Materiały źródłowe

• #1 Pathogenesis of myasthenia gravis: update on disease types, models, and mechanisms

  https://pmc.ncbi.nlm.nih.gov/articles/PMC4926737/

  Myasthenia gravis is an autoimmune disease of the neuromuscular junction (NMJ) caused by antibodies that attack components of the postsynaptic membrane, impair neuromuscular transmission, and lead to weakness and fatigue of skeletal muscle. […] The pathogenesis of myasthenia gravis depends upon the target and isotype of the autoantibodies. Most cases are caused by immunoglobulin (Ig)G1 and IgG3 antibodies to the acetylcholine receptor (AChR). They produce complement-mediated damage and increase the rate of AChR turnover, both mechanisms causing loss of AChR from the postsynaptic membrane. […] In a minority of patients, however, the autoantibodies instead bind to muscle-specific kinase (MuSK). MuSK is a transmembrane tyrosine receptor kinase that is crucial for the development and maintenance of AChR clusters at the NMJ. These antibodies are clearly pathogenic, but the mechanisms are only recently beginning to be unravelled.

• #1 Pathogenesis of myasthenia gravis: update on disease types, models, and mechanisms

  https://pmc.ncbi.nlm.nih.gov/articles/PMC4926737/

  AChR autoantibodies are mainly of the IgG1 and 3 subtypes, and so they are divalent and complement activating. Binding of these antibodies to AChRs results in activation of the classical complement pathway with assembly of the membrane attack complex (MAC). Calcium influx through the MAC causes local damage to the membrane, with release of AChR-containing membrane debris into the synaptic cleft. […] Importantly, and not widely appreciated, the complement damage also causes a loss of voltage-gated sodium channels, which are located in the secondary folds, raising the threshold that the EPP must reach to trigger the muscle action potential. […] It seems likely that each of these modulating factors might differ between individuals and between muscles within an individual, explaining to some extent the variation in weakness and fatigue that is characteristic of all forms of MG.

• #1 Pathogenesis of myasthenia gravis: update on disease types, models, and mechanisms

  https://pmc.ncbi.nlm.nih.gov/articles/PMC4926737/

  AChR MG is an immune-mediated disease with most of the effects dependent on the particular characteristics of the IgG antibodies. By contrast, MuSK MG appears to be principally a pharmacological disease, where antibodies act to interfere directly with physiological mechanisms. […] The proposed effect of MuSK autoantibodies upon the mechanisms of postsynaptic differentiation and synaptic function is illustrated in Figure 2. […] Thus, a combination of cell culture and mouse studies suggests that MuSK autoantibodies, which are mainly of the IgG4 type, block the natural activation of MuSK, leading to progressive loss of AChRs from the motor endplate and synaptic failure. […] Different subsets of MG patients develop autoantibodies with distinct target specificities, isotypes, and pathogenic mechanisms. Different pathogenic mechanisms then converge to cause loss of postsynaptic AChRs and increasing failure of neuromuscular transmission.

• #2 Myasthenia Gravis: Epidemiology, Pathophysiology and Clinical Manifestations

  https://pmc.ncbi.nlm.nih.gov/articles/PMC8196750/

  Myasthenia gravis (MG) is an autoimmune neurological disorder characterized by defective transmission at the neuromuscular junction. […] MG is considered a classic example of antibody-mediated autoimmune disease. Most patients with MG have autoantibodies against the acetylcholine receptors (AChRs). […] These autoantibodies disrupt cholinergic transmission between nerve terminals and muscle fibers by causing downregulation, destruction, functional blocking of AChRs, or disrupting the clustering of AChRs in the postsynaptic membrane. […] Although MG is mediated by autoantibodies, different subtypes of T cells and their cytokines also play important roles in the pathogenesis. […] The predominant mechanism is the binding of the antibody and activation of the complement cascade, leading to the formation of the membrane attack complex (MAC), which causes damage of the postsynaptic membrane and destruction of synaptic folds which contain AChRs and associated proteins, including voltage-gated sodium channels.

