Pathophysiology Of Myasthenia Gravis Research Articles

Dysregulated Long Non-coding RNAs in Myasthenia Gravis- A Mini-Review.

Myasthenia gravis (MG) is an acquired autoimmune disease that is mediated by humoral immunity, supplemented by cellular immunity, along with participation of the complement system. The pathogenesis of MG is complex; although autoimmune dysfunction is clearly implicated, the specific mechanism remains unclear. Long non-coding RNAs (lncRNAs) are a class of non-coding RNA molecules with lengths greater than 200 nucleotides, with increasing evidence of their rich biological functions and high-level structure conservation. LncRNAs can directly interact with proteins and microRNAs to regulate the expression of target genes at the transcription and post-transcription levels. In recent years, emerging studies have suggested that lncRNAs play roles in the differentiation of immune cells, secretion of immune factors, and complement production in the human body. This suggests the involvement of lncRNAs in the occurrence and progression of MG through various mechanisms. In addition, the differentially expressed lncRNAs in peripheral biofluid may be used as a biomarker to diagnose MG and evaluate its prognosis. Moreover, with the development of lncRNA expression regulation technology, it is possible to regulate the differentiation of immune cells and influence the immune response by regulating the expression of lncRNAs, which will provide a potential therapeutic option for MG. Here, we review the research progress on the role of lncRNAs in different pathophysiological events contributing to MG, focusing on specific lncRNAs that may largely contribute to the pathophysiology of MG, which could be used as potential diagnostic biomarkers and therapeutic targets.

Pathophysiology of Childhood-Onset Myasthenia: Abnormalities of Neuromuscular Junction and Autoimmunity and Its Background.

The pathophysiology of myasthenia gravis (MG) has been largely elucidated over the past half century, and treatment methods have advanced. However, the number of cases of childhood-onset MG is smaller than that of adult MG, and the treatment of childhood-onset MG has continued to be based on research in the adult field. Research on pathophysiology and treatment methods that account for the unique growth and development of children is now desired. According to an epidemiological survey conducted by the Ministry of Health, Labour and Welfare of Japan, the number of patients with MG by age of onset in Japan is high in early childhood. In recent years, MG has been reported from many countries around the world, but the pattern of the number of patients by age of onset differs between East Asia and Western Europe, confirming that the Japanese pattern is common in East Asia. Furthermore, there are racial differences in autoimmune MG and congenital myasthenic syndromes according to immunogenetic background, and their pathophysiology and relationships are gradually becoming clear. In addition, treatment options are also recognized in different regions of the world. In this review article, I will present recent findings focusing on the differences in pathophysiology.

Future perspectives in myasthenia gravis (Review)

Myasthenia gravis (MG) is a rare, highly polygenic autoimmune disease mainly caused by target‑specific pathogenic antibodies, and its fluctuating course through the patient's life, often entails hospitalizations and difficulties in everyday life. The pathophysiology of MG is complex with a number of contributing factors, involving genetic, epigenetic and environmental factors are responsible for a limited immune tolerance. This heterogenic disease appears to have a common genetic background with other diseases and a number of single nucleotide polymorphisms (SNPs) have been found to be associated with different forms of MG through genome‑wide association studies; i.e, the cholinergic receptor nicotinic alpha 1 subunit (<em>CHRNA1</em>) that encodes for subunit α of the acetylcholine receptor includes a SNP allele associated with MG. Additionally, specific genes or even genomic regions can be differentiated by a set of epigenetic factors, including methylations, non‑coding RNAs and histone modifications. The role of epigenetics in MG has been reported in monozygotic twin studies, where the combination of specific methylations and numerous small changes in gene expression have been shown to contribute to the development of the disease, demonstrating a stronger genetic predisposition for MG. Establishing the genetic and epigenetic background of MG in the realm of autoimmune diseases can further promote basic research and the development of novel therapeutic approaches that can be used to overcome the limitations of current clinical practices.

