RESUMO
The nicotinic acetylcholine receptor (nAChR) family, the archetype member of the pentameric ligand-gated ion channels, is ubiquitously distributed in the central and peripheral nervous systems, and its members are the targets for both genetic and acquired forms of neurological disorders. In the central nervous system, nAChRs contribute to the pathological mechanisms of neurodegenerative disorders, such as Alzheimer and Parkinson diseases. In the peripheral nerve-muscle synapse, the vertebrate neuromuscular junction, "classical" myasthenia gravis (MG) and other forms of neuromuscular transmission disorders are antibody-mediated autoimmune diseases. In MG, antibodies to the nAChR bind to the postsynaptic receptors and activate the classical complement pathway culminating in the formation of the membrane attack complex, with the subsequent destruction of the postsynaptic apparatus. Divalent nAChR-antibodies also cause internalization and loss of the nAChRs. Loss of receptors by either mechanism results in the muscle weakness and fatigability that typify the clinical manifestations of the disease. Other targets for antibodies, in a minority of patients, include muscle specific kinase (MuSK) and low-density lipoprotein related protein 4 (LRP4). This brief Review analyzes the current status of muscle-type nAChR in relation to the pathogenesis of autoimmune diseases affecting the peripheral cholinergic synapse.
Assuntos
Autoanticorpos/imunologia , Miastenia Gravis/imunologia , Junção Neuromuscular/imunologia , Receptores Nicotínicos/imunologia , Animais , Humanos , Transmissão Sináptica/imunologiaRESUMO
Neuroinflammation is a recognized pathogenic mechanism underlying motor neuron degeneration in amyotrophic lateral sclerosis (ALS), but the inflammatory mechanisms influencing peripheral motor axon degeneration remain largely unknown. A recent report showed a pathogenic role for c-Kit-expressing mast cells mediating inflammation and neuromuscular junction denervation in muscles from SOD1G93A rats. Here, we have explored whether mast cells infiltrate skeletal muscles in autopsied muscles from ALS patients. We report that degranulating mast cells were abundant in the quadriceps muscles from ALS subjects but not in controls. Mast cells were associated with myofibers and motor endplates and, remarkably, interacted with neutrophils forming large extracellular traps. Mast cells and neutrophils were also abundant around motor axons in the extensor digitorum longus muscle, sciatic nerve, and ventral roots of symptomatic SOD1G93A rats, indicating that immune cell infiltration extends along the entire peripheral motor pathway. Postparalysis treatment of SOD1G93A rats with the tyrosine kinase inhibitor drug masitinib prevented mast cell and neutrophil infiltration, axonal pathology, secondary demyelination, and the loss of type 2B myofibers, compared with vehicle-treated rats. These findings provide further evidence for a yet unrecognized contribution of immune cells in peripheral motor pathway degeneration that can be therapeutically targeted by tyrosine kinase inhibitors.
Assuntos
Esclerose Lateral Amiotrófica/imunologia , Mastócitos/imunologia , Neurônios Motores/patologia , Junção Neuromuscular/patologia , Neutrófilos/imunologia , Esclerose Lateral Amiotrófica/tratamento farmacológico , Esclerose Lateral Amiotrófica/patologia , Animais , Axônios/efeitos dos fármacos , Axônios/imunologia , Axônios/patologia , Benzamidas , Degranulação Celular/efeitos dos fármacos , Degranulação Celular/imunologia , Modelos Animais de Doenças , Humanos , Masculino , Mastócitos/efeitos dos fármacos , Neurônios Motores/citologia , Neurônios Motores/imunologia , Músculo Esquelético/citologia , Músculo Esquelético/inervação , Músculo Esquelético/patologia , Junção Neuromuscular/efeitos dos fármacos , Junção Neuromuscular/imunologia , Infiltração de Neutrófilos/efeitos dos fármacos , Neutrófilos/efeitos dos fármacos , Piperidinas , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Piridinas , Ratos , Ratos Transgênicos , Superóxido Dismutase/genética , Superóxido Dismutase-1/genética , Tiazóis/farmacologia , Tiazóis/uso terapêutico , Resultado do TratamentoRESUMO
Recently characterized as an immune-mediated channelopaty, Isaacs' syndrome (also known as acquired neuromyotonia) was first described in 1961 in two men with persistent, generalized muscle stiffness, in addition to spontaneous, rapid discharges of motor-unit potentials on electromyography. In the peripheral nervous system, antibodies targeted to voltage-gated potassium channels induce hyperexcitability of motor axons, resulting in signs of muscle stiffness or of pseudomyotonia. A spontaneous burst of single motor-unit activity, and myokymic and neuromyotonic discharges, are the most characteristic features found in electromyography studies. This report describes Isaacs' syndrome in a child, in whom the diagnosis was made by clinical features of acquired, spontaneous muscle overactivity and typical electromyographic findings.
