RESUMEN
Using the same mouse strain and two Trypanosoma cruzi sub-populations (CA-I and RA) it is possible to induce pathology in different target tissues: skeletal muscle (CA-I) or sciatic nerve and spinal cord (RA). On the other hand, T cells are directly involved in tissue injury in a strain-dependent way, resembling the abnormalities of chronic Chagas' disease. In the present work, we examined the TCRBV repertoire and the CDR3 sequence polymorphism of T cells infiltrating spinal cord, sciatic nerve and skeletal muscle in chronically infected mice. The TCRBV9 segment was systematically over-represented in the target tissues for each T. cruzi strain: sciatic nerve and spinal cord in RA and skeletal muscle in CA-I-infected mice. The analysis of CDR3 sequence polymorphism in the same tissues showed a high proportion of identical TCRBV9 clones in RA-infected mice: 66.6% of the TCRBV9 clones found in sciatic nerve and spinal cord expressed one out of four major CDR3 rearrangements. Sequence identity was shared among clones from sciatic nerve and spinal cord, tissues that are also damaged by passive transfer of CD8 + TL. Those observations are consistent with an antigen driven T-cell expansion sequestered at the inflammation site and demonstrate -- for the first time -- the presence of an oligoclonal repertoire in the antigen recognition site of over-represented T cells in nervous system tissues in chronic Chagas' disease.
Asunto(s)
Enfermedad de Chagas/inmunología , Enfermedades Neuromusculares/parasitología , Receptores de Antígenos de Linfocitos T alfa-beta/inmunología , Linfocitos T/parasitología , Trypanosoma cruzi/inmunología , Secuencia de Aminoácidos , Animales , Enfermedad de Chagas/parasitología , Células Clonales , Regiones Determinantes de Complementariedad/genética , Regiones Determinantes de Complementariedad/inmunología , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C3H , Datos de Secuencia Molecular , Músculo Esquelético/inmunología , Músculo Esquelético/parasitología , Enfermedades Neuromusculares/inmunología , Polimorfismo Genético , Receptores de Antígenos de Linfocitos T alfa-beta/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Nervio Ciático/inmunología , Nervio Ciático/parasitología , Médula Espinal/inmunología , Médula Espinal/parasitología , Linfocitos T/inmunología , Trypanosoma cruzi/genéticaRESUMEN
Evidence accumulated by our investigations over the years give adequate proof for the existence of circulating antibodies in Chagas disease which bind to beta adrenergic and muscarinic cholinergic receptor of myocardium. The interaction of agonist-like antibodies with neurotransmitter receptors, triggers in the cells intracellular signal transductions that alter the physiological behaviour of the target organs. These events convert the normal cells into pathologically active cells. The interaction of antibodies with heart beta adrenergic and cholinergic receptors triggers physiologic, morphologic, enzymatic and molecular alterations, leading to tissue damage. The analysis of the prevalence and distribution of these antibodies reveals a strong association with cardiac and esophageal autonomic dysfunction in seropositive patients in comparison with those without alteration of the heart and esophagus autonomic disorders: therefore, the presence of these antibodies may partially explain the cardiomyoneurophathy and achalasia of Chagas disease, in which the sympathetic and parasympathetic systems are affected. The deposit of autoantibodies behaving like an agonist on neurotransmitter receptors, induceds desensitization and/or down regulation of the receptors. This in turn, could lead to a progressive blockade of neurotransmitter receptors, with sympathetic and parasympathetic dennervation, a phenomenon that has been described during the course of Chagas cardioneuropathy and achalasia. The clinical relevance of these findings is the demonstration, using biomolecules, of a strong association between the existence of circulating autoantibodies against peptides corresponding to the second extracellular loop of the human heart beta, adrenoceptor and M2 cholinoceptor in chagasic patients, and the presence of dysautonomic symptoms, making these autoantibodies a proper early marker of heart and digestive autonomic dysfunction.
Asunto(s)
Autoanticuerpos/metabolismo , Cardiomiopatía Chagásica/inmunología , Acalasia del Esófago/inmunología , Enfermedades Neuromusculares/inmunología , Receptores Adrenérgicos beta/metabolismo , Receptores Colinérgicos/metabolismo , Anticuerpos Antiprotozoarios/inmunología , Anticuerpos Antiprotozoarios/metabolismo , Cardiomiopatía Chagásica/complicaciones , Cardiomiopatía Chagásica/metabolismo , Acalasia del Esófago/complicaciones , Acalasia del Esófago/metabolismo , Humanos , Inmunoglobulina G/inmunología , Inmunoglobulina G/metabolismo , Enfermedades Neuromusculares/metabolismo , Receptores de Neurotransmisores/metabolismoRESUMEN
Evidence accumulated by our investigations over the years give adequate proof for the existence of circulating antibodies in Chagas disease which bind to beta adrenergic and muscarinc cholinergic receptor of myocardium. The interaction of agonist-like antibodies with neurotransmitter receptors, triggers in the cells intracellular signal transductions that alter the physiological behaviour of the target organs. These events convert the normal cells into pathologically active cells. The interaction of antibodies with heart beta adrenergic and cholinergic receptors triggers physiologic, morphologic, enzymatic and molecular alterations, leading to tissue damage. The analysis of the prevalence and distribution of these antibodies reveals a strong association with cardiac and esophageal autonomic dysfunction in seropositive patients in comparison with those without alteration of the heart and esophagus autonomic disorders: therefore, the presence of these antibodies may partially explain the cardiomyoneurophathy and achalasia of Chagas disease, in which the sympathetic and parasympathetic systems are affected. The deposit of autoantibodies behaving like an agonist on neurotransmitter receptors, induceds desensitization and/or down regulation of the receptors. This is turn, could lead to a progressive blockade of neurotransmitter receptors, with sympathetic and parasympathetic dennervation, a phenomenon that has been described during the course of Chagas cardioneuropathy and achalasia. The clinical relevance of these findings is the demonstration, using biomolecules, of a strong association between the existence of circulating autoantibodies against peptides corresponding to the second extracellular loop of the human heart beta, adrenoceptor and M2 cholinoceptor in chagasic patients, and the presence of dysautonomic symptoms, making these autoantibodies a proper early marker of heart and digestive autonomic dysfunction. (AU)
