Inhibitory receptors are expressed by Trypanosoma cruzi-specific effector T cells and in hearts of subjects with chronic Chagas disease.

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.

The impact of socioeconomic conditions on chronic Chagas disease progression.

INTRODUCTION AND OBJECTIVES: The extent to which a patient's socioeconomic conditions determine the persistence or control of chronic Chagas disease has not been previously investigated. The aim of this study was to evaluate the effect of socioeconomic conditions on clinical and serologic measures of disease progression. METHODS: Data on the following socioeconomic variables were obtained by questioning as part of medical history taking at admission: birth in a rural area, time of residence in endemic and urban areas (in years), overcrowding index (i.e. number of inhabitants/number of bedrooms), absence of toilet facilities, years of education, employed or unemployed, and health insurance coverage (i.e. private contributory medical insurance cover). The study endpoints for the Cox regression analysis were: consistently negative results on serologic tests and on tests for markers of cardiomyopathy progression by the end of the study. RESULTS: The study included 801 Argentine patients (mean age 42 years) who were followed up for a mean of 10 years between 1990 and 2005. After adjustment for age and antiparasitic treatment, negative seroconversion was associated with a short time of residence in an endemic area (hazard ratio [HR]=0.97; 95% confidence interval [CI], 0.96-0.99; P=.004), a low overcrowding index (HR=0.82; 95% CI, 0.70-0.97; P=.022) and medical insurance cover (HR=1.46; 95% CI, 1.01-2.09; P=.04). After adjustment for age, sex, ECG abnormalities and antiparasitic treatment, a low rate of cardiomyopathy progression was associated with more years of education (HR=0.88; 95% CI, 0.80-0.97; P=.01) and higher medical insurance cover (HR=0.49; 95% CI, 0.30-0.81; P=.005). CONCLUSIONS: Socioeconomic conditions had a significant effect on chronic Chagas disease progression which was independent of antiparasitic treatment and clinic characteristics.

El impacto de las condiciones socioeconómicas en la evolución de la enfermedad de Chagas crónica / The impact of socioeconomic conditions on chronic Chagas disease progression

Introducción y objetivos. Las condiciones socioeconómicas del huésped no han sido evaluadas como determinantes de la persistencia o el control de la enfermedad de Chagas crónica. El objetivo fue valorar el impacto de las condiciones socioeconómicas sobre la evolución clínica y serológica. Métodos. Las variables socioeconómicas en estudio fueron obtenidas por interrogatorio como parte de la historia clínica de ingreso: nacimiento en área rural, tiempo de residencia en área endémica y urbana (años), índice de hacinamiento (número de habitantes/número de dormitorios), ausencia de instalaciones sanitarias, años de educación, ocupación/desocupación y cobertura social (planes de asistencia médica por aportación privada). La negativización de las pruebas serológicas y los indicadores de progresión de la cardiopatía al concluir el estudio fueron los puntos finales de evaluación para el análisis de regresión de Cox. Resultados. Se incluyó a 801 pacientes, de 42 años de edad y 10 años de seguimiento promedio, en Argentina, entre los años 1990 y 2005. Un aumento de la seroconversión negativa, ajustada para edad y tratamiento etiológico, se asoció con un menor tiempo de residencia en área endémica (hazard ratio [HR] = 0,97 [0,96-0,99]; p = 0,004), menor índice de hacinamiento (HR = 0,82 [0,70-0,97]; p = 0,022) y mayor cobertura social (HR = 1,46 [1,01-2,09]; p = 0,04). Una disminución de la progresión de la cardiopatía, ajustada para edad, sexo, electrocardiograma anormal y tratamiento etiológico, se observó en pacientes con más años de educación (HR = 0,88 [0,80-0,97]; p = 0,01) y con cobertura social (HR = 0,49 [0,30-0,81]; p = 0,005). Conclusiones. Las condiciones socioeconómicas mostraron un significativo impacto sobre la evolución de la enfermedad de Chagas crónica independientemente del tratamiento antiparasitario y las características clínicas (AU)

Introduction and objectives. The extent to which a patient’s socioeconomic conditions determine the persistence or control of chronic Chagas disease has not been previously investigated. The aim of this study was to evaluate the effect of socioeconomic conditions on clinical and serologic measures of disease progression. Methods. Data on the following socioeconomic variables were obtained by questioning as part of medical history taking at admission: birth in a rural area, time of residence in endemic and urban areas (in years), overcrowding index (ie, number of inhabitants/number of bedrooms), absence of toilet facilities, years of education, employed or unemployed, and health insurance coverage (ie, private contributory medical insurance cover). The study endpoints for the Cox regression analysis were consistently negative results on serologic tests and on tests for markers of cardiomyopathy progression by the end of the study. Results. The study included 801 Argentine patients (mean age, 42 years) who were followed up for a mean of 10 years between 1990 and 2005. After adjustment for age and antiparasitic treatment, negative seroconversion was associated with a short time of residence in an endemic area (hazard ratio [HR] = 0.97; 95% confidence interval [CI], 0.96-0.99; P=.004), a low overcrowding index (HR=0.82; 95% CI, 0.70-0.97; P=.022) and medical insurance cover (HR=1.46; 95% CI, 1.01-2.09; P=.04). After adjustment for age, sex, ECG abnormalities, and antiparasitic treatment, a low rate of cardiomyopathy progression was associated with more years of education (HR=0.88; 95% CI, 0.80-0.97;P=.01) and higher medical insurance cover (HR=0.49; 95% CI, 0.30-0.81; P=.005). Conclusions. Socioeconomic conditions had a significant effect on chronic Chagas disease progression which was independent of antiparasitic treatment and clinic characteristics (AU)

HLA Class I-T cell epitopes from trans-sialidase proteins reveal functionally distinct subsets of CD8+ T cells in chronic Chagas disease.

BACKGROUND: Previously, we identified a set of HLA-A020.1-restricted trans-sialidase peptides as targets of CD8+ T cell responses in HLA-A0201+ individuals chronically infected by T. cruzi. METHODS AND FINDINGS: Herein, we report the identification of peptides encoded by the same trans-sialidase gene family that bind alleles representative of the 6 most common class I HLA-supertypes. Based on a combination of bioinformatic predictions and HLA-supertype considerations, a total of 1001 epitopes predicted to bind to HLA A01, A02, A03, A24, B7 and B44 supertypes was selected. Ninety-six supertype-binder epitopes encoded by multiple trans-sialidase genes were tested for the ability to stimulate a recall CD8+ T cell response in the peripheral blood from subjects with chronic T. cruzi infection regardless the HLA haplotype. An overall hierarchy of antigenicity was apparent, with the A02 supertype peptides being the most frequently recognized in the Chagas disease population followed by the A03 and the A24 supertype epitopes. CD8+ T cell responses to promiscuous epitopes revealed that the CD8+ T cell compartment specific for T. cruzi displays a functional profile with T cells secreting interferon-gamma alone as the predominant pattern and very low prevalence of single IL-2-secreting or dual IFN-gamma/IL-2 secreting T cells denoting a lack of polyfunctional cytokine responses in chronic T. cruzi infection. CONCLUSIONS: This study identifies a set of T. cruzi peptides that should prove useful for monitoring immune competence and changes in infection and disease status in individuals with chronic Chagas disease.