Myasthenia Gravis Without Acetylcholine-Receptor Antibody: A Distinct Disease Entity

Mossman, Stuart; Vincent, Angela; Newsom‐Davis, John

doi:10.1016/s0140-6736(86)92259-2

Cited by 213 publications

(106 citation statements)

References 8 publications

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“…It has been established that altered nAChR function can modulate the electrical activity of muscle cells and could in turn increase nAChR gene expression via activation of second messengers such as Ca 2ϩ (66). As the impairment of electrical activity is clear in seronegative patients (67), the most likely hypothesis is that a muscle activity pathway is involved in the compensatory mechanism induced in seronegative MG muscles. However, we found that the monoclonal antibody directed against the MIR region part of the nAChR induced a loss of nAChR expression at the TE671 cell surface and human myotube membrane, which was then compensated for by an upregulation of nAChR messengers.…”

Section: Discussionmentioning

confidence: 99%

Regulation of acetylcholine receptor gene expression in human myasthenia gravis muscles. Evidences for a compensatory mechanism triggered by receptor loss.

Guyon

Wakkach²,

Poea³

et al. 1998

J. Clin. Invest.

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Myasthenia gravis (MG) is a neuromuscular disorder mediated by antibodies directed against the acetylcholine receptor (nAChR) resulting in a functional nAChR loss. To analyze the molecular mechanisms involved at the muscular target site, we studied the expression of nAChR subunits in muscle biopsy specimens from MG patients. By using quantitative PCR with an internal standard for each subunit, we found that the levels of ␤ -, ␦ -, and ⑀ -subunit mRNA coding for the adult nAChR were increased in severely affected MG patients, matching our previous data on the ␣ -subunit. Messenger levels were highly variable in MG patients but

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Section: Discussionmentioning

confidence: 99%

Regulation of acetylcholine receptor gene expression in human myasthenia gravis muscles. Evidences for a compensatory mechanism triggered by receptor loss.

Guyon

Wakkach²,

Poea³

et al. 1998

J. Clin. Invest.

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“…[50] A number of studies over many years have tried to define the nature of the antibodies in these patients.…”

Section: Myasthenia Gravis Without Acetylcholine Receptor Antibodiesmentioning

confidence: 99%

Autoimmune disorders of the neuromuscular junction

Lang

Vincent

2009

Current Opinion in Pharmacology

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The neuromuscular junction (NMJ) is a prototypic synapse although its structure is rather different from those of the central nervous system (CNS). The unmyelinated motor nerve terminals are separated from the postsynaptic membrane by a cleft that contains a basal lamina. This includes many proteins such as collagens, laminins, fibronectin and perlecan which help anchor some of the key elements involved in NMJ The neuromuscular junction (NMJ) is a specialized synapse with a complex structural and functional organization. It is a target for a variety of immunological disorders and these diseases usually respond well to immunotherapies. The understanding of the immunological basis of myasthenia gravis, the most common neuromuscular junction disorder, has improved in the recent years. Most patients have antibodies to the acetylcholine receptor (AChR), but around 10% have AChR antibodies that are only identified by novel methods, and up to 5% have muscle-speciÞ c kinase antibodies which deÞ ne a different subgroup of myasthenia. The spectrum of antibodies and their pathophysiological aspects are being elucidated. Even though less common, Lambert Eaton myasthenic syndrome (LEMS) is important to recognize. The abnormality in LEMS is a presynaptic failure to release enough packets of ACh, caused by antibodies to the presynaptic voltage-gated calcium channels. More than half these patients have a small cell carcinoma of lung. Acquired neuromyotonia (NMT) is a condition associated with muscle hyperactivity. Clinical features include muscle stiffness, cramps, myokymia, pseudomyotonia and weakness. The immune mechanisms of acquired NMT relate to loss of voltage-gated potassium channel function. This review will focus on the important recent developments in the immunemediated disorders of the NMJ.Key words: Gravis, Lambert Eaton myasthenic syndrome, neuromyotonia, neuromuscular junction, autoimmunity, acetylcholine receptor, voltage-gated channel development and function; for instance acetylcholine esterase (AChE) is localized via ColQ, a collagen-like molecule, to the basal lamina. Agrin and neuregulins, secreted from the nerve terminal, are bound by the basal lamina and interact with their receptors, playing an important role in the location of postsynaptic membrane proteins, voltage-gated calcium channels and the dystroglycans. The postsynaptic membrane at the NMJ forms a series of deep folds. The acetylcholine receptors (AChRs) are found at the top one-third of these folds, whereas the voltage-gated sodium channels are anchored at the bottom of the folds. The development of the NMJ is a fascinating area of research [1] and many of the proteins involved are relevant to disease ([ Figure 1] for a simple representation).The nerve action potential opens voltage-gated calcium channels (VGCCs) that are located in the motor nerve terminal [ Figure 1]. The resulting influx of calcium leads to the release of about 30 (in human muscle) individual packets of acetylcholine (ACh). Some of the ACh is hydrolysed by AChE but about 65%...

