RESUMEN
Background: Kawasaki disease (KD), an acute febrile illness and systemic vasculitis, is the leading cause of acquired heart disease in children in industrialized countries. KD leads to the development of coronary artery aneurysms (CAA) in affected children, which may persist for months and even years after the acute phase of the disease. There is an unmet need to characterize the immune and pathological mechanisms of the long-term complications of KD. Methods: We examined cardiovascular complications in the Lactobacillus casei cell wall extract (LCWE) mouse model of KD-like vasculitis over 4 months. The long-term immune, pathological, and functional changes occurring in cardiovascular lesions were characterized by histological examination, flow cytometric analysis, immunofluorescent staining of cardiovascular tissues, and transthoracic echocardiogram. Results: CAA and abdominal aorta dilations were detected up to 16 weeks following LCWE injection and initiation of acute vasculitis. We observed alterations in the composition of circulating immune cell profiles, such as increased monocyte frequencies in the acute phase of the disease and higher counts of neutrophils. We determined a positive correlation between circulating neutrophil and inflammatory monocyte counts and the severity of cardiovascular lesions early after LCWE injection. LCWE-induced KD-like vasculitis was associated with myocarditis and myocardial dysfunction, characterized by diminished ejection fraction and left ventricular remodeling, which worsened over time. We observed extensive fibrosis within the inflamed cardiac tissue early in the disease and myocardial fibrosis in later stages. Conclusion: Our findings indicate that increased circulating neutrophil counts in the acute phase are a reliable predictor of cardiovascular inflammation severity in LCWE-injected mice. Furthermore, long-term cardiac complications stemming from inflammatory cell infiltrations in the aortic root and coronary arteries, myocardial dysfunction, and myocardial fibrosis persist over long periods and are still detected up to 16 weeks after LCWE injection.
Asunto(s)
Pared Celular , Modelos Animales de Enfermedad , Fibrosis , Lacticaseibacillus casei , Síndrome Mucocutáneo Linfonodular , Vasculitis , Animales , Ratones , Pared Celular/inmunología , Vasculitis/inmunología , Vasculitis/etiología , Vasculitis/patología , Síndrome Mucocutáneo Linfonodular/inmunología , Síndrome Mucocutáneo Linfonodular/complicaciones , Masculino , Miocarditis/etiología , Miocarditis/patología , Miocarditis/inmunología , Inflamación/inmunologíaRESUMEN
Th17 cells are recognized as indispensable in inducing protective immunity against bacteria and fungi, as they promote the integrity of mucosal epithelial barriers. It is believed that Th17 cells also play a central role in the induction of autoimmune diseases. Recent advances have evaluated Th17 effector functions during viral infections, including their critical role in the production and induction of pro-inflammatory cytokines and in the recruitment and activation of other immune cells. Thus, Th17 is involved in the induction both of pathogenicity and immunoprotective mechanisms seen in the host's immune response against viruses. However, certain Th17 cells can also modulate immune responses, since they can secrete immunosuppressive factors, such as IL-10; these cells are called non-pathogenic Th17 cells. Here, we present a brief review of Th17 cells and highlight their involvement in some virus infections. We cover these notions by highlighting the role of Th17 cells in regulating the protective and pathogenic immune response in the context of viral infections. In addition, we will be describing myocarditis and multiple sclerosis as examples of immune diseases triggered by viral infections, in which we will discuss further the roles of Th17 cells in the induction of tissue damage.
Asunto(s)
Miocarditis/inmunología , Células Th17/metabolismo , Virosis/inmunología , Adenoviridae , Animales , Enfermedades Autoinmunes/inmunología , Virus Chikungunya , Citocinas/inmunología , Virus del Dengue , Humanos , Sistema Inmunológico , Inmunosupresores/farmacología , Inflamación , Interleucina-10/biosíntesis , Linfocitos/citología , Esclerosis Múltiple/inmunología , Esclerosis Múltiple/metabolismo , Esclerosis Múltiple/virología , Miocarditis/metabolismo , Miocarditis/virología , Orthomyxoviridae , SARS-CoV-2 , Simplexvirus , Células TH1/citología , Células Th2/citología , Virosis/tratamiento farmacológico , Virosis/metabolismo , Virus ZikaRESUMEN
Chronic Chagas cardiomyopathy is the main infectious myocarditis worldwide. Almost 30% of Trypanosoma cruzi infected individuals develop slow and progressive myocarditis that leads to ventricular dilation and heart failure. Heart transplantation is an established, valuable therapeutic option for end-stage Chagas disease patients. Although the pathophysiology of Chagas disease has been addressed for decades by numerous groups, the cardiac immunologic mechanisms involved in the progression of clinical manifestation are still unknown. Growing evidence demonstrates that hypoxia-inducible factor (HIF)-1α plays indispensable roles in driving immune response by triggering the expression of CD73 purinergic ecto-enzyme. Purinergic system controls the duration and magnitude of purine signals directed to modulate immune cells through the conversion of extracellular ATP (microbicide/proinflammatory) to the immunoregulatory metabolite adenosine. In the present work, we described that infiltrating leukocytes within cardiac explants from patients with end-stage Chagas cardiomyopathy up-regulated HIF-1α and CD73 expression. Moreover, the number of HIF-1α+ and CD73+ leukocytes positively correlated with the myocarditis severity and the local parasite load. Furthermore, we demonstrated a direct relationship between tissue parasite persistence and the influx of immune cells to the infected hearts, which ultimately determine the severity of the myocarditis. These findings provide evidence that CD73-dependent regulatory pathways are locally triggered in the myocardium of patients with end-stage Chagas disease.
