Assuntos
Autoanticorpos/imunologia , Cardiomiopatia Chagásica/tratamento farmacológico , Cardiomiopatia Chagásica/imunologia , Nitroimidazóis/farmacologia , Receptor Muscarínico M2/imunologia , Receptores Adrenérgicos beta/imunologia , Animais , Autoanticorpos/sangue , Modelos Animais de Doenças , Cães , Humanos , Imunossupressores/farmacologiaRESUMO
High levels of antibodies (Abs) against the C-terminal end of the Trypanosoma cruzi ribosomal P2ß protein, defined by the R13 peptide, are detected in sera from patients with chronic Chagas heart disease (cChHD). These Abs can cross-react with the ß1-adrenergic receptor (ß1-AR), inducing a functional response in cardiomyocytes. In this study, we report that a monoclonal Ab against the R13 peptide, called mAb 17.2, and its single-chain Fv fragment (scFv), C5, caused apoptosis of murine adult cardiac HL-1 cells, and this effect was inhibited by pre-incubation with the ß-blocker, propranolol. In addition, apoptosis induced by mAb 17.2 might involve the mitochondrial pathway evidenced by an increase in pro-apoptotic molecule, Bax/anti-apoptotic molecule, Bcl(XL), mRNA levels. HL-1 cells also underwent apoptosis after incubation with nine of 23 IgGs from cChHD patients (39.1%) that presented reactivity against R13 peptide and ß1-AR. The apoptotic effect caused by these IgGs was partially abolished by pre-incubation with R13 peptide or propranolol, suggesting the involvement of the C-terminal end of ribosomal P proteins and the ß-adrenergic pathway. Moreover, we observed high rates of cardiomyocyte apoptosis in two tissue samples from cChHD patients by using a TUNEL assay and staining of active caspase-3. Our data demonstrate that Abs developed during T. cruzi infection have a strong cardiomyocyte apoptosis inducing ability, which could contribute to the heart disease developed in patients with cChHD.
Assuntos
Anticorpos Antiprotozoários/imunologia , Antígenos de Protozoários/imunologia , Apoptose , Miócitos Cardíacos/fisiologia , Fosfoproteínas/imunologia , Proteínas Ribossômicas/imunologia , Trypanosoma cruzi/imunologia , Animais , Anticorpos Monoclonais/imunologia , Caspase 3/metabolismo , Linhagem Celular , Reações Cruzadas , Feminino , Humanos , Marcação In Situ das Extremidades Cortadas , Masculino , Camundongos , Pessoa de Meia-Idade , Receptores Adrenérgicos beta/imunologia , Anticorpos de Cadeia Única/imunologiaRESUMO
INTRODUCTION: Chagas disease is the main cause of chronic myocardiopathy in Central America. The mechanisms proposed for this cardiac pathology during the chronic phase remain controversial. Several studies have detected the presence of circulating autoantibodies against beta-adrenergic and cholinergic muscarinic receptors of the myocardium in patients with Chagas disease. These autoantibodies can trigger intracellular signals and modify the cardiac function during the progression of the disease. OBJECTIVES: The serological frequency of these autoantibodies was compared among patients with chronic Chagas disease, patients with other cardiopathies and healthy controls. MATERIALS AND METHODS: The prevalence of autoantibodies against beta-adrenergic and cholinergic muscarinic receptors was determined in four groups of Panamenian patients: 53 chagasic patients, 25 serologically negative patients with cardiac insufficiency, 25 patients with cardiac arrhythmia and 25 healthy individuals. RESULTS: The antibodies against autonomic receptors were more frequently observed in patients with chronic chagasic cardiomyopathy (24.5%) compared to the cardiac insufficiency group (20.0%) and the cardiac arrhythmia group (16.0%). The proportion of autoantibodies was significantly different between the groups with chronic chagasic cardiomyopathy and healthy controls (24.5% versus 0%; p = 0.015). Of the 53 chronically infected chagasic patients, 48 (90%) showed some degree of cardiac dysfunction. CONCLUSIONS: The frequency of autoantibodies against autonomic receptors is significantly increased in patients with chronic Chagas disease and in patients with other cardiopathies.