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“…These antibodies can be detected in the patients' sera with a radioimmunoassay, using human antigen labeled with 125 I␣-bungarotoxin (seropositive myasthenia gravis; SPMG) (Bartoccioni et al, 1980;Lindstrom, 1977). Anti-AChR antibody is not detected with this test in 15% to 20% of patients with generalized MG (seronegative myasthenia gravis; SNMG) (Evoli et al, 1989;Mossman et al, 1986). These SNMG patients frequently complain of severe prominent ocular and bulbar weakness, which shows an unsatisfactory response to oral anticholinesterases, although improving with plasmapheresis and immunosuppressive therapy (oculobulbar SNMG) ( Evoli et al, 1996).…”

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confidence: 99%

“…These SNMG patients frequently complain of severe prominent ocular and bulbar weakness, which shows an unsatisfactory response to oral anticholinesterases, although improving with plasmapheresis and immunosuppressive therapy (oculobulbar SNMG) ( Evoli et al, 1996). It has been shown that plasma or purified immunoglobulins from SNMG patients can transfer the neuromuscular transmission defect in mice (Burges et al, 1994;Mossman et al, 1986;Provenzano et al, 1988). Blaes and coworkers (2000) have shown that IgG from some SNMG patients bind to a surface antigen, distinct from the AChR, on the TE671 rhabdomyosarcoma cell line.…”

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confidence: 99%

Anti-P110 Autoantibodies Identify a Subtype of “Seronegative” Myasthenia Gravis with Prominent Oculobulbar Involvement

Scuderi

Marino

Colonna

et al. 2002

Laboratory Investigation

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SUMMARY:Myasthenia gravis (MG) is an autoimmune disease characterized by muscle weakness and pathogenetic autoantibodies directed against the nicotinic acetylcholine receptor (seropositive myasthenia gravis; SPMG). Nearly 15% to 20% of MG patients do not have these antibodies (seronegative myasthenia gravis; SNMG), but several evidence indicate that these patients have circulating pathogenic autoantibodies directed against other muscle antigens. Using the TE671 rhabdomyosarcoma cell line as an antigen source, we analyzed sera from 63 SNMG and 26 SPMG patients and 26 healthy blood donors by FACS analysis. We found that 40 of 63 SNMG patients and only 1 of 26 SPMG patients had IgG binding to the TE671 cell line. None of the sera bound to the unrelated MRC5 cell line. To identify the antigen, we analyzed sera immunoreactivity in more detail by immunoprecipitation of biotinylated membrane proteins from TE671 cells. When the immunoprecipitated proteins were separated by SDS-PAGE electrophoresis and then transferred to nitrocellulose membranes, we found that SNMG IgG identify a band corresponding to a protein with a molecular weight of 110 kDa (P110), which is not recognized by seropositive MG sera. This anti-P110 immunoreactivity is significantly associated with a distinct clinical picture characterized by a prominent involvement of ocular and bulbar muscles, with frequent respiratory problems (p Ͻ 0.005), and is recognized by a specific antimuscle specific kinase (MuSK) antiserum. In a recent article, the presence of anti-MuSK antibodies was described in SNMG. Our results confirm the presence of these antibodies in SNMG and suggest that anti-P110/MuSK autoantibodies identify a subtype of SNMG in which the different pathogenesis induces the distinct clinical picture. (Lab Invest 2002, 82:1139 -1146.

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Myasthenia Gravis Without Acetylcholine-Receptor Antibody: A Distinct Disease Entity

Cited by 213 publications

References 8 publications

Regulation of acetylcholine receptor gene expression in human myasthenia gravis muscles. Evidences for a compensatory mechanism triggered by receptor loss.

Regulation of acetylcholine receptor gene expression in human myasthenia gravis muscles. Evidences for a compensatory mechanism triggered by receptor loss.

Autoimmune disorders of the neuromuscular junction

Anti-P110 Autoantibodies Identify a Subtype of “Seronegative” Myasthenia Gravis with Prominent Oculobulbar Involvement

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