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Muscle-specific tyrosine kinase myasthenia gravis (MuSK MG) is an autoimmune disease that causes life-threatening muscle weakness due to anti-MuSK autoantibodies that disrupt neuromuscular junction signaling. To avoid chronic immunosuppression from current therapies, we engineered T cells to express a MuSK chimeric autoantibody receptor with CD137-CD3ζ signaling domains (MuSK-CAART) for precision targeting of B cells expressing anti-MuSK autoantibodies. MuSK-CAART demonstrated similar efficacy as anti-CD19 chimeric antigen receptor T cells for depletion of anti-MuSK B cells and retained cytolytic activity in the presence of soluble anti-MuSK antibodies. In an experimental autoimmune MG mouse model, MuSK-CAART reduced anti-MuSK IgG without decreasing B cells or total IgG levels, reflecting MuSK-specific B cell depletion. Specific off-target interactions of MuSK-CAART were not identified in vivo, in primary human cell screens or by high-throughput human membrane proteome array. These data contributed to an investigational new drug application and phase 1 clinical study design for MuSK-CAART for the treatment of MuSK autoantibody-positive MG.
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Miastenia Gravis Autoimune Experimental , Receptores Colinérgicos , Humanos , Camundongos , Animais , Receptores Colinérgicos/uso terapêutico , Autoantígenos/uso terapêutico , Miastenia Gravis Autoimune Experimental/tratamento farmacológico , Linfócitos T , Autoanticorpos/uso terapêutico , Imunoglobulina G , Proteínas Tirosina Quinases/uso terapêutico , MúsculosRESUMO
Muscle-specific kinase (MuSK) myasthenia gravis (MG) is a neuromuscular autoimmune disease belonging to a growing group of IgG4 autoimmune diseases (IgG4-AIDs), in which the majority of pathogenic autoantibodies are of the IgG4 subclass. The more prevalent form of MG with acetylcholine receptor (AChR) antibodies is caused by IgG1-3 autoantibodies. A dominant role for IgG4 in autoimmune disease is intriguing due to its anti-inflammatory characteristics. It is unclear why MuSK autoantibodies are predominantly IgG4. We hypothesized that MuSK MG patients have a general predisposition to generate IgG4 responses, therefore resulting in high levels of circulating IgG4. To investigate this, we quantified serum Ig isotypes and IgG subclasses using nephelometric and turbidimetric assays in MuSK MG and AChR MG patients not under influence of immunosuppressive treatment. Absolute serum IgG1 was increased in both MuSK and AChR MG patients compared to healthy donors. In addition, only MuSK MG patients on average had significantly increased and enriched serum IgG4. Although more MuSK MG patients had elevated serum IgG4, for most the IgG4 serum levels fell within the normal range. Correlation analyses suggest MuSK-specific antibodies do not solely explain the variation in IgG4 levels. In conclusion, although serum IgG4 levels are slightly increased, the levels do not support ubiquitous IgG4 responses in MuSK MG patients as the underlying cause of dominant IgG4 MuSK antibodies.
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Imunoglobulina G , Miastenia Gravis , Humanos , AutoanticorposRESUMO
OBJECTIVE: To determine whether rituximab is safe and potentially beneficial, warranting further investigation in an efficacy trial for acetylcholine receptor antibody-positive generalized MG (AChR-Ab+ gMG). METHODS: The B-Cell Targeted Treatment in MG (BeatMG) study was a randomized, double-blind, placebo-controlled, multicenter phase-2 trial that utilized a futility design. Individuals 21-90 years of age, with AChR-Ab+ gMG (MG Foundation of America Class II-IV) and receiving prednisone ≥15 mg/day were eligible. The primary outcome was a measure of steroid-sparing effect, defined as the proportion achieving ≥75% reduction in mean daily prednisone dose in the 4-weeks prior to week 52 and with clinical improvement or no significant worsening as compared to the 4-week period prior to randomization. The co-primary outcome was safety. Secondary outcomes included MG-specific clinical assessments. Fifty-two individuals were randomized (1:1) to either a two-cycle rituximab/placebo regimen, with follow-up through 52-weeks. RESULTS: Of the 52 participants included, mean (±SD) age at enrollment was 55.1 (±17.1) years; 23 (44.2%) were female, and 31 (59.6%) were MGFA Class II. The mean (±SD) baseline prednisone dose was 22.1 (±9.7) mg/day. The primary steroid-sparing outcome was achieved in 60% of those on rituximab vs. 56% on placebo. The study reached its futility endpoint (p=0.03) suggesting that the pre-defined clinically meaningful improvement of 30% due to rituximab over placebo was unlikely to be achieved in a subsequent, larger trial. No safety issues identified. CONCLUSIONS: While rituximab was safe and well-tolerated, these results suggest that there is a low probability of observing the defined clinically meaningful steroid-sparing effect over a 12-month period in a phase-3 trial of mild-moderately symptomatic AChR-Ab+ gMG. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that for mild-to-moderate AChR-Ab+ gMG, compared with placebo, rituximab is safe but unlikely to reduce steroid use by an absolute difference of at least 30% at 1 year. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02110706.
