Immunization with neuronal nicotinic acetylcholine receptor induces neurological autoimmune disease

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.

Molecular outcomes of neuromyelitis optica (NMO)-IgG binding to aquaporin-4 in astrocytes

“…M1 and M23 cDNAs and stably transfected clones of HEK-293 were produced as described (2,4). DNA encoding AQP4 extracellular loop C was PCR amplified and cloned into pET 4T vector (Stratagene) to produce and purify GST-ECD-C fusion protein (26).…”

Neuronal nicotinic acetylcholine receptor expression and function on nonneuronal cells

“…Further, GluR3 has a granzyme B site at the autoimmune epitope. 81 Lennon et al 82 have suggested that immune responses generated against nAChR may also result in seizure and dementia.…”

Sudomotor dysfunction in autoimmune autonomic ganglionopathy

“…1 Ganglionic ␣3 nicotinic acetylcholine receptor (nAChR) antibodies are found in serum of about half of reported cases, correlate to disease severity, and have been shown to be pathogenic. [2][3][4][5][6][7] Accordingly, AAG has been shown to respond to immunotherapy with IV immunoglobulin, plasma exchange, and immunosuppressants. 8 It has been reported that 74% of ␣3 nAChR patients have clinically significant issues with thermoregulation including reduced sweating and heat intolerance.…”