Novel genes/loci validate the small effect size of ERBB2 in patients with myasthenia gravis.
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ABSTRACT:
SUBMITTER: Zhu Z
PROVIDER: S-EPMC9459313 | biostudies-literature | 2022 Sep
REPOSITORIES: biostudies-literature
Publications
Novel genes/loci validate the small effect size of ERBB2 in patients with myasthenia gravis.
Zhu Zijun Z Chen Xinyu X Wang Chao C Cheng Liang L
Proceedings of the National Academy of Sciences of the United States of America 20220815 36
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Project description:Myasthenia gravis (MG), a prototype autoimmune neurological disease, had its therapy centred on corticosteroids, non-steroidal broad-spectrum immunotherapy and cholinesterase inhibitors for several decades. Treatment-refractory MG and long-term toxicities of the medications have been major concerns with the conventional therapies. Advances in the immunology and pathogenesis of MG have ushered in an era of newer therapies which are more specific and efficacious. Complement inhibitors and neonatal Fc receptor blockers target disease-specific pathogenic mechanisms linked to myasthenia and have proven their efficacy in pivotal clinical studies. B cell-depleting agents, specifically rituximab, have also emerged as useful for the treatment of severe MG. Many more biologicals are in the pipeline and in diverse stages of development. This review discusses the evidence for the novel therapies and the specific issues related to their clinical use.
| S-EPMC10082579 | biostudies-literature
Project description:BackgroundRecent years have seen a rapid growth in the number of online health communities targeted at patients with long-term conditions. Myasthenia Gravis (MG) is a rare neurological disease for which such communities have not been analysed before. The aim of this study was to better understand the needs of the MG population through the collation and categorisation of questions that users of MG social media were asking fellow users on these platforms.MethodologySystematic observation of four MG Facebook groups was conducted over a 2-month period. Groups were selected for analysis based on the following systematic criteria: Language (English), Membership (≥ 5,000 members), group activity (≥ 2 posts per week), target audience (general MG population) and researcher engagement with group administrators. The study protocol was reviewed by the institutional review board of the Charité-Universitätsmedizin Berlin (EA2/106/22). During the observation period, data were extracted from individual posts featuring questions made across each group using a systematic and objective coding scheme. All data points were coded directly from the source and collated into an SPSS database (IBM SPSS V.27, SPSS). Absolute and relative frequencies were calculated for categorical variables and proportions were compared across groups to validate the credibility and relevance of different requests.ResultsOf the 2,062 posts observed (N = 2,062), 1,392 featured questions (n = 1,392). Questions were asked by 787 unique users: 531 were identified as one-time users (67%) and 256 were identified as repeat users (33%). Six hundred and fifty six users were classified as presumed diagnosed (83%), 61 as seeking diagnosis (8%), 69 as family and/or friends (9%) and as other (<0%). Eight unique categories of questions were observed including MG treatment (31%), Symptoms (19%), Living with MG (12%), Diagnosis (10%), non-MG medication (11%), Tests (8%), Location (4%) and Other (4%).ConclusionMembers of the MG population make active use of online health communities to seek and discuss practical information concerning various aspects of the disease, its diagnosis and care. The openness and willingness of the sample population to share sensitive medical information shows a high need for information not entirely catered to by the medical profession.
| S-EPMC11483605 | biostudies-literature
Project description:Background Myasthenia gravis (MG) is an autoimmune disorder with fluctuating muscle weakness, divided into generalized and localized (ocular) forms. Maternal antibodies to acetylcholine receptors cross the placenta and may cause transient neonatal myasthenia gravis (TNMG). We present a case of seronegative maternal ocular MG and delayed TNMG. Case A 29-year-old G3P1011 underwent cesarean birth of a male infant who developed oxygen desaturation requiring supplemental oxygen on day of life (DOL) 3. Based on the clinical course and after exclusion of other diagnoses, the infant was diagnosed with TNMG. Infant's condition improved spontaneously and he was weaned off supplemental oxygen and discharged home on DOL 12. Conclusion Infants born to mothers with seronegative localized (ocular) MG are also susceptible to TNMG which may be late in onset.