• #2 Myasthenia Gravis: Epidemiology, Pathophysiology and Clinical Manifestations

  https://pmc.ncbi.nlm.nih.gov/articles/PMC8196750/

  The mechanism by which MuSK antibodies exert their pathogenic effect on the neuromuscular junction is via binding to the Ig-like domain of the protein, preventing its phosphorylation, and subsequently disrupting the Agrin-Lrp4-MuSK-Dok-7 signaling pathway. […] Neuromuscular junction disorders such as MG disrupt the cascade of events that lead to reliable muscle contraction. […] The resultant inefficient neuromuscular transmission is reflected in decremental response in the amplitude of compound muscle action potential (CMAP) during repetitive nerve stimulation (RNS) and abnormal jitter or blocking in single fiber EMG. […] B cell tolerance is mediated by clonal deletion or receptor editing in newly generated B cell clones in the bone marrow when they reach the stage of immature B cells.

• #2 Myasthenia Gravis: Epidemiology, Pathophysiology and Clinical Manifestations

  https://pmc.ncbi.nlm.nih.gov/articles/PMC8196750/

  A break in tolerance is also supported by data from deep sequencing of BCR repertoire showing distinct gene segment usage biases in both VH and VL sequences within the nave and memory compartments in AChR-MG and MuSK-MG. […] The T cell selection process takes place in the thymus, mainly in the thymic medulla, where they undergo negative selection for self-antigens. […] The presence of ectopic germinal centers is associated with early-onset AChR-MG, but not with MuSK-associated MG. […] The ensuing T cell subset imbalance and cytokine dysregulation leads to the activation of B cells in germinal centers and differentiation into autoreactive B cells and plasma cells. […] A deeper understanding of MG subgroups and their distinct immunopathogenic mechanisms will result in the identification of therapeutic targets and the development of targeted treatment strategies.

• #3 Myasthenia Gravis: Practice Essentials, Background, Anatomy

  https://emedicine.medscape.com/article/1171206-overview

  Myasthenia gravis (MG) is a relatively rare acquired, autoimmune disorder caused by an antibody-mediated blockade of neuromuscular transmission resulting in skeletal muscle weakness and rapid muscle fatigue. The autoimmune attack occurs when autoantibodies form against the nicotinic acetylcholine postsynaptic receptors at the neuromuscular junction of skeletal muscles. […] The basic pathology is a reduction in the number of ACh receptors (AChRs) at the postsynaptic muscle membrane brought about by an acquired autoimmune reaction producing anti-AChR antibodies. […] The decrease in the number of postsynaptic AChRs is believed to be due to an autoimmune process whereby anti-AChR antibodies are produced and block the AChR. It causes an increase in the turnover of the AChR, and damage of the postsynaptic membrane in a complement-mediated manner.

• #3 Myasthenia Gravis: Practice Essentials, Background, Anatomy

  https://emedicine.medscape.com/article/1171206-overview

  The exact mechanism of loss of immunologic tolerance to AChR, a self-antigen, is not understood. MG can be considered a B cell-mediated disease, in that it derives from antibodies (a B cell product) against AChR. However, the importance of T cells in the pathogenesis of MG is becoming increasingly apparent. […] It is thought that both the initiation and maintenance of MG occurs in a process that involves type-II hypersensitivity reactions. The production of autoantibodies implies that it is a B-cell-mediated autoimmune disorder. The initiation of the process is dependent on T-cell help. […] The activated B lymphocytes grow and undergo clonal expansion into antibody-synthesizing plasma cells. These plasma cells secrete IgG anti-AChR antibodies that bind to the nicotinic ACh-R. […] Binding of AChR antibodies to AChR results in impairment of neuromuscular transmission in several ways, including the following: Cross-linking 2 adjacent AChRs with anti-AChR antibody, thus accelerating internalization and degradation of AChR molecules; Causing complement-mediated destruction of junctional folds of the postsynaptic membrane; Blocking the binding of ACh to AChR; Decreasing the number of AChRs at the NMJ by simplification of the junctional folds on the postsynaptic membrane, thereby reducing the surface area available for insertion of newly synthesized AChRs. […] The role of the thymus in the pathogenesis of MG is not entirely clear, but 75% of patients with MG have some degree of thymus abnormality (eg, hyperplasia or thymoma).

