RRNMF Neuromuscular Journal最新文献

{"title":"Assay Development and Measurement of Autoantibody-Mediated Complement Activity in Myasthenia Gravis","authors":"Abeer H. Obaid","doi":"10.17161/rrnmf.v4i3.19545","DOIUrl":"https://doi.org/10.17161/rrnmf.v4i3.19545","url":null,"abstract":"Autoantibodies against the acetylcholine receptor (AChR) play a critical role in myasthenia gravis, where autoantibody-mediated complement activation has been implicated in neuromuscular junction damage. However, the exact pathogenic role of the autoantibodies in complement activation remains unclear. We developed a cell-based assay that measures AChR autoantibody–mediated complement membrane attack complex (MAC) formation. A modified HEK293T cell line using CRISPR/Cas9 genome editing to disrupt expression of the complement regulator genes (CD46, CD55, and CD59)—was used to measure AChR autoantibody–mediated membrane attack complex (MAC) formation through flow cytometry. We observed a modest correlation between autoantibody-mediated complement mediated activity and disease burden suggesting heterogeneity in autoantibody-mediated activation of complement system. ","PeriodicalId":309700,"journal":{"name":"RRNMF Neuromuscular Journal","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"126282493","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Symptomatic, pharmacological treatment of myasthenia gravis.","authors":"L. Remijn-Nelissen, Wisse Bakker, T. van Gelder, M. Tannemaat, J. Verschuuren","doi":"10.17161/rrnmf.v4i3.19548","DOIUrl":"https://doi.org/10.17161/rrnmf.v4i3.19548","url":null,"abstract":"Myasthenia gravis (MG) is a chronic antibody-mediated autoimmune disease. The most frequent form is MG with antibodies directed against the acetylcholine receptor on the postsynaptic membrane. The first step in the treatment of autoimmune myasthenia gravis consists of symptomatic therapy. If this is insufficiently effective, the next step is to start immunosuppressive treatment with corticosteroids, usually prednisolone. A corticoid-sparing agent is often added because of the long long-term side effects of high doses of corticosteroids. The position of emerging immunomodulatory therapies targeting B-and T-cells, the complement cascade, the neonatal Fc receptor, and cytokines associated with antibody production in the treatment of MG is currently unclear. However, it is likely that symptomatic treatment will remain the cornerstone in the management of patients with MG in the foreseeable future. In this review, we provide an overview of currently available symptomatic treatments and recent advances in this field.","PeriodicalId":309700,"journal":{"name":"RRNMF Neuromuscular Journal","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"131120158","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Corticosteroids in Generalized Autoimmune Myasthenia Gravis: A Narrative Review","authors":"T. Sharshar, A. Mazeraud, S. Birnbaum","doi":"10.17161/rrnmf.v4i3.19542","DOIUrl":"https://doi.org/10.17161/rrnmf.v4i3.19542","url":null,"abstract":"No abstract is required for a review article as per instructions","PeriodicalId":309700,"journal":{"name":"RRNMF Neuromuscular Journal","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"125742065","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Diagnostic challenges in myasthenia gravis: a clinical approach","authors":"R. De Meel","doi":"10.17161/rrnmf.v4i3.19549","DOIUrl":"https://doi.org/10.17161/rrnmf.v4i3.19549","url":null,"abstract":"The development of antibody tests and neurophysiological techniques have aided in confirming the diagnosis of myasthenia gravis (MG) over the years. However, there still remains an unmet diagnostic need in the subgroup of MG patients with weakness restricted to ocular muscles (OMG) as routine diagnostic tests are less sensitive in this group: around 50% of these patients have no positive antibody test and around 71% have no significant decrement with repetitive stimulation EMG. Moreover, virtually all disorders that can cause a pupil-sparing ptosis or diplopia have been reported to be confused with OMG. Among the most mentioned mimicks for OMG are (concomitant) Graves ophtalmopathy, cranial nerve palsies, ocular tendinomuscular deficits (such as levator dehiscence), myopathy, demyelinating disease and stroke. Diagnostic delay and confusion of OMG with mimicking disorders might lead to a worse prognosis due to a possible increased risk of generalization of disease and the need of emergency treatments. A careful clinical follow-up of patients with suspected OMG by systematically assessing changes in ocular weakness patterns between visits can aid in confirming the diagnosis. In addition, the ice pack test can be a diagnostic aid in cases of both evident ptosis as ophtalmoparesis. In the foreseeable future, cell-based assays (CBA) might aid in the diagnostic confirmation of OMG. There is a need of studies that investigates the yield of new and not-routinely used diagnostic tests in suspected OMG with negative antibody and inconclusive EMG and SF-EMG, such as the repetitive ocular vestibular evoked myogenic potentials (RoVEMP) test and CBA. Lastly, the effect of early immunosuppressive treatment should be further investigated in OMG.","PeriodicalId":309700,"journal":{"name":"RRNMF Neuromuscular