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OBJECTIVES: To approximate the rate of familial myasthenia gravis and the coexistence of other autoimmune disorders in the patients and their families. DESIGN: Retrospective cohort study. SETTING: Clinics across North America. PARTICIPANTS: The study included 1032 patients diagnosed with acetylcholine receptor antibody (AChR)-positive myasthenia gravis. METHODS: Phenotype information of 1032 patients diagnosed with AChR-positive myasthenia gravis was obtained from clinics at 14 centres across North America between January 2010 and January 2011. A critical review of the epidemiological literature on the familial rate of myasthenia gravis was also performed. RESULTS: Among 1032 patients, 58 (5.6%) reported a family history of myasthenia gravis. A history of autoimmune diseases was present in 26.6% of patients and in 28.4% of their family members. DISCUSSION: The familial rate of myasthenia gravis was higher than would be expected for a sporadic disease. Furthermore, a high proportion of patients had a personal or family history of autoimmune disease. Taken together, these findings suggest a genetic contribution to the pathogenesis of myasthenia gravis.
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Miastenia Gravis , Autoanticorpos , Humanos , Miastenia Gravis/epidemiologia , Miastenia Gravis/genética , América do Norte/epidemiologia , Receptores Colinérgicos , Estudos RetrospectivosRESUMO
Thirty to fifty percent of patients with acetylcholine receptor (AChR) antibody (Ab)-negative myasthenia gravis (MG) have Abs to muscle specific kinase (MuSK) and are referred to as having MuSK-MG. MuSK is a 100 kD single-pass post-synaptic transmembrane receptor tyrosine kinase crucial to the development and maintenance of the neuromuscular junction. The Abs in MuSK-MG are predominantly of the IgG4 immunoglobulin subclass. MuSK-MG differs from AChR-MG, in exhibiting more focal muscle involvement, including neck, shoulder, facial and bulbar-innervated muscles, as well as wasting of the involved muscles. MuSK-MG is highly associated with the HLA DR14-DQ5 haplotype and occurs predominantly in females with onset in the fourth decade of life. Some of the standard treatments of AChR-MG have been found to have limited effectiveness in MuSK-MG, including thymectomy and cholinesterase inhibitors. Therefore, current treatment involves immunosuppression, primarily by corticosteroids. In addition, patients respond especially well to B cell depletion agents, e.g., rituximab, with long-term remissions. Future treatments will likely derive from the ongoing analysis of the pathogenic mechanisms underlying this disease, including histologic and physiologic studies of the neuromuscular junction in patients as well as information derived from the development and study of animal models of the disease.
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Músculos/patologia , Miastenia Gravis/enzimologia , Miastenia Gravis/patologia , Corticosteroides/uso terapêutico , Animais , Feminino , Subtipos Sorológicos de HLA-DR/genética , Haplótipos , Humanos , Imunoglobulina G/imunologia , Camundongos , Miastenia Gravis/tratamento farmacológico , Miastenia Gravis/genética , Receptores Proteína Tirosina Quinases/genética , Receptores Colinérgicos/genéticaRESUMO
INTRODUCTION: There are no validated, practical, and quantitative measures of disease severity in Lambert-Eaton myasthenia (LEM). METHODS: Data from the Effectiveness of 3,4-Diaminopyridine in Lambert-Eaton Myasthenic Syndrome (DAPPER) trial were analyzed to assess triple timed up-and-go (3TUG) reproducibility and relationships between 3TUG times and other measures of LEM severity. RESULTS: The coverage probability technique showed ≥0.90 probability for an acceptable 3TUG difference of ≤0.2, indicating that it is reproducible in LEM patients. The correlation between 3TUG times and lower extremity function scores was significant in subjects who continued and in those who were withdrawn from 3,4-diaminopyridine free base. Worsening patient-reported Weakness Self-Assessment Scale and Investigator Assessment of Treatment Effect scores corresponded with prolongation of 3TUG times. DISCUSSION: The 3TUG is reproducible, demonstrates construct validity for assessment of lower extremity function in LEM patients, and correlates with changes in patient and physician assessments. These findings, along with prior reliability studies, indicate 3TUG is a valid measure of disease severity in LEM.
