Nicotinic Acetylcholine Receptor Antibodies Research Articles

Home Noninvasive Ventilation in Myasthenia Gravis.

Noninvasive ventilation (NIV) plays an important role in avoiding endotracheal intubation during myasthenic crisis, yet there are few published data concerning long-term home NIV in stable out-patients with myasthenia gravis (MG). The aim of this study was to describe the prevalence of NIV in a cohort of subjects with stable MG and to analyze contributing factors that could predict the need of NIV. We performed a cross-sectional study that included subjects diagnosed with MG managed in the respiratory care unit over the previous year. Subjects underwent clinical analysis including demographic, clinical, and functional respiratory data. Of the 50 subjects included, 35 (70%) were positive for nicotinic acetylcholine receptor antibodies, and 68% had a diagnosis of generalized MG. Bulbar symptoms developed in 16 (32%), and 10 (20%) subjects needed long-term home NIV. The only variable predicting the need for long-term NIV was MG severity measured with Myasthenia Gravis Foundation of America (MGFA), mainly grades IIB (odds ratio 0.14 [95% CI 0.02-0.85], P = .03) and IIIB (odds ratio 0.02 [95% CI 0.01-0.34], P = .01). Home NIV was needed in a substantial percentage of medically stable subjects with MG, mainly in those with generalized type and with oropharyngeal and/or respiratory muscle involvement (MGFA grades IIB and IIIB).

Correlation of anti-γ/ε nicotinic acetylcholine receptor antibody levels with anti-desmoglein 1,3 antibody levels and disease severity in pemphigus vulgaris.

A role for nondesmoglein antigens in the pathogenesis of pemphigus vulgaris (PV) has been suggested in several studies. Acetylcholine receptors (AchR), are one of the most important groups of these antigens. However, the exact role of both antimuscarinic (m) and nicotinic (n) AchR antibodies (Abs) is still controversial. To evaluate anti-desmoglein (Dsg)1, Dsg 3 and anti-γ/ε nAchR Abs values in patients with PV before and 3months after rituximab (RTX) treatment, and to assess their correlation with disease severity. In total, 75 patients with PV (26 men, 49 women) who were planned to receive RTX were enrolled. Disease activity was assessed by using the Pemphigus Disease Area Index (PDAI). Using ELISA, anti-Dsg1,3 and anti-γ/ε nAchR Abs were determined at baseline and 3months after RTX treatment. At baseline, 53.33% patients had positive values for anti-Dsg1, 89.33% for anti-Dsg3 and 13.33% for anti-γ/ε nAchR Abs. All patients with positive anti-γ/ε nAchR Abs had the mucocutaneous phenotype. PDAI, anti-Dsg1,3 and anti-γ/ε nAchR values were dramatically decreased 3months after RTX infusion (P<0.001). There was a significant positive correlation between disease activity and anti-γ/ε nAchR values at baseline (P=0.04), whereas no significant correlation was observed between anti-Dsg1,3 and anti-γ/ε nAchR values at baseline and 3months after RTX infusion. The reduction in anti-γ/ε nAchR Abs with clinical improvement in this study may suggest a synergic role for anti-γ/ε nAchR Abs with anti-Dsg1,3 Abs, or it could be an epiphenomenon.

