RESUMEN
The pro-inflammatory cytokines play a critical role in the initiation and propagation of ocular autoimmune diseases. Regulation of these cytokines is generally mediated by the immunoregulatory cytokine such as IL-10 or TGF-beta. In this study, we investigated the immunoregulatory cytokine profile and frequency of natural regulatory T cells (nTregs) in patients with Vogt-Koyanagi-Harada (VKH). We obtained the peripheral blood mononuclear cells (PBMC) from patients with VKH and healthy controls. The cytokine profile from supernatants of PBMC cultured with or without phytohaemagglutinin (PHA) was measured by ELISA, the percentage of CD4(+) Foxp3(+) and CD25(high)Foxp3(+) T regulatory cells were analysed by flow cytometry, and the transcriptional level of Foxp3 expression was analysed by real-time quantitative PCR. The immunoregulatory cytokines, TGF-beta and IL-10, increased in patients with VKH in the inactive stage of the disease. We observed no significant difference in the CD4(+) Foxp3(+) and CD25(high)Foxp3(+) T cells as well as no reduction in FOXP3 mRNA expression in the patients with VKH when compared to healthy controls. We showed in our work, an increase in IFN-gamma secretion by PBMC of patients with VKH in the active stage of the disease when compared to healthy controls and patients in the inactive stage. Our data suggest that IL-10 and TGF-beta cytokines, rather than nTregs are associated with the resolution phase of the disease and may have a more relevant role in controlling this disease.
Asunto(s)
Factores de Transcripción Forkhead/inmunología , Interleucina-10/inmunología , Linfocitos T Reguladores/inmunología , Factor de Crecimiento Transformador beta/inmunología , Síndrome Uveomeningoencefálico/inmunología , Adulto , Antígenos CD4/inmunología , Femenino , Citometría de Flujo , Factores de Transcripción Forkhead/genética , Humanos , Subunidad alfa del Receptor de Interleucina-2/inmunología , Leucocitos Mononucleares/inmunología , Masculino , Persona de Mediana Edad , ARN/química , ARN/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Adulto JovenRESUMEN
BACKGROUND: Many patients with common variable immunodeficiency (CVID) have a clinical history suggestive of allergic respiratory disease. However, in such individuals, the prevalence of asthma and the role of atopy have not been well established. The objective of this study was to evaluate pulmonary function and identify asthma in patients with CVID. We also investigated the role of IgE as a trigger of asthma in these patients. METHODS: Sixty-two patients diagnosed with CVID underwent spirometry, as well as skin prick testing and in vitro determination of serum-specific IgE levels for aeroallergens, together with bronchial provocation with histamine and allergen. RESULTS: The most common alteration identified through spirometry was obstructive lung disease, which was observed in 29 (47.5%) of the 62 patients evaluated. Eighteen (29.0%) of the 62 patients had a clinical history suggestive of allergic asthma. By the end of the study, asthma had been diagnosed in nine (14.5%) patients and atopy had been identified in six (9.7%). In addition, allergic asthma had been diagnosed in four patients (6.5% of the sample as a whole; 22.2% of the 18 patients with a clinical history suggestive of the diagnosis). CONCLUSION: In this study, CVID patients testing negative for specific IgE antibodies and suspected of having allergic asthma presented a positive response to bronchial provocation tests with allergens. To our knowledge, this is the first such study. When CVID patients with a history suggestive of allergic asthma test negative on traditional tests, additional tests designed to identify allergic asthma might be conducted.