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Síndrome Miastênica de Lambert-Eaton/fisiopatologia , Extremidade Inferior/fisiopatologia , Debilidade Muscular/fisiopatologia , Humanos , Programas de Rastreamento/métodos , Debilidade Muscular/tratamento farmacológico , Bloqueadores dos Canais de Potássio/uso terapêutico , Reprodutibilidade dos Testes , Índice de Gravidade de DoençaAssuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/diagnóstico , Neoplasias Pulmonares/tratamento farmacológico , Miastenia Gravis/diagnóstico , Timoma/tratamento farmacológico , Anticorpos Monoclonais Humanizados/efeitos adversos , Antineoplásicos Imunológicos/efeitos adversos , Antígeno B7-H1/antagonistas & inibidores , Feminino , Humanos , Pessoa de Meia-Idade , Miastenia Gravis/etiologia , Metástase Neoplásica , Estadiamento de Neoplasias , Timectomia , Timoma/cirurgiaRESUMO
INTRODUCTION: 3,4-diaminopyridine has been used to treat Lambert-Eaton myasthenia (LEM) for 30 years despite the lack of conclusive evidence of efficacy. METHODS: We conducted a randomized double-blind placebo-controlled withdrawal study in patients with LEM who had been on stable regimens of 3,4-diaminopyridine base (3,4-DAP) for ≥ 3 months. The primary efficacy endpoint was >30% deterioration in triple timed up-and-go (3TUG) times during tapered drug withdrawal. The secondary endpoint was self-assessment of LEM-related weakness (W-SAS). RESULTS: Thirty-two participants were randomized to continuous 3,4-DAP or placebo groups. None of the 14 participants who received continuous 3,4-DAP had > 30% deterioration in 3TUG time versus 72% of the 18 who tapered to placebo (P < 0.0001). W-SAS similarly demonstrated an advantage for continuous treatment over placebo (P < 0.0001). Requirement for rescue and adverse events were more common in the placebo group. DISCUSSION: This trial provides significant evidence of efficacy of 3,4-DAP in the maintenance of strength in LEM. Muscle Nerve 57: 561-568, 2018.
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Amifampridina/uso terapêutico , Desprescrições , Síndrome Miastênica de Lambert-Eaton/tratamento farmacológico , Debilidade Muscular/tratamento farmacológico , Fármacos Neuromusculares/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Método Duplo-Cego , Feminino , Humanos , Síndrome Miastênica de Lambert-Eaton/complicações , Quimioterapia de Manutenção , Masculino , Pessoa de Meia-Idade , Debilidade Muscular/etiologia , Adulto JovemRESUMO
Dabigatran is a direct thrombin inhibitor used to reduce the risk of stroke in patients with nonvalvular atrial fibrillation. For patients who present with an acute stroke despite dabigatran therapy, clinical data on the use of intravenous tissue plasminogen activator (IV-tPA) is limited. There is an anticipated increased risk of symptomatic intracranial hemorrhage (sICH) when using IV-tPA in patients on dabigatran therapy. In 2015, the humanized monoclonal antibody fragment idarucizumab was approved for rapid (minutes) reversal of anticoagulant effects of dabigatran. Dabigatran reversal with idarucizumab before administration of IV-tPA might reduce the risk of sICH. We report a case of a 69-year-old stroke patient on dabigatran for paroxysmal atrial fibrillation who presented with an initial National Institutes of Health Stroke Scale (NIHSS) of 12. There was no early evidence of ischemic stroke or hemorrhage on head computed tomography, and coagulation studies implied therapeutic dabigatran levels. After controlling blood pressure, dabigatran was reversed with idarucizumab, and IV-tPA was administrated beginning 197 minutes after he was last seen at his baseline. Subsequent brain magnetic resonance imaging showed 2 punctate infarcts in the left temporal lobe and occipital lobe with no evidence of hemorrhage. The patient was discharged with an NIHSS of 1. Telephone follow-up 2 months later indicated that he was at his prestroke baseline, except for a complaint of worsened short-term memory. Idarucizumab reversal of dabigatran may reduce the risk of sICH and should be considered for acute stroke patients arriving in the IV-tPA time window.
