scholarly journals Isolation and characterization of rare circulating autoantibody-producing cells from patients with muscle-specific kinase myasthenia gravis

2018 ◽  
Author(s):  
Kazushiro Takata ◽  
Panos Stathopoulos ◽  
Michelangelo Cao ◽  
Marina Mane-Damas ◽  
Miriam Fichtner ◽  
...  
Keyword(s):  
B Cells ◽  
Neuromuscular Junction ◽  
Tyrosine Kinase ◽  
Myasthenia Gravis ◽  
Neuromuscular Junctions ◽  
Ex Vivo ◽  
Autoimmune Disorder ◽  
C2c12 Myotubes ◽  
Isolation And Characterization ◽  
Achr Clustering

Myasthenia gravis (MG) is a chronic autoimmune disorder characterized by muscle weakness and caused by autoantibodies that bind to functional membrane proteins at the neuromuscular junction. Most patients have autoantibodies to the acetylcholine receptor (AChR), but a subset of patients instead have autoantibodies to muscle specific tyrosine kinase (MuSK). MuSK is an essential component of the Agrin/Lipoprotein receptor-related protein 4(LRP4)/MuSK/downstream of tyrosine kinase 7 (DOK7) pathway that is responsible for synaptic differentiation, including clustering of AChRs at the neuromuscular junction, both during development and in adult muscle. Nerve-released Agrin binds to LRP4 which then binds to MuSK, stimulating autophosphorylation and recruitment of DOK7 to complete the membrane component of the pathway. Serum-derived IgG4 subclass MuSK autoantibodies prevent the binding of LRP4 to MuSK, subsequently impairing autophosphorylation, resulting in the loss of Agrin-induced AChR clustering in the mouse myotube-forming C2C12 line. Although this autoimmune mechanism appears well understood, MuSK autoantibodies from patients are polyclonal. Most are IgG4 but IgG1, 2 and 3 are also present and can achieve similar results on AChR clustering. In addition, most bind the first Ig-like domain in MuSK, however some patients harbor serum autoantibodies that recognize other domains in MuSK. We sought to establish individual MuSK IgG clones so that the disease mechanisms could be better understood. We isolated MuSK autoantibody-expressing B cells from MuSK MG patients with a fluorescent-tagged MuSK antigen multimer and generated a panel of human monoclonal autoantibodies (mAbs) from these cells. We produced 77 mAbs from single B cells collected from six MuSK MG patients. Here we focused on three highly specific mAbs that bound quantitatively to MuSK in solution, to MuSK-expressing HEK cells and at mouse neuromuscular junctions where they co-localized with AChRs. These three IgG isotype mAbs (two IgG4 and one IgG3 subclass) recognized the Ig-like domain 2 of MuSK. The three MuSK mAbs inhibited Agrin induced-AChR clustering in C2C12 myotubes, but intriguingly, they enhanced rather than inhibited MuSK phosphorylation. This approach for ex vivo isolation of MuSK MG autoantibody-producing cells and production of human recombinant mAbs has identified distinct autoantibody specificities and likely divergent effector mechanisms. Collectively, these findings will enable a better understanding of MuSK autoantibody-mediated pathology.

scholarly journals Simultaneous Presence of Acetylcholine Receptor and Muscle Specific Tyrosine Kinase Antibodies in Myasthenia Gravis

2019 ◽  
Vol 4 (4) ◽  
pp. 128-130
Author(s):  
Maryam Poursadeghfard ◽  
Sara Azhdari
Keyword(s):  
Neuromuscular Junction ◽  
Tyrosine Kinase ◽  
Myasthenia Gravis ◽  
Acetylcholine Receptor ◽  
Receptor Tyrosine Kinase ◽  
Good Condition ◽  
Autoimmune Disorder ◽  
Simultaneous Presence ◽  
Specific Receptor ◽  
Progressive Course

Myasthenia gravis (MG) is known as an autoimmune disorder which affects transmission in neuromuscular junction. The serologic tests used for diagnosis include acetylcholine receptor and muscle specific receptor tyrosine kinase antibodies. Studies often have reported that patients with formal antibody are negative for the latter one. However, very limited studies have reported positive anti-muscle specific receptor tyrosine kinase antibody in a small percentage of patients with acetylcholine receptor antibody. Here, we reported a young woman who was diagnosed with MG and had a rapid and progressive course of the disease. She was seropositive for both acetylcholine receptor and muscle-specific receptor tyrosine kinase antibodies simultaneously. However, she discharged from the hospital with good condition after treatment.