• #4

  https://link.springer.com/article/10.1007/s00415-016-8045-z

  Antibodies against muscle-specific tyrosine kinase (MuSK) are of the non-complement binding IgG4 type and prevent the interaction of low-density lipoprotein receptor-related protein 4 (LRP4) with MuSK disturbing the agrin-induced architecture of the neuromuscular junction. […] The thymus exhibits pathological changes in the majority of patients with AChR antibodies (most patients with OMG, EOMG, LOMG and TAMG), which seem to be of central importance for the impairment of central and peripheral tolerance and initiation of immunopathogenesis of MG. […] The intrathymic autoimmune inflammatory process in EOMG seems to be self-perpetuating likely due to dysfunctional regulatory T cells that have been described in the EOMG thymus and blood. […] The autoimmune focus of EOMG is largely on the AChR, the spectrum of autoantibody targets in individual patients with TAMG can be much broader.

• #5 Myasthenia gravis – Wikipedia

  https://en.wikipedia.org/wiki/Myasthenia_gravis

  Myasthenia gravis is an autoimmune disease of the neuromuscular junction which results from antibodies that block or destroy nicotinic acetylcholine receptors (AChR) at the junction between the nerve and muscle. […] Most cases are due to immunoglobulin G1 (IgG1) and IgG3 antibodies that attack AChR in the postsynaptic membrane, causing complement-mediated damage and muscle weakness. […] Myasthenia gravis is an autoimmune synaptopathy. The disorder occurs when the immune system malfunctions and generates antibodies that attack the body’s tissues. The antibodies in MG attack a normal human protein, the nicotinic acetylcholine receptor, or a related protein called MuSK, a muscle-specific kinase. […] Other, less frequent antibodies are found against LRP4, agrin, and titin proteins. […] The thymus gland cells form part of the body’s immune system. In those with myasthenia gravis, the thymus gland is large and abnormal. It sometimes contains clusters of immune cells that indicate lymphoid hyperplasia, and the thymus gland may give wrong instructions to immune cells.

• #6

  https://www.jci.org/articles/view/29894

  The postsynaptic transmembrane protein, muscle-specific tyrosine kinase (MuSK), is the main autoantigen in some MG patients. […] The EPP generated in normal NMJs is larger than the threshold needed to generate an action potential. […] Anti-AChR Abs affect neuromuscular transmission by at least 3 mechanisms: (a) binding and activation of complement at the NMJ; (b) accelerated degradation of AChR molecules crosslinked by Ab (a process known as antigenic modulation); and (c) functional AChR block. […] The NMJs of MG patients and EAMG animals contain activation fragments of complement component 3 (C3), the terminal and lytic complement component 9 (C9), and the membrane attack complex (MAC). […] Antigenic modulation is the ability of an Ab to cross-link 2 antigen molecules, thereby triggering a cellular signal that causes accelerated endocytosis and degradation of the cross-linked molecules.

• #6

  https://www.jci.org/articles/view/29894

  Functional AChR block due to Ab binding to the ACh-binding site is an uncommon pathogenic mechanism in MG, yet it may be clinically important. […] Pathogenic anti-AChR Abs are high-affinity IgGs, whose synthesis requires that activated CD4+ T cells interact with B cells, resulting in low-affinity anti-AChR Abs. […] The pathogenic role of anti-AChR CD4+ T cells in MG and EAMG explains the important role of MHC class II molecules, which present the antigen epitopes to the specific CD4+ T cells. […] MG patients have abundant anti-AChR Th1 cells in the blood that recognize many AChR epitopes and induce synthesis of pathogenic anti-AChR Abs when grafted together with B cells and macrophages from the same patient into SCID mice. […] The resistance to EAMG induction conferred by genetic deficiency in TNF- or TNF receptor proteins is overcome by treatment with IL-12, confirming that sensitization and differentiation of Th1 cells is important for EAMG development. […] The rich epitope repertoire of anti-AChR CD4+ T cells in MG patients reduces the therapeutic potential of approaches that interfere with activation of specific CD4+ T cells; targeting only a few epitopes may not significantly reduce the anti-AChR response.