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Anticorpos Monoclonais Humanizados/uso terapêutico , Antitrombinas/uso terapêutico , Coagulação Sanguínea/efeitos dos fármacos , Coagulantes/uso terapêutico , Dabigatrana/uso terapêutico , Fibrinolíticos/administração & dosagem , Acidente Vascular Cerebral/tratamento farmacológico , Terapia Trombolítica , Ativador de Plasminogênio Tecidual/administração & dosagem , Administração Intravenosa , Idoso , Antitrombinas/efeitos adversos , Dabigatrana/efeitos adversos , Imagem de Difusão por Ressonância Magnética , Fibrinolíticos/efeitos adversos , Humanos , Hemorragias Intracranianas/induzido quimicamente , Hemorragias Intracranianas/prevenção & controle , Masculino , Acidente Vascular Cerebral/sangue , Acidente Vascular Cerebral/diagnóstico por imagem , Acidente Vascular Cerebral/etiologia , Terapia Trombolítica/efeitos adversos , Ativador de Plasminogênio Tecidual/efeitos adversos , Resultado do TratamentoAssuntos
Miastenia Gravis , Estudos de Coortes , Inibidores Enzimáticos , Humanos , ImunossupressoresRESUMO
OBJECTIVE: To develop formal consensus-based guidance for the management of myasthenia gravis (MG). METHODS: In October 2013, the Myasthenia Gravis Foundation of America appointed a Task Force to develop treatment guidance for MG, and a panel of 15 international experts was convened. The RAND/UCLA appropriateness methodology was used to develop consensus guidance statements. Definitions were developed for goals of treatment, minimal manifestations, remission, ocular MG, impending crisis, crisis, and refractory MG. An in-person panel meeting then determined 7 treatment topics to be addressed. Initial guidance statements were developed from literature summaries. Three rounds of anonymous e-mail votes were used to attain consensus on guidance statements modified on the basis of panel input. RESULTS: Guidance statements were developed for symptomatic and immunosuppressive treatments, IV immunoglobulin and plasma exchange, management of impending and manifest myasthenic crisis, thymectomy, juvenile MG, MG associated with antibodies to muscle-specific tyrosine kinase, and MG in pregnancy. CONCLUSION: This is an international formal consensus of MG experts intended to be a guide for clinicians caring for patients with MG worldwide.
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Miastenia Gravis/terapia , Adulto , Criança , Consenso , Feminino , Objetivos , Humanos , Imunoglobulinas Intravenosas/uso terapêutico , Imunossupressores/uso terapêutico , Troca Plasmática , Gravidez , TimectomiaRESUMO
OBJECTIVE: To determine whether discontinuation or marked reduction of mycophenolate mofetil (MMF) in patients with myasthenia gravis (MG) causes MG exacerbations. METHODS: We identified 88 patients with MG who took MMF during the 5-year period 2007-2011 at our MG clinic. We then performed detailed chart reviews and recorded all MG exacerbations and their relationship to MMF and other treatment changes. We also recorded demographic data and disease characteristics (including antibody status and Myasthenia Gravis Foundation of America status). RESULTS: There were 14 patients who had an MG exacerbation during the study period. Of these, 13 had discontinued MMF therapy, with a median time until exacerbation of 16 weeks after discontinuation (9 patients) or marked dose reduction (4 patients) of MMF therapy (exacerbation in the absence of change in any other component of the immunosuppressive regimen). Using the cluster option in a Cox regression analysis, the MMF coefficient was -5.32, with a standard error of 1.05 and a p value of 0.0002, corresponding to an estimated hazard ratio of 204. CONCLUSIONS: This retrospective cohort study suggests that discontinuation/marked reduction of MMF therapy may increase the risk of MG exacerbation many fold, supporting the hypothesis that MMF plays a role in the maintenance of MG remission/minimal manifestation status. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that in patients with MG taking MMF, discontinuation or marked reduction of MMF causes MG exacerbation.