| S-EPMC4794443 | biostudies-other
Project description:Purpose of reviewThis review summarizes recent insights into the immunopathogenesis of autoimmune myasthenia gravis (MG). Mechanistic understanding is presented according to MG disease subtypes and by leveraging the knowledge gained through the use of immunomodulating biological therapeutics.Recent findingsThe past two years of research on MG have led to a more accurate definition of the mechanisms through which muscle-specific tyrosine kinase (MuSK) autoantibodies induce pathology. Novel insights have also emerged from the collection of stronger evidence on the pathogenic capacity of low-density lipoprotein receptor-related protein 4 autoantibodies. Clinical observations have revealed a new MG phenotype triggered by cancer immunotherapy, but the underlying immunobiology remains undetermined. From a therapeutic perspective, MG patients can now benefit from a wider spectrum of treatment options. Such therapies have uncovered profound differences in clinical responses between and within the acetylcholine receptor and MuSK MG subtypes. Diverse mechanisms of immunopathology between the two subtypes, as well as qualitative nuances in the autoantibody repertoire of each patient, likely underpin the variability in therapeutic outcomes. Although predictive biomarkers of clinical response are lacking, these observations have ignited the development of assays that might assist clinicians in the choice of specific therapeutic strategies.SummaryRecent advances in the understanding of autoantibody functionalities are bringing neuroimmunologists closer to a more detailed appreciation of the mechanisms that govern MG pathology. Future investigations on the immunological heterogeneity among MG patients will be key to developing effective, individually tailored therapies.
| S-EPMC9458626 | biostudies-literature
Project description:The benefits of physical exercise for healthy individuals are well-established, particularly in relation to reducing the risks of chronic lifestyle related diseases. Furthermore, physical exercise has been seen to provide beneficial effects in many chronic diseases such as multiple sclerosis, rheumatoid arthritis, and chronic obstructive pulmonary disease and is therefore recommended as part of the treatment regimen. Myasthenia Gravis (MG) is a chronic autoimmune disease that causes neuromuscular transmission failure resulting in abnormal fatigable skeletal muscle weakness. In spite of this fluctuating skeletal muscle weakness, it is reasonable to assume that MG patients, like healthy individuals, could benefit from some of the positive effects of physical exercise. Yet exercise-related research in the field of MG is sparse and does not provide any guidelines on how MG patients should perform physical training in order to obtain exercise's favorable effects without risking disease deterioration or more pronounced muscle fatigue. A handful of recent studies report that MG patients with mild disease activity can adhere safely to general exercise recommendations, including resistance training and aerobic training regimens, without subjective or objective disease deterioration. These findings indicate that MG patients can indeed improve their functional muscle status as a result of aerobic and high-resistance strength training. This knowledge is important in order to establish collective as well as personalized guidelines on physical exercise for MG patients. This review discusses the present knowledge on physical exercise in MG.
| S-EPMC7403401 | biostudies-literature
Project description:Abnormal overexpression of CXCL13 is observed in many inflamed tissues and in particular in autoimmune diseases. Myasthenia gravis (MG) is a neuromuscular disease mainly mediated by anti-acetylcholine receptor autoantibodies. Thymic hyperplasia characterized by ectopic germinal centers (GCs) is a common feature in MG and is correlated with high levels of anti-AChR antibodies. We previously showed that the B-cell chemoattractant, CXCL13 is overexpressed by thymic epithelial cells in MG patients. We hypothesized that abnormal CXCL13 expression by the thymic epithelium triggered B-cell recruitment in MG. We therefore created a novel transgenic (Tg) mouse with a keratin 5 driven CXCL13 expression. The thymus of Tg mice overexpressed CXCL13 but did not trigger B-cell recruitment. However, in inflammatory conditions, induced by Poly(I:C), B cells strongly migrated to the thymus. Tg mice were also more susceptible to experimental autoimmune MG (EAMG) with stronger clinical signs, higher titers of anti-AChR antibodies, increased thymic B cells, and the development of germinal center-like structures. Consequently, this mouse model finally mimics the thymic pathology observed in human MG. Our data also demonstrated that inflammation is mandatory to reveal CXCL13 ability to recruit B cells and to induce tertiary lymphoid organ development.
