Immunization with neuronal nicotinic acetylcholine receptor induces neurological autoimmune disease

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

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)907-913
Number of pages7
JournalJournal of Clinical Investigation
Volume111
Issue number6
DOIs
StatePublished - Mar 2003

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Small Cell Carcinoma
Nicotinic Receptors
Autoimmunity
Autoimmune Diseases
Immunization
Epilepsy
Channelopathies
Sympathetic Ganglia
Small Cell Lung Carcinoma
Movement Disorders
Pupil
Nervous System Diseases
Synaptic Transmission
Autoantibodies
Cholinergic Agents
Dementia
Vertebrates
Lung Neoplasms
Urinary Bladder
Rabbits

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Immunization with neuronal nicotinic acetylcholine receptor induces neurological autoimmune disease. / Lennon, Vanda A.; Ermilov, Leonid G.; Szurszewski, Joseph H.; Vernino, Sreven.

In: Journal of Clinical Investigation, Vol. 111, No. 6, 03.2003, p. 907-913.

Research output: Contribution to journalArticle

Lennon, Vanda A. ; Ermilov, Leonid G. ; Szurszewski, Joseph H. ; Vernino, Sreven. / Immunization with neuronal nicotinic acetylcholine receptor induces neurological autoimmune disease. In: Journal of Clinical Investigation. 2003 ; Vol. 111, No. 6. pp. 907-913.
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