Assuntos
Arritmias Cardíacas/imunologia , Autoanticorpos/sangue , Autoantígenos/imunologia , Cardiomiopatia Chagásica/imunologia , Insuficiência Cardíaca/imunologia , Receptores Adrenérgicos beta/imunologia , Receptores Muscarínicos/imunologia , Adulto , Idoso , Arritmias Cardíacas/sangue , Arritmias Cardíacas/fisiopatologia , Autoimunidade , Cardiomiopatia Chagásica/sangue , Cardiomiopatia Chagásica/fisiopatologia , Doença Crônica , Progressão da Doença , Feminino , Insuficiência Cardíaca/sangue , Insuficiência Cardíaca/fisiopatologia , Humanos , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , Masculino , Pessoa de Meia-Idade , PanamáRESUMO
UNLABELLED: We previously demonstrated correlation between parasympathetic dysfunction and brain white matter lesions in chronic chagasic patients. OBJECTIVE: To correlate serum functional circulating antibodies with beta adrenergic (Ab-beta), muscarinic (Ab-M) or muscarinic and beta adrenergic (Ab-Mbeta) activity, the autonomic system function and brain lesions in chronic chagasic patients. METHOD: In fifteen consecutive chagasic patients, the autonomic nervous system was evaluated and brain magnetic resonance imaging (MRI) was performed. The sera of all patients were tested to the presence of circulating functional antibodies. RESULTS: Sera from 11 of 15 chronic chagasic patients had some activity (Ab-beta: 7; Ab-M: 1; Ab-Mbeta: 3); however, there was no significant correlation between the presence of antibodies and the autonomic system function or the presence of hyperintensities in MRI. CONCLUSION: The mechanism involved in the genesis of hyperintense lesions seen in brain MRI of chronic chagasic patients is still unresolved, although apparently related to parasympathetic dysfunction.
Assuntos
Autoanticorpos/sangue , Doenças do Sistema Nervoso Autônomo , Encéfalo , Doença de Chagas , Receptores Adrenérgicos beta/imunologia , Receptores Muscarínicos/imunologia , Animais , Doenças do Sistema Nervoso Autônomo/imunologia , Doenças do Sistema Nervoso Autônomo/patologia , Doenças do Sistema Nervoso Autônomo/fisiopatologia , Encéfalo/imunologia , Encéfalo/patologia , Doença de Chagas/imunologia , Doença de Chagas/patologia , Doença de Chagas/fisiopatologia , Doença Crônica , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Coelhos , Trypanosoma cruziRESUMO
We previously demonstrated correlation between parasympathetic dysfunction and brain white matter lesions in chronic chagasic patients. OBJECTIVE: To correlate serum functional circulating antibodies with beta adrenergic (Ab-β), muscarinic (Ab-M) or muscarinic and beta adrenergic (Ab-Mβ) activity, the autonomic system function and brain lesions in chronic chagasic patients. METHOD: In fifteen consecutive chagasic patients, the autonomic nervous system was evaluated and brain magnetic resonance imaging (MRI) was performed. The sera of all patients were tested to the presence of circulating functional antibodies. RESULTS: Sera from 11 of 15 chronic chagasic patients had some activity (Ab-β: 7; Ab-M: 1; Ab-Mβ: 3); however, there was no significant correlation between the presence of antibodies and the autonomic system function or the presence of hyperintensities in MRI. CONCLUSION: The mechanism involved in the genesis of hyperintense lesions seen in brain MRI of chronic chagasic patients is still unresolved, although apparently related to parasympathetic dysfunction.