Asunto(s)
Asma/complicaciones , Asma/inmunología , Inmunodeficiencia Variable Común/complicaciones , Inmunodeficiencia Variable Común/inmunología , Adolescente , Adulto , Anciano , Asma/epidemiología , Inmunodeficiencia Variable Común/epidemiología , Femenino , Humanos , Inmunoglobulina E/sangre , Masculino , Persona de Mediana Edad , Prevalencia , Pruebas de Función Respiratoria , Pruebas Cutáneas , Adulto JovenRESUMEN
Common Variable Immunodeficiency (CVID) is a primary immunodeficiency disease characterized by defective immunoglobulin production and often associated with autoimmunity. We used flow cytometry to analyze CD4(+)CD25(HIGH)FOXP3(+) T regulatory (Treg) cells and ask whether perturbations in their frequency in peripheral blood could underlie the high incidence of autoimmune disorders in CVID patients. In this study, we report for the first time that CVID patients with autoimmune disease have a significantly reduced frequency of CD4(+)CD25(HIGH)FOXP3(+) cells in their peripheral blood accompanied by a decreased intensity of FOXP3 expression. Notably, although CVID patients in whom autoimmunity was not diagnosed had a reduced frequency of CD4(+)CD25(HIGH)FOXP3(+) cells, FOXP3 expression levels did not differ from those in healthy controls. In conclusion, these data suggest compromised homeostasis of CD4(+)CD25(HIGH)FOXP3(+) cells in a subset of CVID patients with autoimmunity, and may implicate Treg cells in pathological mechanisms of CVID.
Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Inmunodeficiencia Variable Común/inmunología , Factores de Transcripción Forkhead/inmunología , Subunidad alfa del Receptor de Interleucina-2/inmunología , Adolescente , Adulto , Anciano , Autoinmunidad/inmunología , Linfocitos T CD4-Positivos/citología , Linfocitos T CD4-Positivos/metabolismo , Linfocitos T CD8-positivos/citología , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Inmunodeficiencia Variable Común/sangre , Inmunodeficiencia Variable Común/genética , Femenino , Citometría de Flujo , Factores de Transcripción Forkhead/genética , Expresión Génica , Humanos , Recuento de Linfocitos , Masculino , Persona de Mediana Edad , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Linfocitos T Reguladores/citología , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/metabolismo , Adulto JovenRESUMEN
OBJECTIVE AND DESIGN: We investigated the influence of acute inflammation in skin isograft acceptance. METHODS: Two mouse lines selected for maximal (AIRMAX) or minimal inflammatory response (AIRMIN) were transplanted with syngeneic skin. Cellular infiltrates and cytokine production were measured 1, 3, 7 or 14 days post-transplantation. The percentage of CD4+CD25+Foxp3+ cells in the lymph nodes was also evaluated. RESULTS: Grafts were totally accepted in 100% of AIRMAX and in 26% of AIRMIN mice. In the latter, partial acceptance was observed in 74% of the animals. Emigrated cells were basically PMN and were enhanced in AIRMAX transplants. IL-10 production by graft infiltrating cells showed no interline differences. IFN-gamma was increased in AIRMIN grafts at day 14 and lower percentages of CD4+CD25+Foxp3+ cells in the lymph nodes were observed in these mice. CONCLUSIONS: Our data suggest that differences in graft acceptance might be due to a lack of appropriate regulation of the inflammatory response in AIRMIN mice compromising the self/non-self recognition.
Asunto(s)
Supervivencia de Injerto/fisiología , Inflamación/patología , Macrófagos/patología , Neutrófilos/patología , Trasplante de Piel/fisiología , Trasplante Isogénico/patología , Animales , Antígenos CD4/metabolismo , Factores de Transcripción Forkhead/metabolismo , Inflamación/metabolismo , Interferón gamma/metabolismo , Interleucina-10/metabolismo , Subunidad alfa del Receptor de Interleucina-2/metabolismo , Ganglios Linfáticos/metabolismo , Ganglios Linfáticos/patología , Macrófagos/metabolismo , Ratones , Ratones Endogámicos , Modelos Animales , Neutrófilos/metabolismo , Trasplante de Piel/patología , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
BACKGROUND: Efforts have been made to correctly characterize the role of the immune response in endometriosis. The objective of this study was to analyse the interaction between Th1 and Th2 immune response patterns and endometriosis by evaluating a panel of cytokines. METHODS: Between January 2004 and November 2005, 98 patients, classified into two groups according to the histologically confirmed presence (Group A) or absence of endometriosis (Group B), were evaluated. Interleukins (IL) 2, 4 and 10, tumour necrosis factor-alpha and interferon-gamma (IFN-gamma) were measured by flow cytometry in the peripheral blood and peritoneal fluid of all patients. RESULTS: IFN-gamma and IL-10 levels were significantly higher in the peritoneal fluid of patients with endometriosis compared to those without endometriosis (P < 0.05). There was a significant alteration in the IL-4/IFN-gamma (P < 0.001), IL-4/IL-2 (P = 0.006), IL-10/IFN-gamma (P < 0.001) and the IL-10/IL-2 ratios (P < 0.001) in the peritoneal fluid of patients with endometriosis, with a predominance of IL-4 and IL-10, reflecting a shift towards Th2 immune response despite the increase in IFN-gamma concentrations. CONCLUSIONS: Endometriosis is an inflammatory disease involving a possible shift towards Th2 immune response component, as demonstrated by the relative increase in cytokines characteristic of this pattern of immune response.
