Induction of Anti-agrin Antibodies Causes Myasthenia Gravis in Mice

Myasthenia gravis (MG) is an autoantibody-mediated disease that compromises the acetylcholine receptors or associated structures of the postsynaptic membrane of the neuromuscular junction. This leads to impaired neuromuscular transmission and subsequent fluctuating fatigability and weakness of ocular, bulbar, and limb skeletal muscles. Over the past few decades, there have been significant advances in our understanding of the disease pathophysiology and improvements in prognosis due to intensive care medicine and immunomodulation. Despite this, an estimated 10–20% of patients with MG do not achieve an adequate response, are intolerant to conventional treatment, or require chronic treatment with intravenous immunoglobulins or plasma separation procedures. Such patients are regarded as having MG that is ‘refractory’ to treatment and may represent a distinct clinical subgroup. Because the majority of patients with MG have well-controlled disease, the burden of illness in the minority with refractory disease is poorly understood and may be underestimated. However, clinically these patients are liable to experience extreme fatigue, considerable disability owing to uncontrolled symptoms, and frequent myasthenic crises and hospitalizations. Both acute adverse effects and an increased risk of comorbidity from treatment regimens may contribute to reduced quality of life. As yet, little is known concerning the impact of refractory MG on mental health and health-related quality of life. This review aims to highlight the burden of disease and unmet needs in patients with refractory MG.

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“…2,3 Increasing evidence also suggests a role for anti-agrin autoantibodies, although this remains to be confirmed in humans. 4–6…”

Section: Introductionmentioning

confidence: 99%

Understanding the burden of refractory myasthenia gravis

Schneider‐Gold

Hagenacker

Melzer

et al. 2019

Ther Adv Neurol Disord

112

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“…Importantly, patients with agrin antibodies presented with mild to severe symptoms and moderate response to treatment, thus their early detection could aid in disease management (81). Agrin antibodies appear to be pathogenic, since in in vitro studies they were capable of inhibiting MuSK activation by agrin and AChR clustering (108), while immunization of mice with neural, but not muscle, agrin induced MG-like symptoms (109).…”

Section: Antibodies Against Other Antigensmentioning

confidence: 99%

Autoantibody Specificities in Myasthenia Gravis; Implications for Improved Diagnostics and Therapeutics

2020

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Myasthenia gravis (MG) is an autoimmune disease characterized by muscle weakness and fatiguability of skeletal muscles. It is an antibody-mediated disease, caused by autoantibodies targeting neuromuscular junction proteins. In the majority of patients (∼85%) antibodies against the muscle acetylcholine receptor (AChR) are detected, while in 6% antibodies against the muscle-specific kinase (MuSK) are detected. In ∼10% of MG patients no autoantibodies can be found with the classical diagnostics for AChR and MuSK antibodies (seronegative MG, SN-MG), making the improvement of methods for the detection of known autoantibodies or the discovery of novel antigenic targets imperative. Over the past years, using cell-based assays or improved highly sensitive immunoprecipitation assays, it has been possible to detect autoantibodies in previously SN-MG patients, including the identification of the low-density lipoprotein receptor-related protein 4 (LRP4) as a third MG autoantigen, as well as AChR and MuSK antibodies undetectable by conventional methods. Furthermore, antibodies against other extracellular or intracellular targets, such as titin, the ryanodine receptor, agrin, collagen Q, K v 1.4 potassium channels and cortactin have been found in some MG patients, which can be useful biomarkers. In addition to the improvement of diagnosis, the identification of the patients' autoantibody specificity is important for their stratification into respective subgroups, which can differ in terms of clinical manifestations, prognosis and most importantly their response to therapies. The knowledge of the autoantibody profile of MG patients would allow for a therapeutic strategy tailored to their MG subgroup. This is becoming especially relevant as there is increasing progress toward the development of antigen-specific therapies, targeting only the specific autoantibodies or immune cells involved in the autoimmune response, such as antigen-specific immunoadsorption, which have shown promising results. We will herein review the advances made by us and others toward development of more sensitive detection methods and the identification of new antibody targets in MG, and discuss their significance in MG diagnosis and therapy. Overall, the development of novel autoantibody assays is aiding in the more accurate diagnosis and classification of MG patients, supporting the development of advanced therapeutics and ultimately the improvement of disease management and patient quality of life.