A correlação entre disfunção parassimpática e lesões de substância branca cerebral em pacientes chagásicos já foi previamente demonstrada. OBJETIVO: Correlacionar a presença de anticorpos circulantes funcionais com atividade beta-adrenérgica (Ab-β), muscarínica (Ab-M) ou muscarínica e beta adrenérgica (Ab-Mβ), a presença de disautonomia e lesões de substância branca cerebral em pacientes chagásicos crônicos. MÉTODO: Em quinze pacientes chagásicos consecutivos, foram realizados a avaliação do sistema nervoso autônomo e ressonância magnética (RM) do crânio. O soro dos pacientes foi testado para a presença de anticorpos funcionais circulantes. RESULTADOS: O soro de 11 dos 15 pacientes chagásicos apresentou alguma atividade (Ab-β: 7; Ab-M: 1; Ab-Mβ: 3); porém não houve correlação significativa entre a presença de anticorpos circulantes e disautonomia ou de hiperintensidades à RM. CONCLUSÃO: O mecanismo envolvido na gênese das lesões hiperintensas à RM do crânio dos pacientes chagásicos crônicos não está esclarecida ainda, apesar de aparentemente relacionada à disfunção parassimpática.
Assuntos
Animais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Coelhos , Doenças do Sistema Nervoso Autônomo , Autoanticorpos/sangue , Encéfalo , Doença de Chagas , Receptores Adrenérgicos beta/imunologia , Receptores Muscarínicos/imunologia , Doenças do Sistema Nervoso Autônomo/imunologia , Doenças do Sistema Nervoso Autônomo/patologia , Doenças do Sistema Nervoso Autônomo/fisiopatologia , Encéfalo/imunologia , Encéfalo/patologia , Doença Crônica , Doença de Chagas/imunologia , Doença de Chagas/patologia , Doença de Chagas/fisiopatologia , Estudos Prospectivos , Trypanosoma cruziRESUMO
Chagas' disease is a serious health problem in Latin America. Between 25 to 30% of the infected patients develop the chronic form of the disease, with progressive myocardial damage and often, sudden death. Adrenergic or cholinergic antibodies with G-protein coupled membrane receptor activity may be present in the sera of these patients. The present study discusses the etiology and the contribution of antibodies to the physiopathology of Chagas' disease.
Assuntos
Autoanticorpos/imunologia , Doença de Chagas/imunologia , Animais , Anticorpos Antiprotozoários/imunologia , Doença de Chagas/etiologia , Doença de Chagas/fisiopatologia , Doença Crônica , Humanos , Receptores Adrenérgicos beta/imunologia , Receptores Colinérgicos/imunologia , Trypanosoma cruzi/imunologiaRESUMO
A doença de Chagas é um sério problema de saúde na América Latina. Entre 25 por cento e 30 por cento dos pacientes infectados evoluem para a forma crônica (CCC), observando-se danos miocárdicos progressivos e, freqüentemente, morte súbita. Anticorpos com atividade para receptores de membrana acoplados a proteína G, adrenérgicos ou colinérgicos podem estar presentes no soro desses pacientes. No presente artigo serão discutidas a etiologia e a contribuição dos anticorpos na fisiopatologia da doença de Chagas.
Chagas' disease is a serious health problem in Latin America. Between 25 to 30% of the infected patients develop the chronic form of the disease, with progressive myocardial damage and often, sudden death. Adrenergic or cholinergic antibodies with G-protein coupled membrane receptor activity may be present in the sera of these patients. The present study discusses the etiology and the contribution of antibodies to the physiopathology of Chagas' disease.