Asunto(s)
5'-Nucleotidasa/biosíntesis , Cardiomiopatía Chagásica/inmunología , Subunidad alfa del Factor 1 Inducible por Hipoxia/biosíntesis , Leucocitos/inmunología , Miocarditis/inmunología , Adulto , Cardiomiopatía Chagásica/complicaciones , Cardiomiopatía Chagásica/patología , Femenino , Proteínas Ligadas a GPI/biosíntesis , Humanos , Leucocitos/metabolismo , Masculino , Persona de Mediana Edad , Miocarditis/etiología , Miocarditis/patología , Miocardio/inmunología , Miocardio/patologíaRESUMEN
Myocarditis is a serious complication of varicella zoster virus infection. A 15 year-old boy was admitted to the Emergency Department for chest pain, tachycardia and hypotension. An electrocardiogram showed sinus tachyicardia. Cardiac biomarkers were elevated and echocardiography revealed left ventricular apical, inferolateral, septal hypokinesis, and mitral regurgitation. Varicella zoster virus serum immunoglobulin M antibody was positive. The patient was discharged without any sequelae.
La miocarditis es una complicación grave de la infección por el virus de la varicela-zóster. Un varón de 15 años ingresó a la sala de emergencias debido a dolor torácico, taquicardia e hipotensión. En el electrocardiograma se observó taquicardia sinusal. Los biomarcadores cardíacos estaban elevados. En el ecocardiograma se notó hipocinesia apical, septal, e inferolateral del ventrículo izquierdo e insuficiencia mitral. Los anticuerpos IgM en suero para el virus de la varicela-zóster eran positivos. El paciente recibió el alta sin secuelas.
Asunto(s)
Miocarditis/virología , Infección por el Virus de la Varicela-Zóster/complicaciones , Enfermedad Aguda , Adolescente , Electrocardiografía , Humanos , Inmunocompetencia , Masculino , Miocarditis/diagnóstico , Miocarditis/inmunología , Infección por el Virus de la Varicela-Zóster/diagnóstico , Infección por el Virus de la Varicela-Zóster/inmunologíaRESUMEN
Chagas disease affects millions of people mainly in Latin America and is a protozoan illness caused by the parasite Trypanosoma cruzi. Chagasic cardiomyopathy is the leading cause of mortality of infected patients, due to compromised electrical and mechanical cardiac function induced by tissue remodeling, especially fibrosis, and lymphocytic infiltration. Some cellular biochemical pathways can be protective to the heart, and we tested if the in vivo activation of the autophagic machinery by rapamycin could reduce parasite-induced myocarditis. Regarding the expression of LC3, an autophagy marker, we observed its upregulation in the cardiac tissue of infected untreated mice. However, after rapamycin treatment, an autophagy inducer, infected mice showed reduced electrical cardiac dysfunctions, myocarditis, cardiac damage, and reduced production of pro-inflammatory cytokines by the heart. On the other hand, the parasite's life cycle was not affected, and we observed no modulations in cardiac tissue or blood parasitemia. Our data indicate that, at least partially, autophagy induction controls inflammation in the heart¸ illustrating the complexity of the pathways that concur to the development of the infection.
Asunto(s)
Enfermedad de Chagas/tratamiento farmacológico , Miocarditis/tratamiento farmacológico , Sirolimus/farmacología , Trypanosoma cruzi/inmunología , Enfermedad Aguda , Animales , Enfermedad de Chagas/inmunología , Enfermedad de Chagas/patología , Masculino , Ratones , Proteínas Asociadas a Microtúbulos/inmunología , Miocarditis/inmunología , Miocarditis/parasitología , Miocarditis/patologíaRESUMEN
CD43 (leukosialin) is a large sialoglycoprotein abundantly expressed on the surface of most cells from the hematopoietic lineage. CD43 is directly involved in the contact between cells participating in a series of events such as signaling, adherence and host parasite interactions. In this study we examined the role of CD43 in the immune response against Trypanosoma cruzi, the protozoan parasite that causes Chagas' disease, a potential life-threatening illness endemic in 21 Latin American countries according to the WHO. The acute stage of infection is marked by intense parasitemia and cardiac tissue parasitism, resulting in the recruitment of inflammatory cells and acute damage to the heart tissue. We show here that CD43-/- mice were more resistant to infection due to increased cytotoxicity of antigen specific CD8+ T cells and reduced inflammatory infiltration in the cardiac tissue, both contributing to lower cardiomyocyte damage. In addition, we demonstrate that the induction of acute myocarditis involves the engagement of CD43 cytoplasmic tripeptide sequence KRR to ezrin-radixin-moiesin cytoskeletal proteins. Together, our results show the participation of CD43 in different events involved in the pathogenesis of T. cruzi infection, contributing to a better overall understanding of the mechanisms underlying the pathogenesis of acute chagasic cardiomyopathy.
