Detection and characterization of MuSK antibodies in seronegative myasthenia gravis

McConville, John; Farrugia, Maria Elena; Beeson, David; Kishore, Uday; Metcalfe, Richard; Newsom‐Davis, John; Vincent, Angela

doi:10.1002/ana.20061

Cited by 399 publications

(318 citation statements)

References 20 publications

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“…Transfer of purified IgG4 from MuSK MG patients into immune-deficient mice causes myasthenic weakness that mimics the pathophysiology of patients with MuSK MG (13). Thus, these autoantibodies exert their pathogenic effects independent of the immune system by binding to MuSK and interfering with normal neuromuscular physiology.…”

Section: Discussionmentioning

confidence: 99%

MuSK IgG4 autoantibodies cause myasthenia gravis by inhibiting binding between MuSK and Lrp4

Huijbers¹,

Zhang

Klooster³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

252

207

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Myasthenia gravis (MG) is a severely debilitating autoimmune disease that is due to a decrease in the efficiency of synaptic transmission at neuromuscular synapses. MG is caused by antibodies against postsynaptic proteins, including (i) acetylcholine receptors, the neurotransmitter receptor, (ii) muscle-specific kinase (MuSK), a receptor tyrosine kinase essential for the formation and maintenance of neuromuscular synapses, and (iii)

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Section: Discussionmentioning

confidence: 99%

MuSK IgG4 autoantibodies cause myasthenia gravis by inhibiting binding between MuSK and Lrp4

Huijbers¹,

Zhang

Klooster³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

252

207

View full text Add to dashboard Cite

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“…MuSK antibodies showed no decrease in AChR or evidence of antigen-antibody complex [39], although C3 is rarely detected at junctions of MuSK-positive patients [39,40]. MuSK antibodies have been identified as predominantly IgG 4 and do not activate complement [39,40].…”

Section: Autoantibodies In Mgmentioning

confidence: 98%

“…MuSK antibodies have been identified as predominantly IgG 4 and do not activate complement [39,40]. Animals immunized with MuSK epitopes demonstrate weakness and reduced AChR clustering [36,[41][42][43].…”

Section: Autoantibodies In Mgmentioning

confidence: 99%

Effect of complement and its regulation on myasthenia gravis pathogenesis

Kusner¹,

Kaminski²,

Šoltýs³

2008

Expert Review of Clinical Immunology

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Myasthenia gravis (MG) is primarily caused by antibodies directed towards the skeletal muscle acetylcholine receptor, leading to muscle weakness. Although these antibodies may induce compromise of neuromuscular transmission by blocking acetylcholine receptor function or antigenic modulation, the predominant mechanism of injury to the neuromuscular junction is complement-mediated lysis of the postsynaptic membrane. The vast majority of data to support the role of complement derives from experimentally acquired MG (EAMG). In this article, we review studies that demonstrate the central role of complement in EAMG and MG pathogenesis along with the emerging role of complement in T-and B-cell function, as well as the potential for complement inhibitor-based therapy to treat human MG.

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“…[46] Secondly, the disease is associated with HLA DR14-DQ5 [58] suggesting that the genetic susceptibility is very different from typical MG [ Table 1]. Moreover, the MuSK antibodies are mainly IgG4 [59] unlike the IgG1 and IgG3 of AChR antibodies. IgG4 is not a strong activator of complement and complement deposition was not found at MuSK NMJs in one study of limb muscle biopsies.…”

Section: Myasthenia Gravis With Muscle-speciþ C Kinase 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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Detection and characterization of MuSK antibodies in seronegative myasthenia gravis

Cited by 399 publications

References 20 publications

MuSK IgG4 autoantibodies cause myasthenia gravis by inhibiting binding between MuSK and Lrp4

MuSK IgG4 autoantibodies cause myasthenia gravis by inhibiting binding between MuSK and Lrp4

Effect of complement and its regulation on myasthenia gravis pathogenesis

Autoimmune disorders of the neuromuscular junction

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