Assuntos
Animais , Humanos , Autoanticorpos/imunologia , Doença de Chagas/imunologia , Anticorpos Antiprotozoários/imunologia , Doença Crônica , Doença de Chagas/etiologia , Doença de Chagas/fisiopatologia , Receptores Adrenérgicos beta/imunologia , Receptores Colinérgicos/imunologia , Trypanosoma cruzi/imunologiaRESUMO
BACKGROUND: The mechanisms underlying inappropriate sinus tachycardia are not fully known. An autonomic imbalance seems to play a role, but no attempts have been made to investigate a relationship between this arrhythmia and the antiautonomic membrane receptor antibodies found in other heart disorders and arrhythmias. OBJECTIVE: The purpose of this study was to investigate the prevalence and the functional and biochemical effects of circulating antiautonomic receptor antibodies in patients with inappropriate sinus tachycardia. METHODS: We studied 21 patients with inappropriate sinus tachycardia and 15 healthy volunteers. The chronotropic effects of the IgG fractions (also of affinity-purified anti-beta1 adrenergic receptor antibodies in selected cases) were assessed on cultured cardiomyocytes before and after exposure to atropine and propranolol. The effects of the IgG fractions from five patients and five healthy volunteers on cAMP production were evaluated in COS-7 cells transfected with genes encoding for beta1 or beta2 adrenergic receptor. RESULTS: The IgG fractions from patients with inappropriate sinus tachycardia exerted a positive chronotropic action with a high prevalence of anti-beta receptor antibodies (52%) and induced a clear-cut and long lasting increment of cAMP. No anti-M2 cholinergic receptor antibodies were found. The IgG fractions from healthy volunteers did not contain antiautonomic receptor antibodies. CONCLUSIONS: Our results suggest, for the first time, a link between inappropriate sinus tachycardia and circulating anti-beta adrenergic receptor antibodies that induce a persistent increment in cAMP production. This finding offers new insight into the physiopathology of inappropriate sinus tachycardia with potential therapeutic consequences.
Assuntos
Autoanticorpos/imunologia , Doenças do Sistema Imunitário/complicações , Miocárdio/metabolismo , Receptores Adrenérgicos beta/metabolismo , Taquicardia Sinusal/etiologia , Adolescente , Adulto , Animais , Anticorpos Anti-Idiotípicos/imunologia , Biomarcadores/metabolismo , Feminino , Humanos , Doenças do Sistema Imunitário/imunologia , Doenças do Sistema Imunitário/metabolismo , Técnicas Imunoenzimáticas , Imunoglobulina G/imunologia , Masculino , Pessoa de Meia-Idade , Miocárdio/patologia , Ratos , Receptores Adrenérgicos beta/imunologia , Taquicardia Sinusal/imunologia , Taquicardia Sinusal/metabolismoRESUMO
OBJECTIVE: The aim of this work was to analyze beta-adrenergic receptor (betaAR) regulation of T-lymphocyte proliferation in mice according to different thyroid hormone statuses. METHODS: T cells from eu-, hypo- (by propylthiouracil treatment) and hyperthyroid (by thyroxine, T4 administration) mice were purified and specific radioligand binding assays were performed. The effects of the beta-agonist isoproterenol (ISO) on intracellular levels of cyclic AMP (cAMP) were determined. Mitogen-induced T-cell proliferation was measured by [(3)H]-thymidine incorporation. Finally, protein kinase C (PKC) activity in cytosol and membrane fractions were determined using radiolabelled enzymatic substrates. RESULTS: Adecrease or a non-significant increase in betaAR number was found on T lymphocytes from hypo- and hyperthyroid mice compared to euthyroid controls. ISO stimulation of cAMP levels was lower in hypothyroid and higher in hyperthyroid T lymphocytes compared to controls. T-selective mitogen-induced proliferation was increased in T4-treated animals, but decreased in hypothyroid mice. During the peak of proliferation, downregulation of betaAR was observed in all animals. However, a higher or a lower decrease was observed in hyper- and hypothyroid T cells, respectively. In parallel, a higher translocation of PKC activity was observed in hyperthyroid cells, and a lower one was found in hypothyroid lymphocytes with respect to controls. CONCLUSIONS: These results indicate that intracellular signals triggered by mitogen activation, namely PKC, would be related to differential betaAR downregulation in T lymphocytes depending on the thyroid hormone status, contributing to the distinct proliferative responses found in hypo- or hyperthyroidism compared to the euthyroid state.
