RESUMO
Autoantibodies to muscle-specific kinase (MuSK) can cause myasthenia gravis (MG). The pathophysiological mechanism remains unknown. We report in vitro electrophysiological and histological studies of the neuromuscular junction in a MuSK MG patient. Low levels of presynaptic acetylcholine release and small miniature endplate potentials were found. This combination of pre- and postsynaptic abnormalities was supported by histology, revealing partially denervated postsynaptic areas, and some degeneration of postsynaptic folds. Results suggest that anti-MuSK antibodies reduce the stability of muscle-nerve contact.
Assuntos
Miastenia Gravis/fisiopatologia , Junção Neuromuscular/fisiopatologia , Receptores Proteína Tirosina Quinases/imunologia , Receptores Colinérgicos/imunologia , Adulto , Autoanticorpos/imunologia , Eletrofisiologia , Feminino , Humanos , Placa Motora/imunologia , Placa Motora/fisiopatologia , Debilidade Muscular/imunologia , Debilidade Muscular/fisiopatologia , Músculo Esquelético/imunologia , Músculo Esquelético/fisiopatologia , Miastenia Gravis/imunologia , Junção Neuromuscular/imunologiaRESUMO
In dermatomyositis (DM) there is strong histopathological evidence of a microvascular pathogenesis, including endothelial microtubular inclusions. In nonspecific myositis, perimysial and perivascular infiltrates in the muscle biopsy similar to DM are found. Microtubular inclusions in endothelial cells were systematically searched for and found in 4 of the 20 muscle biopsies of nonspecific myositis patients (20%). Three had a CTD (SLE, scleroderma, and Sjogren syndrome). Ten patients with DM and 5 patients with sporadic inclusion body myositis served as positive and negative controls, respectively.
Assuntos
Dermatomiosite/patologia , Endotélio Vascular/ultraestrutura , Corpos de Inclusão/ultraestrutura , Microtúbulos/ultraestrutura , Músculo Esquelético/irrigação sanguínea , Adulto , Idoso , Artrite Reumatoide/patologia , Biópsia , Capilares/ultraestrutura , Feminino , Humanos , Lúpus Eritematoso Discoide/patologia , Masculino , Microscopia Eletrônica de Transmissão/métodos , Pessoa de Meia-Idade , Doença Mista do Tecido Conjuntivo/patologia , Músculo Esquelético/patologia , Escleroderma Sistêmico/patologia , Síndrome de Sjogren/patologiaRESUMO
Myasthenia gravis is usually caused by autoantibodies to the acetylcholine receptor (AChR). The AChR is clustered and anchored in the postsynaptic membrane of the neuromuscular junction (NMJ) by a cytoplasmic protein called rapsyn. We previously showed that resistance to experimental autoimmune myasthenia gravis (EAMG) in aged rats correlates with increased rapsyn concentration at the NMJ. It is possible, therefore, that endogenous rapsyn expression may be an important determinant of AChR loss and neuromuscular transmission failure in the human disease, and that upregulation of rapsyn expression could be used therapeutically. To examine first a potential therapeutic application of rapsyn upregulation, we induced acute EAMG in young rats by passive transfer of AChR antibody, mAb 35, and used in vivo electroporation to over-express rapsyn unilaterally in one tibialis anterior. We looked at the compound muscle action potentials (CMAPs) in the tibialis anterior, at rapsyn and AChR expression by quantitative radioimmunoassay and immunofluorescence, and at the morphology of the NMJs, comparing the electroporated and untreated muscles, as well as the control and EAMG rats. In control rats, transfected muscle fibres had extrasynaptic rapsyn aggregates, as well as slightly increased rapsyn and AChR concentrations at the NMJ. In EAMG rats, despite deposits of the membrane attack complex, the rapsyn-overexpressing muscles showed no decrement in the CMAPs, no loss of AChR, and the majority had normal postsynaptic folds, whereas endplates of untreated muscles showed typical AChR loss and morphological damage. These data suggest not only that increasing rapsyn expression could be a potential treatment for selected muscles of myasthenia gravis patients, but also lend support to the hypothesis that individual differences in innate rapsyn expression could be a factor in determining disease severity.