Journal","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"117031894","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pediatric Myasthenia Gravis","authors":"E. Tiongson","doi":"10.17161/rrnmf.v4i3.18743","DOIUrl":"https://doi.org/10.17161/rrnmf.v4i3.18743","url":null,"abstract":"Abstract: \u0000Pediatric myasthenia gravis (MG) is a relatively rare, but very treatable condition. Prognosis in pediatric myasthenia gravis is favorable for minimal manifestation status (MMS) or remission when compared to adults. Ocular only presentations are more common, though severe refractory generalized MG presentations also occur. An observational examination is key to the diagnosis and follow-up of pediatric MG patients in the clinic setting. Treatment options are limited by side effect and growth considerations, as well as lack of approved MG medications in the pediatric population. Multidisciplinary care should be considered for pediatric MG, similar to other neuromuscular conditions seen in specialty care settings.","PeriodicalId":309700,"journal":{"name":"RRNMF Neuromuscular Journal","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"121503187","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"MiR-146a in myasthenia gravis thymus: from uncontrolled innate immunity to B cell-mediated autoimmunity","authors":"P. Cavalcante, M. Tarasco, Nicola Iacomino, C. Antozzi, R. Mantegazza","doi":"10.17161/rrnmf.v4i3.19526","DOIUrl":"https://doi.org/10.17161/rrnmf.v4i3.19526","url":null,"abstract":"The thymus is the main site of autoimmunity development in myasthenia gravis (MG) associated with anti-acetylcholine receptor (AChR) autoantibodies, a prototypic autoimmune disease affecting neuromuscular junction. Most MG patients with early-onset disease presents follicular hyperplastic changes of the thymus, that are critically implicated in the initiation and perpetuation of the autoimmune response against the AChR. Uncontrolled activation of Toll-like receptor (TLR)-mediated innate immune responses, chronic inflammation and ectopic germinal center (GC) formation are key pathological features of hyperplastic thymus in MG, indicating that a close link between innate immunity and B cell-mediated autoimmunity underlies the intra-thymic pathogenesis of MG. \u0000MiR-146a, an “immune-miR” acting as key modulator of both innate and adaptive immunity, is a potent inhibitor of TLR signaling pathways, able to prevent and avoid an overstimulation of the inflammatory response by targeting the NF-κB signaling transducers IRAK1 and TRAF6. At the same time, miR-146a modulates the expression of c-REL, ICOS and ICOSL, which are crucial regulators of B cell function and GC response. Dysregulation of miR-146a expression is a common molecular event in several autoimmune disorders. Our recent findings revealed defective expression of miR-146a, associated with over-expression of its TLR- and B cell-related target genes, in follicular hyperplastic MG thymuses, indicating that loss of regulatory functions of this miRNA may significantly contribute to the immunopathological steps leading to MG. Of note, corticosteroids were found to increase the miR-146a expression levels, thus suggesting the miRNA capacity to mediate the effects of these drugs in inducing immunosuppression and autoimmunity control.  \u0000In this review, we discuss the role of miR-146a as a molecular bridge between innate and adaptive immunity, and summarize the current knowledge on the miRNA contribution to the pathogenesis of MG. Based on our and literature data, we highlight the miR-146a potential as biomarker for therapeutic monitoring, as well as target of future advanced RNA-based therapies to modulate the immune system and counteract the autoimmune response in MG.","PeriodicalId":309700,"journal":{"name":"RRNMF Neuromuscular Journal","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"124334609","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Biomarker Development, Methodological Challenges","authors":"Gary Cutter","doi":"10.17161/rrnmf.v4i3.18973","DOIUrl":"https://doi.org/10.17161/rrnmf.v4i3.18973","url":null,"abstract":"Biomarker development is a common endeavor in medical research.  The purpose is to find indicators of disease occurrence or prognostic markers for response.   The process of development of biomarkers often starts with showing mean differences between responders and non-responders  or those with a disease or condition versus those without.  However, these statistically significant mean differences, while necessary are not sufficient to validate a biomarker.  Sensitivity, specificity, positive and negative predictive value are at least as important and the relative increase in performance using the biomarker over the usual clinical variables should be demonstrated.  This paper discusses the various assessments in the context of use for the biomarker,  the need for characteristics in addition to mean differences and the importance of independent validation of putative biomarkers.  