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Progressão da Doença , Imunossupressores/administração & dosagem , Miastenia Gravis/diagnóstico , Miastenia Gravis/tratamento farmacológico , Ácido Micofenólico/análogos & derivados , Suspensão de Tratamento/tendências , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Ácido Micofenólico/administração & dosagem , Estudos Retrospectivos , Adulto JovemAssuntos
Pesquisa Biomédica/tendências , Miastenia Gravis/diagnóstico , Miastenia Gravis/terapia , Ensaios Clínicos como Assunto/tendências , Previsões , Humanos , Debilidade Muscular/diagnóstico , Debilidade Muscular/fisiopatologia , Debilidade Muscular/terapia , Miastenia Gravis/fisiopatologia , Junção Neuromuscular/fisiopatologia , Timectomia/tendênciasRESUMO
Pre-clinical evaluations often provide the rationale for therapeutic assessments in humans; however, in many diseases an agent found successful in animal models does not show efficacy in human subjects. Our contention is that the approach of rigorous, clinical trials can be used to inform how preclinical assessments should be performed. Clinical trials in humans are carefully designed investigations executed with consideration of critical methodological issues, such as pre-specified entrance criteria and validated, outcome measures coupled with power analysis to identify sample size. Blinding of evaluators of subjective measures and randomization of subjects are also critical aspects of trial performance. Investigative agents are also tested in subjects with active disease, rather than prior to disease induction as in some pre-clinical assessments. Application of standard procedures, including uniform reporting standards, would likely assist in reproducibility of pre-clinical experiments. Adapting methods of clinical trial performance will likely improve the success rate of therapeutics to ultimately achieve human use.
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Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos/métodos , Miastenia Gravis , Projetos de Pesquisa/normas , Animais , Ensaios Clínicos como Assunto , HumanosRESUMO
Disorders affecting the presynaptic, synaptic, and postsynaptic portions of the neuromuscular junction arise from various mechanisms in children and adults, including acquired autoimmune or toxic processes as well as genetic mutations. Disorders include autoimmune myasthenia gravis associated with acetylcholine receptor, muscle specific kinase or Lrp4 antibodies, Lambert-Eaton myasthenic syndrome, nerve terminal hyperexcitability syndromes, Guillain Barré syndrome, botulism, organophosphate poisoning and a number of congenital myasthenic syndromes. This review focuses on the various molecular and pathophysiological mechanisms of these disorders, characterization of which has been crucial to the development of treatment strategies specific for each pathogenic mechanism. In the future, further understanding of the underlying processes may lead to more effective and targeted therapies of these disorders. This article is part of a Special Issue entitled: Neuromuscular Diseases: Pathology and Molecular Pathogenesis.
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Botulismo , Síndrome de Guillain-Barré , Síndrome Miastênica de Lambert-Eaton , Miastenia Gravis , Intoxicação por Organofosfatos , Adolescente , Adulto , Autoanticorpos/imunologia , Autoanticorpos/metabolismo , Botulismo/genética , Botulismo/imunologia , Botulismo/metabolismo , Botulismo/patologia , Criança , Pré-Escolar , Síndrome de Guillain-Barré/genética , Síndrome de Guillain-Barré/imunologia , Síndrome de Guillain-Barré/metabolismo , Síndrome de Guillain-Barré/patologia , Humanos , Proteínas Relacionadas a Receptor de LDL/genética , Proteínas Relacionadas a Receptor de LDL/imunologia , Proteínas Relacionadas a Receptor de LDL/metabolismo , Síndrome Miastênica de Lambert-Eaton/genética , Síndrome Miastênica de Lambert-Eaton/imunologia , Síndrome Miastênica de Lambert-Eaton/metabolismo , Síndrome Miastênica de Lambert-Eaton/patologia , Miastenia Gravis/genética , Miastenia Gravis/imunologia , Miastenia Gravis/metabolismo , Miastenia Gravis/patologia , Junção Neuromuscular/genética , Junção Neuromuscular/imunologia , Junção Neuromuscular/metabolismo , Junção Neuromuscular/patologia , Intoxicação por Organofosfatos/genética , Intoxicação por Organofosfatos/imunologia , Intoxicação por Organofosfatos/metabolismo , Intoxicação por Organofosfatos/patologia , Receptores Colinérgicos/genética , Receptores Colinérgicos/imunologia , Receptores Colinérgicos/metabolismoRESUMO
BACKGROUND: Magnetic resonance imaging (MRI) criteria play an important role in making an earlier diagnosis of multiple sclerosis (MS) in patients presenting with clinically isolated syndrome. OBJECTIVE: The objective of this paper is to determine whether MRI criteria may be used to distinguish MS from primary and secondary central nervous system (CNS) vasculitis, lupus, and Sjogren's syndrome. METHODS: MRI criteria were applied retrospectively to images for patients with clinically definite MS (CDMS), primary CNS vasculitis, secondary CNS vasculitis, and autoimmune disorders including systemic lupus erythematosus (SLE) and Sjogren's syndrome. Classical statistics and Bayesian analyses were performed. RESULTS: Overall modified Barkhof's MRI criteria were statistically significant in distinguishing CDMS (60%) from SLE/Sjogren's syndrome (17%, p = 0.0173) but not in distinguishing CDMS from primary CNS vasculitis (50%, p = 0.7376) or secondary CNS vasculitis (58%, p = 1.0000). Four of the five other MRI criteria tested were demonstrated to be superior to modified Barkhof's criteria in predicting MS: nine or more T2 lesions (a component of Barkhof's criteria), one or more ovoid periventricular T2 lesions, one or more perpendicular periventricular T2 lesions, and one or more T2 lesions larger than 6 mm. CONCLUSIONS: MRI criteria, including the modified Barkhof's criteria, were unsuccessful in distinguishing MS from primary CNS vasculitis or secondary CNS vasculitis and mildly successful in distinguishing MS from SLE/Sjogren's syndrome.