Assuntos
Proliferação de Células/efeitos dos fármacos , Mitógenos/farmacologia , Neuroimunomodulação/imunologia , Receptores Adrenérgicos beta/efeitos dos fármacos , Linfócitos T/metabolismo , Glândula Tireoide/metabolismo , Agonistas Adrenérgicos beta/farmacologia , Animais , AMP Cíclico/metabolismo , Regulação para Baixo/efeitos dos fármacos , Regulação para Baixo/imunologia , Feminino , Hipertireoidismo/induzido quimicamente , Hipertireoidismo/imunologia , Hipertireoidismo/metabolismo , Hipotireoidismo/induzido quimicamente , Hipotireoidismo/imunologia , Hipotireoidismo/metabolismo , Isoproterenol/farmacologia , Camundongos , Camundongos Endogâmicos BALB C , Neuroimunomodulação/genética , Propiltiouracila/farmacologia , Proteína Quinase C/metabolismo , Transporte Proteico/efeitos dos fármacos , Transporte Proteico/imunologia , Agregação de Receptores/efeitos dos fármacos , Agregação de Receptores/imunologia , Receptores Adrenérgicos beta/imunologia , Receptores Adrenérgicos beta/metabolismo , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Timidina/metabolismo , Glândula Tireoide/imunologia , Tiroxina/farmacologiaRESUMO
High levels of antibodies against the C-terminus of the Trypanosoma cruzi TcP2 beta ribosomal protein, defined by the peptide EEEDDDMGFGLFD, named R13, have been measured in sera from patients with chronic Chagas' Heart Disease (cChHD). These antibodies also recognize an epitope on the second extracellular loop of the beta 1-adrenergic receptor, inducing a functional response on cardiomyocytes. The aim of this study was to gain novel insights into the structural basis of this cross-reactivity as well as to evaluate the origin of anti-M2- cholinergic receptor antibodies, which are also commonly found in cChHD patients. To address these questions we immunopurified anti-R13 antibodies and studied the structural requirements of epitope recognition. Results showed that the immunopurified antibodies recognized a conformation of R13 in which the third Glu residue was essential for binding, explaining their low affinity for the mammalian homologue (peptide H13: EESDDDMGFGLFD). Alanine mutation scanning showed individual variations in epitope recognition in each of the studied patients. The importance of a negatively charged residue at position 3 for the recognition of anti-R13 antibodies was further confirmed by competition experiments using a Ser3-phosphorylated H13 analogue, which had 10 times more affinity for the anti-R13 antibody than the native H13 peptide. Moreover, anti-R13 antibodies stimulated either the beta 1-adrenergic or the M2-cholinergic receptor, in strict agreement with the functional properties of the IgG fractions from which they derived, demonstrating that the same parasite antigen may generate antibody specificities with different functional properties. This may be a clue to explain the high variability of electrophysiological disturbances found in cChHD.
Assuntos
Anticorpos Antiprotozoários/sangue , Doença de Chagas/imunologia , Miócitos Cardíacos/imunologia , Proteínas Ribossômicas/imunologia , Trypanosoma cruzi/imunologia , Animais , Anticorpos Antiprotozoários/imunologia , Células Cultivadas , Reações Cruzadas , Ensaio de Imunoadsorção Enzimática/métodos , Mapeamento de Epitopos , Epitopos/imunologia , Humanos , Ratos , Ratos Sprague-Dawley , Receptores Adrenérgicos beta/imunologia , Receptores Colinérgicos/imunologiaAssuntos
Taquicardia Sinusal/diagnóstico , Taquicardia Sinusal/fisiopatologia , Receptores Adrenérgicos beta/química , Receptores Adrenérgicos beta/imunologia , Autoanticorpos/análise , Autoanticorpos/imunologia , Arritmias Cardíacas/complicações , Taquicardia Sinusal/complicações , Imunoglobulina G/análise , Imunoglobulina G/imunologiaRESUMO
