Lennon, Vanda A.

Antibodies specific for the neuronal ganglionic nicotinic acetylcholine receptor (nAChR) are found in high titer in serum of patients with subacute autonomic failure. This clinical disorder is known as autoimmune autonomic neuropathy (AAN). Rabbits immunized with a neuronal nAChR α3 subunit fusion protein produce ganglionic nAChR antibodies and develop autonomic failure (experimental AAN, or EAAN). We used quantitative measures of autonomic function to demonstrate that this animal model of neuronal nAChR autoimmunity recapitulates the cardinal autonomic features of AAN in humans. The severity of dysautonomia in the rabbit ranges from isolated cardiovagal impairment to severe panautonomic failure with fixed mydriasis, gastroparesis, dry eyes, impaired heart rate variability, hypotension, and low plasma catecholamines. The severity of autonomic failure correlates with serum antibody levels. Immunohistochemical staining of superior cervical ganglia and myenteric plexus neurons demonstrates intact presynaptic nerve terminals and intact postsynaptic neurons containing cytoplasmic nAChR, but lacking surface nAChR. These findings define the autonomic physiology and histopathology of this novel animal model and support the concept that AAN in humans is a disorder of ganglionic cholinergic synaptic transmission caused by ganglionic nAChR antibodies.

Abstract Purpose: Determine muscle and neuronal autoantibody frequencies in patients with thymoma, with and without paraneoplastic neurological accompaniments. Experimental Design: Analysis of IgG autoantibodies in stored serum collected between 1985 and 2003 from 201 patients with histologically diagnosed thymoma (including six with thymic carcinoma). Contemporary assays quantitated antibodies reactive with muscle and neuronal cation channels, muscle sarcomeric proteins and neuronal cytoplasmic, and nuclear proteins. Results: Neurological diagnoses included myasthenia gravis (MG), myositis, encephalitis, neuromuscular hyperexcitability, autonomic neuropathy, and subacute hearing loss, a previously unrecognized accompaniment of thymoma. Muscle acetylcholine receptor (AChR) binding antibodies were found in all patients with a diagnosis of MG. Muscle autoantibodies (AChR-binding, AChR-modulating, or striational) were also found in 59% of patients without any neurological disorder. One or more neuronal autoantibodies were found in 41% of patients without any neurological disorder, 43% of patients with MG only, and 78% of patients with other neurological disorders. Neuronal autoantibody specificities were, in descending order of frequency, as follows: glutamic acid decarboxylase, voltage-gated potassium channel, collapsin response-mediator protein-5, ganglionic AChR, and antineuronal nuclear antibody-type 1 (ANNA-1). Conclusions: Neuronal autoantibodies complement skeletal muscle autoantibodies as serological markers of thymoma in patients with and without clinical evidence of a neurological disorder. The high prevalence of glutamic acid decarboxylase autoantibody, not previously considered a paraneoplastic marker, justifies its consideration as a marker of thymoma-related neurological autoimmunity. Serological evaluation of a patient’s profile of neuronal and muscle autoantibodies may aid in preoperative identification of an indeterminate mediastinal mass.

Neuromyelitis optica (NMO) is an inflammatory demyelinating disease that selectively affects optic nerves and spinal cord. It is considered a severe variant of multiple sclerosis (MS), and frequently is misdiagnosed as MS, but prognosis and optimal treatments differ. A serum immunoglobulin G autoantibody (NMO-IgG) serves as a specific marker for NMO. Here we show that NMO-IgG binds selectively to the aquaporin-4 water channel, a component of the dystroglycan protein complex located in astrocytic foot processes at the blood-brain barrier. NMO may represent the first example of a novel class of autoimmune channelopathy.

ABSTRACT P/Q‐type voltage‐dependent calcium channel CACNA1A mutations cause dominantly inherited migraine, episodic ataxia, and cerebellar atrophy in humans and cause recessively inherited ataxia, episodic dyskinesia, cerebellar atrophy, and absence epilepsy in mice. The basis of these species differences and the disease mechanism(s) are not understood. To address this question and to identify required P/Q function in vivo , we created a germline Cacna1a null mutation (designated Cacna1a Fcrtm1 ) by gene targeting. Null mice develop dystonia and late‐onset cerebellar degeneration in a specific pattern. This indicates a requirement for P/Q function for survival in a subset of cerebellar neurons. Homozygous null mice completely lack P/Q‐type channel activity, and they also lack ω‐CTx‐MVIIC receptors, indicating that a single gene encodes P/Q channel activity. An increase of L‐and N‐type current densities is detected in P/Q‐null granule cells. Heterozygous Cacna1a Fcrtm1 /+ mice are phenotypically normal, despite having a 50% reduction in current density, indicating that reduced current density is not itself sufficient to cause the pathophysiology of spontaneous mouse mutants with ataxia and seizures.