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Diagnóstico Diferencial , Lúpus Eritematoso Sistêmico/diagnóstico , Imageamento por Ressonância Magnética , Esclerose Múltipla/diagnóstico , Síndrome de Sjogren/diagnóstico , Vasculite do Sistema Nervoso Central/diagnóstico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Teorema de Bayes , Feminino , Humanos , Interpretação de Imagem Assistida por Computador/métodos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Adulto JovemRESUMO
To develop antigen-specific immunotherapies for autoimmune diseases, knowledge of the molecular structure of targeted immunological hotspots will guide the production of reagents to inhibit and halt production of antigen specific attack agents. To this end we have identified three noncontiguous segments of the Torpedo nicotinic acetylcholine receptor (AChR) α-subunit that contribute to the conformationally sensitive immunological hotspot on the AChR termed the main immunogenic region (MIR): α(1-12), α(65-79), and α(110-115). This region is the target of greater than 50% of the anti-AChR Abs in serum from patients with myasthenia gravis (MG) and animals with experimental autoimmune myasthenia gravis (EAMG). Many monoclonal antibodies (mAbs) raised in one species against an electric organ AChR cross react with the neuromuscular AChR MIR in several species. Probing the Torpedo AChR α-subunit with mAb 132A, a disease inducing anti-MIR mAb raised against the Torpedo AChR, we have determined that two of the three MIR segments, α(1-12) and α(65-79), form a complex providing the signature components recognized by mAb 132A. These two segments straddle a third, α(110-115), that seems not to contribute specific side chains for 132A recognition, but is necessary for optimum antibody binding. This third segment appears to form a foundation upon which the three-dimensional 132A epitope is anchored.
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Miastenia Gravis/imunologia , Receptores Nicotínicos/química , Sequência de Aminoácidos , Animais , Anticorpos Monoclonais/imunologia , Sítios de Ligação de Anticorpos/imunologia , Proteínas de Fluorescência Verde/genética , Humanos , Dados de Sequência Molecular , Miastenia Gravis/sangue , Fragmentos de Peptídeos/imunologia , Ligação Proteica/imunologia , Conformação Proteica , Estrutura Terciária de Proteína , Receptores Nicotínicos/imunologia , Proteínas Recombinantes de Fusão/genética , Análise de Sequência de Proteína , TorpedoRESUMO
Antimuscle-specific kinase (anti-MuSK) myasthenia (AMM) differs from antiacetylcholine receptor myasthenia gravis in exhibiting more focal muscle involvement (neck, shoulder, facial, and bulbar muscles) with wasting of the involved, primarily axial, muscles. AMM is not associated with thymic hyperplasia and responds poorly to anticholinesterase treatment. Animal models of AMM have been induced in rabbits, mice, and rats by immunization with purified xenogeneic MuSK ectodomain, and by passive transfer of large quantities of purified serum IgG from AMM patients into mice. The models have confirmed the pathogenic role of the MuSK antibodies in AMM and have demonstrated the involvement of both the presynaptic and postsynaptic components of the neuromuscular junction. The observations in this human disease and its animal models demonstrate the role of MuSK not only in the formation of this synapse but also in its maintenance.