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“…Anti-agrin antibodies (Y5 in Figure 1) have been detected in some of MG patients with or without antibodies against AChR, MuSK, and Lrp4 (Gasperi et al, 2014;Zhang et al, 2014;Cordts et al, 2017;Yan et al, 2018b). Induction of anti-agrin antibodies was proved to cause MG in mice by an impairment of agrin-Lrp4 interaction (Yan et al, 2018a). We must be cautious of the antigen used for agrin-antibody assay because of the abovementioned difference of functional structure between neural agrin and muscle agrin.…”

Section: Anti-agrin Antibodiesmentioning

confidence: 99%

Myasthenia Gravis: From the Viewpoint of Pathogenicity Focusing on Acetylcholine Receptor Clustering, Trans-Synaptic Homeostasis and Synaptic Stability

Takamori

2020

Front. Mol. Neurosci.

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Myasthenia gravis (MG) is a disease of the postsynaptic neuromuscular junction (NMJ) where nicotinic acetylcholine (ACh) receptors (AChRs) are targeted by autoantibodies. Search for other pathogenic antigens has detected the antibodies against musclespecific tyrosine kinase (MuSK) and low-density lipoprotein-related protein 4 (Lrp4), both causing pre-and post-synaptic impairments. Agrin is also suspected as a fourth pathogen. In a complex NMJ organization centering on MuSK: (1) the Wnt non-canonical pathway through the Wnt-Lrp4-MuSK cysteine-rich domain (CRD)-Dishevelled (Dvl, scaffold protein) signaling acts to form AChR prepatterning with axonal guidance; (2) the neural agrin-Lrp4-MuSK (Ig1/2 domains) signaling acts to form rapsyn-anchored AChR clusters at the innervated stage of muscle; (3) adaptor protein Dok-7 acts on MuSK activation for AChR clustering from "inside" and also on cytoskeleton to stabilize AChR clusters by the downstream effector Sorbs1/2; (4) the trans-synaptic retrograde signaling contributes to the presynaptic organization via: (i) Wnt-MuSK CRD-Dvl-β catenin-Slit 2 pathway; (ii) Lrp4; and (iii) laminins. The presynaptic Ca 2+ homeostasis conditioning ACh release is modified by autoreceptors such as M1-type muscarinic AChR and A2A adenosine receptors. The post-synaptic structure is stabilized by: (i) lamininnetwork including the muscle-derived agrin; (ii) the extracellular matrix proteins (including collagen Q/perlecan and biglycan which link to MuSK Ig1 domain and CRD); and (iii) the dystrophin-associated glycoprotein complex. The study on MuSK ectodomains (Ig1/2 domains and CRD) recognized by antibodies suggested that the MuSK antibodies were pathologically heterogeneous due to their binding to multiple functional domains. Focussing one of the matrix proteins, biglycan which functions in the manner similar to collagen Q, our antibody assay showed the negative result in MG patients. However, the synaptic stability may be impaired by antibodies against MuSK ectodomains because of the linkage of biglycan with MuSK Ig1 domain and CRD. The pathogenic diversity of MG is discussed based on NMJ signaling molecules.

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Induction of Anti-agrin Antibodies Causes Myasthenia Gravis in Mice

Cited by 33 publications

References 53 publications

Understanding the burden of refractory myasthenia gravis

Understanding the burden of refractory myasthenia gravis

Autoantibody Specificities in Myasthenia Gravis; Implications for Improved Diagnostics and Therapeutics

Myasthenia Gravis: From the Viewpoint of Pathogenicity Focusing on Acetylcholine Receptor Clustering, Trans-Synaptic Homeostasis and Synaptic Stability

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