INTRODUCCION: El síndrome de taquicardia inapropiada (STSI) se ha atribuído a un aumento de la frecuencia intrínseca del nódulo sinusal, asociado con hipersensibilidad -adrenérgica y atenuación de la respuesta a la estimulación vagal. No se ha explorado la posibilidad de que en su patogenia intervenga una alteración inmunorregulatoria que involucre a los receptores -adrenérgicos. OBJETIVO: Evaluar la presencia de anticuerpos antirreceptores -adrenérgicos (Ac anti-) y antirreceptores M2-colinérgicos (Ac anti-M2) en pacientes con STSI. MATERIAL Y METODOS: Se incluyeron 10 mujeres de 21 a 64 años portadoras del síndrome y 10 voluntarias sanas. La presencia de Ac anti- y Ac anti-M2 se determinó por el efecto cronotrópico de la IgG sobre cultivos de miocardiocitos de ratas neonatas en condiciones basales y luego de adicionar los bloqueantes atropina (10-7 mol/L) y propanolol (10-7 mol/L). RESULTADOS: La IgG de las voluntarias sanas no presentó anticuerpos antirreceptores autonómicos. En cambio, 8 de las 10 pacientes con STSI presentaron Ac anti- (80 por ciento, p= 0,0004), pero en ninguna de ellas se detectaron Ac anti-M2. CONCLUSION: Un porcentaje elevado de las pacientes con STSI presentan anticuerpos que reconocen y estimulan los receptores ß-adrenérgicos. Esta observación inédita sugiere la posibilidad de que en la patogenia de este síndrome participe una anormalidad inmunorregulatoria que involucra a esos receptores.
Assuntos
Humanos , Adulto , Feminino , Pessoa de Meia-Idade , Arritmias Cardíacas , Autoanticorpos , Receptores Adrenérgicos beta/imunologia , Receptores Adrenérgicos beta/química , Receptores Colinérgicos/imunologia , Taquicardia Sinusal , AMP Cíclico/metabolismo , Arritmias Cardíacas , Imunoglobulina G , Taquicardia SinusalRESUMO
INTRODUCCION: El síndrome de taquicardia inapropiada (STSI) se ha atribuído a un aumento de la frecuencia intrínseca del nódulo sinusal, asociado con hipersensibilidad -adrenérgica y atenuación de la respuesta a la estimulación vagal. No se ha explorado la posibilidad de que en su patogenia intervenga una alteración inmunorregulatoria que involucre a los receptores -adrenérgicos. OBJETIVO: Evaluar la presencia de anticuerpos antirreceptores -adrenérgicos (Ac anti-) y antirreceptores M2-colinérgicos (Ac anti-M2) en pacientes con STSI. MATERIAL Y METODOS: Se incluyeron 10 mujeres de 21 a 64 años portadoras del síndrome y 10 voluntarias sanas. La presencia de Ac anti- y Ac anti-M2 se determinó por el efecto cronotrópico de la IgG sobre cultivos de miocardiocitos de ratas neonatas en condiciones basales y luego de adicionar los bloqueantes atropina (10-7 mol/L) y propanolol (10-7 mol/L). RESULTADOS: La IgG de las voluntarias sanas no presentó anticuerpos antirreceptores autonómicos. En cambio, 8 de las 10 pacientes con STSI presentaron Ac anti- (80 por ciento, p= 0,0004), pero en ninguna de ellas se detectaron Ac anti-M2. CONCLUSION: Un porcentaje elevado de las pacientes con STSI presentan anticuerpos que reconocen y estimulan los receptores ß-adrenérgicos. Esta observación inédita sugiere la posibilidad de que en la patogenia de este síndrome participe una anormalidad inmunorregulatoria que involucra a esos receptores. (AU)
Assuntos
Humanos , Adulto , Feminino , Pessoa de Meia-Idade , Taquicardia Sinusal/diagnóstico , Taquicardia Sinusal/fisiopatologia , Receptores Adrenérgicos beta/química , Receptores Adrenérgicos beta/imunologia , Autoanticorpos/análise , Autoanticorpos/imunologia , Arritmias Cardíacas/imunologia , Receptores Colinérgicos/imunologia , Taquicardia Sinusal/imunologia , AMP Cíclico/metabolismo , Arritmias Cardíacas/complicações , Taquicardia Sinusal/complicações , Imunoglobulina G/análise , Imunoglobulina G/imunologiaRESUMO
BACKGROUND: The relationship between anti-beta-adrenergic (anti-betaR) and anti-M(2)-cholinergic (anti-M2R) receptor antibodies (Abs) and cardiac arrhythmias and their biochemical effects have not been systematically investigated. METHODS AND RESULTS: We studied 41 patients, 28 with ventricular arrhythmias (primary or due to Chagas' heart disease or idiopathic dilated cardiomyopathy; group I), 13 with sinus node dysfunction (primary or caused by Chagas' heart disease; group II), and 10 healthy controls (group III). The chronotropic effects of the IgG and immunopurified anti-beta(1)RAbs or anti-M2RAbs were assessed on cultured cardiomyocytes before and after exposure