MicroRNA expression profiles of peripheral blood and mononuclear cells in myasthenia gravis: A systematic review

BackgroundStudies have described the role of microRNAs (miRNAs) in thymic function, along with directly observing the altered expression of miRNAs in thymuses of myasthenia gravis (MG) patients; so, miRNAs became a core component in the pathophysiology of MG. However, because the miRNA analysis results are contradictory, the identification of MG-related miRNAs is daunting. ObjectiveWe did a systematic review of studies analyzing the miRNA expression profile of peripheral blood and mononuclear cells for patients with MG. MethodsWe ran a database search in PubMed, Scopus, and Web of Science on August 17, 2021. Original articles that analyzed miRNA profiles in peripheral blood (serum, plasma, and whole blood) and peripheral blood mononuclear cells (PBMCs) for patients with MG in comparison with a non-MG or healthy control (HC) group were eligible. The quality of studies was assessed using the Quality Assessment of Diagnostic Accuracy Studies 2 (QUADAS-2). Results26 studies were included. The quality of studies was fair (median score, 5). Among 226 different miRNAs that were deregulated in at least one study (range, 1–87), ten miRNAs were significantly deregulated in three or more studies. Five miRNAs (50%) showed the same deregulation: miR-106b-3p and miR-21-5p were consistently upregulated, and miR-20b, miR-15b, and miR-16 were consistently downregulated. Also, there were five miRNAs that were mostly upregulated, miR-150-5p, miR-146a, miR-30e-5p, and miR-338-3p, or downregulated, miR-324-3p, across studies. ConclusionThese miRNAs contribute to different pathways, importantly neural apoptosis and autophagy, inflammation, T regulatory cell development, and T helper cell balance. Prior to being used for diagnostic and therapeutic purposes, it is required to pursue molecular mechanisms these consistently and mostly dysregulated miRNAs specifically use in the context of MG.

Practical Management for Use of Eculizumab in the Treatment of Severe, Refractory, Non-Thymomatous, AChR + Generalized Myasthenia Gravis: A Systematic Review.

Myasthenia gravis (MG) is a rare autoimmune disorder caused by specific autoantibodies at the neuromuscular junction. MG is classified by the antigen specificity of these antibodies. Acetylcholine receptor (AChR) antibodies are the most common type (74–88%), followed by anti-muscle specific kinase (MuSK) and other antibodies. While all these antibodies lead to neuromuscular transmission failure, the immuno-pathogenic mechanisms are distinct. Complement activation is a primary driver of AChR antibody-positive MG (AChR+ MG) pathogenesis. This leads to the formation of the membrane attack complex and destruction of AChR receptors and the postsynaptic membrane resulting in impaired neurotransmission and muscle weakness characteristic of MG. Broad-based immune-suppressants like corticosteroids are effective in controlling MG; however, their long-term use can be associated with significant adverse effects. Advances in translational research have led to the development of more directed therapeutic agents that are likely to alter the future of MG treatment. Eculizumab is a humanized monoclonal antibody that inhibits the cleavage of complement protein C5 and is approved for use in generalized MG. In this review, we discuss the pathophysiology of MG; the therapeutic efficacy and tolerability of eculizumab, as well as the practical guidelines for its use in MG; future studies exploring the role of eculizumab in different stages and subtypes of MG subtypes; the optimal duration of therapy and its discontinuation; the characterization of non-responder patients; and the use of biomarkers for monitoring therapy are highlighted. Based on the pathophysiologic mechanisms, emerging therapies and new therapeutic targets are also reviewed.

Myastenia Gravis Hastalarının Klinik Özellikleri: 138 Hastanın Değerlendirilmesi

Aim: The aim of this study was to evaluate the demographic characteristics, clinical presentation, antibody, and electrophysiological characteristics of patients with the diagnosis of Myasthenia Gravis (MG).&#x0D; Materials and Methods: The demographic characteristics, clinical presentation, antibody, electrophysiological and radiological (thoracic tomography) characteristics of the patients who were followed in the Neuromuscular and Muscular Diseases Polyclinic of the hospital between 2014-2019 were analyzed.&#x0D; Results: The mean age of the patients was 53.8±16.67 years. The mean disease duration was 4.8±5.05 years. Ptosis was the most common complaint in 79% (n=109) of our patients. The number of patients followed as pure ocular MG was 61.6% (n=85). There were 26 patients who presented with ptosis or diplopia at the first presentation and follow-up generalized MG with bulbar findings and weakness. Acetylcholine receptor antibody (AntiAChRAb) positivity was found in 78.3% (n=108) of the patients and thymus pathology was detected in thorax tomography in 37.7% (n=52).&#x0D; Conclusions: The initial complaint provides little insight into the course of the disease. The important factor is clinical follow-up. Although MG treatment is known, the pathophysiology of MG remains to be elucidated, and other autoimmune conditions cause changes in treatment choice. Clarifying the pathophysiology of MG will enable the development of more effective diagnostic and treatment methods.