Asunto(s)
Endometriosis/inmunología , Células Th2/inmunología , Adolescente , Adulto , Líquido Ascítico/química , Femenino , Humanos , Interferón gamma/análisis , Interleucina-10/análisis , Interleucina-2/análisis , Interleucina-4/análisis , Células TH1/inmunología , Factor de Necrosis Tumoral alfa/análisisRESUMEN
Susceptibility to experimental autoimmune uveitis (EAU) in inbred mice has been associated with a dominant Th1 response. Elevated anti-inter-photoreceptor retinoid-binding protein (anti-IRBP) IgG2a/IgG1 antibody ratios have been implicated as candidate markers to predict disease severity. In the present study, both the anti-IRBP antibody isotype and severity of EAU phenotypes were examined in 4 non-isogenic genetically selected mouse lines to determine if they can be used as general markers of disease. Mice between 8 and 12 weeks old selected for high (H(III)) or low (L(III)) antibody response and for maximum (AIR(MAX)) or minimum (AIR(MIN)) acute inflammatory reaction (AIR) were immunized with IRBP. Each experiment was performed with at least 5 mice per group. EAU was evaluated by histopathology 21 days after immunization and the minimal criterion was inflammatory cell infiltration of the ciliary body, choroid and retina. Serum IgG1- and IgG2a-specific antibodies were determined by ELISA. EAU was graded by histological examination of the enucleated eyes. The incidence of EAU was lower in AIR(MIN) mice whereas in the other strains approximately 40% of the animals developed the disease. Low responder animals did not produce anti-IRBP IgG2a antibodies or interferon-gamma. No correlation was observed between susceptibility to EAU and anti-IRBP isotype profiles. Susceptibility to EAU is related to the intrinsic capacity to mount higher inflammatory reactions and increased production of anti-IRBP IgG2a isotype is not necessarily a marker of this immunologic profile.
Asunto(s)
Anticuerpos Monoclonales/biosíntesis , Enfermedades Autoinmunes/inmunología , Proteínas del Ojo/inmunología , Inmunoglobulina G/biosíntesis , Interferón gamma/biosíntesis , Proteínas de Unión al Retinol/inmunología , Uveítis/inmunología , Animales , Enfermedades Autoinmunes/patología , Biomarcadores , Modelos Animales de Enfermedad , Susceptibilidad a Enfermedades/inmunología , Ensayo de Inmunoadsorción Enzimática , Ratones , Ratones Transgénicos , Índice de Severidad de la Enfermedad , Células TH1/inmunología , Células Th2/inmunología , Uveítis/patologíaRESUMEN
Susceptibility to experimental autoimmune uveitis (EAU) in inbred mice has been associated with a dominant Th1 response. Elevated anti-inter-photoreceptor retinoid-binding protein (anti-IRBP) IgG2a/IgG1 antibody ratios have been implicated as candidate markers to predict disease severity. In the present study, both the anti-IRBP antibody isotype and severity of EAU phenotypes were examined in 4 non-isogenic genetically selected mouse lines to determine if they can be used as general markers of disease. Mice between 8 and 12 weeks old selected for high (H III) or low (L III) antibody response and for maximum (AIR MAX) or minimum (AIR MIN) acute inflammatory reaction (AIR) were immunized with IRBP. Each experiment was performed with at least 5 mice per group. EAU was evaluated by histopathology 21 days after immunization and the minimal criterion was inflammatory cell infiltration of the ciliary body, choroid and retina. Serum IgG1- and IgG2a-specific antibodies were determined by ELISA. EAU was graded by histological examination of the enucleated eyes. The incidence of EAU was lower in AIR MIN mice whereas in the other strains approximately 40 percent of the animals developed the disease. Low responder animals did not produce anti-IRBP IgG2a antibodies or interferon-gamma. No correlation was observed between susceptibility to EAU and anti-IRBP isotype profiles. Susceptibility to EAU is related to the intrinsic capacity to mount higher inflammatory reactions and increased production of anti-IRBP IgG2a isotype is not necessarily a marker of this immunologic profile.
