Thymic myoid cells express high levels of muscle genes

Mesnard-Rouiller, Laurence; Bismuth, Jacky; Wakkach, Abdelilah; Poëa-Guyon, Sandrine; Berrih‐Aknin, Sonia

doi:10.1016/j.jneuroim.2003.11.013

Cited by 45 publications

(36 citation statements)

References 35 publications

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“…Moreover, in the thymic medulla, and sometimes surrounding or within the germinal centers, there are muscle-like myoid cells that express fetal AChR [42] and other muscle proteins. [43] It is known that the thymic cells can actively produce AChR antibody when cultured in vitro [44] and removal of the thymus results in a moderate fall in AChR antibody although the levels usually plateau out after some months; [45] nowadays most patients are also given immunosuppressive treatments. Further work on the thymic pathology has also shown that complement is activated on the abnormal epithelium, and on the myoid cells; it seems very likely that the AChRs expressed by these myoid cells initiate or maintain the immune response in early-onset MG. [46] A recent report describes some of the factors that control AChR expression in these cells.…”

Section: The Thymus In Myasthenia Gravismentioning

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: The Thymus In Myasthenia Gravismentioning

confidence: 99%

Autoimmune disorders of the neuromuscular junction

Lang

Vincent

2009

Current Opinion in Pharmacology

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“…The primers were purchased from Eurobio and the human sequences were previously described (34). For the mouse ␤-AChR, the sequences of the primer set used were: 5Ј-CAAGGCACCATGCTCAGC CTC and 5Ј-TCAGGAGCTACGAGAGGTCAT.…”

Section: Rt-pcrmentioning

confidence: 99%

“…AChR transcripts are detectable in TECs, although at a much lower level than in MITCs (34). We thus tested the effects of cytokines on the transcript levels of AChR subunits in these cells.…”

Section: Up-regulation Of Achr Expression Triggered By Cytokines In Tecsmentioning

confidence: 99%

“…We also investigated the effect of these cytokines on the mRNA expression of the other AChR subunits because TECs express mRNA for all AChR subunits (34). As IFN-␥ and TNF-␣ mixture was the most efficient for the up-regulation of AChR transcripts, we analyzed all the subunits using these conditions.…”

Section: Up-regulation Of Achr Expression Triggered By Cytokines In Tecsmentioning

confidence: 99%

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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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“…[10][11][12] They possess the antigenic characteristics of skeletal muscle cells and express MyoD, desmin, troponin T, rapsyn, utrophin and the acetylcholine receptor. [11][12][13] Under the term 'myoid cells', defining muscle-like cells, different cells have been described. In testis, myoid cells are involved in the contraction of seminiferous tubules.…”

Section: Introductionmentioning

confidence: 99%

Thymic myoid cells protect thymocytes from apoptosis and modulate their differentiation: implication of the ERK and Akt signaling pathways

Panse

Berrih‐Aknin

2005

Cell Death Differ

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Thymic myoid cells correspond to a muscle-like cell population present in the thymic medulla. They are well conserved throughout species evolution, but their biological role is not known. We demonstrated that myoid cells protected thymocytes from apoptosis as evidenced by a strong decrease of annexin-V-FITC positive thymocytes. This effect was (1) specific of myoid cells compared to thymic epithelial cells; (2) dependent on direct cell-to-cell contacts and (3) triggered rapidly after 2 h in cocultures. This protective phenomenon was due to the activation of prosurvival mechanisms. Indeed, myoid cells activated extracellular-regulated kinases (ERK1/2) and Akt in thymocytes. Myoid cells also influenced thymocyte maturation. We observed an increase in CD4 þ and a decrease in CD8 þ single positive (SP) thymocytes when cocultured with myoid cells, independently of a CD8 þ SP increased death or a CD4 þ SP overproliferation. Consequently, thymic myoid cells protect thymocytes from apoptosis and could also modulate their differentiation process.

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Thymic myoid cells express high levels of muscle genes

Cited by 45 publications

References 35 publications

Autoimmune disorders of the neuromuscular junction

Autoimmune disorders of the neuromuscular junction

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

Thymic myoid cells protect thymocytes from apoptosis and modulate their differentiation: implication of the ERK and Akt signaling pathways

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