scholarly journals Functional monovalency amplifies the pathogenicity of anti-MuSK IgG4 in myasthenia gravis

2021 ◽  
Vol 118 (13) ◽  
pp. e2020635118
Author(s):  
Dana L. E. Vergoossen ◽  
Jaap J. Plomp ◽  
Christoph Gstöttner ◽  
Yvonne E. Fillié-Grijpma ◽  
Roy Augustinus ◽  
...  
Keyword(s):  
Stochastic Process ◽  
Autoimmune Disease ◽  
Myasthenia Gravis ◽  
Muscle Weakness ◽  
Binding Sites ◽  
Antiinflammatory Activity ◽  
Autoimmune Response ◽  
Cross Link ◽  
Muscle Specific Kinase ◽  
Opposing Effects

Human immunoglobulin (Ig) G4 usually displays antiinflammatory activity, and observations of IgG4 autoantibodies causing severe autoimmune disorders are therefore poorly understood. In blood, IgG4 naturally engages in a stochastic process termed “Fab-arm exchange” in which unrelated IgG4s exchange half-molecules continuously. The resulting IgG4 antibodies are composed of two different binding sites, thereby acquiring monovalent binding and inability to cross-link for each antigen recognized. Here, we demonstrate that this process amplifies autoantibody pathogenicity in a classic IgG4-mediated autoimmune disease: muscle-specific kinase (MuSK) myasthenia gravis. In mice, monovalent anti-MuSK IgG4s caused rapid and severe myasthenic muscle weakness, whereas the same antibodies in their parental bivalent form were less potent or did not induce a phenotype. Mechanistically this could be explained by opposing effects on MuSK signaling. Isotype switching to IgG4 in an autoimmune response thereby may be a critical step in the development of disease. Our study establishes functional monovalency as a pathogenic mechanism in IgG4-mediated autoimmune disease and potentially other disorders.

scholarly journals Functional monovalency amplifies the pathogenicity of anti-MuSK IgG4 in myasthenia gravis

2020 ◽  
Author(s):  
Dana L.E. Vergoossen ◽  
Jaap J. Plomp ◽  
Christoph Gstöttner ◽  
Yvonne E. Fillié-Grijpma ◽  
Roy Augustinus ◽  
...  
Keyword(s):  
Stochastic Process ◽  
Autoimmune Disease ◽  
Myasthenia Gravis ◽  
Muscle Weakness ◽  
Binding Sites ◽  
Autoimmune Disorders ◽  
Autoimmune Response ◽  
Cross Link ◽  
Muscle Specific Kinase ◽  
Opposing Effects

AbstractHuman IgG4 usually displays anti-inflammatory activity, and observations of IgG4 autoantibodies causing severe autoimmune disorders are therefore poorly understood. In blood, IgG4 antibodies naturally engage in a stochastic process termed Fab-arm exchange in which unrelated IgG4s exchange half-molecules continuously. The resulting IgG4 antibodies are composed of two different binding sites, thereby acquiring monovalent binding and inability to cross-link for each antigen recognized. Here, we demonstrate this process amplifies autoantibody pathogenicity in a classic IgG4-mediated autoimmune disease: muscle-specific kinase (MuSK) myasthenia gravis (MG). In mice, monovalent anti-MuSK IgG4s caused rapid and severe myasthenic muscle weakness, whereas the same antibodies in their parental bivalent form were less potent or did not induce a phenotype. Mechanistically this could be explained by opposing effects on MuSK signaling. Isotype switching to IgG4 in an autoimmune response thereby may be a critical step in the development of disease. Our study establishes functional monovalency as a novel pathogenic mechanism in IgG4-mediated autoimmune disease and potentially other disorders.Graphical abstract

scholarly journals Thymocyte Fas Expression Is Dysregulated in Myasthenia Gravis Patients With Anti-Acetylcholine Receptor Antibody

Blood ◽  
1997 ◽  
Vol 89 (9) ◽  
pp. 3287-3295 ◽  
Author(s):  
Nathalie Moulian ◽  
Jocelyne Bidault ◽  
Frédérique Truffault ◽  
Ana Maria Yamamoto ◽  
Philippe Levasseur ◽  
...  
Keyword(s):  
Autoimmune Disease ◽  
Myasthenia Gravis ◽  
Acetylcholine Receptor ◽  
Peripheral Blood ◽  
Proliferative Response ◽  
Peripheral Blood Lymphocytes ◽  
Autoimmune Response ◽  
Human Autoimmune Disease ◽  
Autoreactive Cells ◽  
Anti Acetylcholine

