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

Guyon, Thierry; Wakkach, Abdelilah; Poea, Sandrine; Mouly, Vincent; Klingel-Schmitt, Isabelle; Levasseur, P; Beeson, David; Asher, Orna; Tzartos, Socrates J.; Berrih‐Aknin, Sonia

doi:10.1172/jci1248

Cited by 62 publications

(44 citation statements)

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“…[32,33] Interestingly, there was an increase in synthesis rate of new AChRs [34] in these experiments and in MG muscle biopsies, there is an increase in expression of the AChR. [35] Probably the most important mechanism of AChR loss is complement-mediated destruction of the postsynaptic membrane. [36] The AChR antibodies are usually IgG1 or IgG which are both complement-activating subclasses.…”

Section: Mechanisms Of Diseasementioning

confidence: 60%

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: Mechanisms Of Diseasementioning

confidence: 60%

Autoimmune disorders of the neuromuscular junction

Lang

Vincent

2009

Current Opinion in Pharmacology

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“…Finally, it is important to underline that the consequences of the inflammatory activity are different in the thymus and the muscle. Although in both organs, they lead to up-regulation of AChR expression, this increase is detrimental in the thymus because it could contribute to the autoimmune response while the increase of AChR in the muscle could represent a beneficial compensatory mechanism as shown in the MG patients (51).…”

Section: Dual Effects Of Cytokines In the Thymus And The Musclementioning

confidence: 99%

Effects of Cytokines on Acetylcholine Receptor Expression: Implications for Myasthenia Gravis

Poëa-Guyon

Christadoss

Panse

et al. 2005

The Journal of Immunology

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Myasthenia gravis is an autoimmune disease associated with thymic pathologies, including hyperplasia. In this study, we investigated the processes that may lead to thymic overexpression of the triggering Ag, the acetylcholine receptor (AChR). Using microarray technology, we found that IFN-regulated genes are more highly expressed in these pathological thymic tissues compared with age- and sex-matched normal thymus controls. Therefore, we investigated whether proinflammatory cytokines could locally modify AChR expression in myoid and thymic epithelial cells. We found that AChR transcripts are up-regulated by IFN-γ, and even more so by IFN-γ and TNF-α, as assessed by real-time RT-PCR, with the α-AChR subunit being the most sensitive to this regulation. The expression of AChR protein was increased at the cytoplasmic level in thymic epithelial cells and at the membrane in myoid cells. To examine whether IFN-γ could influence AChR expression in vivo, we analyzed AChR transcripts in IFN-γ gene knock-out mice, and found a significant decrease in AChR transcript levels in the thymus but not in the muscle, compared with wild-type mice. However, up-regulation of AChR protein expression was found in the muscles of animals with myasthenic symptoms treated with TNF-α. Altogether, these results indicate that proinflammatory cytokines influence the expression of AChR in vitro and in vivo. Because proinflammatory cytokine activity is evidenced in the thymus of myasthenia gravis patients, it could influence AChR expression and thereby contribute to the initiation of the autoimmune anti-AChR response.

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“…Sabe-se que existe comprovadamente, nessa entidade patológica, alteração nos receptores pós-sinápticos, e evidências com experimentação com genes mutantes apontam para alterações nas subunidades a ou b, na dependência do tipo da síndrome miastênica. Interessante observar que a síntese da subunidade g não ocorre nesta doença auto-imune 12,13 . Como resposta às alterações nos receptores nicotínicos musculares, há nesses pacientes um aumento do número de moléculas de acetilcolina.…”

Section: Discussionunclassified

“…It is known that this pathology presents post-synaptic receptor changes, and evidences with mutant genes point to changes in a or b subunits depending on the type of myasthenic syndrome. It is interesting to observe that g subunit synthesis is not present in this auto-immune disease 12,13 . These patients have an increase in the number of acetylcholine molecules in response to changes in muscle nicotinic receptors.…”

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confidence: 99%