to atropine and propranolol. The biochemical effects of the IgG from 9 patients from group I, 6 from group II, and 6 controls were evaluated on COS7 cells transfected with genes encoding for beta(1),beta(2)-adrenergic receptors (cAMP increment) or M(2)-cholinergic receptors (phosphatidylinositol increment). The IgG from group I patients exerted a positive chronotropic action, with a high prevalence of anti-betaRAbs (75%) and low prevalence of anti-M2RAbs (10.7%) and induced a clear-cut and long-lasting increment in cAMP. The IgG from group II patients depressed chronotropism, with a high prevalence of anti-M2RAbs (76.9%) and low prevalence of anti-betaRAbs (15.4%) and evoked a marked augmentation of phosphatidylinositol. CONCLUSIONS: Our results demonstrate a strong correlation between anti-betaRAbs and ventricular arrhythmias and anti-M2RAbs and sinus node dysfunction. Anti-betaRAbs increase and anti-M2RAbs inhibit cAMP production. These findings offer new insight into the etiology and pathophysiology of cardiac arrhythmias, with therapeutic implications.
Assuntos
Arritmia Sinusal/imunologia , Arritmias Cardíacas/imunologia , Autoanticorpos/imunologia , Receptores Adrenérgicos beta/imunologia , Receptores Colinérgicos/imunologia , Adulto , Idoso , Sequência de Aminoácidos , Animais , Arritmia Sinusal/complicações , Arritmias Cardíacas/complicações , Atropina/farmacologia , Autoanticorpos/análise , Células COS , Cardiomiopatia Dilatada/complicações , Cardiomiopatia Dilatada/imunologia , Cardiomiopatia Chagásica/complicações , Cardiomiopatia Chagásica/imunologia , AMP Cíclico/metabolismo , Eletrocardiografia , Feminino , Frequência Cardíaca/efeitos dos fármacos , Humanos , Imunoglobulina G/análise , Imunoglobulina G/imunologia , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Fosfatidilinositóis/metabolismo , Propranolol/farmacologia , Receptores Adrenérgicos beta/química , Receptores Adrenérgicos beta/genética , Receptores Colinérgicos/química , Receptores Colinérgicos/genética , Sistemas do Segundo Mensageiro/efeitos dos fármacosRESUMO
OBJECTIVE: Cardiac tissue from chagasic mice was studied to evaluate the expression and biological activity of beta-adrenoceptors in association with circulating beta-adrenoceptor-related autoantibodies. METHODS: BALB/c inbred mice that were either treated or not treated with atenolol (2.5 mg/kg) and infected or not infected with 1 x 10(4) trypomastigotes (CA-1 strain) were sacrificed weekly up to week nine. Morphological, binding and contractility studies were performed on the four different groups of animals. The effect of their serum antibodies was also assayed in binding and contractility studies on normal heart preparations. RESULTS: Hearts from chagasic myocarditis mice showed a beta-adrenoceptor-related dysfunction, with a decrease in heart contractility, impaired response to exogenous beta-adrenoceptor agonist and a significant reduction in beta-adrenergic binding sites. Those effects were maximum at eight-nine weeks post-infection and were improved by treating infected mice with atenolol. In addition, serum or IgG from chagasic myocarditis mice was capable of interacting with cardiac beta-adrenoceptors, reducing the number of binding sites and inhibiting the contractile response to exogenous norepinephrine. IgG effects that were observed in normal myocardium, were highest in sera from mice eight-nine weeks post-infection and correlate with the degree of myocarditis. Moreover, chagasic autoantibodies from infected mice recognized a peptide corresponding to the sequence of the second extracellular loop of the human beta 1-adrenoceptor. CONCLUSIONS: (1) The development of alterations in beta-adrenergic receptors, related to cardiac dysfunction, may be associated with the presence of circulating antibodies against these receptors and (2) it is possible that the chronic deposits of these autoantibodies in cardiac beta-adrenoceptors could lead to a progressive blockade with sympathetic denervation, a phenomenon that has been described in the course of chagasic myocarditis.
