Apoptotic cell clearance of Leishmania major-infected neutrophils by dendritic cells inhibits CD8⁺ T-cell priming in vitro by Mer tyrosine kinase-dependent signaling.

Neutrophils are the predominant recruited and infected cells during the early stages of Leishmania major infection in the skin, and depletion of neutrophils promotes immunity to infection transmitted by sand fly bite. In order to better understand how the acute neutrophilic response suppresses immunity, we assessed the consequences of the interaction between neutrophils recovered from the skin-inoculation site and bone marrow-derived dendritic cells (DCs) in vitro. The capture of infected, apoptotic neutrophils by the DCs completely inhibited their cross-presentation function that was dependent on engagement of the receptor tyrosine kinase Mer on the DCs. The capture of uninfected neutrophils, or neutrophils infected with Toxoplasma gondii, had only slight immunomodulatory effects. These studies define the clearance of infected, apoptotic neutrophils by DCs and Mer receptor signaling as central to the early immune evasion strategies of L. major, with relevance to other vector-borne pathogens delivered by bite to the skin.

Endothelin-1 receptors play a minor role in the protection against acute Trypanosoma cruzi infection in mice.

Chagas' disease, caused by the protozoan Trypanosoma cruzi, is a major cause of cardiovascular disability in countries where it is endemic. Damage to the heart microvasculature has been proposed to be an important factor in the pathogenesis of heart dysfunction. Endothelin-1 (ET-1) is a potent vasoconstrictor and exerts its effects via specific ET A and ET B receptors. A few studies have suggested a role for ET-1 and its receptors in the pathogenesis of Chagas' disease. We investigated the effects of treatment with bosentan, an ET A/ET B receptor antagonist, on the course of T. cruzi infection (Y strain) in C57Bl/6 mice. Treatment with bosentan (100 mg kg-1 day-1) was given per os starting day 0 after infection until sacrifice. Bosentan significantly increased myocardial inflammation, with no effects on parasitemia. Although the total number of nests was similar, a lower number of intact amastigote nests was found in the heart of bosentan-treated animals. Bosentan failed to affect the infection-associated increase in the cardiac levels of the cytokines IFN-g and TNF-a and the chemokines CCL2/MCP-1, CCL3/MIP-1a and CCL5/RANTES. In vitro, pre-incubation with ET-1 (0.1 microM) 4 h before infection enhanced the uptake of the parasites by peritoneal macrophages, and this effect was abrogated when macrophages were pre-treated with bosentan (1 microM) 15 min before incubation with ET-1. However, ET-1 did not alter killing of intracellular parasites after 48 h of in vitro infection. Our data suggest that bosentan-treated mice have a delay in controlling parasitism which is compensated for exacerbated inflammation. Infection is eventually controlled in these animals and lethality is unchanged, demonstrating that ET-1 plays a minor role in the protection against acute murine T. cruzi infection.

Endothelin-1 receptors play a minor role in the protection against acute Trypanosoma cruzi infection in mice

Chagas' disease, caused by the protozoan Trypanosoma cruzi, is a major cause of cardiovascular disability in countries where it is endemic. Damage to the heart microvasculature has been proposed to be an important factor in the pathogenesis of heart dysfunction. Endothelin-1 (ET-1) is a potent vasoconstrictor and exerts its effects via specific ET A and ET B receptors. A few studies have suggested a role for ET-1 and its receptors in the pathogenesis of Chagas' disease. We investigated the effects of treatment with bosentan, an ET A/ET B receptor antagonist, on the course of T. cruzi infection (Y strain) in C57Bl/6 mice. Treatment with bosentan (100 mg kg-1 day-1) was given per os starting day 0 after infection until sacrifice. Bosentan significantly increased myocardial inflammation, with no effects on parasitemia. Although the total number of nests was similar, a lower number of intact amastigote nests was found in the heart of bosentan-treated animals. Bosentan failed to affect the infection-associated increase in the cardiac levels of the cytokines IFN-g and TNF-a and the chemokines CCL2/MCP-1, CCL3/MIP-1a and CCL5/RANTES. In vitro, pre-incubation with ET-1 (0.1 æM) 4 h before infection enhanced the uptake of the parasites by peritoneal macrophages, and this effect was abrogated when macrophages were pre-treated with bosentan (1 æM) 15 min before incubation with ET-1. However, ET-1 did not alter killing of intracellular parasites after 48 h of in vitro infection. Our data suggest that bosentan-treated mice have a delay in controlling parasitism which is compensated for exacerbated inflammation. Infection is eventually controlled in these animals and lethality is unchanged, demonstrating that ET-1 plays a minor role in the protection against acute murine T. cruzi infection.