• #7 Myasthenia Gravis: Epidemiology, Pathophysiology and Clinical Manifestations

  https://www.mdpi.com/2077-0383/10/11/2235

  The predominant mechanism is the binding of the antibody and activation of the complement cascade, leading to the formation of the membrane attack complex (MAC), which causes damage of the postsynaptic membrane and destruction of synaptic folds which contain AChRs and associated proteins, including voltage-gated sodium channels. […] The role of AChE in the hydrolyzation of ACh is therefore crucial, as it prevents a single molecule of ACh from repetitively activating AChRs. The effectiveness of neuromuscular junction transmission is also determined by the amount of ACh released by the nerve terminal, the density of ACh receptors in the postsynaptic membrane, and the density of voltage-gated sodium channels at the endplate. […] Neuromuscular junction disorders such as MG disrupt the cascade of events that lead to reliable muscle contraction. In addition, there is a reduction in the number of AChRs and voltage-gated sodium channels as the result of complement-related injury to the postsynaptic membrane in MG.

• #7 Myasthenia Gravis: Epidemiology, Pathophysiology and Clinical Manifestations

  https://www.mdpi.com/2077-0383/10/11/2235

  The T cell selection process may be impaired in thymic hyperplasia and thymoma. The latter can have defective AIRE expression and can lack thymic medulla, which is involved in the negative selection of T cells, therefore contributing to the release of autoreactive CD4+ and CD8+ T cells. […] A deeper understanding of MG subgroups and their distinct immunopathogenic mechanisms will result in the identification of therapeutic targets and the development of targeted treatment strategies.

• #8 Pathophysiology of Neuromuscular Control: Issues with Neuromuscular Junction (Myasthenia Gravis) – Pathology

  https://pressbooks.bccampus.ca/pathology/chapter/carter-valeries-pathophysiology-of-neuromuscular-junction-myasthenia-gravis/

  Myasthenia Gravis (MG) is an autoimmune disorder, meaning it is caused by the bodys immune system mistakenly identifying normal parts of the body as foreign and mounting an immune response against them. […] The identification of self peptides as foreign by helper T-cells leads to B-cells production of autoantibodies (antibodies against self) to a variety of proteins involving ACh transmission at the NMJ. […] This interrupts acetylcholine action at the neuromuscular junction (NMJ), preventing the neural control of voluntary motor movement. […] The AChR autoantibodies are thought to block transmission through the NMJ by three mechanisms: a) Autoantibodies competitively antagonize AChR therefore inhibiting ACh binding […] b) Promoting endocytosis (internalization) of AChR into the muscle fibre so it is no longer at the cell surface.

• #9 Myasthenia Gravis: Making Progress for More Accurate Diagnoses and Targeted Treatments

  https://practicalneurology.com/diseases-diagnoses/neuromuscular/myasthenia-gravis-making-progress-for-more-accurate-diagnoses-and-targeted-treatments/32114/

  Myasthenia gravis (MG) is the prototypical autoimmune disorder affecting the postsynaptic portion of the neuromuscular junction (NMJ). In roughly 85% of cases, generalized MG is caused by antibodies to the acetylcholine receptor (AChR); this is true in about half of purely ocular cases. These antibodies exert their pathogenic effect in 1 of 3 ways. First, they can functionally block the AChR, not allowing for the binding of acetylcholine. Second, they can crosslink AChRs, leading to increased internalization and degradation. Third, they can bind to AChRs and activate complement, leading to destruction of the NMJ. About 7% of all cases of generalized MG are caused by antibodies to muscle-specific tyrosine kinase (MuSK), and 1% are caused by antibodies against lipoprotein-related protein 4 (LRP4), both of which play a role in clustering of AChRs on the postsynaptic membrane, interference with which also leads to impaired neuromuscular transmission.