Assuntos
Autoanticorpos/imunologia , Síndrome de Isaacs/diagnóstico , Síndrome de Isaacs/fisiopatologia , Músculo Esquelético/fisiopatologia , Canais de Potássio de Abertura Dependente da Tensão da Membrana/imunologia , Espasmo/etiologia , Adolescente , Fatores Etários , Anticonvulsivantes/uso terapêutico , Carbamazepina/análogos & derivados , Carbamazepina/uso terapêutico , Diagnóstico Diferencial , Eletromiografia , Humanos , Síndrome de Isaacs/imunologia , Masculino , Doença dos Neurônios Motores/imunologia , Doença dos Neurônios Motores/fisiopatologia , Neurônios Motores/imunologia , Músculo Esquelético/imunologia , Músculo Esquelético/inervação , Condução Nervosa/imunologia , Junção Neuromuscular/imunologia , Junção Neuromuscular/fisiopatologia , Espasmo/fisiopatologia , Resultado do TratamentoRESUMO
In order to search for early changes induced by the application of human immunoglobulin G (IgG) on motor nerve terminals, IgG from patients with amyotrophic lateral sclerosis (ALS) and control subjects was injected subcutaneously into the levator auris muscle of mice. A week or a month after the last injection, endplate potentials were recorded. No changes in quantal content of transmitter release were observed. In control and ALS IgG-treated muscles, neurotransmitter release remained sensitive to P/Q-type and insensitive to N-type voltage-sensitive calcium channel (VSCC) blockers as in untreated muscles. In contrast, IgG from 5 of 8 different ALS patients induced a significant reduction in quantal content of the evoked response after incubation with nitrendipine, indicating that a novel sensitivity to this calcium channel blocker appears in these motor nerve terminals. These results indicate that ALS IgG induces plastic changes at nerve terminals. The expression of transmitter release coupled to L-type VSCC indicate that ALS IgGs are capable of inducing plastic changes at the nerve terminals that may participate in the process leading to neuronal death.
Assuntos
Bloqueadores dos Canais de Cálcio/farmacologia , Canais de Cálcio Tipo L/fisiologia , Imunoglobulina G/farmacologia , Doença dos Neurônios Motores/imunologia , Junção Neuromuscular/fisiologia , Adulto , Idoso , Animais , Potenciais Evocados/efeitos dos fármacos , Potenciais Evocados/fisiologia , Feminino , Humanos , Imunoglobulina G/sangue , Masculino , Camundongos , Pessoa de Meia-Idade , Músculo Esquelético/inervação , Junção Neuromuscular/efeitos dos fármacos , Junção Neuromuscular/imunologia , Nitrendipino/farmacologia , Valores de Referência , ômega-Agatoxina IVA/farmacologia , ômega-Conotoxina GVIA/farmacologiaRESUMO
La principal inspiración de esta actualización proviene de las publicaciones periódicas que hace la New York Academy of Sciences, la cual destina un número, cada 3-4 años, a tratar los nuevos aspectos tanto clínicos como de ciencias básicas sobre el comportamiento anormal de la transmisión neuromuscular en la Miastenia Gravis. Una parte breve del trabajo se destina a la historia fascinante del descubrimiento de la Miastenia autoinmune experimental. Enseguida se revisa parcialmemte la composición molecular del receptor nicotímico de la Acetilcolina (RAc) en el músculo. Posteriormente se suceden las referencias a la producción de anticuerpos de la clase IgG contra las subunidades alfa del receptor de Ac, la interacción de los linfocitos B como células presentadoras en el contexto del complejo mayor de histocompatibilidad de la clase II y su participación de la tríada, que se completa con el antígeno y los receptores de los linfocitos T. Se alude al empleo de los polipéptidos sintéticos que reproducen secuencias aminoácidas de las subunidades de los receptores del músculo humano y que permitirían, eventualmente, utilizarlos como una suerte de inactivadores de las células T autoinmunes. Una sección importante se refiere a la presencia en la Miastenia Gravis de clonos patológicos de las células T en el suero de los pacientes, contra las cadenas alfa del RAc, pero también se enfatiza la presencia de clonos de células T autoinmunes en el sistema inmunitario normal. Se señala que no se sabe con certeza por qué se rompe la tolerancia autoinmunitaria. Termina la revisión analizando extensamente la participación del Timo en la formación de anticuerpos contra la placa motora sin eludir la complejidad y el misterio que reside en la intimidad histológica y molecular de dicho proceso. Se plantea la duda que sea el Timo el factor causal de la MG y se postula que su patología hiperplásica o tumoral sería un epifenómeno de un proceso más general de alteración autoinmunitaria