The treatment effect on peripheral B cell markers in antibody positive myasthenia gravis patients

B cells play a major role in the pathophysiology of myasthenia gravis (MG) with their ability to produce disease specific, pathogenic antibodies. However, their status during disease development and follow-up stages of the disease in the peripheral blood may need further studies to determine useful markers. In this study, we aimed to detect B cell associated factors concerning immunosuppressive treatment in generalized non-thymomatous MG patients. Although CD19+ B cell distribution did not vary among disease subgroups, expressions of both CD38 and BAFFR were altered on B cells in MG patients under immunosuppressive therapy. Serum levels of BAFF were elevated in untreated MG patients as compared to treated MG patients and healthy controls. B cell activation factors may show profound alterations due to immunosuppression.

Pain, Headache, and Other Non-motor Symptoms in Myasthenia Gravis.

Myasthenia gravis (MG) is traditionally conceptualized as a disease with purely motor manifestations. This paper reviews the supporting evidence and pathophysiology of non-motor symptoms in MG, including pain, headache, special sense and autonomic dysfunction, sleep disturbance, and cognitive and psychosocial issues. Work in this area has been limited. Recent studies have identified bodily pain and headache as common complaints in patients with MG. A growing literature also suggests that there may be an association of MG and sleep disturbance (both obstructive sleep apnea and sleep cycle dysfunction). Few studies suggest some measurable abnormalities of olfaction, gustation, audition, and autonomic function. The cognitive and psychosocial aspects of MG represent an emerging area of clinical and research interest, but large-scale data is sparse in the USA. The pathophysiology of MG is complex, and our understanding of the immunologic basis of this disease is expanding. The classic view of MG as a purely motor disorder may be incomplete. Recent work highlights non-motor symptoms that may impact patient management and quality of life.

B cells in the pathophysiology of myasthenia gravis.

Myasthenia gravis (MG) is an archetypal autoimmune disease. The pathology is characterized by autoantibodies to the acetylcholine receptor (AChR) in most patients or to muscle-specific tyrosine kinase (MuSK) in others and to a growing number of other postsynaptic proteins in smaller subsets. A decrease in the number of functional AChRs or functional interruption of the AChR within the muscle end plate of the neuromuscular junction is caused by pathogenic autoantibodies. Although the molecular immunology underpinning the pathology is well understood, much remains to be learned about the cellular immunology contributing to the production of autoantibodies. This Review documents research concerning the immunopathology of MG, bringing together evidence principally from human studies with an emphasis on the role of adaptive immunity and B cells in particular. Proposed mechanisms for autoimmunity, which take into account that different types of MG may incorporate divergent immunopathology, are offered. Muscle Nerve 57: 172-184, 2018.

Expression of Interleukin‐22 in Myasthenia Gravis

IL-17 and IL-22 are implicated in the pathogenesis of autoimmune diseases. The roles of IL-22 in the pathophysiology of myasthenia gravis (MG) remain unsettled. The aim of this study was to investigate the possible relationship between serum IL-22, IL-17 levels, anti-acetylcholine receptor antibody (anti-AChR Ab) titres and clinical parameters in patients with MG. The serum IL-22, IL-17 levels and anti-AChR Ab titres were tested by enzyme-linked immunosorbent assay (ELISA), while the expression of IL-22 and IL-17 mRNAs in peripheral blood mononuclear cells (PBMC) from healthy and MG subjects were detected by quantitative real-time PCR (qRT-PCR). Furthermore, PBMC from 12 patients with generalized MG were purified and treated with recombinant human IL-22 (rhIL-22), the IL-17 levels of supernatant were detected by ELISA. We found that the IL-17 levels were significantly increased, but IL-22 levels were significantly decreased in the serum of patients with MG compared with healthy controls. Consistantly, a significant decrease in IL-22 mRNA levels and an increase in IL-17 mRNA levels were detected in PBMC collected from patients with MG, compared with healthy controls. A negative correlation between IL-22 mRNA in PBMC, serum IL-22 and serum anti-AChR Ab levels was found in patients with MG. Moreover, in cultured MG PBMC treated with recombinant human IL-22 (rhIL-22), the IL-17 levels were decreased in a dose-dependent manner. Our findings indicated a possible role of IL-22 as a protective factor in MG.