Asunto(s)
Animales , Ratones , Anticuerpos Monoclonales/biosíntesis , Enfermedades Autoinmunes/inmunología , Proteínas del Ojo/inmunología , Inmunoglobulina G/biosíntesis , Interferón gamma/biosíntesis , Proteínas de Unión al Retinol/inmunología , Uveítis/inmunología , Enfermedades Autoinmunes/patología , Biomarcadores , Modelos Animales de Enfermedad , Susceptibilidad a Enfermedades/inmunología , Ensayo de Inmunoadsorción Enzimática , Ratones Transgénicos , Índice de Severidad de la Enfermedad , Células TH1/inmunología , /inmunología , Uveítis/patologíaRESUMEN
We have previously demonstrated that Phytomonas serpens, a tomato parasite, shares antigens with Trypanosoma cruzi, the protozoa that causes Chagas' disease. These antigens are recognized by human sera and induce protective immunity in Balb/c mice. In the present study, inducible nitric oxide synthase (iNOS) knockout (KO) mice and C57BL/6 mice treated with the nitric oxide inhibitor, aminoguanidine (AG, 50 mg kg(-1)) infected with T. cruzi, were used to demonstrate the role of nitric oxide (NO) to host protection against T. cruzi infection achieved by oral immunization with live P. serpens. A reduction in parasitaemia and an increase in survival were observed in C57BL/6 infected mice and previously immunized with P. serpens, when compared to non-immunized mice. iNOS (KO) mice immunized and C57BL/6 immunized and treated with AG presented parasitaemia and mortality rates comparable to those of infected and non-immunized mice. By itself, immunization with P. serpens did not induce inflammation in the myocardium, but C57BL/6 mice so immunized showed fewer amastigotes nests in the heart following an acute T. cruzi infection than those in non-immunized mice. These results suggest that protective immunity against T. cruzi infection induced by immunization with P. serpens is dependent upon enhanced NO production during the acute phase of T. cruzi infection.
Asunto(s)
Enfermedad de Chagas/prevención & control , Inmunoterapia Activa , Óxido Nítrico Sintasa/fisiología , Óxido Nítrico/fisiología , Trypanosoma cruzi/inmunología , Trypanosomatina/inmunología , Administración Oral , Animales , Sangre/parasitología , Enfermedad de Chagas/genética , Corazón/parasitología , Ratones , Ratones Noqueados , Miocardio/patología , Óxido Nítrico/metabolismo , Óxido Nítrico Sintasa/genética , Óxido Nítrico Sintasa de Tipo IIRESUMEN
The development of microchimerism was evaluated at different time points after infusion of a mixed population of bone marrow and spleen cells from (BALB/c x C57Bl/6)F1 mice in the presence or absence of a cardiac transplant. Microchimerism was observed in the spleen, bone marrow and thymus of transplanted BALB/c mice even after graft rejection. In the absence of transplantation, donor cells persisted especially in the thymus. The results show that despite augmentation of graft survival after donor cell infusion compared to nontreated controls, the development of microchimerism did not sustain cardiac semihistocompatible grafts. Moreover, the persistence of donor cells in the thymus in both situations suggests a role for this organ in the increased graft survival in our model.