Other Proven and Putative Autoimmune Disorders of the Peripheral Nervous System

2017 ◽  
Author(s):  
Doris G. Leung
Keyword(s):  
Neuromuscular Junction ◽  
Myasthenia Gravis ◽  
Nicotinic Acetylcholine Receptors ◽  
Acetylcholine Receptors ◽  
Autoimmune Disorder ◽  
Synaptic Proteins ◽  
Disease Treatment ◽  
Nicotinic Acetylcholine ◽  
System P ◽  
Presynaptic Calcium

Myasthenia gravis is in most cases an autoimmune disorder of the neuromuscular junction in which antibodies are directed at nicotinic acetylcholine receptors or other synaptic proteins, such as the MusK protein that is involved in the formation of the formation and maturation of the motor endplate. Less commonly, myasthenia gravis can result from antibodies directed to presynaptic calcium channels as a side effect of paraneoplastic antibodies (Lambert-Eaton syndrome) or from a developmental paucity of acetylcholine receptors in the neonatal form of the disease. Treatment is usually a combination of aceetylcoholinesterase inhibitors such as pyridostigmine to prolong the life of acetylcholine released at the neuromuscular junction and/or drugs such as corticosteroids aimed at reducing inflammation.

scholarly journals Muscle-Specific Tyrosine Kinase-Associated Myasthenia Gravis: A Neuromuscular Surprise

2021 ◽  
Vol 2021 ◽  
pp. 1-3
Author(s):  
Hassam Ali ◽  
Rahul Pamarthy ◽  
Nayab Ahsan ◽  
WashmaAwan ◽  
Shiza Sarfraz
Keyword(s):  
Neuromuscular Junction ◽  
Tyrosine Kinase ◽  
Myasthenia Gravis ◽  
Muscle Weakness ◽  
Acetylcholine Receptors ◽  
Muscular Contraction ◽  
Skeletal Muscle Weakness ◽  
Hypoxic Respiratory Failure ◽  
Receptor Antibodies

Myasthenia gravis is a neuromuscular autoimmune disease that results in skeletal muscle weakness that worsens after periods of activity and improves after rest. Myasthenia gravis means “grave (serious), muscle weakness.” Although not completely curable, it can be managed well with a relatively high quality of life and expectancy. In myasthenia gravis, antibodies against the acetylcholine receptors at the neuromuscular junction interfere with regular muscular contraction. Although most commonly caused by antibodies to the acetylcholine receptor, antibodies against MuSK (muscle-specific kinase) protein can also weaken transmission at the neuromuscular junction. Muscle-specific tyrosine kinase myasthenia gravis (MuSK-Ab MG) is a rare subtype of myasthenia gravis with distinct pathogenesis and unique clinical features. Diagnosis can be challenging due to its atypical presentation as compared to seropositive myasthenia gravis. It responds inconsistently to steroids, but plasma exchange and immunosuppressive therapies have shown promising results. We report a case of a 49-year-old female who presented with acute hypoxic respiratory failure. Our patient experienced progressive, undiagnosed MuSK-Ab MG for years without a diagnosis.

scholarly journals Myasthenia Gravis Exacerbation and Myasthenic Crisis Associated With COVID19: Case Series and Literature Review.

2021 ◽  
Author(s):  
Cleonisio Leite Rodrigues ◽  
Hermany Capistrano Freitas ◽  
Paulo Reges Oliveira Lima ◽  
Pedro Helder de Oliveira Junior ◽  
José Marcelino Aragão Fernandes ◽  
...  
Keyword(s):  
Literature Review ◽  
Neuromuscular Junction ◽  
Hospital Mortality ◽  
Myasthenia Gravis ◽  
Viral Infections ◽  
Case Series ◽  
Previous Treatment ◽  
Autoimmune Disorder ◽  
Myasthenic Crisis

Abstract Myasthenia Gravis (MG) is an autoimmune disorder of the neuromuscular junction that can be exacerbated by many viral infections, including COVID19. Management of MG exacerbations is challenging in this scenario. We report 8 cases of MG exacerbation or myasthenic crisis associated with COVID19 and discuss prognosis and treatment based on a literature review. Most patients were female (7/8), with an average age of 47.1 years. Treatment was immunoglobulin (IVIG) in 3 patients, plasma exchange (PLEX) in 2 patients, and adjustment of baseline drugs in 3. In-hospital mortality was 25% and 37.5% in 2-month follow-up. This is the largest case series of MG exacerbation or myasthenic crisis due to COVID19 to this date. Mortality was considerably higher than in myasthenic crisis of other etiologies. Previous treatment for MG or acute exacerbation treatment did not seem to interfere with prognosis, although sample size was too small to draw definitive conclusions. Further studies are needed to understand the safety and effectiveness of interventions in this setting, particularly of PLEX, IVIG, rituximab and tocilizumab.