Myasthenia gravis in dogs with an emphasis on treatment and critical care management

To review the human and veterinary literature on the pathophysiology of myasthenia gravis (MG) and describe treatment options for clinical use in people and animals. Human and veterinary clinical reports, studies and reviews, textbooks, and recent research findings in MG from 1996 present, with a focus on treatment and patient management. MG is a well-described condition in people with new research and treatment options available. Many of the newest therapeutic options available in veterinary medicine for MG are based on current strategies used in people with this condition. Seronegative MG is well described in people and provides insight to clinical cases encountered in veterinary medicine when the index of suspicion is high though serologic tests are negative. Previous studies in veterinary medicine focused on the use of acetylcholinesterase inhibitors as the main form of treatment in canine MG. Recent studies, mainly case series and case reports, emphasize the use of immunomodulatory treatments as an alternative for long-term treatment. However, there are no randomized, controlled studies on treatment with immunomodulatory therapy for MG in dogs available to assess the efficacy of this treatment strategy. Although early recognition of clinical signs is most important in the outcome of patients with MG, further understanding the pathophysiology of MG may lead to earlier diagnosis and novel treatment strategies. The discovery of additional autoantibodies against striated muscle proteins in dogs, should enhance our understanding of diseases affecting the neuromuscular junction. In addition, clinical data for canine MG could be applied to other autoimmune disorders.

Sugammadex is Safe and Effective for Patients with Myasthenia Gravis

Thymoma, which can be surgically treated under general anesthesia, is associated with the pathophysiology of myasthenia gravis. Muscle weakness is a hallmark of myasthenia gravis; therefore, these patients are hypersensitive to the effects of nondepolarizing muscle relaxants. Neuromuscular blockers can cause prolonged postoperative muscle relaxation, leading to decreased respiratory function. Therefore, careful administration of muscle relaxants during the perioperative period is important. The neuromuscular antagonist, sugammadex, has been used to counteract problems associated with muscle relaxants. By encapsulating nondepolarizing muscle relaxants, sugammadex can reverse the neuromuscular blockade. Here we report three cases of myasthenia gravis. In each case, perioperative management included use of a train-of-four (TOF) monitor to minimize muscle relaxant use during surgery. Sugammadex was administered postoperatively, was safe for use in patients with myasthenia gravis, and may effectively reduce the risk of postoperative respiratory complications.

Identification of CTLA-4 isoforms produced by alternative splicing and their association with myasthenia gravis

Myasthenia gravis (MG) is an autoimmune disease characterized by muscle weakness induced by autoantibodies against the acetylcholine receptor. CTLA-4 (CD152) plays an inhibitory role in the immune response and has been suggested to be involved in the pathophysiology of MG. In this study, we focused on alternative CTLA-4 mRNA expression in PBMCs from MG patients. We defined two new isoforms of CTLA-4 mRNA that arise due to alternative splicing. By semi-quantitative RT-PCR analysis, we observed a lower expression of sCTLA-4 mRNA relative to the membrane form in MG patients. In addition, the MG patients had lower levels of sCTLA-4 mRNA in PBMCs compared to healthy controls, as assessed by real-time PCR. One of the spliced isoforms (LCTLA-4) was more prevalent in MG patients compared to healthy controls. The alternative splicing was not associated with sex, thymectomy, serum levels of anti-AChR, immunosuppressive treatment or the four CTLA-4 gene polymorphisms analyzed. This study reveals an abnormal spectrum of mRNA expression of CTLA-4 in MG patients, which marks the importance of studying gene expression of alternative splicing.