• #9 Myasthenia Gravis: Making Progress for More Accurate Diagnoses and Targeted Treatments

  https://practicalneurology.com/diseases-diagnoses/neuromuscular/myasthenia-gravis-making-progress-for-more-accurate-diagnoses-and-targeted-treatments/32114/

  The treatment of MG has evolved considerably over time, especially over the past 6 years. Most individuals are initially treated with acetylcholinesterase inhibitors, such as pyridostigmine. These agents are modestly effective in treating individuals with ocular MG; however, they are rarely effective alone in treating individuals with generalized disease. Corticosteroids, therefore, are almost always started at the time of diagnosis of generalized MG to control symptoms quickly and effectively, with most individuals experiencing initial benefit within 2 weeks. […] Although initially studied in a more treatment-refractory population, complement inhibitors are approved for the treatment of all individuals with AChR antibody-positive generalized myasthenia. By inhibiting complement, these agents prevent 1 of the key pathophysiologic mechanisms of AChR antibody-mediated disease.

• #9 Myasthenia Gravis: Making Progress for More Accurate Diagnoses and Targeted Treatments

  https://practicalneurology.com/diseases-diagnoses/neuromuscular/myasthenia-gravis-making-progress-for-more-accurate-diagnoses-and-targeted-treatments/32114/

  Both efgartigimod and rozanolixizumab bind with high affinity to the FcRns located in endosomes within endothelial cells. The FcRns themselves serve to spare immunoglobulin G (IgG) antibodies, including pathogenic AChR IgG antibodies, from lysosomal degradation, and allow them to be recycled back into circulation. By blocking these receptors, both efgartigimod and rozanolixizumab lead to a reduction in circulating AChR antibodies, and less interference with, or damage to, the NMJ. […] MuSK MG has a unique immunopathogenesis and treatment paradigm. This form of MG has been demonstrated to respond robustly to treatment with anti-B-cell therapies, such as rituximab. However, because MuSK MG is an IgG4-mediated disorder and this subclass of IgG does not fix complement, complement inhibitors do not have a role in the treatment of MuSK MG.

• #10 Pathogenesis of myasthenia gravis: update on… | F1000Research

  https://f1000research.com/articles/5-1513

  AChR autoantibodies are mainly of the IgG1 and 3 subtypes, and so they are divalent and complement activating. Binding of these antibodies to AChRs results in activation of the classical complement pathway with assembly of the membrane attack complex (MAC). Calcium influx through the MAC causes local damage to the membrane, with release of AChR-containing membrane debris into the synaptic cleft. […] The damaged postsynaptic membrane shows a diminished response to acetylcholine, as measured electrophysiologically by reduced amplitudes of EPPs and mEPPs. […] Importantly, and not widely appreciated, the complement damage also causes a loss of voltage-gated sodium channels, which are located in the secondary folds, raising the threshold that the EPP must reach to trigger the muscle action potential.

• #10 Pathogenesis of myasthenia gravis: update on… | F1000Research

  https://f1000research.com/articles/5-1513

  The proposed effect of MuSK autoantibodies upon the mechanisms of postsynaptic differentiation and synaptic function is illustrated in Figure 2. […] Thus, a combination of cell culture and mouse studies suggests that MuSK autoantibodies, which are mainly of the IgG4 type, block the natural activation of MuSK, leading to progressive loss of AChRs from the motor endplate and synaptic failure.