Abstract Myasthenia gravis (MG) is a human autoimmune disease mediated by anti-acetylcholine receptor (AChR) antibodies. The thymus is probably the site where the autoimmune response is triggered and maintained. Recent reports have linked various autoimmune disease with defective Fas expression. We thus analyzed Fas expression in thymocytes and peripheral blood lymphocytes (PBL) from MG patients. The proportion of a thymocyte subpopulation with strong Fas expression (Fashi) was markedly enhanced in MG patients with anti-AChR antibodies (P < .0003, compared with controls). In this group of patients, the proportion of CD4+Fashi and CD4+CD8+Fashi thymocytes were significantly increased (P < .002 for both subsets). Fashi thymocytes were enriched in activated cells and showed intermediate CD3 expression. They were preferentially Vβ5.1-expressing cells, previously shown to be enriched in potentially autoreactive cells. The proliferative response of thymocytes from MG patients to peptides from the AChR was abolished after depletion of Fashi cells. Fashi thymocytes were sensitive to an agonistic anti-Fas antibody. In peripheral blood, Fashi lymphocytes proportion was not significantly modified in MG patients whatever their anti-AChR antibody titer, compared with controls. Altogether, these results indicate that Fashi thymocytes, which accumulate in MG patients with anti-AChR antibodies, could be involved in the autoimmune response that targets the AChR.

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.

Diagnosis, assessment, and management of myasthenia gravis and paramyasthenic syndromes

2016 ◽  
Author(s):  
Ugan Reddy ◽  
Nicholas Hirsch
Keyword(s):  
Autoimmune Disease ◽  
Myasthenia Gravis ◽  
Muscle Weakness ◽  
Motor Nerve ◽  
Neuromuscular Blocking ◽  
Myasthenic Crisis ◽  
Igg Antibodies ◽  
Limb Weakness ◽  
Myasthenic Syndrome ◽  
Long Acting

Diseases that affect the neuromuscular junction (NMJ) interfere with normal nerve transmission and cause weakness of voluntary muscles. The two most commonly encountered are acquired myasthenia gravis (MG) and the Lambert–Eaton myasthenic syndrome (LEMS). Acquired MG is an autoimmune disease in which antibodies are directed towards receptors at the NMJ. In 85% of patients, IgG antibodies against the postsynaptic acetylcholine receptor (AChR) are found (seropositive MG). The thymus gland appears to be involved in the production of these which cause an increase rate of degradation of AChR resulting in a decreased receptor density resulting in a reduced postsynaptic end-plate potential following motor nerve stimulation and leading to muscle weakness. Although all voluntary muscles can be affected, ocular, bulbar, respiratory, and proximal limb weakness predominates. In the majority of seronegative patients, an antibody directed towards a NMJ protein called muscle specific tyrosine kinase (MUSK) is found. Anti-MUSK MG is characterized by severe bulbar and respiratory muscle weakness. Diagnosis of MG requires a high degree of clinical suspicion coupled with pharmacological and electrophysiological testing, and detection of the various causative antibodies. Treatment of MG involves enhancing neuromuscular transmission with long-acting anticholinesterase agents and immunosuppression. Acute exacerbations are treated with either plasma exchange or intravenous immunoglobulin. Myasthenic crisis is associated with severe muscle weakness that necessitates tracheal intubation and mechanical ventilation. LEMS is an autoimmune disease in which IgG antibodies are directed towards the pre-synaptic voltage-gated calcium channels at the NMJ. It is often associated with malignant disease (usually small cell carcinoma of the lung). Autonomic dysfunction is prominent and patients show abnormal responses to neuromuscular blocking drugs.