Asunto(s)
Enfermedad de Chagas/metabolismo , Inflamación/patología , Leucosialina/metabolismo , Miocardio/patología , Animales , Antígenos de Protozoos/inmunología , Linfocitos T CD8-positivos/inmunología , Diferenciación Celular , Enfermedad de Chagas/inmunología , Enfermedad de Chagas/patología , Citotoxicidad Inmunológica , Susceptibilidad a Enfermedades , Masculino , Ratones Endogámicos C57BL , Mutación/genética , Miocarditis/inmunología , Miocarditis/parasitología , Miocarditis/patología , Parasitemia/inmunología , Fagocitos/patología , Bazo/inmunología , Análisis de SupervivenciaRESUMEN
Macrophage influx and galectin 3 production have been suggested as major players driving acute inflammation and chronic fibrosis in many diseases. However, their involvement in the pathogenesis of viral myocarditis and subsequent cardiomyopathy are unknown. Our aim was to characterise the role of macrophages and galectin 3 on survival, clinical course, viral burden, acute pathology, and chronic fibrosis in coxsackievirus B3 (CVB3)-induced myocarditis. Our results showed that C3H/HeJ mice infected with CVB3 and depleted of macrophages by liposome-encapsulated clodronate treatment compared with infected untreated mice presented higher viral titres but reduced acute myocarditis and chronic fibrosis, compared with untreated infected mice. Increased galectin 3 transcriptional and translational expression levels correlated with CVB3 infection in macrophages and in non-depleted mice. Disruption of the galectin 3 gene did not affect viral titres but reduced acute myocarditis and chronic fibrosis compared with C57BL/6J wild-type mice. Similar results were observed after pharmacological inhibition of galectin 3 with N-acetyl-d-lactosamine in C3H/HeJ mice. Our results showed a critical role of macrophages and their galectin 3 in controlling acute viral-induced cardiac injury and the subsequent fibrosis. Moreover, the fact that pharmacological inhibition of galectin 3 induced similar results to macrophage depletion regarding the degree of acute cardiac inflammation and chronic fibrosis opens up the possibility of new pharmacological strategies for viral myocarditis.
Asunto(s)
Infecciones por Coxsackievirus/complicaciones , Galectina 3/fisiología , Macrófagos/inmunología , Miocarditis/inmunología , Animales , Línea Celular , Enterovirus , Fibrosis , Masculino , Ratones Endogámicos C3H , Ratones Endogámicos C57BL , Ratones Noqueados , Miocarditis/metabolismo , Miocarditis/virologíaRESUMEN
Objective: This study aimed to investigate whether interleukin-28A (IL-28A) plays a role in murine myocarditis induced by coxsackievirus B3 (CVB3), and to explore its possible mechanism involved. Methods: Male BALB/c mice both infected and not infected by CVB3 were randomly divided into four groups (n = 40), untreated or treated with different doses of IL-28A for 4 days, and then sacrificed on days 4 and 7 post-infection. The heart samples were collected for histopathologic examination. Cardiac viral load was determined by a plaque assay. Additionally, immunoblot analysis, TUNEL assay, and immunohistochemistry were performed to examine the expression of signal transducer, activator of transcription 1 and 2 (STAT1 and STAT2), CVB3-induced apoptosis and the expression of Bcl-2, BAX and Caspase-3. Results: Compared to uninfected mice, the CVB3 infected mice exhibited higher mortality rate (p < 0.001), apparent inflammation and myocardial lesion (p < 0.01), and higher cardiac viral load (p < 0.01). After CVB3 infection, IL-28A treated mice presented no death (p < 0.001), reduced inflammation and myocardial lesion (p < 0.01), and lower viral load (p < 0.01) compared to untreated mice. Besides, treatment with IL-28A markedly increased the expressions of STAT1 and STAT2, and inhibited CVB3-induced apoptosis in myocardial cells with increased ratio of Bcl-2/BAX. Conclusion: The antiviral and myocyte protective effects of IL-28A in CVB3-inducedmyocarditis are regulated by STAT1 and STAT2. .