• #11

  https://www.jci.org/articles/view/179742

  The clinical phenotype of MG is driven by destruction of the NMJs, leading to impaired neurotransmission between motor neurons and muscle fibers. […] Neuromuscular transmission failure occurs owing to a reduction in the number or activity of AChR molecules at the NMJ, leading to a decrease in the end-plate potential (EPP). […] Individuals with MG produce autoantibodies that mediate disruption of the NMJ leading to compromised neuromuscular transmission. […] AChR antibodies impair neuromuscular transmission through three mechanisms. […] Evidence in both humans and animal models has demonstrated the importance of complement activation in mediating disease in patients with AChR antibody-positive MG. […] MuSK antibodies interfere with clustering of AChR on the postsynaptic muscle surface directly opposed to the nerve terminal.

• #11

  https://www.jci.org/articles/view/179742

  Substantial advancements in understanding MG pathophysiology have led to growing recognition of various mechanisms contributing to disease development in different patient groups. […] Uniformly, MG is an antibody-mediated disease, with B cells requiring T cell help; increasing appreciation of fundamental dysregulation of T cell function leading to compromised immune checkpoints highlights autoreactive B cells as a driver of pathology. […] The thymus is the organ of T cell maturation and establishment of central tolerance. […] The MG thymus also has muscle-like cells and thymic epithelial cells that express AChR-like proteins. […] These observations have led to the hypothesis that ongoing complement attack of myoid and epithelial cells promotes germinal center formation. […] Development of MG requires the generation of autoreactive T cells within the tumor and subsequent exit of these T cells to the periphery and is further associated with a reduction of Tregs.

• #11

  https://www.jci.org/articles/view/179742

  The autoimmune regulatory protein AIRE, which is responsible for expression of self-epitopes to allow for negative selection of autoreactive T cells, is absent in close to all thymomas irrespective of the presence of MG. […] The definition of MG subtypes has led to the recognition that MG is not a singular disease but rather should be classified as an autoimmune disorder affecting postsynaptic transmission.

• #11

  https://www.jci.org/articles/view/179742

  Myasthenia gravis (MG) stands as a prototypical antibody-mediated autoimmune disease: it is dependent on T cells and characterized by the presence of autoantibodies targeting proteins located on the postsynaptic surface of skeletal muscle, known as the neuromuscular junction. […] Recent decades have witnessed substantial progress in understanding the underlying pathophysiology, leading to the delineation of distinct subcategories within MG, including MG linked to AChR or MuSK antibodies as well as age-based distinction, thymoma-associated, and immune checkpoint inhibitor-induced MG. […] Notably, the FDA has recently approved therapeutic inhibitors of complement and the IgG receptor FcRn, a testament to our improved comprehension of autoantibody effector mechanisms in MG. […] Autoimmune destruction of the neuromuscular junctions (NMJs) that transmit motor neuron impulses to muscle fibers causes weakness in voluntary muscles that varies widely in severity and scope among affected individuals.

• #12 Myasthenia Gravis: Pathogenic Effects of Autoantibodies on Neuromuscular Architecture

  https://www.mdpi.com/2073-4409/8/7/671

  The loss of AChRs by (1) and (2) has consequences for neuromuscular transmission as reduced AChR densities lead to reduced sensitivity for acetylcholine, reduced mEPPs, and reduced EPPs, and an overall reduction of the safety factor. […] Interestingly, it was found that patients with AChR antibodies show an increased quantal content, which suggests a retrograde signal from the muscle to the nerve in an attempt to compensate for reduced AChR levels by an increase of ACh release. […] MuSK antibodies behave fundamentally different from AChR antibodies. They belong to the IgG4 subclass, which does not activate the classical complement system or immune cells, due to structural differences in the Fc region. […] This has also been demonstrated for MuSK autoantibodies. In fact, an estimate of 99% of IgG4 and MuSK IgG4 is therefore bi-specific, or functionally monovalent, which means they cannot cross-link an antigen of the same kind, excluding antigenic modulation as pathogenic mechanism.