Asunto(s)
Supervivencia de Injerto/inmunología , Trasplante de Corazón/inmunología , Quimera por Trasplante , Animales , Secuencia de Bases , Biomarcadores , Cartilla de ADN , Modelos Animales de Enfermedad , Hipoxantina Fosforribosiltransferasa/genética , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Reacción en Cadena de la Polimerasa , Trasplante HomólogoRESUMEN
Objetivo: A nefropatia primária da IgA (NIgA) e adeficiência de IgA (DIgA) constituem as formas maiscomuns de glomerulonefrite e de deficiência primáriade anticorpos, respectivamente, despertando interesseespecial o fato de ambas envolverem distúrbios contrastantes da produção da IgA. O objetivo deste trabalho foi comparar os níveis de citocinas possivelmente implicadas na produção da IgA (IL-4, IL-5, IL-6, IL-10) em pacientes com NIgA ou DIgA. Casuística e Métodos: Foram estudados 18 pacientes com NIgA (hematúria microscópica e proteinúria persistente ou intermitente e biópsia renal percutânea com depósito de IgA em mesângio glomerular detectado por imunofluorescência), sendo nove do gênero masculino e nove do feminino, com média de idade de 33,2 anos; 17 pacientes com DIgA (níveis séricos de IgA menores do que 7 mg/dL e níveis normais ou elevados de IgG e IgM), sendo 13 do gênero masculino e quatro do feminino, com média de idade de 25,5 anos; dez voluntários sadios (dois do gênero masculino e oito do feminino com média de idade de 30,7 anos). As citocinas foram quantificadas por método imunoenzimático em sobrenadante de cultura de PMBC após 48 horas de estímulo com fitohemaglutinina . Resultados: Foram observados: 1) níveis elevadosde IL-5 e de IL-10 e baixos de IL-6 em pacientes com NIgA em relação aos pacientes com DIgA e controlessadios; 2) níveis semelhantes de IL-4 em ambos gruposde pacientes e mais elevados na NIgA em comparaçãoaos controles sadios; 3) níveis similares de todasas citocinas testadas em pacientes com DIgA e controlessadios. Conclusões: Os níveis elevados de IL-5 encontrados na NIgA reforçam a importância desta citocina na síntese de IgA, cujos níveis séricos estão aumentados em aproximadamente 50 per cent dos casos; os níveis elevados de IL-4 e IL-5 encontrados nestes pacientes sugerem que estas duas citocinas possam estar envolvidas na glicosilação da IgA e seu conseqüente depósito em mesângio renal; os níveis elevados de IL-10 e baixos de IL-6 observados em pacientes com NIgA reforçam a hipótese de que a IL-10 esteja implicada na síntese da IgA em humanos e sugerem que esta citocina possa desempenhar um papel regulador sobre a produção deIL-6.
Asunto(s)
Humanos , Masculino , Femenino , Adulto , Pruebas Inmunológicas de Citotoxicidad , Glomerulonefritis por IGA , Técnicas In VitroRESUMEN
Objetivo: Avaliação da morte celular por ativação em linfócitos T de pacientes com imunodeficiência comum variável (CVID) e de outros parâmetros da resposta imune. Métodos: Células mononucleares obtidas a partir de sangue periférico (PBMC) de 32 pacientes com CVID e 32 indivíduos normais foram utilizadas para o estudo da expressão de CD40L, linfoproliferação e apoptose, Para a análise de marcadores de ativação (CD25 e CD69) e de interação entre células T e B (CD70) PBMC foram estimuladas por diferentes tempos (24, 48, 72 e 96 horas), Os sobrenadantes de cultura foram utilizados para quantificação de citocinas (IL-2, IL-4, IL-5 e IFN-y) por ELISA. Todos os testes laboratoriais foram aplicados no grupo controle de voluntários sadios. Os resultados foram analisados utilizando testes de diferença de proporções, ANOV A, Kruskal-Wallis e a prova de Mann-Whitney. Resultados: O grupo de pacientes com CVID demonstrou aumento percentual de linfócitos CD3/CD4 que sofreram apoptose em relação ao grupo controle (p< (Au) pacientes. destes anticorpos por mediada e celular resposta da prejuízo conseqüente com Th2, citocinas de diminuída síntese além CD70, CD69 CD25, CD40L, expressão circulantes, B T células nas decréscimo pelo responsável seja fenômeno este que sugere ativadas morte aumento O Conclusões: normais. indivíduos grupo o comparados quando CVID pacientes.