Ganglionic Antibody Level as a Predictor of Severity of Autonomic Failure

ObjectiveTo assess antibody level as a test of autonomic failure (AF) associated with ganglionic nicotinic acetylcholine receptor antibody (AChR-Ab) autoimmunity. Patients and MethodsWe searched the Mayo Clinic laboratory database of 926 ganglionic AChR-Ab–seropositive patients seen at our institution between October 1, 1997, and April 1, 2015, for initial level of 0.05 nmol/L or higher and contemporaneous autonomic reflex screen (standardized evaluation of adrenergic, cardiovagal, and sudomotor functions) from which Composite Autonomic Scoring Scale (CASS) scores could be calculated. ResultsOf 289 patients who met inclusion criteria, 163 (56.4%) were women, median age was 54 years (range, 10-87 years), median antibody level was 0.11 nmol/L (range, 0.05-22.10 nmol/L), and median CASS total score was 2.0 (range, 0-10). Using receiver operating characteristic curve analysis, a level above 0.40 nmol/L predicted severe AF (CASS score, ≥7) with 92% specificity and 56% sensitivity. For at least moderate AF (CASS score ≥4 and anhidrosis ≥25%), a level of at least 0.20 nmol/L had 80% specificity and 59% sensitivity. Levels below 0.20 nmol/L were not predictive of the presence or absence of AF. For predicting orthostatic hypotension, ganglionic AChR-Ab level had excellent specificity above 0.4 nmol/L but lacked sensitivity. Autoantibodies to additional targets were present in 61 patients (21.1%). ConclusionGanglionic AChR-Ab level of at least 0.40 nmol/L is a moderately sensitive and highly specific marker for severe AF, as is a level of at least 0.20 nmol/L for moderate AF if CASS score is coupled with anhidrosis of 25% or more, among patients with suspected ganglionic AChR-Ab autoimmune autonomic ganglionopathy. Antibody levels of less than 0.20 nmol/L have little clinical importance in the absence of clinical AF.

Spontaneous remission of localized myasthenia gravis manifested as megaesophagus in a dog

A 2.5-year-old male German shepherd-cross dog was admitted for progressively deteriorating regurgitations ofone-month duration. Physical examination was unremarkable, apart from a poor body condition; also, neurological examination did not reveal any abnormality. In thoracic survey radiographs, a generalized esophageal dilation, consistent with megaesophagus, was well visualized. An increased nicotinic acetylcholine receptor antibody titer confirmed the diagnosis of acquired focal myasthenia gravis expressed as megaesophagus in this patient. The only help offered to the dog was a modification of its feeding habits (upright position, small and frequent meals). Within two months of the initial admission and prior to institution of specific treatment for myasthenia gravis, the dog experienced spontaneous and complete clinical remission and remained healthy for the next two years, eating again the normal way, but unfortunately was lost to follow-up. The favourable outcome of megaesophagus due to localized myasthenia gravis is discussed accordingly.

Autoimmune Autonomic Ganglionopathy

To evaluate postganglionic autonomic and somatic nerve fiber involvement in a patient with chronic autoimmune autonomic ganglionopathy. Case report. Department of Neurological Sciences, University Federico II of Naples. A patient with a 16-year history of severe autonomic failure and a high nicotinic acetylcholine receptor antibody titer underwent an extensive laboratory evaluation. Evaluation of sympathetic and parasympathetic functions and sural nerve and skin biopsies. Clinical and laboratory evaluations showed the involvement of cardiovascular, pupillary, sudomotor, gastrointestinal, and bladder functions. Sudomotor function study and skin biopsy findings revealed postganglionic autonomic damage. Moreover, sural nerve and skin biopsy specimens provided clear evidence of somatic nerve fiber involvement. We demonstrated postganglionic autonomic damage that could be related to a prolonged and severe impaired synaptic transmission and we report, for the first time to our knowledge, a somatic nerve fiber involvement in autoimmune autonomic ganglionopathy.

Presynaptic Targeting of α4β2 Nicotinic Acetylcholine Receptors Is Regulated by Neurexin-1β