• #12 Myasthenia Gravis: Pathogenic Effects of Autoantibodies on Neuromuscular Architecture

  https://www.mdpi.com/2073-4409/8/7/671

  Myasthenia gravis (MG) is an autoimmune disease of the neuromuscular junction (NMJ). Autoantibodies target key molecules at the NMJ, such as the nicotinic acetylcholine receptor (AChR), muscle-specific kinase (MuSK), and low-density lipoprotein receptor-related protein 4 (Lrp4), that lead by a range of different pathogenic mechanisms to altered tissue architecture and reduced densities or functionality of AChRs, reduced neuromuscular transmission, and therefore a severe fatigable skeletal muscle weakness. […] MG (at least the subtypes with autoantibodies against AChR and MuSK) fulfills the Witebsky postulates that determine whether a disease is of autoimmune origin. These include: 1) The presence of pathogenic autoantibodies or self-reactive T cells, 2) the reproduction of disease by the passive transfer of patient antibodies or T-cells to experimental animals, and 3) circumstantial evidence from clinical cues.

• #13 Myasthenia Gravis: What It Is, Causes, Symptoms & Treatment

  https://my.clevelandclinic.org/health/diseases/17252-myasthenia-gravis-mg

  Myasthenia gravis is an autoimmune condition that causes skeletal muscle weakness. […] Myasthenia gravis (autoimmune type) happens when your bodys immune system mistakenly attacks itself. Researchers arent sure why this happens. Studies suggest that certain immune system cells in your thymus gland have trouble identifying whats a threat to your body (like bacteria or viruses) versus healthy components. […] If you have myasthenia gravis, antibodies destroy the receptor sites, blocking nerve-muscle communication. The catcher cant catch the ball, and communication becomes sluggish or doesnt work at all. […] Many people with myasthenia gravis have thymus gland conditions that may trigger symptoms. The thymus is a small organ in your upper chest. Its part of your lymphatic system. It makes white blood cells that fight infections. Two-thirds of people with myasthenia gravis have overactive thymic cells (thymic hyperplasia). About 1 in 10 people with myasthenia gravis have thymus gland tumors called thymomas, which may be benign (not cancer) or cancerous.

• #14 Myasthenia gravis – Symptoms and causes – Mayo Clinic

  https://www.mayoclinic.org/diseases-conditions/myasthenia-gravis/symptoms-causes/syc-20352036

  The thymus gland, a part of your immune system situated in the upper chest beneath the breastbone, may trigger or maintain the production of antibodies that result in the muscle weakness. […] Researchers believe that the thymus gland makes or helps produce the antibodies that block acetylcholine. […] In some adults with myasthenia gravis, however, the thymus gland is larger than usual. Some people with myasthenia gravis also have tumors of the thymus gland, called thymomas.

• #15

• #15 Overview of biomarkers in myasthenia gravis

  https://www.explorationpub.com/Journals/ent/Article/100429

• #16 IL-6 and Akt are involved in muscular pathogenesis in myasthenia gravis | Acta Neuropathologica Communications | Full Text

  https://actaneurocomms.biomedcentral.com/articles/10.1186/s40478-014-0179-6

  Anti-acetylcholine receptor (AChR) autoantibodies target muscles in spontaneous human myasthenia gravis (MG) and its induced experimental autoimmune model MG (EAMG). The aim of this study was to identify novel functional mechanisms occurring in the muscle pathology of myasthenia. […] A transcriptome analysis performed on muscle tissue from MG patients (compared with healthy controls) and from EAMG rats (compared with control rats) revealed a deregulation of genes associated with the Interleukin-6 (IL-6) and Insulin-Like Growth Factor 1 (IGF-1) pathways in both humans and rats. […] Anti-AChR antibodies alter IL-6 production by muscle cells, suggesting a putative novel functional mechanism of action for the anti-AChR antibodies. IL-6 is a myokine with known effects on signaling pathways such as Akt/mTOR (mammalian Target of Rapamycin). Since Akt plays a key role in multiple cellular processes, the reduced phosphorylation of Akt by the anti-AChR antibodies may have a significant impact on the muscle fatigability observed in MG patients.