Asunto(s)
Animales , Masculino , Ratones , Antivirales/uso terapéutico , Infecciones por Coxsackievirus , Interleucinas/metabolismo , Miocarditis/virología , Apoptosis , /inmunología , /metabolismo , Infecciones por Coxsackievirus/tratamiento farmacológico , Infecciones por Coxsackievirus/inmunología , Infecciones por Coxsackievirus/metabolismo , Immunoblotting , Inmunohistoquímica , Etiquetado Corte-Fin in Situ , Interleucinas/inmunología , Ratones Endogámicos BALB C , Miocarditis/inmunología , Miocarditis/metabolismo , /inmunología , /metabolismo , Factor de Transcripción STAT1/inmunología , Factor de Transcripción STAT1/metabolismo , /inmunología , /metabolismo , Carga Viral , /inmunología , /metabolismoRESUMEN
BACKGROUND: To further understand the role of platelets in the pathogenesis of viral infections we explored platelet interaction with Coxsackieviruses B (CVB) 1 and 3. CVB is a group of viruses that cause the majority of human enterovirus-related viral myocarditis; their receptor (CAR) is expressed on the platelet surface and there is a well-characterized CVB3-induced myocarditis murine model. METHODS: Human platelets were infected with CVB1 and 3 and viruses were detected in pellets and in supernatants. C57BL/6J mice with or without platelet depletion were inoculated with CVB3 and peripheral blood and heart samples collected at different times post-infection. RESULTS: CVB1 and 3 RNA and a capsid protein were detected in infected platelets. Despite the fact that titration assays in Vero cells showed increasing infectivity titers over time, supernatants and pellets from infected platelets showed similar levels, suggesting that platelets were not susceptible to a replicative infectivity cycle. CVB binding was CAR-independent and resulted in P-selectin and phosphatidylserine (PS) exposure. CVB3-infected mice showed a rapid thrombocytopenia that correlated with an increase in platelet PS exposure and platelet-leukocyte aggregates without modification of platelet P-selectin expression or von Willebrand factor levels. Mortality, viremia, heart viral titers and myocarditis were significantly higher in platelet-depleted than normal animals. Type I IFN levels were not changed but IgG levels were lower in infected and platelet-depleted mice. CONCLUSIONS: Our data reveal that platelets play a critical role in host survival and immune response against CVB3 infection.
Asunto(s)
Plaquetas/virología , Infecciones por Coxsackievirus/sangre , Infecciones por Coxsackievirus/virología , Enterovirus Humano B/patogenicidad , Miocarditis/sangre , Miocarditis/virología , Animales , Plaquetas/inmunología , Plaquetas/metabolismo , Proteínas de la Cápside/sangre , Proteínas de la Cápside/genética , Chlorocebus aethiops , Infecciones por Coxsackievirus/inmunología , Modelos Animales de Enfermedad , Enterovirus Humano B/genética , Enterovirus Humano B/inmunología , Enterovirus Humano B/metabolismo , Femenino , Interacciones Huésped-Patógeno , Humanos , Inmunoglobulina G/sangre , Masculino , Ratones Endogámicos C57BL , Miocarditis/inmunología , Selectina-P/sangre , Fosfatidilserinas/sangre , ARN Viral/sangre , Trombocitopenia/sangre , Trombocitopenia/virología , Factores de Tiempo , Células Vero , Replicación ViralRESUMEN
OBJECTIVE: This study aimed to investigate whether interleukin-28A (IL-28A) plays a role in murine myocarditis induced by coxsackievirus B3 (CVB3), and to explore its possible mechanism involved. METHODS: Male BALB/c mice both infected and not infected by CVB3 were randomly divided into four groups (n=40), untreated or treated with different doses of IL-28A for 4 days, and then sacrificed on days 4 and 7 post-infection. The heart samples were collected for histopathologic examination. Cardiac viral load was determined by a plaque assay. Additionally, immunoblot analysis, TUNEL assay, and immunohistochemistry were performed to examine the expression of signal transducer, activator of transcription 1 and 2 (STAT1 and STAT2), CVB3-induced apoptosis and the expression of Bcl-2, BAX and Caspase-3. RESULTS: Compared to uninfected mice, the CVB3 infected mice exhibited higher mortality rate (p<0.001), apparent inflammation and myocardial lesion (p<0.01), and higher cardiac viral load (p<0.01). After CVB3 infection, IL-28A treated mice presented no death (p<0.001), reduced inflammation and myocardial lesion (p<0.01), and lower viral load (p<0.01) compared to untreated mice. Besides, treatment with IL-28A markedly increased the expressions of STAT1 and STAT2, and inhibited CVB3-induced apoptosis in myocardial cells with increased ratio of Bcl-2/BAX. CONCLUSION: The antiviral and myocyte protective effects of IL-28A in CVB3-induced myocarditis are regulated by STAT1 and STAT2.