Asunto(s)
Humanos , Cardiomiopatía Chagásica/inmunología , Enfermedades Neuromusculares/inmunología , Acalasia del Esófago/inmunología , Receptores Colinérgicos/metabolismo , Receptores Adrenérgicos beta/metabolismo , Autoanticuerpos/inmunología , Enfermedades Neuromusculares/etiología , Enfermedades Neuromusculares/fisiopatología , Acalasia del Esófago/etiología , Acalasia del Esófago/fisiopatología , Cardiomiopatía Chagásica/complicaciones , Cardiomiopatía Chagásica/fisiopatología , Receptores de Neurotransmisores/metabolismoRESUMEN
Evidence accumulated by our investigations over the years give adequate proof for the existence of circulating antibodies in Chagas disease which bind to beta adrenergic and muscarinc cholinergic receptor of myocardium. The interaction of agonist-like antibodies with neurotransmitter receptors, triggers in the cells intracellular signal transductions that alter the physiological behaviour of the target organs. These events convert the normal cells into pathologically active cells. The interaction of antibodies with heart beta adrenergic and cholinergic receptors triggers physiologic, morphologic, enzymatic and molecular alterations, leading to tissue damage. The analysis of the prevalence and distribution of these antibodies reveals a strong association with cardiac and esophageal autonomic dysfunction in seropositive patients in comparison with those without alteration of the heart and esophagus autonomic disorders: therefore, the presence of these antibodies may partially explain the cardiomyoneurophathy and achalasia of Chagas disease, in which the sympathetic and parasympathetic systems are affected. The deposit of autoantibodies behaving like an agonist on neurotransmitter receptors, induceds desensitization and/or down regulation of the receptors. This is turn, could lead to a progressive blockade of neurotransmitter receptors, with sympathetic and parasympathetic dennervation, a phenomenon that has been described during the course of Chagas cardioneuropathy and achalasia. The clinical relevance of these findings is the demonstration, using biomolecules, of a strong association between the existence of circulating autoantibodies against peptides corresponding to the second extracellular loop of the human heart beta, adrenoceptor and M2 cholinoceptor in chagasic patients, and the presence of dysautonomic symptoms, making these autoantibodies a proper early marker of heart and digestive autonomic dysfunction.
Asunto(s)
Humanos , Autoanticuerpos/inmunología , Cardiomiopatía Chagásica/inmunología , Acalasia del Esófago/inmunología , Enfermedades Neuromusculares/inmunología , Receptores Adrenérgicos beta/metabolismo , Receptores Colinérgicos/metabolismo , Cardiomiopatía Chagásica/complicaciones , Cardiomiopatía Chagásica/fisiopatología , Acalasia del Esófago/etiología , Acalasia del Esófago/fisiopatología , Enfermedades Neuromusculares/etiología , Enfermedades Neuromusculares/fisiopatología , Receptores de Neurotransmisores/metabolismoAsunto(s)
Enfermedades Neuromusculares/inmunología , Adolescente , Cuba/epidemiología , Brotes de Enfermedades , Humanos , Inmunoglobulina G/líquido cefalorraquídeo , Enfermedades Neuromusculares/líquido cefalorraquídeo , Enfermedades Neuromusculares/epidemiología , Albúmina Sérica/líquido cefalorraquídeoRESUMEN
Fifty-nine percent of 49 patients with motor neuron disease and 25% of 91 control subjects had IgM antibodies to ganglioside GM1 but usually not to GD1b at titers less than 1:80. This suggests that antibodies to GM1 may be part of the normal human antibody repertoire. However, given the higher incidence of antibodies to GM1 in patients with motor neuron disease, there may be specific epitopes important in antiganglioside antibodies associated with motor neuron disease.
Asunto(s)
Autoanticuerpos/sangre , Gangliósido G(M1)/inmunología , Gangliósidos/inmunología , Neuronas Motoras/metabolismo , Enfermedades Neuromusculares/inmunología , Femenino , Humanos , Cadenas mu de Inmunoglobulina , Masculino , Persona de Mediana EdadRESUMEN
In this work, we describe skeletal muscle, neuromuscular junction, nerve and spinal cord lesions in the mouse model system of Chagas' disease. Myositis was a common finding and Trypanosoma cruzi amastigote nests were frequently found in the muscle fibers. Angular atrophy, targetoid fibers, groups of atrophic fibers, fibrosis, myofiber necrosis and phagocytosis of cellular debris were also observed. The neuromuscular junction studies showed degeneration of intramuscular nerve fibers, swelling and distortion of nerve endings and multiple ramifications on the same muscle fiber. Collateral, terminal and ultraterminal axonal sprouts were also present. Inflammatory neuropathy was seen in all of the infected mice. Demyelination, axonal degeneration, remyelination and axonal regeneration were observed in the transverse sections. There was an average reduction of 29% in the total number of myelin fibers. The teasing of single myelin fibers showed segmental and paranodal demyelination and remyelination more frequently than axonal degeneration and regeneration. The lumbar spinal cords presented inflammatory cell infiltration associated with tissue destruction. Amastigote nests were found in 3 out of the 8 infected mice studied. There was a mean loss of 21% of the large cytoneurons of the anterior horn of the lumbar spinal cord.