RESUMO
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.
Assuntos
Predisposição Genética para Doença/genética , Miastenia Gravis/genética , Polimorfismo Genético/genética , Transdução de Sinais/genética , Adulto , Feminino , Expressão Gênica/genética , Frequência do Gene/genética , Loci Gênicos/genética , Estudo de Associação Genômica Ampla/métodos , Humanos , Masculino , Músculo Esquelético/patologia , Receptores Colinérgicos/genética , Receptores Nicotínicos/genéticaRESUMO
Within the last 5 years, the US Food and Drug Administration (FDA) has approved complement and neonatal Fc receptor (FcRN) inhibitors for treatment of generalized myasthenia gravis, and several other therapies are in late-stage clinical trials or under regulatory review. However, questions about which patients are most likely to benefit from which therapies, and the relative effectiveness of these very expensive drugs, has resulted in uncertainty around the place that they should occupy in the existing therapeutic armamentarium. MGNet (a Rare Diseases Clinical Research Consortium funded by the National Institute of Neurological Diseases and Stroke) held two meetings during the 14th International Conference of the Myasthenia Gravis Foundation of America to discuss the most critical needs for clinical trial readiness and biomarker development in the context of therapy development for myasthenia gravis. Herein we provide a summary of these discussions, but not a consensus opinion, and offer a series of recommendations to guide focused research in the most critical areas. We welcome ongoing discussion through comments on this work.
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Miastenia Gravis , Estados Unidos , Recém-Nascido , Humanos , Miastenia Gravis/tratamento farmacológico , Estudos LongitudinaisRESUMO
Myasthenia gravis (MG) is a neuromuscular, autoimmune disease caused by autoantibodies that target postsynaptic proteins, primarily the acetylcholine receptor (AChR) and inhibit signaling at the neuromuscular junction. The majority of patients under 50 y with AChR autoantibody MG have thymic lymphofollicular hyperplasia. The MG thymus is a reservoir of plasma cells that secrete disease-causing AChR autoantibodies and although thymectomy improves clinical scores, many patients fail to achieve complete stable remission without additional immunosuppressive treatments. We speculate that thymus-associated B cells and plasma cells persist in the circulation after thymectomy and that their persistence could explain incomplete responses to resection. We studied patients enrolled in a randomized clinical trial and used complementary modalities of B cell repertoire sequencing to characterize the thymus B cell repertoire and identify B cell clones that resided in the thymus and circulation before and 12 mo after thymectomy. Thymus-associated B cell clones were detected in the circulation by both mRNA-based and genomic DNA-based sequencing. These antigen-experienced B cells persisted in the circulation after thymectomy. Many circulating thymus-associated B cell clones were inferred to have originated and initially matured in the thymus before emigration from the thymus to the circulation. The persistence of thymus-associated B cells correlated with less favorable changes in clinical symptom measures, steroid dose required to manage symptoms, and marginal changes in AChR autoantibody titer. This investigation indicates that the diminished clinical response to thymectomy is related to persistent circulating thymus-associated B cell clones.
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Linfócitos B/metabolismo , Contagem de Linfócitos , Miastenia Gravis/sangue , Timo/metabolismo , Adolescente , Adulto , Autoanticorpos/imunologia , Linfócitos B/imunologia , Biomarcadores , Evolução Clonal/genética , Seleção Clonal Mediada por Antígeno , Suscetibilidade a Doenças , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Biológicos , Miastenia Gravis/etiologia , Radioimunoensaio , Receptores Colinérgicos/imunologia , Timectomia , Timo/citologia , Timo/imunologia , Recombinação V(D)J , Adulto JovemRESUMO
Due to the precautions put in place during the COVID-19 pandemic, utilization of telemedicine has increased quickly for patient care and clinical trials. Unfortunately, teleconsultation is closer to a video conference than a medical consultation, with the current solutions setting the patient and doctor into an evaluation that relies entirely on a two-dimensional view of each other. We are developing a patented telehealth platform that assists with diagnostic testing of ocular manifestations of myasthenia gravis. We present a hybrid algorithm combining deep learning with computer vision to give quantitative metrics of ptosis and ocular muscle fatigue leading to eyelid droop and diplopia. The method works both on a fixed image and frame by frame of the video in real-time, allowing capture of dynamic muscular weakness during the examination. We then use signal processing and filtering to derive robust metrics of ptosis and l ocular misalignment. In our construction, we have prioritized the robustness of the method versus accuracy obtained in controlled conditions in order to provide a method that can operate in standard telehealth conditions. The approach is general and can be applied to many disorders of ocular motility and ptosis.