Asunto(s)
Antivirales/uso terapéutico , Infecciones por Coxsackievirus , Interleucinas/metabolismo , Miocarditis/virología , Animales , Apoptosis , Caspasa 3/inmunología , Caspasa 3/metabolismo , Infecciones por Coxsackievirus/tratamiento farmacológico , Infecciones por Coxsackievirus/inmunología , Infecciones por Coxsackievirus/metabolismo , Immunoblotting , Inmunohistoquímica , Etiquetado Corte-Fin in Situ , Interleucinas/inmunología , Masculino , Ratones , Ratones Endogámicos BALB C , Miocarditis/inmunología , Miocarditis/metabolismo , Proteínas Proto-Oncogénicas c-bcl-2/inmunología , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Factor de Transcripción STAT1/inmunología , Factor de Transcripción STAT1/metabolismo , Factor de Transcripción STAT2/inmunología , Factor de Transcripción STAT2/metabolismo , Carga Viral , Proteína X Asociada a bcl-2/inmunología , Proteína X Asociada a bcl-2/metabolismoRESUMEN
Myocarditis is an uncommon manifestation of dengue fever. We describe a case of a 69-year-old Hispanic male who presented to an emergency room in New York City 3 days after returning from a trip to the Dominican Republic complaining of a 1-day history of chest pain and fever. His first electrocardiogram showed a new left bundle branch block, and initial cardiac enzymes included troponin of 5 ng/dL, creatine kinase-MB of 9 ng/mL, and myoglobin of 234 ng/mL. Dengue fever antibodies were found to be elevated: immunoglobulin M (IgM) titer was 2.48 (reference range < 0.9), and immunoglobulin G (IgG) titer was 4.26 (reference range < 0.9). The patient was diagnosed with myocarditis caused by dengue fever. He improved after 1 week with conservative management in a telemetry unit and was discharged home.
Asunto(s)
Anticuerpos Antivirales/sangre , Virus del Dengue , Dengue/patología , Miocarditis/patología , Anciano , Creatina Quinasa/sangre , Dengue/complicaciones , Dengue/inmunología , Dengue/virología , República Dominicana , Humanos , Masculino , Miocarditis/complicaciones , Miocarditis/inmunología , Miocarditis/virología , Mioglobina/sangre , Viaje , Troponina/sangreRESUMEN
Chagas disease, caused by Trypanosoma cruzi (Tc), is an important cause of heart disease. Resistance to Tc infection is multifactorial and associated with Th1 response. IL-18 plays an important role in regulation of IFN-γ production/development of Th1 response. However, the role of IL-18 in the setting of Tc infection remains unclear. Therefore, we investigated the role of IL-18 in the modulation of immune response and myocarditis in Tc infection. C57BL/6 and IL-18 KO mice were infected with Tc (Y or Colombian strain) and parasitemia, immune response and pathology were evaluated. Y strain infection of IL-18 KO did not alter any parameters when compared with C57BL/6 mice. However, during the acute phase (20 and 40 days post infection-dpi), Colombian strain infected-IL-18 KO mice displayed higher serum levels of IL-12 and IFN-γ, respectively, and at the chronic phase (100 dpi) an increase in splenic IFN-γ-producing CD4(+) and CD8(+) T memory cells. There was an IL-10, FOXP3 and CD4(+)CD25(+) cells reduction during acute infection in spleen. Additionally, there was a significant reduction in leukocyte infiltration and parasite load in myocardium of chronically infected IL-18 KO mice. Collectively, these data indicate that IL-18 contributes to the pathogenesis of Tc-induced myocarditis when infected with Colombian but not Y strain. These observations also underscore that parasite and host strain differences are important in evaluation of experimental Tc infection pathogenesis.
Asunto(s)
Enfermedad de Chagas/inmunología , Interleucina-18/inmunología , Miocarditis/inmunología , Trypanosoma cruzi/patogenicidad , Animales , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Células Cultivadas , Enfermedad de Chagas/complicaciones , Interacciones Huésped-Parásitos , Interferón gamma/sangre , Interleucina-12/sangre , Interleucina-18/genética , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Miocarditis/complicaciones , Miocarditis/parasitología , Miocardio/patología , Bazo/citología , Bazo/inmunología , Bazo/parasitologíaRESUMEN
Infectious myocarditis (IM) is a commonly undiagnosed condition that may cause several heart diseases, including dilated cardiomyopathy and chronic heart failure. The understanding of the physiopathology of myocardial inflammation is crucial for a timely diagnosis and for the control of the tissue damage, which may occur in some cases of IM. Of note, some experimental studies suggest that dilated cardiomyopathy could be a consequence of untreated IM. However, further research is required to address the molecular mechanisms that may link these two clinical entities. Here we review the mechanisms involved in the regulation at different levels of the immune response during IM, with a special focus on diagnostic and therapeutic perspectives of molecules that have been linked to the development of IM and the resulting chronic heart diseases.