CCR2-64I and CCR5Δ32 Polymorphisms in Korean Patients with Myasthenia Gravis

Background and purposeChemokines participate in the regulation of immune and inflammatory responses by interacting with their receptors, which are primarily expressed on immune and inflammatory cells such as B- and T-lymphocytes and antigen-presenting cells. Chemokines and their receptors are therefore considered to mediate inflammation and tissue damage in autoimmune disorders. Chemokine receptor (CCR) genotypes were recently identified, and the importance of their genetic polymorphisms in some autoimmune and infectious disorders has been demonstrated. To define the roles of the polymorphism of the CCR2 gene at codon 64 (CCR2-64I) and the 32-bp deletion in the coding region of CCR5 (CCR5Δ32) in Korean patients with myasthenia gravis (MG), we compared these genotypes in MG cases and healthy controls and investigated the clinical features associated with these genotypes.MethodsOne hundred and fifteen healthy controls (51 men and 64 women) and 109 MG patients (44 men and 65 women) from three University hospitals were included. We examined each patient for clinical features using electrophysiology tests, laboratory tests, and thymic pathology. The CCR2-64I and CCR5Δ32 polymorphisms were determined by the PCR-RFLP method.ResultsWe detected no difference in the frequencies of CCR2-64I polymorphism between MG patients and healthy controls. All of the MG patients and the healthy controls were homozygous for the wild-type CCR5 genotype. The results of electrophysiological tests and thymic pathologies were not influenced by the type of CCR2-64I polymorphism. However, the anti-acetylcholine-receptor (AChR) antibody titer was higher in the CCR2 G/G genotype (13.34±12.71 nmol/L) than in the CCR2 A/A genotype (5.83±2.56 nmol/L).ConclusionsWe found no evidence of an increased risk for MG associated with the CCR2-64I and CCR5Δ32 polymorphisms. However, the increased anti-AChR antibody titer in the patients with the CCR2 G/G genotype suggests that the CCR2 gene play a role in the pathophysiology of MG.

Interleukine-6 (IL-6) may be a link between myasthenia gravis and myoepithelioma of the parotid gland

Myoepithelioma is a rare benign neoplasm of the salivary glands occurring more frequently in the parotids. Myasthenia gravis (MG) is a chronic, T-cell dependent, antibody and complement-mediated autoimmune neuromuscular transmission disorder. Interleukine-6 (IL-6) is an immune protein belonging to the family of the hematopoietins, liberated in response to infection, burns, trauma, and neoplastic diseases. It seems that an overproduction of IL-6 might play an important role in the pathophysiology of MG. Moreover, it has been discussed the possible role of IL-6 as a modulating factor either in proliferation or in differentiation of pleomorphic adenoma cell line into myoepithelioma. The authors present a rare case of parotid myoepithelioma occurred in a patient affected by myasthenia gravis and suppose a possible IL-6 mediated relationship between myasthenia gravis and parotid myoepithelioma.

Raised prolactin levels in myasthenia gravis: two case reports and a study of two patient populations

To describe two patients with myasthenia gravis (MG) and prolactinoma and analyze the associations between MG and prolactin (PRL) levels. Two case reports and a case-control study of PRL levels in 192 patients with MG. The Immunological Research Laboratory, Center for Molecular Medicine, Department of Medicine and the Department of Neurology, Karolinska Institutet, Stockholm, Sweden; St Petersburg Medical Academy for Postgraduate Studies, and St Petersburg State Medical Pediatric Academy, Russia. Two women with MG and thymic hyperplasia accompanied by prolactinomas are described. The levels of plasma PRL were raised in 101 women with MG, but not in 91 men. There was an association between high PRL levels and high levels of autoantibodies against the acetylcholine receptor. There is an association of MG with raised levels of PRL in women. PRL has stimulating effects on immune activation and the increased levels might thus be implied in the pathophysiology of MG.

Inhibition of IL‐6 overproduction by steroid treatment before transsternal thymectomy for myasthenia gravis: does it help stabilize perioperative condition?