Assuntos
COVID-19 , Miastenia Gravis , Telemedicina , Humanos , Pandemias , COVID-19/diagnóstico , Miastenia Gravis/diagnóstico , Exame FísicoRESUMO
Myasthenia gravis (MG) is an autoimmune disease in which Abs target neuromuscular junction proteins, in particular the acetylcholine receptor. We previously identified the antiapoptotic protein survivin in the autoreactive B cells and plasma cells of MG patients. To further define the role of survivin in MG, we have assessed PBMCs from 29 patients with MG and 15 controls. We confirmed the increased expression of survivin in CD20+ lymphocytes from MG patients compared with controls. Furthermore, the CD20+ population of cells from MG patients contained a higher percentage of extracellular survivin compared with controls. The analysis of CD4+ cells showed an increased percentage of intracellular survivin in MG patients compared with controls, whereas the extracellular survivin CD4+ percentage was unaffected. In an experimental mouse model of MG, we assessed the therapeutic potential of an Ab raised to a modified survivin peptide but cross-reactive to survivin. Ab treatment reduced disease severity, lowered acetylcholine receptor-specific Abs, and decreased CD19+ survivin+ splenocytes. The ability to target survivin through Ab recognition of autoreactive cells offers the potential for a highly specific therapeutic agent for MG.
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Linfócitos B/metabolismo , Miastenia Gravis/imunologia , Survivina/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Anticorpos/metabolismo , Antígenos CD20/metabolismo , Autoantígenos/imunologia , Linfócitos B/imunologia , Modelos Animais de Doenças , Feminino , Humanos , Imunidade Humoral , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Peptídeos/imunologia , Adulto JovemRESUMO
INTRODUCTION/AIMS: Telemedicine may be particularly well-suited for myasthenia gravis (MG) due to the disorder's need for specialized care, its hallmark fluctuating muscle weakness, and the potential for increased risk of virus exposure among patients with MG during the coronavirus disease 2019 (COVID-19) pandemic during in-person clinical visits. A disease-specific telemedicine physical examination to reflect myasthenic weakness does not currently exist. METHODS: This paper outlines step-by-step guidance on the fundamentals of a telemedicine assessment for MG. The Myasthenia Gravis Core Exam (MG-CE) is introduced as a MG-specific, telemedicine, physical examination, which contains eight components (ptosis, diplopia, facial strength, bulbar strength, dysarthria, single breath count, arm strength, and sit to stand) and takes approximately 10 minutes to complete. RESULTS: Pre-visit preparation, remote ascertainment of patient-reported outcome scales and visit documentation are also addressed. DISCUSSION: Additional knowledge gaps in telemedicine specific to MG care are identified for future investigation.
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COVID-19/prevenção & controle , Miastenia Gravis/diagnóstico , Educação de Pacientes como Assunto/métodos , Exame Físico/métodos , Médicos , Telemedicina/métodos , Feminino , Humanos , Masculino , Miastenia Gravis/terapia , Educação de Pacientes como Assunto/normas , Exame Físico/normas , Médicos/normas , Telemedicina/normasRESUMO
BACKGROUND: The immunopathology of autoimmune seronegative myasthenia gravis (SN MG) is poorly understood. Our objective was to determine immune profiles associated with a diagnosis of SN MG. METHODS: We performed high-dimensional flow cytometry on blood samples from SN MG patients (N = 68), healthy controls (N = 46), and acetylcholine receptor antibody (AChR+) MG patients (N = 27). We compared 12 immune cell subsets in SN MG to controls using logistic modeling via a discovery-replication design. An exploratory analysis fit a multinomial model comparing AChR+ MG and controls to SN MG. RESULTS: An increase in CD19+ CD20- CD38hi plasmablast frequencies was associated with lower odds of being a SN MG case in both the discovery and replication analyses (discovery P-value = .0003, replication P-value = .0021). Interleukin (IL) -21 producing helper T cell frequencies were associated with a diagnosis of AChR+ MG (P = .004). CONCLUSIONS: Reduced plasmablast frequencies are strongly associated with a SN MG diagnosis and may be a useful diagnostic biomarker in the future.