Asunto(s)
Humanos , Anexinas , Inmunodeficiencia Variable Común , Citocinas , Técnicas In Vitro , Interleucinas , Linfocitos T , Muerte Celular , Inmunidad Celular , MétodosRESUMEN
It has been suggested for many years that the regulation of the immune system for the maintenance of peripheral tolerance may involve regulatory/suppressor T cells. In the past few years, several investigators have demonstrated that these cells can be generated in vitro. It has also been shown that they can inhibit the progression of various autoimmune disease models when infused into susceptible mice. We have generated two murine T cell lines in the presence of KLH-specific T cell clones from BALB/c or DBA2 mice. The lines are characterized by a low proliferative response to mitogens, the capacity to secrete high amounts of IL-10 and TGF-beta, and small amounts of IFN-gamma. Interestingly, these cells are unable to produce IL-2, IL-4 or IL-5. The study of the surface phenotype of both lines revealed CD4+, CD25high, CD44low and CTLA-4- cells. When injected intravenously in (CBy.D2) F1 mice, these cells were able to inhibit 50-100% of the TNP-specific antibody production, when the hapten was coupled to KLH. In the present study we offer another evidence for the existence of regulatory T cells in the T lymphocyte repertoire, suggesting that they can also regulate immune responses to foreign antigens. Furthermore, we demonstrate an alternative pathway to generate these cells different from approaches used thus far.
Asunto(s)
Adyuvantes Inmunológicos , Traslado Adoptivo/métodos , Enfermedades Autoinmunes/terapia , Linfocitos T CD4-Positivos , Línea Celular , Hemocianinas/inmunología , Animales , Formación de Anticuerpos/inmunología , Técnicas de Cultivo de Célula/métodos , Células Clonales/inmunología , Citocinas/inmunología , Interferón gamma/análisis , Interleucina-10/análisis , Interleucina-2/análisis , Interleucina-4/análisis , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos DBA , Linfocitos T/inmunología , Factor de Crecimiento Transformador beta/análisisRESUMEN
Toxoplasma gondii is an intracellular parasite whose life cycle may include the man as an intermediate host. Close to a billion people are infected with this parasite worldwide. Ocular lesions may occur in up to 25% of those individuals infected. The infection may occur intra-uterus, through the placenta when the mother is infected during pregnancy. The parasite may also infect adults after the ingestion of contaminated food products, most notably meats or water. We have shown that although congenital and post-natal (acquired) infection results in similar ocular lesions, the immunological mechanisms behind the development of disease are different. On the other hand, contrary to published data obtained in mice, we were unable to find evidence that the T. gondii express superantigen activity for human lymphocytes. Our findings are important because they suggest that superantigen activity is not important as a pathological mechanism in human disease. Our data also suggest that, whereas the ocular lesion caused by infection after birth is the result of an excessive or dysfunctional immune response, the lesions caused by congenital infection may be due to a lack of an appropriate response to the parasite.
Asunto(s)
Toxoplasmosis Congénita/inmunología , Toxoplasmosis Ocular/inmunología , Animales , Humanos , Superantígenos/inmunología , Linfocitos T/inmunología , Toxoplasma/genéticaRESUMEN
One-third of all Trypanosoma cruzi -infected patients eventually develop chronic Chagas' disease cardiomyopathy (CCC), a particularly lethal inflammatory dilated cardiomyopathy, where parasites are scarce and heart-infiltrating mononuclear cells seem to be the effectors of tissue damage. Since T. cruzi is a major inducer of interleukin-12 production, the role of inflammatory cytokines in the pathogenesis of CCC was investigated. We assayed cytokine production by peripheral blood mononuclear cells (PBMC) from CCC and asymptomatic T. cruzi -infected (ASY) individuals, as well as by T cell lines from endomyocardial biopsies from CCC patients. PBMC from CCC and ASY patients produced higher IFN-gamma levels than normal (N) individuals in response to B13 protein and phytohaemagglutinin PHA; IFN-gamma high responders (> or =1 ng/ml) were 2-3 fold more frequent among CCC patients than ASY individuals. Conversely, IL-4 production in response to the same stimuli was suppressed among T. cruzi -infected patients. The frequency of PHA-induced IFN gammaproducing cells on PBMC was significantly higher among CCC than ASY and N individuals. IFN-gamma and TNF-alpha were produced by ten out of ten PHAstimulated T cell lines from CCC patients; IL-2 and IL-10 were produced by four out of ten and one out of ten lines, respectively; IL-4, IL-1alpha, IL-1beta, IL-6 and IL-12 were undetectable. Our results suggest that CCC and ASY patients may respond differentially to the IFN-gamma-inducing stimulus provided by T. cruzi infection. Given the T(1)-type cytokine profile of heart-infiltrating T cell lines from CCC patients, the ability to mount a vigorous IFN-gamma response may play a role on the differential susceptibility to CCC development.
