Passive transfer of seronegative myasthenia gravis to mice

Burges, Judith; Vincent, Angela; Molenaar, Peter; Newsom‐Davis, John; Peers, Chris; Wray, Dennis

doi:10.1002/mus.880171208

Cited by 172 publications

(49 citation statements)

References 36 publications

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“…MuSK is essential for the development of the NMJ [51] but its role in adult muscle is less clear although it probably plays an important role in maintaining the structure of the postsynaptic membrane. [52] MuSK-MG often presents with ocular involvement, but frequently evolves to include severe bulbar and facial weakness, sometimes with marked muscle atrophy in these muscles.…”

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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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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“…Blood was collected, and serum was prepared at 0. 25,6,24,30,48,72,96,144,192, and 240 h after the injection. A specific ELISA was used to determine 1G3 and mIgG1 serum concentration as described in Materials and Methods.…”

Section: High Affinity Binding Of 1g3 To Rat Fcrn and Competition Formentioning

confidence: 99%

“…Up to 90% of MG patients have detectable Abs against AChR, whereas ϳ10 -15% of the patients are negative for anti-AChR Abs (seronegative MG; SNMG) (3,4). However, Igs from sera of SNMG patients bind to muscle cells that do not express AChR (5), and they induce reductions in miniature endplate potential amplitudes upon passive transfer to mice (6). Moreover, it has been shown that 47-70% of SNMG patients have serum IgG autoantibodies against the muscle-specific receptor tyrosine kinase.…”

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confidence: 99%

Amelioration of Experimental Autoimmune Myasthenia Gravis in Rats by Neonatal FcR Blockade

García

Santoro

et al. 2007

The Journal of Immunology

106

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The neonatal FcR (FcRn) plays a critical role in IgG homeostasis by protecting it from a lysosomal degradation pathway. It has been shown that IgG has an abnormally short half-life in FcRn-deficient mice and that FcRn blockade significantly increases the catabolism of serum IgG in mice. Therefore, reduction of serum IgG half-life may have therapeutic benefits in Ab-mediated autoimmune diseases. We have studied the therapeutic effects of an anti-rat FcRn mAb, 1G3, in two rat models of myasthenia gravis, a prototypical Ab-mediated autoimmune disease. Passive experimental autoimmune myasthenia gravis was induced by administration of an anti-acetylcholine receptor (AChR) mAb, and it was shown that treatment with 1G3 resulted in dose-dependent amelioration of the disease symptoms. In addition, the concentration of pathogenic Ab in the serum was reduced significantly. The effect of 1G3 was also studied in an active model of experimental autoimmune myasthenia gravis in which rats were immunized with AChR. Treatment with 1G3 significantly reduced the severity of the disease symptoms as well as the levels of total IgG and anti-AChR IgG relative to untreated animals. These data suggest that FcRn blockade may be an effective way to treat Ab-mediated autoimmune diseases.

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“…Les études menées dans les années 90 ont permis de confirmer que le facteur humoral est bien à l'origine de la myasthénie séronégative. Il faut notamment citer ici l'effet bénéfique des échanges plasmatiques dans ce groupe de patients ainsi que la présence de troubles de la transmission neuromusculaire chez la souris recevant du sérum de patients myasthéniques séronégatifs [6]. Deux hypothèses ont été émises pour expliquer ce phénomène de « séronégativité » : 1/ que la technique de radioimmunoprécipita-tion (RIPA) pourrait ne pas être suffisamment sensible pour détecter les anticorps anti-RACh à faible concentration et 2/ qu'il existerait peut-être d'autres anticorps impliqués dans la pathophysiologie de la myasthénie auto-immune.…”

Section: « Nouveaux Anticorps » : Physiopathologie Et Aspects Cliniquesunclassified

Myasthénie auto-immune séronégative

Catar¹,

Aubé-Nathier²,

Nadaj‐Pakleza³

2017

Med Sci (Paris)

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> La myasthénie est une maladie auto-immune avec, dans 80 % des cas, des anticorps dirigés contre le récepteur de l'acétylcholine (anti-RACh) positifs et deux formes cliniques distinctes, oculaire et généralisée. Les formes séronégatives sont relativement rares et cliniquement hétérogènes. Le diagnostic de la myasthénie séronégative reste souvent difficile, notamment pour les formes oculaires et est essentiellement basé sur une symptomatologie fluctuante caractéristique. La décou-verte des anticorps anti-RACh à faible affinité et des nouveaux anticorps comme les antiMuSK (dirigés contre le récepteur spécifique de la tyrosine kinase), les anti-LRP4 (dirigés contre la protéine 4 reliée au récepteur des lipoprotéines de faible densité), les antiagrine ou les anti-cortactine constitue un avancement considérable dans la compréhen-sion de la physiopathologie de la myasthénie. Selon le profil sérologique, il est possible de prévoir la gravité potentielle de la maladie, la réponse aux traitements et le risque de pathologie thymique associée. < Myasthénie auto-immune séronégativeOana Catar, Anne-Catherine Aubé-Nathier, Aleksandra Nadaj-Pakleza Diagnostic de la myasthénie séronégative En l'absence d'anticorps spécifiques (anti-RACh ou anti-MuSK), le diagnostic de la myasthénie séro-négative repose avant tout sur le tableau clinique caractéristique qui se manifeste essentiellement par une fatigabilité musculaire excessive à l'effort. La fluctuation des symptômes cliniques, le déficit moteur réversible et non systématisé constituent des éléments essentiels dans le diagnostic de la myasthénie ; diagnostic qui devrait encore être confirmé : -par la présence d'un défaut de transmission neuromusculaire mise en évidence par une étude électroneuromyographique (décré-ment significatif sur plusieurs couples nerf-muscles supérieur à 10 % ou allongement du « jitter » lors de l'étude en fibre unique) ; -et/ou par la réponse positive au traitement anticholinestéras-ique (test pharmacologique à l'édrophonium par voie intraveineuse ou traitement oral avec la pyridostigmine ou l'ambénonium) [1]. Il existe un intérêt à refaire le dosage des anticorps anti-RACh à distance du diagnostic de la myasthénie, notamment à 6-12 mois si le premier dosage a été négatif [2]. Par ailleurs, il est nécessaire de rechercher des arguments en faveur d'une coexistence avec une autre pathologie auto-immune ; la plus fréquente étant la dysthyroïdie [1,3]. Dans le diagnostic différentiel, il est essentiel de prendre en compte le syndrome myasthénique congénital à début tardif dont les manifestations cliniques peuvent être quasi identiques à celles observées dans la myasthénie auto-immune séronégative [4]. L'ensemble des éléments cliniques et paracliniques doit être analysé attentivement (Tableau I). Par conséquent, l'existence d'un ou de plusieurs éléments parmi les suivants doit faire penser au syndrome myasthénique congénital : -une amyotrophie et/ou un déficit musculaire permanent ; -des rétractions tendineuses ; -des antécédents familiaux de maladie neurom...

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Passive transfer of seronegative myasthenia gravis to mice

Cited by 172 publications

References 36 publications

Autoimmune disorders of the neuromuscular junction

Autoimmune disorders of the neuromuscular junction

Amelioration of Experimental Autoimmune Myasthenia Gravis in Rats by Neonatal FcR Blockade

Myasthénie auto-immune séronégative

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