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Autoanticorpos/sangue , Miastenia Gravis/sangue , Plasmócitos/citologia , Receptores Colinérgicos/sangue , Adulto , Idoso , Biomarcadores/sangue , Feminino , Citometria de Fluxo/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Miastenia Gravis/diagnóstico , Receptores Colinérgicos/imunologia , Adulto JovemRESUMO
INTRODUCTION: Quantitative Myasthenia Gravis (QMG) and Myasthenia Gravis Activities of Daily Living (MG-ADL) scales were compared using the data from the Thymectomy Trial in Non-Thymomatous Myasthenia Gravis Patients Receiving Prednisone Therapy (MGTX) study. METHODS: Correlation between QMG and MG-ADL raw and change-from-baseline scores was calculated every 3 months for 60 months based on treatment groups and minimal manifestation status (MMS). RESULTS: QMG and MG-ADL change-from-baseline scores correlated significantly, with increasing strength of correlation over time, in both treatment groups. QMG and MG-ADL raw scores correlated significantly in both treatment groups, with increasing correlation only in the prednisone-alone group. Correlation between raw scores was weaker in patients who were in MMS, demonstrating a "floor effect" on the MG-ADL scale. Raw QMG scores could be modeled assuming a normal distribution, whereas raw MG-ADL scores could not be modeled this way. DISCUSSION: The floor effect and skewed distribution of the MG-ADL measure should be taken into account in the design of myasthenia gravis clinical trials.
Assuntos
Atividades Cotidianas , Miastenia Gravis/fisiopatologia , Avaliação de Resultados em Cuidados de Saúde , Terapia Combinada , Glucocorticoides/uso terapêutico , Humanos , Miastenia Gravis/terapia , Prednisona/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto , TimectomiaRESUMO
BACKGROUND: Thymectomy has been a mainstay in the treatment of myasthenia gravis, but there is no conclusive evidence of its benefit. We conducted a multicenter, randomized trial comparing thymectomy plus prednisone with prednisone alone. METHODS: We compared extended transsternal thymectomy plus alternate-day prednisone with alternate-day prednisone alone. Patients 18 to 65 years of age who had generalized nonthymomatous myasthenia gravis with a disease duration of less than 5 years were included if they had Myasthenia Gravis Foundation of America clinical class II to IV disease (on a scale from I to V, with higher classes indicating more severe disease) and elevated circulating concentrations of acetylcholine-receptor antibody. The primary outcomes were the time-weighted average Quantitative Myasthenia Gravis score (on a scale from 0 to 39, with higher scores indicating more severe disease) over a 3-year period, as assessed by means of blinded rating, and the time-weighted average required dose of prednisone over a 3-year period. RESULTS: A total of 126 patients underwent randomization between 2006 and 2012 at 36 sites. Patients who underwent thymectomy had a lower time-weighted average Quantitative Myasthenia Gravis score over a 3-year period than those who received prednisone alone (6.15 vs. 8.99, P<0.001); patients in the thymectomy group also had a lower average requirement for alternate-day prednisone (44 mg vs. 60 mg, P<0.001). Fewer patients in the thymectomy group than in the prednisone-only group required immunosuppression with azathioprine (17% vs. 48%, P<0.001) or were hospitalized for exacerbations (9% vs. 37%, P<0.001). The number of patients with treatment-associated complications did not differ significantly between groups (P=0.73), but patients in the thymectomy group had fewer treatment-associated symptoms related to immunosuppressive medications (P<0.001) and lower distress levels related to symptoms (P=0.003). CONCLUSIONS: Thymectomy improved clinical outcomes over a 3-year period in patients with nonthymomatous myasthenia gravis. (Funded by the National Institute of Neurological Disorders and Stroke and others; MGTX ClinicalTrials.gov number, NCT00294658.).