Asunto(s)
Cardiomiopatía Dilatada/etiología , Insuficiencia Cardíaca/etiología , Miocarditis/inmunología , Animales , Cardiomiopatía Dilatada/inmunología , Cardiomiopatía Dilatada/fisiopatología , Enfermedad Crónica , Insuficiencia Cardíaca/inmunología , Insuficiencia Cardíaca/fisiopatología , Humanos , Inflamación/etiología , Inflamación/inmunología , Inflamación/fisiopatología , Miocarditis/complicaciones , Miocarditis/diagnóstico , Factores de TiempoRESUMEN
The endocrine heart produces the polypeptide hormones Atrial Natriuretic Factor (ANF or ANP) and Brain Natriuretic Peptide (BNP). Through the peripheral actions of these hormones the heart contributes to the regulation of the cardiac preload and afterload. More recently, new functions for these hormones have been described including the modulation of the immune response. Plasma levels of BNP but not those of ANF, increase following an acute rejection episode of a cardiac allotransplant but return to levels pre-rejection with successful treatment. This observation constitutes the first observation leading to characterizing the interactions of BNP with the immune response. Several other pathologies with an inflammatory component are now known to be associated with an increase in the production of BNP. Such an increase is due to an increase in the transcriptional activity of the BNP gene induced by cytokines and related substances. In vitro investigations have shown that an increase in BNP directly modulates immunological activity. Inflammation and hemodynamic changes co-exist in several cardiovascular diseases and therefore it may be beneficial to measure circulating levels of both ANF and BNP as biomarkers of changes in intravascular volume and of changes in intravascular volume plus inflammation, respectively. Changes in plasma ANF, that are relatively larger than those of BNP, might be an indication of hemodynamic deterioration while important changes in circulating BNP could indicate a worsening of the inflammatory process.
Asunto(s)
Factor Natriurético Atrial/metabolismo , Inflamación/metabolismo , Miocitos Cardíacos/metabolismo , Péptido Natriurético Encefálico/metabolismo , Animales , Factor Natriurético Atrial/inmunología , Investigación Biomédica , Hemodinámica/inmunología , Humanos , Miocarditis/inmunología , Miocarditis/metabolismo , Péptido Natriurético Encefálico/genética , Péptido Natriurético Encefálico/inmunología , Sepsis/inmunología , Sepsis/metabolismoRESUMEN
The endocrine heart produces the polypeptide hormones Atrial Natriuretic Factor (ANF or ANP) and Brain Natriuretic Peptide (BNP). Through the peripheral actions of these hormones the heart contributes to the regulation of the cardiac preload and afterload. More recently, new functions for these hormones have been described including the modulation of the immune response. Plasma levels of BNP but not those of ANF, increase following an acute rejection episode of a cardiac allotransplant but return to levels pre-rejection with successful treatment. This observation constitutes the first observation leading to characterizing the interactions of BNP with the immune response. Several other pathologies with an inflammatory component are now known to be associated with an increase in the production of BNP. Such an increase is due to an increase in the transcriptional activity of the BNP gene induced by cytokines and related substances. In vitro investigations have shown that an increase in BNP directly modulates immunological activity. Inflammation and hemodynamic changes co-exist in several cardiovascular diseases and therefore it may be beneficial to measure circulating levels of both ANF and BNP as biomarkers of changes in intravascular volume and of changes in intravascular volume plus inflammation, respectively. Changes in plasma ANF, that are relatively larger than those of BNP, might be an indication of hemodynamic deterioration while important changes in circulating BNP could indicate a worsening of the inflammatory process.
Asunto(s)
Factor Natriurético Atrial/metabolismo , Inflamación/metabolismo , Miocitos Cardíacos/metabolismo , Péptido Natriurético Encefálico/metabolismo , Animales , Factor Natriurético Atrial/inmunología , Hemodinámica/inmunología , Humanos , Miocarditis/inmunología , Miocarditis/metabolismo , Péptido Natriurético Encefálico/genética , Péptido Natriurético Encefálico/inmunología , Investigación Biomédica , Sepsis/inmunología , Sepsis/metabolismoRESUMEN
The endocrine heart produces the polypeptide hormones Atrial Natriuretic Factor (ANF or ANP) and Brain Natriuretic Peptide (BNP). Through the peripheral actions of these hormones the heart contributes to the regulation of the cardiac preload and afterload. More recently, new functions for these hormones have been described including the modulation of the immune response. Plasma levels of BNP but not those of ANF, increase following an acute rejection episode of a cardiac allotransplant but return to levels pre-rejection with successful treatment. This observation constitutes the first observation leading to characterizing the interactions of BNP with the immune response. Several other pathologies with an inflammatory component are now known to be associated with an increase in the production of BNP. Such an increase is due to an increase in the transcriptional activity of the BNP gene induced by cytokines and related substances. In vitro investigations have shown that an increase in BNP directly modulates immunological activity. Inflammation and hemodynamic changes co-exist in several cardiovascular diseases and therefore it may be beneficial to measure circulating levels of both ANF and BNP as biomarkers of changes in intravascular volume and of changes in intravascular volume plus inflammation, respectively. Changes in plasma ANF, that are relatively larger than those of BNP, might be an indication of hemodynamic deterioration while important changes in circulating BNP could indicate a worsening of the inflammatory process.