Asunto(s)
Cardiomiopatía Chagásica/inmunología , Interferón gamma/biosíntesis , Trypanosoma cruzi/inmunología , Adulto , Animales , Línea Celular , Movimiento Celular/inmunología , Cardiomiopatía Chagásica/patología , Enfermedad Crónica , Citocinas/biosíntesis , Femenino , Humanos , Masculino , Persona de Mediana Edad , Miocardio/inmunología , Miocardio/patología , Células TH1/inmunología , Células TH1/metabolismo , Células Th2/inmunología , Células Th2/metabolismoRESUMEN
Toxoplasma gondii is an obligatory intracellular parasite whose life cycle may include man as an intermediate host. More than 500 million people are infected with this parasite worldwide. It has been previously reported that T. gondii contains a superantigen activity. The purpose of the present study was to determine if the putative superantigen activity of T. gondii would manifest towards human T cells. Peripheral blood mononuclear cells (PBMC) from individuals with no previous contact with the parasite were evaluated for proliferation as well as specific Vá expansion after exposure to Toxoplasma antigens. Likewise, PBMC from individuals with the congenital infection were evaluated for putative Vá family deletions in their T cell repertoire. We also evaluated, over a period of one year, the PBMC proliferation pattern in response to Toxoplasma antigens in patients with recently acquired infection. Some degree of proliferation in response to T. gondii was observed in the PBMC from individuals never exposed to the parasite, accompanied by specific Vá expansion, suggesting a superantigen effect. However, we found no specific deletion of Vá (or Valpha) families in the blood of congenitally infected individuals. Furthermore, PBMC from recently infected individuals followed up over a period of one year did not present a reduction of the Vá families that were originally expanded in response to the parasite antigens. Taken together, our data suggest that T. gondii does not have a strong superantigen activity on human T cells
Asunto(s)
Humanos , Adulto , Persona de Mediana Edad , Animales , Superantígenos/inmunología , Linfocitos T/inmunología , Toxoplasma/inmunología , Toxoplasmosis Congénita/inmunología , Citometría de Flujo , Estudios de Seguimiento , Leucocitos Mononucleares/inmunología , Toxoplasmosis Congénita/inmunologíaRESUMEN
Toxoplasma gondii is an obligatory intracellular parasite whose life cycle may include man as an intermediate host. More than 500 million people are infected with this parasite worldwide. It has been previously reported that T. gondii contains a superantigen activity. The purpose of the present study was to determine if the putative superantigen activity of T. gondii would manifest towards human T cells. Peripheral blood mononuclear cells (PBMC) from individuals with no previous contact with the parasite were evaluated for proliferation as well as specific Vbeta expansion after exposure to Toxoplasma antigens. Likewise, PBMC from individuals with the congenital infection were evaluated for putative Vbeta family deletions in their T cell repertoire. We also evaluated, over a period of one year, the PBMC proliferation pattern in response to Toxoplasma antigens in patients with recently acquired infection. Some degree of proliferation in response to T. gondii was observed in the PBMC from individuals never exposed to the parasite, accompanied by specific Vbeta expansion, suggesting a superantigen effect. However, we found no specific deletion of Vbeta (or Valpha) families in the blood of congenitally infected individuals. Furthermore, PBMC from recently infected individuals followed up over a period of one year did not present a reduction of the Vbeta families that were originally expanded in response to the parasite antigens. Taken together, our data suggest that T. gondii does not have a strong superantigen activity on human T cells.