Assuntos
Glucocorticoides/administração & dosagem , Miastenia Gravis/tratamento farmacológico , Miastenia Gravis/cirurgia , Prednisona/administração & dosagem , Timectomia , Adolescente , Adulto , Idoso , Terapia Combinada , Feminino , Hospitalização , Humanos , Masculino , Pessoa de Meia-Idade , Miastenia Gravis/classificação , Índice de Gravidade de Doença , Método Simples-Cego , Resultado do Tratamento , Adulto JovemRESUMO
INTRODUCTION: The Myasthenia Gravis Patient Registry (MGR) is a voluntary, patient-submitted database dedicated to improve understanding of care/burden of myasthenia gravis (MG). METHODS: In this study we present analyses of baseline records through July 2017 (n = 1140) containing data on the MG-Activities of Daily Living (MG-ADL) and the MG 15-item Quality of Life (MG-QOL15) instruments, two validated scales assessing quality of life in MG patients at sign-up into the MGR. RESULTS: Most registrants reported moderate to severe impairment of health-related quality of life, with a median MG-ADL score of 6 and a median MG-QOL15 score of 21. Seventy-one percent of the patients had received pyridostigmine. Corticosteroids, mycophenolate mofetil, and azathioprine were the most common immunomodulators/immunosuppressants, with 85% of participants having ever using one of these agents. Forty-seven registrants reported receiving intravenous immunoglobulin, and 30% received plasma exchange. Twelve percent reported other treatments, and 40% were unsure whether they received less common therapies. Forty percent had undergone thymectomy. DISCUSSION: The MGR data correlate well with other MG cohorts. Many MG patients remain negatively impacted despite treatment.
Assuntos
Atividades Cotidianas , Inibidores da Colinesterase/uso terapêutico , Imunossupressores/uso terapêutico , Miastenia Gravis/fisiopatologia , Miastenia Gravis/terapia , Qualidade de Vida , Corticosteroides/uso terapêutico , Adulto , Idoso , Azatioprina/uso terapêutico , Estudos Transversais , Feminino , Humanos , Imunoglobulinas Intravenosas/uso terapêutico , Fatores Imunológicos/uso terapêutico , Masculino , Pessoa de Meia-Idade , Ácido Micofenólico/uso terapêutico , Troca Plasmática/métodos , Brometo de Piridostigmina/uso terapêutico , Sistema de RegistrosRESUMO
INTRODUCTION: Quality of life (QOL) has been poorly characterized among patients with myasthenia gravis (MG) other than assessments performed within the clinical setting. METHODS: Patients age ≥ 18 years who were diagnosed with MG and registered with the MG patient registry between July 1, 2013, and June 30, 2016, were included. Demographic information, disease related history, and QOL were compared between men and women using multivariable analysis. RESULTS: A total of 1,315 subjects (827 women) were included. Women were significantly younger, had a younger age at symptom onset, and were more likely to have thymoma and thymectomy. The 15-item Myasthenia Gravis Quality of Life scale (MG-QOL15) was significantly worse in women. MG-QOL15 score was comparable between women who had thymectomy and men with or without thymectomy. DISCUSSION: QOL among MG patients is worse in women compared with men, but this disparity is eliminated in women who have undergone thymectomy. Muscle Nerve, 2018.
RESUMO
An array of cytokines influences the pathogenesis of early onset myasthenia gravis (MG) and its animal model, experimental autoimmune myasthenia gravis (EAMG). Patients with MG, in particular those with more severe weakness, have elevations of the pro-inflammatory cytokine IL-17 in the blood. We assessed the role of IL-17A in autoimmunity by inducing EAMG in mice with knockout of IL-17 and found a reduction of EAMG severity, but not a complete ablation of disease. The IL-17ko mice had no evidence of weakness, low levels of acetylcholine receptor antibodies, and retention of acetylcholine receptor at the neuromuscular junction. Splenic germinal center size was reduced in EAMG IL-17ko mice along with elevations of Foxp3 and BCL-6 gene expression, suggesting a shift away from pro-inflammatory signals. The results emphasize the importance of IL-17 in EAMG development and that IL-17 independent pathways drive the autoimmune reaction.
Assuntos
Autoimunidade/imunologia , Interleucina-17/genética , Interleucina-17/fisiologia , Miastenia Gravis Autoimune Experimental/imunologia , Miastenia Gravis Autoimune Experimental/fisiopatologia , Animais , Autoanticorpos , Citocinas/imunologia , Modelos Animais de Doenças , Fatores de Transcrição Forkhead/genética , Humanos , Imunoglobulina G/sangue , Interleucina-17/deficiência , Camundongos , Camundongos Knockout , Proteínas Proto-Oncogênicas c-bcl-6/genética , Reação em Cadeia da Polimerase em Tempo Real , Índice de Gravidade de Doença , Linfócitos T ReguladoresRESUMO
INTRODUCTION: We explore trends in U.S. inpatient costs of care over a 10-year period. METHODS: We compare myasthenia gravis (MG) with multiple sclerosis (MS) and overall U.S. hospital admissions using the Agency for Healthcare Research and Quality Nationwide Inpatient Sample database for 2003-2013. RESULTS: Total costs of MG inpatient care rose 13-fold from 2003 to 2013. This was accounted for by a greater than sixfold increase in discharges and a greater than twofold increase in cost per discharge. The < 17 and >85 years age groups experienced the greatest increases in discharges. Medicare and Medicaid use increased. Regional variations in cost were apparent. There were greater rises in the Midwestern and Southern United States, which is dissimilar to MS and all hospital admissions. DISCUSSION: There was a dramatic and disproportionate rise in the number of MG discharges, most likely because of changes in practice patterns. Muscle Nerve 56: 1114-1118, 2017.