Asunto(s)
Factor Natriurético Atrial/metabolismo , Inflamación/metabolismo , Miocitos Cardíacos/metabolismo , Péptido Natriurético Encefálico/metabolismo , Animales , Factor Natriurético Atrial/inmunología , Investigación Biomédica , Hemodinámica/inmunología , Humanos , Miocarditis/inmunología , Miocarditis/metabolismo , Péptido Natriurético Encefálico/genética , Péptido Natriurético Encefálico/inmunología , Sepsis/inmunología , Sepsis/metabolismoRESUMEN
We had formerly demonstrated that subjects chronically infected with Trypanosoma cruzi show impaired T cell responses closely linked with a process of T cell exhaustion. Recently, the expression of several inhibitory receptors has been associated with T cell dysfunction and exhaustion. In this study, we have examined the expression of the cytotoxic T lymphocyte antigen 4 (CTLA-4) and the leukocyte immunoglobulin like receptor 1 (LIR-1) by peripheral T. cruzi antigen-responsive IFN-gamma (IFN-γ)-producing and total T cells from chronically T. cruzi-infected subjects with different clinical forms of the disease. CTAL-4 expression was also evaluated in heart tissue sections from subjects with severe myocarditis. The majority of IFN-γ-producing CD4(+) T cells responsive to a parasite lysate preparation were found to express CTLA-4 but considerably lower frequencies express LIR-1, irrespective of the clinical status of the donor. Conversely, few IFN-γ-producing T cells responsive to tetanus and diphtheria toxoids expressed CTLA-4 and LIR-1. Polyclonal stimulation with anti-CD3 antibodies induced higher frequencies of CD4(+)CTAL-4(+) T cells in patients with severe heart disease than in asymptomatic subjects. Ligation of CTLA-4 and LIR-1 with their agonistic antibodies, in vitro, reduces IFN-γ production. Conversely, CTLA-4 blockade did not improved IFN-γ production in response to T. cruzi antigens. Subjects with chronic T. cruzi infection had increased numbers of CD4(+)LIR-1(+) among total peripheral blood mononuclear cells, relative to uninfected individuals and these numbers decreased after treatment with benznidazole. CTLA-4 was also expressed by CD3(+) T lymphocytes infiltrating heart tissues from chronically infected subjects with severe myocarditis. These findings support the conclusion that persistent infection with T. cruzi leads to the upregulation of inhibitory receptors which could alter parasite specific T cell responses in the chronic phase of Chagas disease.
Asunto(s)
Antígenos CD/metabolismo , Linfocitos T CD4-Positivos/metabolismo , Antígeno CTLA-4/metabolismo , Enfermedad de Chagas/inmunología , Regulación de la Expresión Génica/inmunología , Corazón/parasitología , Receptores Inmunológicos/metabolismo , Trypanosoma cruzi/patogenicidad , Adulto , Antígenos de Protozoos/inmunología , Linfocitos T CD4-Positivos/efectos de los fármacos , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/parasitología , Enfermedad de Chagas/complicaciones , Enfermedad de Chagas/tratamiento farmacológico , Enfermedad de Chagas/metabolismo , Enfermedad Crónica , Regulación de la Expresión Génica/efectos de los fármacos , Corazón/efectos de los fármacos , Humanos , Interferón gamma/biosíntesis , Receptor Leucocitario Tipo Inmunoglobulina B1 , Masculino , Persona de Mediana Edad , Miocarditis/complicaciones , Miocarditis/inmunología , Miocarditis/metabolismo , Nitroimidazoles/farmacología , Nitroimidazoles/uso terapéutico , Especificidad de la Especie , Trypanosoma cruzi/efectos de los fármacos , Trypanosoma cruzi/inmunologíaRESUMEN
Although metacyclic and blood trypomastigotes are completely functional in relation to parasite-host interaction and/or target cell invasion, they differ in the molecules present on the surface. Thus, aspects related to the variability that the forms of T. cruzi interacts with host cells may lead to fundamental implications on the immune response against this parasite and, consequently, the clinical evolution of Chagas disease. We have shown that BT infected mice presented higher levels of parasitemia during all the acute phase of infection. Moreover, the infection with either MT or BT forms resulted in increased levels of total leukocytes, monocytes and lymphocytes, specifically later for MT and earlier for BT. The infection with BT forms presented earlier production of proinflammatory cytokine TNF-α and later of IFN-γ by both T cells subpopulations. This event was accompanied by an early cardiac inflammation with an exacerbation of this process at the end of the acute phase. On the other hand, infection with MT forms result in an early production of IFN-γ, with subsequent control in the production of this cytokine by IL-10, which provided to these animals an immunomodulatory profile in the end of the acute phase. These results are in agreement with what was found for cardiac inflammation where animals infected with MT forms showed intense cardiac inflammation later at infection, with a decrease in the same at the end of this phase. In summary, our findings emphasize the importance of taking into account the inoculums source of T. cruzi, since vectorial or transfusional routes of T. cruzi infection may trigger distinct parasite-host interactions during the acute phase that may influence relevant biological aspects of chronic Chagas disease.