scholarly journals Seeking spark- ocular myasthenia gravis in a juvenile – an Indian case report

2020 ◽  
Vol 5 (7) ◽  
pp. 190-193
Author(s):  
Dr. Usha BR. ◽  
◽  
Dr. Nandhini K ◽  
Dr. Chaitra MC ◽  
◽  
...  
Keyword(s):  
Case Report ◽  
Neuromuscular Junction ◽  
Myasthenia Gravis ◽  
Autoimmune Disorder ◽  
Bilateral Ptosis ◽  
Ocular Myasthenia ◽  
Ocular Myasthenia Gravis ◽  
History Of ◽  
High Index Of Suspicion

Myasthenia gravis (MG) is a rare autoimmune disorder affecting neuromuscular junction by muscleweakness. Myasthenia gravis can be generalized or localized as ocular myasthenia gravis. Casepresentation: We report an 8-year-old boy who presented with 10 days history of drooping of botheyelids and 8 days history of diplopia. Examination revealed bilateral ptosis. A diagnosis of JuvenileOcular Myasthenia gravis was made when symptoms improved with intramuscular Edrophoniumadministration. He was commenced on oral Neostigmine at a dose of 2mg/Kg/ day,4 hourly individed doses and is on regular follow up and had a good response. Conclusion: Ocular Myastheniagravis (OMG) is a rare disease in itself. A high index of suspicion is required in a juvenile as it iseven rarer.

Rituximab in AChR subtype of myasthenia gravis: systematic review

2020 ◽  
Vol 91 (4) ◽  
pp. 392-395 ◽  
Author(s):  
Vincenzo Di Stefano ◽  
Antonino Lupica ◽  
Marianna Gabriella Rispoli ◽  
Antonio Di Muzio ◽  
Filippo Brighina ◽  
...  
Keyword(s):  
Systematic Review ◽  
Neuromuscular Junction ◽  
Myasthenia Gravis ◽  
Acetylcholine Receptor ◽  
Autoimmune Disorder ◽  
Postsynaptic Membrane ◽  
Receptor Subtype ◽  
Registration Number ◽  
Randomised Controlled ◽  
Time To Relapse

Myasthenia gravis (MG) is a chronic autoimmune disorder of the neuromuscular junction characterised by an autoantibody against acetylcholine receptor (AChR-Ab), autoantibody against muscle-specific kinase (MuSK-Ab), lipoprotein-related protein 4 or agrin in the postsynaptic membrane at the neuromuscular junction. Many patients are resistant to conventional treatment and effective therapies are needed. Rituximab (RTX) is a monoclonal antibody directed against CD20 antigen on B cells which has been successfully employed in anti-MuSK-Ab+MG, but the efficacy in anti-AChR-Ab+MG is still debated. The purpose of this systematic review was to describe the best evidence for RTX in the acetylcholine receptor subtype. The authors undertook a literature search during the period of 1999–2019 according to the Preferred Reporting Items for Systematic Reviews and Meta-Analys methodology, employing (myasthenia)+(gravis)+(RTX) as search terms. The analysis was confined to studies that include at least five patients with confirmed anti-AChR-Ab+MG. Thirteen studies have been selected, showing a good safety. The data obtained were heterogeneous in terms of posology, administration scheme and patients’ evaluation, ranging from a minimum of two to a maximum of three cycles. RTX led to a sustained clinical improvement with prolonged time to relapse, in parallel to a reduction or discontinuation of other immunosuppressive therapies. Treatment with RTX appears to work in some but not all patients with anti-AChR-Ab+MG, but randomised controlled trials are needed. Future studies should take into account the subtype of MG and employ reliable measures of outcome and severity focusing on how to identify patients who may benefit from the treatment. Trial registration number: NCT02110706.

scholarly journals MuSK myasthenia gravis monoclonal antibodies

2019 ◽  
Vol 6 (3) ◽  
pp. e547 ◽  
Author(s):  
Maartje G. Huijbers ◽  
Dana L. Vergoossen ◽  
Yvonne E. Fillié-Grijpma ◽  
Inge E. van Es ◽  
Marvyn T. Koning ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Monoclonal Antibodies ◽  
Myasthenia Gravis ◽  
Binding Sites ◽  
Neuromuscular Junctions ◽  
Affinity Maturation ◽  
Fab Fragments ◽  
Serum Igg4 ◽  
Muscle Specific Kinase ◽  
Achr Clustering