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Custos e Análise de Custo/métodos , Hospitalização/economia , Miastenia Gravis/economia , Miastenia Gravis/terapia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Bases de Dados Factuais/tendências , Feminino , Hospitalização/tendências , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Admissão do Paciente/economia , Admissão do Paciente/tendências , Alta do Paciente/economia , Alta do Paciente/tendências , Adulto JovemRESUMO
To better define the role of IL-17A in myasthenia gravis (MG), we assessed plasma concentrations in 69 adult patients with MG prior to initiation of immunosuppression and monitored their clinical course for the subsequent 2years with quantitative MG scores (QMGS) and Osserman classification. IL-17A was higher among patients than healthy control subjects. Early-onset women without thymoma had greater elevations of IL-17A. Logistic regression analysis indicated that the absence of thymoma rather than women gender or early-onset was the significant determinant associated with IL-17A elevation. Elevated IL-17A levels were associated with more severe MG. In summary, IL-17A has role in the pathogenesis of a subgroup of patients with early-onset women with MG with greater disease severity who are most likely to have thymic hyperplasia. This subgroup may be a target for IL-17 treatments, which are under development.
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Interleucina-17/sangue , Miastenia Gravis/sangue , Adulto , Feminino , Humanos , Masculino , Miastenia Gravis/complicações , Miastenia Gravis/imunologia , Timoma/complicações , Hiperplasia do Timo/complicações , Neoplasias do Timo/complicaçõesRESUMO
INTRODUCTION: The aim of this study was to determine thymectomy-associated morbidity and mortality outcomes among myasthenia gravis (MG) patients. METHODS: Patients undergoing thymectomy were identified from the National Surgical Quality Improvement Program database from 2005 to 2012 using Current Procedural Terminology codes. Patient demographics, clinical characteristics, and postoperative outcomes were stratified by MG diagnosis. Logistic regression was used to identify predictors for morbidity outcomes. The chi-square test was used to examine the association between MG diagnosis and surgical approach. RESULTS: A total of 1,148 subjects underwent thymectomy, and 108 had MG. Compared with control subjects, MG patients had a more severe American Society of Anesthesiologists physical classification and frailty index score, greater corticosteroid usage, and a higher rate of reintubation. There were no deaths among MG patients. The majority of MG patients underwent transsternal thymectomy. CONCLUSION: Although patients with MG have a greater preoperative morbidity and a higher frequency of reintubation, thymectomy was found to be a safe procedure overall.
Assuntos
Miastenia Gravis/cirurgia , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/mortalidade , Timectomia/efeitos adversos , Adulto , Idoso , American Medical Association , Distribuição de Qui-Quadrado , Bases de Dados Factuais/estatística & dados numéricos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Multicêntricos como Assunto , Estudos Retrospectivos , Sociedades Médicas/estatística & dados numéricos , Timectomia/estatística & dados numéricos , Resultado do Tratamento , Estados UnidosRESUMO
We recently demonstrated that hepatic stellate cells induce the differentiation of myeloid-derived suppressor cells (MDSCs) from myeloid progenitors. In this study, we found that adoptive transfer of these MDSCs effectively reversed disease progression in experimental autoimmune myasthenia gravis (EAMG), a T cell-dependent and B cell-mediated model for myasthenia gravis. In addition to ameliorated disease severity, MDSC-treated EAMG mice showed suppressed acetylcholine receptor (AChR)-specific T cell responses, decreased levels of serum anti-AChR IgGs, and reduced complement activation at the neuromuscular junctions. Incubating MDSCs with B cells activated by anti-IgM or anti-CD40 Abs inhibited the proliferation of these in vitro-activated B cells. Administering MDSCs into mice immunized with a T cell-independent Ag inhibited the Ag-specific Ab production in vivo. MDSCs directly inhibit B cells through multiple mechanisms, including PGE2, inducible NO synthase, and arginase. Interestingly, MDSC treatment in EAMG mice does not appear to significantly inhibit their immune response to a nonrelevant Ag, OVA. These results demonstrated that hepatic stellate cell-induced MDSCs concurrently suppress both T and B cell autoimmunity, leading to effective treatment of established EAMG, and that the MDSCs inhibit AChR-specific immune responses at least partially in an Ag-specific manner. These data suggest that MDSCs could be further developed as a novel approach to treating myasthenia gravis and, even more broadly, other diseases in which T and B cells are involved in pathogenesis.