| S-EPMC4884937 | biostudies-literature
Project description:Myasthenia gravis (MG) is an autoimmune disease affecting the neuromuscular junction, whose clinical hallmark is muscle weakness and early fatigability. Azathioprine (AZA) is commonly used in Myasthenia Gravis therapy. AZA is a purine antagonist, which inhibits the cell cycle in the resting and DNA synthesis phases. It is usually used as an immunosuppressant to block T- and B-cell proliferation. AZA, bioconverted to 6-mercaptopurine by glutathione S-transferase (GST), can be metabolized either through the hypoxanthine phosphoribosyl transferase pathway to active 6-thioguanine nucleotides (6-TGN) or through the thiopurine S-methyltransferase (TPMT) pathway to inactive methyl-thiopurine metabolites. The incorporation of active 6-TGNs into DNA, causing breaks in DNA strands resulting in interference with RNA production and thereby protein synthesis, is responsible for the drug effect. The response to AZA is determined by which metabolic pathway is being favored. While balanced use of both HPRT and TPMT pathways results in responsiveness to AZA, hyperactivity of TPMT skews the balance towards the TPMT pathway and results in unresponsiveness to AZA with no pharmacological effect. In contrast, low TPMT activity skews the balance towards the HPRT pathway, resulting in increasing side-effects due to the accumulation of 6-TGNs. Current treatments for MG therapy are often inadequate because less than 40% of patients achieve complete remission with available drugs. This reflects the lack of drugs acting on target sites for which there is strong evidence of pathogenicity and the inability to identify responder patients. No criteria for responsiveness are available, exposing patients to unpredictable failures and unpredictable side effects. These individuals are at particular risk for adverse drug reaction (ADRs) or therapeutic failure. Genetic profiling with the Affymetrix drug metabolizing enzymes and transports genotyping array offers the ability to determine 1,931 variants and 225 genes involved in drug metabolism and disposition. Accordingly, the study of well-known drug-metabolizing genes can be involved in the specific metabolic pathway of a drug, which is more likely to define genotype-phenotype association and thereby genotype profiles relevant to drug response that can be applied as predictive biomarkers for pharmacological treatment.
2016-05-01 | E-MTAB-4489 | biostudies-arrayexpress
Project description:Myasthenia gravis is a chronic autoimmune disease characterized by autoantibody-mediated interference of signal transmission across the neuromuscular junction. We performed a genome-wide association study (GWAS) involving 1,873 patients diagnosed with acetylcholine receptor antibody-positive myasthenia gravis and 36,370 healthy individuals to identify disease-associated genetic risk loci. Replication of the discovered loci was attempted in an independent cohort from the UK Biobank. We also performed a transcriptome-wide association study (TWAS) using expression data from skeletal muscle, whole blood, and tibial nerve to test the effects of disease-associated polymorphisms on gene expression. We discovered two signals in the genes encoding acetylcholine receptor subunits that are the most common antigenic target of the autoantibodies: a GWAS signal within the cholinergic receptor nicotinic alpha 1 subunit (CHRNA1) gene and a TWAS association with the cholinergic receptor nicotinic beta 1 subunit (CHRNB1) gene in normal skeletal muscle. Two other loci were discovered on 10p14 and 11q21, and the previous association signals at PTPN22, HLA-DQA1/HLA-B, and TNFRSF11A were confirmed. Subgroup analyses demonstrate that early- and late-onset cases have different genetic risk factors. Genetic correlation analysis confirmed a genetic link between myasthenia gravis and other autoimmune diseases, such as hypothyroidism, rheumatoid arthritis, multiple sclerosis, and type 1 diabetes. Finally, we applied Priority Index analysis to identify potentially druggable genes/proteins and pathways. This study provides insight into the genetic architecture underlying myasthenia gravis and demonstrates that genetic factors within the loci encoding acetylcholine receptor subunits contribute to its pathogenesis.
| S-EPMC8812681 | biostudies-literature
Project description:IntroductionLabor-market participation is potentially very difficult for patients with refractory myasthenia gravis (MG). In this study, employment status and work absences are compared between refractory and nonrefractory MG.MethodsAdults (aged 18-64 years, all diagnosed ≥2 years previously) were included if enrolled in the Myasthenia Gravis Foundation of America Patient Registry during July 2013 to February 2018.ResultsSeventy-six patients (9.2%) had refractory and 749 (90.8%) had nonrefractory disease; demographic data did not differ between groups. Relative to the nonrefractory group, the refractory group patients were more than twice as likely to work fewer hours per week (odds ratio [95% confidence interval]: currently employed, 2.777 [1.640-4.704]; employed over previous 6 months, 2.643 [1.595-4.380]), but those employed were not more likely to be absent from work.DiscussionBecause absence from the labor market adversely affects quality of life and personal finances, these findings reaffirm the considerable disease burden associated with refractory MG.
| S-EPMC6900169 | biostudies-literature
Project description:The project was focused on the serum proteomic profiling of the neuromuscular autoimmune disease, Myasthenia gravis (MG). The project aimed to identify candidate serum proteins to understand the disease better. To eliminate any typical autoimmune response Rheumatoid arthritis (RA) was included as a reference disease to the sample group.
2024-01-26 | PXD019633 | Pride