ObjectiveTo isolate and characterize muscle-specific kinase (MuSK) monoclonal antibodies from patients with MuSK myasthenia gravis (MG) on a genetic and functional level.MethodsWe generated recombinant MuSK antibodies from patient-derived clonal MuSK-specific B cells and produced monovalent Fab fragments from them. Both the antibodies and Fab fragments were tested for their effects on neural agrin-induced MuSK phosphorylation and acetylcholine receptor (AChR) clustering in myotube cultures.ResultsThe isolated MuSK monoclonal antibody sequences included IgG1, IgG3, and IgG4 that had undergone high levels of affinity maturation, consistent with antigenic selection. We confirmed their specificity for the MuSK Ig-like 1 domain and binding to neuromuscular junctions. Monovalent MuSK Fab, mimicking functionally monovalent MuSK MG patient Fab-arm exchanged serum IgG4, abolished agrin-induced MuSK phosphorylation and AChR clustering. Surprisingly, bivalent monospecific MuSK antibodies instead activated MuSK phosphorylation and partially induced AChR clustering, independent of agrin.ConclusionsPatient-derived MuSK antibodies can act either as MuSK agonist or MuSK antagonist, depending on the number of MuSK binding sites. Functional monovalency, induced by Fab-arm exchange in patient serum, makes MuSK IgG4 antibodies pathogenic.

scholarly journals Myasthenia Gravis – A Review of Current Therapeutic Options

2018 ◽  
Vol 13 (2) ◽  
pp. 86
Author(s):  
Saiju Jacob ◽  
Keyword(s):  
Neuromuscular Junction ◽  
Myasthenia Gravis ◽  
Treatment Options ◽  
Standard Of Care ◽  
Autoimmune Disorder ◽  
Therapeutic Options ◽  
Current Standard ◽  
Autoimmune Attack ◽  
Key Factor ◽  
Randomised Controlled

Myasthenia gravis (MG) is an autoimmune disorder that leads to skeletal muscle weakness and fatigue. The autoimmune attack is caused by autoantibodies against the acetylcholine postsynaptic receptors at the neuromuscular junction of skeletal muscles. However, other antigenic targets that are components of the neuromuscular junction have also been implicated in the pathogenesis of MG. The current standard of care is immunosuppressive therapy; however, many existing therapeutic options have not been validated for use in MG in large randomised controlled trials. Furthermore, around 10% of patients with generalised MG are refractory to treatment. The complement system is involved in numerous inflammatory, neurodegenerative and autoimmune diseases, and is a key factor in the pathogenesis of acetylcholine receptor antibody-related MG. Targeting complement and other components involved in the underlying pathogenesis of the disease may provide useful treatment options, particularly for refractory patients.

Myasthenia Gravis

2013 ◽  
Author(s):  
Aaron E. Miller ◽  
Teresa M. DeAngelis
Keyword(s):  
Surgical Treatment ◽  
Neuromuscular Junction ◽  
Myasthenia Gravis ◽  
Acetylcholine Receptors ◽  
Diagnostic Testing ◽  
Autoimmune Disorder ◽  
Postsynaptic Membrane ◽  
Treatment Recommendations ◽  
Clinical Findings

Myasthenia gravis (MG) is an autoimmune disorder that results in loss of functional acetylcholine receptors (AChR) on the postsynaptic membrane of the neuromuscular junction caused by the presence of antibodies to the AChR. In this chapter, we review the cardinal clinical findings of MG, the standard diagnostic testing including electrophysiological features, and the medical and surgical treatment recommendations.

Update on Ocular Myasthenia Gravis

2019 ◽  
Vol 39 (06) ◽  
pp. 749-760 ◽  
Author(s):  
Meabh O'Hare ◽  
Christopher Doughty
Keyword(s):  
Neuromuscular Junction ◽  
Myasthenia Gravis ◽  
Clinical Features ◽  
Clinical Examination ◽  
Autoimmune Disorder ◽  
Therapeutic Options ◽  
Diagnostic Approach ◽  
Ocular Myasthenia ◽  
Ocular Myasthenia Gravis ◽  
Recent Developments

AbstractMyasthenia gravis is an antibody-mediated autoimmune disorder of the post-synaptic neuromuscular junction resulting in fluctuating, fatigable weakness. Most patients first present with extraocular symptoms (diplopia and/or ptosis), and in 15% of cases symptoms will remain restricted to only the extraocular muscles (ocular myasthenia gravis [OMG]). The history and clinical examination are of the utmost importance in correctly identifying OMG patients, as supportive serologic or electrodiagnostic studies are frequently nondiagnostic. In this review, we outline a diagnostic approach to OMG (focusing on key clinical features), discuss therapeutic options, and highlight recent developments in the understanding of OMG.

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