The mechanisms involved in the targeting of neuronal nicotinic acetylcholine receptors (AChRs), critical for their functional organization at neuronal synapses, are not well understood. We have identified a novel functional association between alpha4beta2 AChRs and the presynaptic cell adhesion molecule, neurexin-1beta. In non-neuronal tsA 201 cells, recombinant neurexin-1beta and mature alpha4beta2 AChRs form complexes. alpha4beta2 AChRs and neurexin-1beta also coimmunoprecipitate from rat brain lysates. When exogenous alpha4beta2 AChRs and neurexin-1beta are coexpressed in hippocampal neurons, they are robustly targeted to hemi-synapses formed between these neurons and cocultured tsA 201 cells expressing neuroligin-1, a postsynaptic binding partner of neurexin-1beta. The extent of synaptic targeting is significantly reduced in similar experiments using a mutant neurexin-1beta lacking the extracellular domain. Additionally, when alpha4beta2 AChRs, alpha7 AChRs, and neurexin-1beta are coexpressed in the same neuron, only the alpha4beta2 AChR colocalizes with neurexin-1beta at presynaptic terminals. Collectively, these data suggest that neurexin-1beta targets alpha4beta2 AChRs to presynaptic terminals, which mature by trans-synaptic interactions between neurexins and neuroligins. Interestingly, human neurexin-1 gene dysfunctions have been implicated in nicotine dependence and in autism spectrum disorders. Our results provide novel insights as to possible mechanisms by which dysfunctional neurexins, through downstream effects on alpha4beta2 AChRs, may contribute to the etiology of these neurological disorders.

Autoimmune myasthenia gravis and dysautonomia in a dog

A two-year-old male entire border collie dog was evaluated for a short history of mixed bowel diarrhoea, coughing, vomiting and stranguria. Physical examination revealed dyspnoea with increased ventral lung sounds and a flaccidly distended bladder. Neurological examination revealed poor pupillary light reflexes, an absent gag reflex and a poor anal tone. Thoracic radiography was consistent with megaoesophagus and aspiration pneumonia. Clinicopathological testing revealed an elevated muscular nicotinic acetylcholine receptor antibody titre. The dog was euthanased because of clinical deterioration. Cerebrospinal fluid (CSF) collected immediately post-mortem revealed macrophagic pleocytosis. Post-mortem histopathological examination was consistent with dysautonomia. This is the first report of coexisting autoimmune myasthenia gravis and dysautonomia in a non-human species. The concomitant diseases may suggest a common immunopathological aetiology.

Evaluating the suitability of nicotinic acetylcholine receptor antibodies for standard immunodetection procedures

Nicotinic acetylcholine receptors play important roles in numerous cognitive processes as well as in several debilitating central nervous system (CNS) disorders. In order to fully elucidate the diverse roles of nicotinic acetylcholine receptors in CNS function and dysfunction, a detailed knowledge of their cellular and subcellular localizations is essential. To date, methods to precisely localize nicotinic acetylcholine receptors in the CNS have predominantly relied on the use of anti-receptor subunit antibodies. Although data obtained by immunohistology and immunoblotting are generally in accordance with ligand binding studies, some discrepancies remain, in particular with electrophysiological findings. In this context, nicotinic acetylcholine receptor subunit-deficient mice should be ideal tools for testing the specificity of subunit-directed antibodies. Here, we used standard protocols for immunohistochemistry and western blotting to examine the antibodies raised against the alpha3-, alpha4-, alpha7-, beta2-, and beta4-nicotinic acetylcholine receptor subunits on brain tissues of the respective knock-out mice. Unexpectedly, for each of the antibodies tested, immunoreactivity was the same in wild-type and knock-out mice. These data imply that, under commonly used conditions, these antibodies are not suited for immunolocalization. Thus, particular caution should be exerted with regards to the experimental approach used to visualize nicotinic acetylcholine receptors in the brain.

Myasthenia Gravis, Thymoma, and Intestinal Pseudo-Obstruction

We report a 28-year-old man who presented with intestinal pseudo-obstruction as the initial manifestation of thymoma, myasthenia gravis, and dysautonomia. The patient's autoantibody profile was characteristic of this constellation of disorders, being positive for both muscle and ganglionic nicotinic acetylcholine receptor antibodies and striational antibody. Inflammatory cell infiltrates were found in the myenteric plexus of the stomach and small intestine. Review of 12 previously reported cases suggests that patients with both myasthenia gravis and dysautonomia in the context of thymoma respond poorly to therapy.