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Linfócitos B/imunologia , Miastenia Gravis Autoimune Experimental , Células Mieloides , Linfócitos T/imunologia , Animais , Autoanticorpos/imunologia , Linfócitos B/patologia , Dinoprostona/imunologia , Células Estreladas do Fígado/imunologia , Células Estreladas do Fígado/patologia , Imunoglobulina G/imunologia , Imunoglobulina M/imunologia , Camundongos , Miastenia Gravis Autoimune Experimental/imunologia , Miastenia Gravis Autoimune Experimental/patologia , Miastenia Gravis Autoimune Experimental/terapia , Células Mieloides/imunologia , Células Mieloides/patologia , Células Mieloides/transplante , Receptores Nicotínicos/imunologia , Linfócitos T/patologiaAssuntos
Miastenia Gravis , Timectomia , Seguimentos , Humanos , Estudos Retrospectivos , Resultado do TratamentoRESUMO
This is a critical time in neurotherapeutics. The prevalence of neurological disease, such as dementia, stroke, and peripheral neuropathy, is large and growing consequent to the aging population. The personal and societal impact of these disorders is enormous, and the number of novel therapies in the pipeline for these disorders has been contracting. Support for the development of neurotherapies must continue from the bench to their ultimate place at the bedside. Academic medicine must continue to play a critical role, in league with industry and government, in the development of novel neurotherapies desperately needed by an ever-expanding population. Critical steps include the identification and adoption of reliable, valid, and reproducible biomarkers to serve as primary endpoints in clinical trials of neurological disease.
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Descoberta de Drogas/normas , Doenças do Sistema Nervoso/tratamento farmacológico , Descoberta de Drogas/estatística & dados numéricos , Humanos , Doenças do Sistema Nervoso/epidemiologiaRESUMO
INTRODUCTION: The site of pathology in myasthenia gravis (MG) is the neuromuscular junction (NMJ). Our goal was to determine the ability to direct complement inhibition to the NMJ. METHODS: A single-chain antibody directed against the alpha subunit of the acetylcholine receptor was synthesized (scFv-35) and coupled to decay-accelerating factor (DAF, scFv-35-DAF). scFv-35-DAF was tested in a passive model of experimentally acquired MG. RESULTS: Administration of scFv-35-DAF to mice deficient in intrinsic complement inhibitors produced no weakness despite confirmation of its localization to the NMJ and no evidence of tissue destruction related to complement activation. Rats with experimentally acquired MG treated with scFV-35-DAF showed less weakness and a reduction of complement deposition. CONCLUSIONS: We demonstrate a method to effectively target a therapeutic agent to the NMJ.
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Antígenos CD55/administração & dosagem , Sistemas de Liberação de Medicamentos/métodos , Miastenia Gravis Autoimune Experimental/tratamento farmacológico , Junção Neuromuscular , Receptores Colinérgicos , Anticorpos de Cadeia Única/uso terapêutico , Animais , Camundongos , Miastenia Gravis Autoimune Experimental/imunologia , Ratos , Anticorpos de Cadeia Única/imunologiaRESUMO
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. Patients with MG exhibit a spectrum of weakness, ranging from limited ocular muscle involvement to life-threatening respiratory failure. 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. This heightened understanding has paved the way for the development of more precise and targeted therapeutic interventions. 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. In this Review, we delve into the various subgroups of MG, stratified by age, autoantibody type, and histology of the thymus with neoplasms. Furthermore, we explore both current and potential emerging therapeutic strategies, shedding light on the evolving landscape of MG treatment.