Prevalence of CD8(+)alpha beta T cells in Trypanosoma cruzi-elicited myocarditis is associated with acquisition of CD62L(Low)LFA-1(High)VLA-4(High) activation phenotype and expression of IFN-gamma-inducible adhesion and chemoattractant molecules.

The determinants of the prevalence of CD8(+) T cells in the inflamed myocardium of Trypanosoma cruzi-infected patients and experimental animals are undefined. Using C3H/He mice infected with the Colombiana strain of T. cruzi, we found that the distribution of CD4(+)/CD8(-) and CD4(-)/CD8(+) T cells in the myocardium mirrors the frequency of cells expressing the CD62L(Low)LFA-1(High)VLA-4(High) activation phenotype among CD4(+)/CD8(-) and CD4(-)/CD8(+ )peripheral blood T cells. Consistently, vascular cell adhesion molecule-1-positive endothelial cells and a fine fibronectin network surrounding VLA-4(+) mononuclear cells were found in the inflamed myocardium. Further, interferon gamma (IFN-gamma) and IFN-gamma-induced chemokines (RANTES, MIG and CRG-2/IP-10), as well as JE/MCP-1 and MIP1-alpha, were found to be the dominant cytokines expressed in situ during acute and chronic myocarditis elicited by T. cruzi. In contrast, interleukin 4 mRNA was only detected during the chronic phase. Altogether, the results indicate that the distribution of T-cell subsets in the myocardium of T. cruzi-infected mice reflects the particular profile of adhesion molecules acquired by most peripheral CD8(+) T lymphocytes and point to the possibility that multiple IFN-gamma-inducible molecules present in the inflamed tissue contribute to the establishment and maintenance of T. cruzi-induced myocarditis.

Lepra: evaluación inmunonológica de contactos intradomiciliarios / Leprosy: an assessment of contacts inmunonológica intradomiciliary

Los contactos intradomiciliarios de pacientes con lepra representan una población con riesgo de infección . El uso combinado de pruebas cutáneas y ELISA revela el grado de sensibilización, la capacidad de respuesta inmunológica y casos subclínicos de la enfermedad. Con base en lo anteriormente expuesto y con la finalidad de justificar el uso de estas pruebas, de rutina en otros contactos, se entrevistó el evaluó clínicamente a 211 contactos intradomiciliarios, de 32 casos de lepra registrados. Se colocó a los contactos lepramina intradérmica y se determinó niveles de anticuerpos específicos contra M. leprae (prueba de ELISA con PGL-1). De la población evaluada, 99.88 por ciento presentó reacción de Fernández negativa y 2/3 de ella presentó una reacción de Mitsuda positiva. Sólo 30.85 por ciento constituyó un grupo de riesgo por presentar reacción de Mitsuda negativa. Al correlacionar las pruebas cutáneas con el ELISA se mostró que ninguno presentaba lepra en fase subclínica y que un sólo caso de ELISA débilmente positivo resultó ser una infección pasada autolimitada. No se justifica usar todas las pruebas inmunológicas, en todos los contactos. Se recomienda usar pruebas cutáneas para detectar grupos de riesgo y para orientar quimiprofilaxis, reservado el uso del ELISA sólo para grupos de riesgo demostrado.

Chagas' disease encephalitis: intense CD8+ lymphocytic infiltrate is restricted to the acute phase, but is not related to the presence of Trypanosoma cruzi antigens.

Central nervous system (CNS) damage can occur during Chagas' disease, especially in children and immunosuppressed patients. During the acute phase, amastigotes are rarely found, but inflammatory infiltrates are scattered throughout the CNS. Moreover, peripheral lymphocytes and antibodies recognizing neural components were described, suggesting the participation of the immune system in the genesis of neural lesions. Herein, we performed a histopathological study of Colombian-infected C3H/He mice, comparing the distribution of CNS-inflammatory infiltrates versus Trypanosoma cruzi antigens. Inflammatory infiltrates were observed during the acute phase, but did not correlate with the presence of detectable T. cruzi antigens. Infiltrates consisted mainly of CD8+ lymphocytes, although macrophages and a few CD4+ cells were observed. In the chronic stage of infection, although neuropathies were a common finding, only mild inflammatory infiltrates could be detected. Our results suggest that the presence of CNS inflammatory infiltrates is not directly related to the presence of parasite antigens and indicate that, different from chronic myocarditis, encephalitis resolves during the acute phase of Chagas' disease.

Expression of extracellular matrix components and their receptors in the central nervous system during experimental Toxoplasma gondii and Trypanosoma cruzi infection.