A limited epidemiological study of seropositive myasthenia gravis in Tayside.

Myasthenia gravis is an acquired disorder of the neuromuscular junction characterised by fatiguable weakness of the limbs, bulbar and facial muscles and may be complicated by respiratory muscle weakness and failure. One often confirms the diagnosis by a simple serological test looking for the presence of the nicotinic acetylcholine receptor antibody. However, seronegative myasthenia constitutes about 20% of cases and in the case of ocular myasthenia, only 50% will have the antibody. Therefore, the diagnosis can be less than straightforward especially if the patient presents with vague symptoms such as fatigue or presents to specialities other than neurology or ophthalmology. The fact that the diagnosis may prove to be challenging, compounded by the fact that the condition is relatively rare and that the antibody to the acetylcholine receptor is not always present, epidemiological data is often less than precise and indeed difficult to acquire. We felt it was necessary to try to establish the epidemiological data on seropositive myasthenia gravis in Tayside, (this has never been carried out) bearing in mind the above pitfalls, and see how the incidence compares with similar and previous studies.

Myasthenia gravis, thymoma, intestinal pseudo‐obstruction, and neuronal nicotinic acetylcholine receptor antibody

Intestinal pseudo-obstruction occurs rarely in patients with myasthenia gravis (MG) and thymoma. The etiology of the intestinal pseudo-obstruction remains to be elucidated, although an autoimmune mechanism is postulated. We present the first report of neuronal nicotinic acetylcholine receptor (AChR)–specific antibody in a patient with seropositive MG, malignant thymoma, and intestinal pseudo-obstruction. This finding provides evidence that intestinal pseudo-obstruction associated with thymoma and possibly other neoplasms may be related to antibodies against the neuronal nicotinic receptors at autonomic ganglia. © 1999 John Wiley & Sons, Inc. Muscle Nerve 22: 1600–1602, 1999

POST-TRAUMATIC UNILATERAL PTOSIS-FOOTBALL 388

HISTORY: A 17 year old Division I collegiate offensive lineman developed painless, partial left ptosis several hours after minor leftsided head trauma during a scrimmage. The finding-remitted overnight, only to recur as a complete ptosis during scrimmage the next morning. Thereafter, the ptosis fluctuated in severity, clearly worsening during heavy physical activity such as weight lifting. There were no other ophthalmologic, neurologic or general medical symptoms. Two years previous, he experienced transient diplopia for two days following an injury to the left temporal area during high school football practice. Two weeks later he developed painless, partial left ptosis for several weeks. A head CT was negative, the symptom remitted and he returned to play. PHYSICAL EXAMINATION: The detailed general and neurolgic examinations were normal except for the following: moderate obesity; left ptosis (palpebral fissures = 14mm OD. 9mm OS) without decrement on 1.5 min. sustained upgaze: positive left Cogan's lid twitch: no evidence of Horner's syndrome. DIFFERENTIAL DIAGNOSIS: Myasthenia Gravis Rare myasthenic-like response seen with low grade, slow growing periorbital neoplastic or vascular lesions involving nerves to the extraocular muscles. TEST AND RESULTS: Hb 133 g/l with normochromic, normocytic indices. CXR. SPEP, TFTs, nicotinic acetylcholine receptor antibodies, Tensilon test, IM Prostigmine test = normal or negative. Electrophysiologic studies: significant decremental response on 2-4 Hz repetitive nerve stimulation to left trapezius. FINAL/WORKING DIAGNOSIS: Myasthenia Gravis. TREATMENT: No contact. OK to exercise. Daily weight, BP. No response to oral mestinon. Transient decremental response of deltoids and neck flexors several hours after strenuous physical activity. Prednisone 60mg qod, with slow taper over months. Symptomatic remission within 6 weeks of starting prednisone. Should he play collegiate football in the future?

