mice with genetically manipulated neuronal nAChR subunits exhibit behavioral or autonomic phenotypes. Here, we report the first model of an acquired neuronal nAChR disorder and evidence for its pertinence to paraneoplastic neurological autoimmunity. Rabbits immunized once with recombinant α3 subunit (residues 1–205) develop profound gastrointestinal hypomotility, dilated pupils with impaired light response, and grossly distended bladders. As in patients with idiopathic and paraneoplastic autoimmune autonomic neuropathy, the severity parallels serum levels of ganglionic nAChR autoantibody. Failure of neurotransmission through abdominal sympathetic ganglia, with retention of neuronal viability, confirms that the disorder is a postsynaptic channelopathy. In addition, we found ganglionic nAChR protein in small-cell carcinoma lines, identifying this cancer as a potential initiator of ganglionic nAChR autoimmunity. The data support our hypothesis that immune responses driven by distinct neuronal nAChR subtypes expressed in small-cell carcinomas account for several lung cancer–related paraneoplastic disorders affecting cholinergic systems, including autoimmune autonomic neuropathy, seizures, dementia, and movement disorders.

Authors

Vanda A. Lennon, Leonid G. Ermilov, Joseph H. Szurszewski, Steven Vernino

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Figure 1

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Clinical outcome of immunization parallels ganglionic nAChR antibody res...
Clinical outcome of immunization parallels ganglionic nAChR antibody response. (a) Serial levels of antibody in serum of 16 responder rabbits expressed for each individual as a percentage of the maximal attained level (mean 9.19 ± 1.84 nmol of [125I]epibatidine-complexed ganglionic nAChR bound per liter) and shown as means ± SEM of all normalized values. Two rabbits of 18 challenged with α3-GST protein remained seronegative. (b) Average daily food intake (± SEM) in rabbits producing ganglionic nAChR antibody and controls. Filled diamonds represent five responder rabbits immunized with α3-GST fusion protein, and open circles represent six rabbits immunized with a control GST protein. (c) Serial weight changes in α3-GST responder and nonresponder rabbits. Filled diamonds represent 16 rabbits producing ganglionic nAChR antibody, open circles represent 12 control rabbits (6 immunized with control GST fusion protein and 6 with adjuvant only), and open diamonds represent 2 individual rabbits that remained seronegative after α3-GST inoculation.
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