• #16 IL-6 and Akt are involved in muscular pathogenesis in myasthenia gravis | Acta Neuropathologica Communications | Full Text

  https://actaneurocomms.biomedcentral.com/articles/10.1186/s40478-014-0179-6

  Despite the vast body of knowledge accumulated in recent years regarding the underlying immunological mechanisms in MG and EAMG, the molecular mechanisms involved in muscle pathology still remain unclear. […] Our analyses revealed the involvement of the IL-6 and IGF-1 signaling pathways. […] The deregulated genes in the IL-6 and IGF1 pathways are listed in Additional file 1: Table S1. […] We have shown that monoclonal anti-AChR antibodies reduce Akt phosphorylation in response to insulin. […] Our results describe a new mechanism of action of the anti-AChR antibodies in the muscle of MG patients and EAMG models, including IL-6 and IGF-1/Akt pathways. This mechanism could be defined as a functional mechanism. The reduced phosphorylation of Akt by the anti-AChR antibodies may have a significant impact on the muscle fatigability observed in MG patients.

• #17 Signaling pathways of genetic variants and miRNAs in the pathogenesis of myasthenia gravis – Qian – Gland Surgery

  https://gs.amegroups.org/article/view/56329/html

  Myasthenia gravis (MG) is a chronic autoimmune neuromuscular disorder causing muscle weakness and characterized by a defect in synaptic transmission at the neuromuscular junction. The pathogenesis of this disease remains unclear. […] We speculate that SNPs cause the genes to be defective or the miRNAs to downregulate the factors that subsequently negatively regulate regulatory T cells and trigger the onset of MG. […] Five genes containing SNPs associated with MG risk were involved in the inflammatory bowel disease (IBD) signaling pathway, and FoxP3 was the key gene. […] The key genes targeted by SNPs and miRNAs are involved in negative regulation of T cell differentiation. […] Overall, the mechanisms of the IBD pathway in MG are unclear, but we speculate that at the DNA level, mutations of Foxp3 apply to Tregs, leading to severe autoimmune diseases via the IBD signaling pathway.

• #18 Pathogenesis of myasthenia gravis: update on disease types, models, and mechanisms. — Oxford Neuroscience

  https://www.neuroscience.ox.ac.uk/publications/635541

  Myasthenia gravis is an autoimmune disease of the neuromuscular junction (NMJ) caused by antibodies that attack components of the postsynaptic membrane, impair neuromuscular transmission, and lead to weakness and fatigue of skeletal muscle. […] The pathogenesis of myasthenia gravis depends upon the target and isotype of the autoantibodies. Most cases are caused by immunoglobulin (Ig)G1 and IgG3 antibodies to the acetylcholine receptor (AChR). They produce complement-mediated damage and increase the rate of AChR turnover, both mechanisms causing loss of AChR from the postsynaptic membrane. […] In a proportion of those patients without AChR antibodies, antibodies to muscle-specific kinase (MuSK), or related proteins such as agrin and low-density lipoprotein receptor-related protein 4 (LRP4), are present. MuSK antibodies are predominantly IgG4 and cause disassembly of the neuromuscular junction by disrupting the physiological function of MuSK in synapse maintenance and adaptation. […] Myasthenia gravis remains a paradigm for autoantibody-mediated conditions and these observations show how much there is still to learn about synaptic function and pathological mechanisms.

• #19 Myasthenia Gravis: New Drugs and a Road to Individualized Treatment > News > Yale Medicine

  https://www.yalemedicine.org/news/myasthenia-gravis-new-drugs-individualized-treatment

  We’re trying to understand the mechanisms within these patient groups more deeply so we can understand why two different patients can have the same disease and autoantibodies, but one patient will respond remarkably well to a particular therapeutic and the other won’t. […] The new therapeutics target specific parts of the immune system. […] Still, all of these therapeutics, while effective, are only eliminating the immunological activity, explaining that researchers want to target the source of that irregular activity. […] Fixing the defect or defects that allow the autoantibodies to be produced would be closer to a cure and eliminate the need for chronic therapy.

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