Assuntos
Humanos , Proteínas do Sistema Complemento , Sistema Imunitário , Miastenia Gravis , Timo , Linfócitos B , Imunoglobulina G , Miastenia Gravis , Miastenia Gravis Autoimune Experimental , Proteínas rac de Ligação ao GTP , Receptores Colinérgicos/imunologia , Receptores Nicotínicos/imunologia , Linfócitos T , Transmissão Sináptica/imunologia , Junção Neuromuscular/imunologiaRESUMO
Human and experimental Chagas' disease causes peripheral nervous system damage involving neuromuscular transmission alterations at the neuromuscular junction. Additionally, autoantibodies directed to peripheral nerves and sarcolemmal proteins of skeletal muscle have been described. In this work, we analyse the ability of serum immunoglobulin factors associated with human chagasic infection to bind the affinity-purified nicotinic acetylcholine receptor (nAChR) from electric organs of Discopyge tschudii and to identify the receptor subunits involved in the interaction. The frequency of serum anti-nAChR reactivity assayed by dot-blot was higher in seropositive chagasic patients than in uninfected subjects. Purified IgG obtained from chagasic patients immunoprecipitated a significantly higher fraction of the solubilized nAChR than normal IgG. Furthermore, immunoblotting assays indicated that alpha and beta are the main subunits involved in the interaction. Chagasic IgG was able to inhibit the binding of alpha-bungarotoxin to the receptor in a concentration-dependent manner, confirming the contribution of the alpha-subunit in the autoantibody-receptor interaction. The presence of anti-nAChR antibodies was detected in 73% of chagasic patients with impairment of neuromuscular transmission in conventional electromyographical studies, indicating a strong association between seropositive reactivity against nAChR and electromyographical abnormalities in chagasic patients. The chronic binding of these autoantibodies to the nAChR could induce a decrease in the population of functional nAChRs at the neuromuscular junction and consequently contribute to the electrophysiological neuromuscular alterations described in the course of chronic Chagas' disease.
Assuntos
Autoanticorpos/sangue , Doença de Chagas/imunologia , Receptores Nicotínicos/imunologia , Autoanticorpos/imunologia , Doença de Chagas/sangue , Humanos , Immunoblotting , Junção Neuromuscular/imunologiaRESUMO
Clinical and experimental evidence support an autoimmune etiopathogenesis for amyotrophic lateral sclerosis (ALS). We have shown that local application of ALS-IgG onto nerve terminals induces dysfunction in transmission at the neuromuscular junction. It has been established that IgG and other circulating serum proteins can be taken up by motor nerve terminals, being immunolocalized in the soma where they accumulate following retrograde axonal transport. In the present study, we investigated the presence of human ALS and control IgG in the soma of mouse motoneurons. IgG was applied onto motor nerve terminals of mice by subcutaneous injections on the left levator auris longus muscle which is innervated by a branch of the facial nerve. After several injections, sections of the brainstem containing the facial nuclei were immunoprocessed to detect human IgG. For all IgG tested, motoneuron labeling was significantly more intense in the facial nucleus ipsilateral to the site of injection. In ALS-IgG-treated animals, ipsilateral labeling was significantly stronger than that found on the ipsilateral side of control IgG-treated animals. Our results are compatible with the concept that motoneurons preferentially take up, transport and/or accumulate ALS-IgG. Uptake of pathogenic antibodies by motoneuron terminals may play a role in the pathogenesis of motoneuron disease.