Asunto(s)
Superantígenos/inmunología , Linfocitos T/inmunología , Toxoplasma/inmunología , Toxoplasmosis Congénita/inmunología , Adulto , Animales , Citometría de Flujo , Estudios de Seguimiento , Humanos , Leucocitos Mononucleares/inmunología , Persona de Mediana Edad , Toxoplasmosis Congénita/parasitologíaRESUMEN
Many persons infected with Toxoplasma gondii develop ocular lesions. Immunologic parameters in the response to T. gondii were evaluated in infected persons with and without ocular lesions and in noninfected controls. Subjects were divided into groups on the basis of presence of serum antibodies to T. gondii, presence of ocular lesions, and clinical history. Production of interleukin-2 and interferon-gamma by peripheral blood mononuclear cells from patients with probable congenital toxoplasmosis was decreased, compared with that in persons with presumed acquired infection. Cell proliferation and delayed-type skin reaction induced by soluble toxoplasma tachyzoite antigen followed the same pattern. Asymptomatic persons showed high levels of interleukin-12 and interferon-gamma, whereas persons with ocular lesions had high interleukin-1 and tumor necrosis factor-alpha responses toward soluble toxoplasma tachyzoite antigen. These data suggest that patients with ocular disease due to congenital infection show tolerance toward the parasite. Furthermore, susceptibility to ocular lesions after acquired toxoplasmosis is associated with high levels of interleukin-1 and tumor necrosis factor-alpha, whereas resistance is associated with high levels of interleukin-12 and interferon-gamma.
Asunto(s)
Antígenos de Protozoos/inmunología , Toxoplasmosis Congénita/inmunología , Toxoplasmosis/inmunología , Adolescente , Adulto , Citocinas/biosíntesis , Femenino , Humanos , Activación de Linfocitos , Masculino , Persona de Mediana Edad , Receptores de Antígenos de Linfocitos T alfa-beta/análisisRESUMEN
Protection from the development of experimental autoimmune uveitis (EAU) can be induced by feeding mice interphotoreceptor retinoid binding protein before uveitogenic challenge with the same protein. Two different regimens are equally effective in inducing protective tolerance, although they seem to do so through different mechanisms: one involving regulatory cytokines (IL-4, IL-10, and TGF-beta), and the other with minimal involvement of cytokines. Here we studied the importance of IL-4 and IL-10 for the development of oral tolerance using mice genetically engineered to lack either one or both of these cytokines. In these animals we were able to protect against EAU only through the regimen inducing cytokine-independent tolerance. When these animals were fed a regimen that in the wild-type animal is thought to predominantly induce regulatory cells and is associated with cytokine secretion, they were not protected from EAU. Interestingly, both regimens were associated with reduced IL-2 production and proliferation in response to interphotoreceptor retinoid binding protein. These findings indicate that both IL-4 and IL-10 are required for induction of protective oral tolerance dependent on regulatory cytokines, and that one cytokine cannot substitute for the other in this process. These data also underscore the fact that oral tolerance, manifested as suppression of proliferation and IL-2 production, is not synonymous with protection from disease.
Asunto(s)
Enfermedades Autoinmunes/inmunología , Proteínas del Ojo , Tolerancia Inmunológica , Interleucina-10/fisiología , Interleucina-4/fisiología , Uveítis/inmunología , Animales , Femenino , Activación de Linfocitos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Proteínas de Unión al Retinol/inmunología , Factor de Crecimiento Transformador beta/fisiologíaRESUMEN
The hallmark of chronic Chagas' disease cardiomyopathy (CCC) is the finding of a T cell-rich inflammatory mononuclear cell infiltrate in the presence of extremely few parasites in the heart lesions. The scarcity of parasites in affected heart tissue casts doubt on the direct participation of Trypanosoma cruzi in CCC heart tissue lesions, and suggests the possible involvement of autoimmunity. The cells in the infiltrate are presumably the ultimate effectors of tissue damage, and there is evidence that such cells recognize cardiac myosin in molecular mimicry with T. cruzi proteins rather than primary reactivity to T. cruzi antigens (Cunha-Neto et al. (1996) Journal of Clinical Investigation, 98: 1709-1712). Recently, we have studied heart-infiltrating T cells at the functional level. In this short review we summarize the studies about the role of cytokines in human and experimental T. cruzi infection, along with our data on heart-infiltrating T cells in human Chagas' cardiomyopathy. The bulk of evidence points to a significant production of IFN-gamma and TNF-alpha which may be linked to T. cruzi-induced IL-12 production.