Assuntos
Autoanticorpos/sangue , Cardiomiopatia Chagásica/metabolismo , Miocárdio/imunologia , Receptores Adrenérgicos beta/imunologia , Receptores Adrenérgicos beta/metabolismo , Antagonistas Adrenérgicos beta/uso terapêutico , Análise de Variância , Animais , Atenolol/uso terapêutico , Cardiomiopatia Chagásica/tratamento farmacológico , Cardiomiopatia Chagásica/imunologia , Imunoglobulina G , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Contração Miocárdica , Fatores de TempoRESUMO
Evidence accumulated over the last decade gives adequate proof for the existence of circulating antibodies in Chagas' disease which bind to beta adrenergic and muscarinic cholinergic receptors of myocardium. The interaction of antibodies with cardiac neurotransmitter receptors behaving as an agonist, triggers intracellular signal transductions in the cells that alter the physiological behaviour of the heart. These events convert the normal to pathologically active cells. The interaction of antibodies against heart beta adrenergic and cholinergic receptors triggers physiologic, morphologic, enzymatic and molecular alterations, leading to cardiac damage. The analysis of the prevalence and distribution of these antibodies shows a strong association with seropositive asymptomatic patients with autonomic dysfunction in comparison with those asymptomatic without alteration of the heart autonomic disorders. The presence of these antibodies may thus partially explain the cardiomyoneuropathy of Chagas' disease, in which the sympathetic and parasympathetic systems are affected. The deposit of autoantibodies on the myocardial neurotransmitter receptors, behaving like an agonist, induced desensitization and/or down regulation of the receptors. This in turn, could lead to a progressive blockade of myocardium neurotransmitter receptors, with sympathetic and parasympathetic dennervation, a phenomenon that has been described in the course of Chagas cardioneuropathy.
Assuntos
Cardiomiopatia Chagásica , Receptores Adrenérgicos beta/metabolismo , Receptores Colinérgicos/metabolismo , Receptores Muscarínicos/metabolismo , Receptores de Neurotransmissores/metabolismo , Cardiomiopatia Chagásica/imunologia , Cardiomiopatia Chagásica/fisiopatologia , Humanos , Miocárdio/imunologia , Miocárdio/metabolismo , Receptores Adrenérgicos beta/imunologia , Receptores Colinérgicos/imunologia , Receptores Muscarínicos/imunologia , Receptores de Neurotransmissores/imunologiaRESUMO
The expression of beta-adrenergic receptors on murine lymphocytes stimulated with concanavalin A was studied. A decrease in beta-adrenoceptor number on T lymphocytes and a diminished response to specific agonist stimulation at the peak of proliferation was found. The blockade of cell proliferation by tyrosine kinases or protein kinase C inhibitors reversed the decrease in beta-adrenoceptor number. PMA plus ionophore or interleukin-2 but not PMA alone were able to induce beta-adrenoceptor down-regulation accompanying cellular proliferation. These results showed that the intracellular signals triggered during lymphocyte activation are involved in beta-adrenoceptor down-regulation and it would represent the loss of a mechanism that exerts negative neuroimmune control of cellular proliferation.