Asunto(s)
Enfermedad de Chagas/inmunología , Enfermedad de Chagas/parasitología , Trypanosoma cruzi/inmunología , Animales , Citocinas/inmunología , Citocinas/metabolismo , Modelos Animales de Enfermedad , Femenino , Interacciones Huésped-Parásitos/inmunología , Inmunofenotipificación , Leucocitos/inmunología , Ratones , Miocarditis/inmunología , Miocarditis/parasitología , Miocarditis/patología , Parasitemia/inmunología , Bazo/inmunología , Linfocitos T/inmunología , Linfocitos T/metabolismo , Factores de TiempoRESUMEN
El lupus eritematoso sistémico (LES) es una de las patologías autoinmunes más frecuentes durante el embarazo, asociándose con distintas complicaciones fetales y neonatales, sobre todo cardíacas, secundario al traspaso de anticuerpos maternos a través de la placenta. Estos anticuerpos se unen a los cardiomioci-tos fetales, desencadenando una respuesta inflamatoria local que determina la aparición de lesiones que pueden ser permanentes y letales. Presentamos el caso de una paciente embarazada con LES, en la cual se observó en el feto la presencia de bloqueo aurículo-ventricular de primer grado y signos sugerentes de miocarditis. Estas complicaciones se caracterizan por un aumento en la morbimortalidad perinatal, por lo que las estrategias actuales están dirigidas a la detección precoz de éstas y también en la prevención de las mismas. Un tratamiento estándar aun es tema de investigación, pese a los reportes que muestran la efectividad de corticoides como la dexametasona. En embarazadas con anticuerpos anti-Ro positivo se recomienda efectuar ecocardiograma fetal seriados cada 1-2 semanas desde la semana 16, para detectar precozmente anomalías cardiacas sobre las cuales pudiese intervenirse.
Systemic lupus erythematosus (SLE) is one of the most common autoimmune disease during pregnancy, associated with various fetal and neonatal complications, especially heart disease, secondary to the transfer of maternal antibodies through the placenta. These antibodies bind to fetal cardiomyocytes, triggering a local inflammatory response that determines the appearance of lesions that may become permanent and deadly. We report a pregnant patient with SLE, in which was observed the presence of atrioventricular block of 1st degree and signs suggestive of myocarditis in the fetus. These complications are characterized by an increase in fetal and neonatal morbidity and mortality, so that current strategies are aimed at early detection of these and also in preventing them. A standard therapy for atrioventricular block is still matter of investigation, although corticosteroids like dexamethasone have been reported to be effective for associated cardiomyo-pathy. Serial echocardiograms and obstetric sonograms, performed at least every 1-2 weeks starting from the 16th week of gestational age, are recommended in anti-Ro/SSA-positive pregnant women to detect early fetal abnormalities that might be a target of preventive therapy.
Asunto(s)
Humanos , Femenino , Embarazo , Recién Nacido , Adulto , Bloqueo Atrioventricular/inmunología , Bloqueo Atrioventricular , Enfermedades Fetales/inmunología , Enfermedades Fetales , Lupus Eritematoso Sistémico/inmunología , Anticuerpos Antinucleares/análisis , Anticuerpos Antinucleares/inmunología , Dexametasona/uso terapéutico , Enfermedades Fetales/tratamiento farmacológico , Miocarditis/inmunología , Miocarditis , Resultado del Embarazo , Ultrasonografía PrenatalRESUMEN
BACKGROUND: There is scarce information on the potential benefits of immunosuppression in children with myocarditis and viral genomes in myocardium. We investigated the occurrence of myocarditis in children with a preliminary diagnosis of dilated cardiomyopathy, the frequency of cardiotropic viruses in the myocardium, and the response to immunosuppression. METHODS: Thirty patients (nine months to 12 years) with left ventricular ejection fraction of 22.8 ± 4.1% were subjected to right cardiac catheterization and endomyocardial biopsy. Specimens were analyzed for the presence of inflammatory elements (Dallas criteria) and viral genome (polymerase chain reaction). Patients with active myocarditis received immunosuppressants (azatioprine and prednisone) and were re-catheterized nine months later. A historical control group of nine patients with myocarditis who did not receive immunosuppressants was included. RESULTS: Active myocarditis was diagnosed in ten patients (five with viral genomes detected). Immunosuppression resulted in a significant increase in left ventricular ejection fraction from 25.2 ± 2.8% to 45.7 ± 8.6% (versus 20.0 ± 4.0% to 22.0 ± 9.0% in historical controls, p<0.01) and cardiac index from 3.28 ± 0.51 L/min/m(2) to 4.40 ± 0.49 L/min/m(2) (versus 3.50 ± 0.40 L/min/m(2) to 3.70 ± 0.50 L/min/m(2) in controls, p<0.01), regardless of the presence of viral genomes (p=0.98 and p=0.22, respectively for the two variables). No relevant clinical events were observed. Non-inflammatory cardiomyopathy was diagnosed in 20 patients (seven with viral genomes). While on conventional therapy, there were four deaths and three assignments to transplantation, and no improvement of left ventricular ejection fraction in the remaining ones (22.5 ± 3.6% to 27.5 ± 10.6%). CONCLUSION: Children with chronic myocarditis seem to benefit from immunosuppressive therapy, regardless of the presence of viral genome in the myocardium.