Differential adrenocortical responses to neural stimuli following intracerebroventricular injection of nicotinic acetylcholine receptor antibodies in rats

The aim of the present study was to investigate the involvement of central nervous system nicotinic receptors for acetylcholine in the adrenocortical responses to neural stimuli. Adult male rats received a daily intraventricular injection of partially purified nicotinic acetylcholine receptor antibodies (anti-AchR), obtained from a patient with myasthenia gravis, for 5 consecutive days. Control animals were treated similarly with immunoglobulins obtained from normal human serum. Blood samples were obtained under basal conditions or following photic, sciatic nerve stimulation, and acoustic stress. Treatment with anti-AchR increased basal ACTH and corticosterone levels (by approximately twofold) but inhibited the response to acoustic stress. The response to photic and sciatic nerve stimulation stress was not affected. This study demonstrated that nicotinic acetylcholine receptors may be differentially in volved in the mediation of adrenocortical responses to neural stimuli.

Monoclonal rat anti- Torpedo electroplax nicotinic acetylcholine receptor antibodies: Immunochemical characterization

The interaction of Torpedo california nicotinic acetylcholine receptor (nAcChoR) with three rat monoclonal antibodies (mcab) directed against nAcChoR (Gomez et al., 1979) was studied by use of four different radioimmunoassay protocols. Each mcab reacts poorly with formalin-fixed Staphylococcus aureus or S. aureus Protein A, which requires that an additional incubation with second antibody (goat anti-rat immunoglobulin G) is included in each radioimmunoassay paradigm. One mcab inhibits 125I-labeled α-bungarotoxin binding to nAcChoR, recognizes a subset of solubilized nAcChoR-toxin complexes, and shows higher titer against nAcChoR in the absence of toxin. Thus, it appears to be directed against nAcChoR antigenic determinants that at least partially overlap with toxin binding sites. Two other mcab react with nAcChoR in a toxin-independent manner. Receptor-mcab dissociation constants are less than 10 nM, according to each assay paradigm. Estimates of antibody titer or concentrations of antibody in stock hybridoma supernatants vary according to the assay used. This predictable result is attributed to differences in design and sensitivity of assay protocols. The data provide a basis for further utilization of monospecific antibodies as probes in characterization of nAcChoR structure and function.

Effect of intracerebroventricular injection of nicotinic acetylcholine receptor antibodies on ACTH, corticosterone and prolactin secretion in the male rat

The aim of the present study was to investigate the involvement of CNS nicotinic receptors for acetylcholine in the secretory activity of the hypothalamo-hypophyseal-adrenal axis and prolactin (PRL). Adult male rats received a daily intraventricular injection of partially purified nicotinic acetylcholine receptor antibodies (anti-AChR) obtained from a female patient with myasthenia gravis, for 5 consecutive days. Control animals were treated similarly with immunoglobulins obtained from a healthy woman. Blood samples were withdrawn either under basal conditions or following ether stress. Treatment with anti-AChR increased basal ACTH and corticosterone (CS) levels (by approximately two-fold) but completely inhibited the responses of these hormones and PRL to ether stress. In control animals, normal basal and stress-induced responses of ACTH, CS and PRL were observed. This study demonstrated the importance for nicotinic acetylcholine receptors in the mediation of basal and stress-induced adrenocortical activity as well as for the mediation of PRL secretion in response to stress.

Juvenile myasthenia gravis.

We studied 32 children with myasthenia gravis over a period of 12 years. The mean age at onset was 7.7 years. Presentation was ocular in 63% of patients. Another major disease in addition to myasthenia occurred in 44% of patients; a seizure disorder was the most commonly associated disease. Serum IgG antibody to nicotinic acetylcholine receptor was present in 53% of patients and did not correlate with severity of disease or treatment. Medical management was effective in 63%; thymectomy was effective in only 28%. We conclude that myasthenia gravis appears commonly before age 10 and is associated with the risk of some disease other than hyperthyroidism. Serum IgG nicotinic acetylcholine receptor antibody is present less frequently than in normal adults, and vigorous medical management should be attempted before thymectomy.