Overproduction of interleukin (IL)-6 plays an important role in the pathophysiology of myasthenia gravis (MG), and thymectomy can cause myasthenic crisis because of surgically induced overproduction of IL-6. Preoperative steroid therapy is beneficial in preventing MG crisis during the perioperative period. The purpose of this study was to clarify the effect of preoperative steroid therapy on proinflammatory mediators during the perioperative period of transsternal thymectomy for MG. The study group comprised 20 consecutive MG patients undergoing transsternal thymectomy during the period March 2002 through March 2004. Seventeen of these patients received dose-escalated steroid therapy before thymectomy (steroid treatment group) and three did not (non-steroid treatment group). Serum concentrations of C-reactive protein (CRP) and IL-6 were determined during the perioperative period; clinical outcomes were reviewed, and the results were compared between the two groups. Peak serum IL-6 and CRP concentrations were significantly lower in the steroid treatment group than in the non-steroid treatment group. Amongst perioperative variables subjected to multiple regression analysis, preoperative steroid treatment were found to be the most significant independent predictor of inhibited IL-6 production on postoperative day 1. No postoperative respiratory failure occurred in the steroid treatment group, but it did occur in the non-steroid treatment group. Preoperative steroid therapy can ameliorate IL-6 overproduction and may help stabilize the patient's postoperative condition.

The role of readthrough acetylcholinesterase in the pathophysiology of myasthenia gravis.

Alternative splicing induces, under abnormal cholinergic neurotransmission, overproduction of the rare "readthrough" acetylcholinesterase variant AChE-R. We explored the pathophysiological relevance of this phenomenon in patients with myasthenia gravis (MG) and rats with experimental autoimmune MG (EAMG), neuromuscular junction diseases with depleted acetylcholine receptors. In MG and EAMG, we detected serum AChE-R accumulation. In EAMG, we alleviated electromyographic abnormalities by nanomolar doses of EN101, an antisense oligonucleotide that selectively lowers AChE-R in blood and muscle yet leaves unaffected the synaptic variant AChE-S. Whereas animals treated with placebo or conventional anticholinesterases continued to deteriorate, a 4 wk daily oral administration of EN101 improved survival, neuromuscular strength and clinical status in moribund EAMG rats. The efficacy of targeting only one AChE splicing variant highlights potential advantages of mRNA-targeted therapeutics for chronic cholinergic malfunctioning.

High serum adenosine deaminase activity and its correlation with lymphocyte subsets in myasthenia gravis

Serum adenosine deaminase (ADA) activity and peripheral lymphocyte subsets of patients with myasthenia gravis (MG) were simultaneously measured. The ADA activity in MG (n = 30) was significantly higher as compared with normal control (n = 150) and multiple sclerosis (n = 12) (P less than 0.05). The ADA activity of generalized MG was higher than that of ocular MG, while a significant elevation of ADA activity was observed in grade IIB as compared with grade I of Osserman's classification (P less than 0.05). A trend of high ADA activity was demonstrated in those whose disease had advanced to a severe degree associated with unstable clinical features (P less than 0.05). In addition, there was a significant elevation of ADA activity in patients who disclosed positive anti-Ach-receptor-antibody as compared with negative one (P less than 0.05). There was no specific trend among the proportions of the subsets of peripheral lymphocytes which could reflect the severity of MG, however, the proportion of OK Ia1+ tended to be higher with advancing the grade of MG. Interestingly enough, a close correlation was found between the ADA activity and the proportion of OK Ia1+ cells (P less than 0.05). From the above results, it was concluded that high ADA may be responsible for the pathophysiology of MG through the alteration of peripheral lymphocyte function.

Antibody to acetylcholine receptor in canine and human myasthenia gravis: differential cross-reactivity with human and rabbit receptor.

Anti-acetylcholine receptor (AChR) antibody (ab) was found in the serum of a dog with acute myasthenia gravis (MG) by the use of Cowan 1 strain Staphylococcus aureus to bind radiolabeled anti-AChR ab-AChR immune complexes. Fifteen months later, when the dog was in remission, there was only a very low level of the anti-AChR ab. These observations strengthen the contention that anti-AChR ab is important in the pathophysiology of myasthenia gravis. Higher titers of the canine ab were measured with rabbit than with human AChR, whereas 17 human MG sera, selected to represent a wide range of anti-AChR ab titers, were all more reactive with human AChR. The degree of cross-reactivity of human anti-AChR ab with rabbit AChR varied widely, indicating a heterogeneous population of anti-AChR ab molecules in human myasthenia gravis sera.