Lastly, it is hoped that the process and thoroughness be considered with recognition that the task is at best a difficult task.","PeriodicalId":309700,"journal":{"name":"RRNMF Neuromuscular Journal","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"122576054","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Refractory myasthenia gravis: the more we learn, the less we know.","authors":"Ali A. Habib","doi":"10.17161/rrnmf.v4i3.19555","DOIUrl":"https://doi.org/10.17161/rrnmf.v4i3.19555","url":null,"abstract":"Refractory myasthenia gravis identifies the group of patients that have inadequate symptom control and persistent muscle weakness and fatigability despite the use of multiple immune modulatory therapies. This manuscript highlights what is currently known about refractory myasthenia gravis and underlines major knowledge gaps, drawing attention to the unmet needs in our understanding of this disease subset. This review raises questions about our current understanding of refractory disease and how emerging data as well as therapies may alter our thinking and patients’ disease course.","PeriodicalId":309700,"journal":{"name":"RRNMF Neuromuscular Journal","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"122006167","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Challenges managing myasthenia gravis: an international perspective","authors":"C. Barnett, Fatmah Alzahmi, Dong Dong, Jeannine Heckman, V. Salutto, H. Shin","doi":"10.17161/rrnmf.v4i3.19553","DOIUrl":"https://doi.org/10.17161/rrnmf.v4i3.19553","url":null,"abstract":"There have been increasing breakthroughs in the diagnosis and treatment of myasthenia gravis over the past decades. However, most published research in myasthenia is conducted in developed regions, such as the US, Canada and Europe. The challenges faced in these regions may be different from other areas of the world, often with fewer resources, such as fewer neurologists, limited or no access to specialised testing for myasthenia, and limited access to some interventions. During the 14th International Conference for Myasthenia Gravis and Myasthenic Disorders, we organized a panel of neurologists and researchers who work with people living with myasthenia in different world regions. The goal was to stimulate discussion around common challenges as well as those that are specific for given areas. Ultimately, we aimed to develop networks of clinicians caring for people living with myasthenia gravis around the world, to improve patient care. We present a summary of challenges using a case format by region, and a discussion around common threads and potential next steps.","PeriodicalId":309700,"journal":{"name":"RRNMF Neuromuscular Journal","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"127932903","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The mechanisms of immunopathology underlying B cell depletion therapy-mediated remission and relapse in patients with MuSK MG","authors":"K. OConnor, M. Fichtner","doi":"10.17161/rrnmf.v4i3.18936","DOIUrl":"https://doi.org/10.17161/rrnmf.v4i3.18936","url":null,"abstract":"The application of reverse translational medicine allows for the understanding of immune pathogenesis via therapeutic intervention. We applied this approach to the MuSK subtype of myasthenia gravis. Treatment with the CD20-specific B cell depletion therapy (BCDT) demonstrated that MuSK MG patients respond remarkably well; the majority invariably reach remission accompanied by a remarkable drop in autoantibody levels. Circulating antibodies are primarily produced by bone marrow resident plasma cells, which do not express CD20. So, how does BCDT diminish MuSK autoantibodies and induce rapid remission? We developed a mechanistic model, which hypothesized that plasmablasts, which are short-lived antibody secreting B cell populations, produce MuSK-specific autoantibodies. Anti-CD20-mediated BCDT is expected to deplete CD20-expressing plasmablasts or CD20 expressing memory cells that supply the plasmablast population. To test this hypothesis, we performed a series of investigations, which were reported over the last seven years and are summarized in this review. First, we isolated plasmablasts from patients and generated human recombinant monoclonal autoantibodies (mAb) which bound MuSK and had pathogenic capacity, demonstrating that MuSK autoantibodies can be produced by this specific cell population. The characterization of the mAbs showed that MuSK autoantibodies can include unique properties including unusually high antigen binding affinity, and an elevated frequency of N-linked glycosylation in their binding domains. Further characterization suggested that MuSK autoantibody-producing cells may form in the early stages of B cell development due to defective tolerance mechanisms. Finally, we sought to determine how these pathogenic B cell clones behave over time. High throughput B cell receptor sequencing was applied to investigate longitudinally collected samples from patients treated with anti-CD20-mediated BCDT. MuSK-specific clonal variants were detected at multiple timepoints spanning more than five years and reemerged after BCDT-induced remission, predating disease relapse by several months. These collective investigations provide a more detailed mechanistic understanding that MuSK MG, the key features of which include production of autoantibodies by circulating plasmablasts that can be targeted by CD20-specific BCDT, and that pathogenic clones can survive BCDT and reemerge prior to manifestation of clinical relapse.","PeriodicalId":309700,"journal":{"name":"RRNMF Neuromuscular Journal","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"125669017","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}