scholarly journals Demyelinating disease in patients with myasthenia gravis

2008 ◽  
Vol 66 (1) ◽  
pp. 5-7 ◽  
Author(s):  
Denis Bernardi Bichuetti ◽  
Tatiane Martins de Barros ◽  
Enedina Maria Lobato Oliveira ◽  
Marcelo Annes ◽  
Alberto Alain Gabbai
Keyword(s):  
Autoimmune Disease ◽  
Autoimmune Diseases ◽  
Myasthenia Gravis ◽  
Muscle Weakness ◽  
Neuromyelitis Optica ◽  
Neuromuscular Transmission ◽  
Demyelinating Disease ◽  
Demyelinating Diseases

Myasthenia gravis (MG) is an autoimmune disease characterized by fluctuating muscle weakness, caused by impaired neuromuscular transmission. Patients with MG can present other autoimmune diseases in association, commonly hypo or hyperthyroidism. The association of MG to demyelinating disease is rare and has been described before. We report on three Brazilian patients with MG that presented distinct demyelinating diseases, two monophasic and one recurrent neuromyelitis optica, several years after the diagnosis of MG, and discuss their clinical courses.

scholarly journals The Intrathymic Pathogenesis of Myasthenia Gravis

2004 ◽  
Vol 11 (3-4) ◽  
pp. 215-220 ◽  
Author(s):  
Arnold I. Levinson ◽  
Decheng Song ◽  
Glen Gaulton ◽  
Yi Zheng
Keyword(s):  
Skeletal Muscle ◽  
Autoimmune Disease ◽  
Myasthenia Gravis ◽  
Muscle Weakness ◽  
Disease Pathogenesis ◽  
Skeletal Muscle Weakness ◽  
New Hypothesis ◽  
Ach Receptors

The thymus is considered to play an important role in the pathogenesis of Myasthenia gravis, an autoimmune disease characterized by antibody-mediated skeletal muscle weakness. However, its role is yet to be defined. The studies described herein summarize our efforts to determine how intrathymic expression of the neuromuscular type of acetylcholine (ACh) receptors is involved in the immunopathogenesis of this autoimmune disease. We review the work characterizing the expression of neuromuscular ACh receptors in the thymus and advance a new hypothesis that examines the intrathymic expression of this autoantigen in disease pathogenesis.

scholarly journals Efgartigimod improves muscle weakness in a mouse model for muscle-specific kinase myasthenia gravis

2019 ◽  
Vol 317 ◽  
pp. 133-143 ◽  
Author(s):  
Maartje G. Huijbers ◽  
Jaap J. Plomp ◽  
Inge E. van Es ◽  
Yvonne E. Fillié-Grijpma ◽  
Samar Kamar-Al Majidi ◽  
...  
Keyword(s):  
Mouse Model ◽  
Myasthenia Gravis ◽  
Muscle Weakness ◽  
Muscle Specific Kinase

scholarly journals The epidemiology of myasthenia gravis

2021 ◽  
Vol 14 (1) ◽  
pp. 7-16
Author(s):  
Ana-Maria Bubuioc ◽  
◽  
◽  
Aigerim Kudebayeva ◽  
Saule Turuspekova ◽  
...  
Keyword(s):  
Risk Factors ◽  
Autoimmune Disease ◽  
Myasthenia Gravis ◽  
Clinical Presentation ◽  
Epidemiological Data ◽  
Postsynaptic Membrane ◽  
Related Protein ◽  
The Past ◽  
Muscle Specific Kinase ◽  
Receptor Muscle

Neuromuscular junction (NMJ) disorders include several dysfunctions that ultimately lead to muscle weakness. Myasthenia gravis (MG) is the most prevalent NMJ disorder with a highly polymorphic clinical presentation and many different faces. Being an autoimmune disease, MG correlates with the presence of detectable antibodies directed against the acetylcholine receptor, muscle-specific kinase, lipoprotein-related protein 4, agrin, titin, and ryanodine in the postsynaptic membrane at the NMJ. MG has become a prototype serving to understand both autoimmunity and the function of the NMJ better. The aim of this review is to synthesize some of the epidemiological data available. Epidemiological data regarding MG are important for postulating hypotheses regarding its etiology and facilitating the description of MG subtypes. Thus, adequate documentation through broad databases is essential. The incidence and prevalence of MG reported around the globe have been rising steadily and consistently over the past decades. Ethnic aspects, gender-related differences, and environmental risk factors have been described, implying that these might contribute to a specific phenotype, further suggesting that MG may be considered an umbrella term that covers several clinical entities.

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