Alterations in extracellular matrix (ECM) expression in the central nervous system (CNS) usually associated with inflammatory lesions have been described in several pathological situations including neuroblastoma and demyelinating diseases. The participation of fibronectin (FN) and its receptor, the VLA-4 molecule, in the migration of inflammatory cells into the CNS has been proposed. In Trypanosoma cruzi infection encephalitis occurs during the acute phase, whereas in Toxoplasma infection encephalitis is a chronic persisting process. In immunocompromised individuals such as AIDS patients. T. cruzi or T. gondii infection can lead to severe CNS damage. At the moment, there are no data available regarding the molecules involved in the entrance of inflammatory cells into the CNS during parasitic encephalitis. Herein, we characterized the expression of the ECM components FN and laminin (LN) and their receptors in the CNS of T. gondii- and T. cruzi-infected mice. An increased expression of FN and LN was detected in the meninges, leptomeninges, choroid plexus and basal lamina of blood vessels. A fine FN network was observed involving T. gondii-free and T. gondii-containing inflammatory infiltrates. Moreover, perivascular spaces presenting a FN-containing filamentous network filled with alpha 4+ and alpha 5+ cells were observed. Although an increased expression of LN was detected in the basal lamina of blood vessels, the CNS inflammatory cells were alpha 6-negative. Taken together, our results suggest that FN and its receptors VLA-4 and VLA-5 might be involved in the entrance, migration and retention of inflammatory cells into the CNS during parasitic infections.

Expression of extracellular matrix components and their receptors in the central nervous system during experimental Toxoplasma gondii and Trypanosoma cruzi infection

Alterations in extracellular matrix (ECM) expression in the central nervous system (CNS) usually associated with inflammatory lesions have been described in several pathological situations including neuroblastoma and demyelinating diseases. The participation of fibronectin (FN) and its receptor, the VLA-4 molecule, in the migration of inflammatory cells into the CNS has been proposed. In Trypanosoma cruzi infection encephalitis occurs during the acute phase, whereas in Toxoplasma infection encephalitis is a chronic persisting process. In immunocompromised individuals such as AIDS patients, T. cruzi or T. gondii infection can lead to severe CNS damage. At the moment, there are no data available regarding the molecules involved in the entrance of inflammatory cells into the CNS during parasitic encephalitis. Herein, we characterized the expression of the ECM components FN and laminin (LN) and their receptors in the CNS of T. gondii- and T. cruzi-infected mice. An increased expression of FN and LN was detected in the meninges, leptomeninges, choroid plexus and basal lamina of blood vessels. A fine FN network was observed involving T. gondii-free and T. gondii-containing inflammatory infiltrates. Moreover, perivascular spaces presenting a FN-containing filamentous network filled with Alpha 4+ and Alpha 5+ cells were observed. Although an increased expression of LN was detected in the basal lamina of blood vessels, the CNS inflammatory cells were alpha 6-negative. Taken together, our results suggest that FN and its receptors VLA-4 and VLA-5 might be involved in the entrance, migration and retention of inflammatory cells into the CNS during parasitic infections

First line treatment with omeprazole provides an effective and superior alternative strategy in the management of dyspepsia compared to antacid/alginate liquid: a multicentre study in general practice.

BACKGROUND: Many patients who present with dyspepsia are prescribed antacid/alginates as their first line and often mainstay therapy. This multicentre study was designed to assess whether early introduction of acid inhibition is an effective strategy in dyspepsia management. METHODS: Dyspeptic patients (n = 674) were randomized to receive either omeprazole 10 mg o.m. or antacid/alginate liquid 10 mL q.d.s. for 4 weeks in an open, parallel group study. RESULTS: Complete relief of the most common symptom at entry, heartburn, was greater in the omeprazole-treated group compared with the antacid/alginate-treated group (64 vs. 30%, respectively, at 4 weeks; P < 0.0001). The percentage of patients who met the stringent health target of complete relief of overall symptoms was higher in the omeprazole-treated group (41% at 4 weeks) compared with the antacid/alginate group (16% at 4 weeks; P < 0.0001). Comparisons of quality of life scores between treatments favoured the omeprazole group at 2 and 4 weeks for both the Psychological General Well-Being Index and the Gastrointestinal Symptom Rating Scale (each P < or = 0.0009). In addition, a greater proportion of patients rated omeprazole to be more effective in symptom relief and more convenient to use (each P = 0.0001) than antacid/alginate. CONCLUSION: This study demonstrates that, compared to antacid/alginate liquid 10 mL q.d.s., omeprazole 10 mg o.m. is more effective in the management of dyspepsia symptoms and is the patients' preferred treatment.