CXCL-16, IL-17, and bone morphogenetic protein 2 (BMP-2) are associated with overweight and obesity conditions in middle-aged and elderly women.

BACKGROUND: The current concept of overweight/obesity is most likely related to a combination of increased caloric intake and decreased energy expenditure. Widespread inflammation, associated with both conditions, appears to contribute to the development of some obesity-related comorbidities. Interventions that directly or indirectly target individuals at high risk of developing obesity have been largely proposed because of the increasing number of overweight/obese cases worldwide. The aim of the present study was to assess CXCL16, IL-17, and BMP-2 plasma factors in middle-aged and elderly women and relate them to an overweight or obese status. In total, 117 women were selected and grouped as eutrophic, overweight, and obese, according to anthropometric parameters. Analyses of anthropometric and circulating biochemical parameters were followed by plasma immunoassays for CXCL-16, IL-17, and BMP-2. RESULTS: Plasma mediators increased in all overweight and obese individuals, with the exception of BMP-2 in the elderly group, whereas CXCL16 levels were shown to differentiate overweight and obese individuals. Overweight and/or obese middle-aged and elderly individuals presented with high LDL, triglycerides, and glycemia levels. Anthropometric parameters indicating increased-cardiovascular risk were positively correlated with CXCL-16, BMP-2, and IL-17 levels in overweight and obese middle-aged and elderly individuals. CONCLUSION: This study provides evidence that CXCL-16, IL-17, and BMP-2 are potential plasma indicators of inflammatory status in middle-aged and elderly women; therefore, further investigation of obesity-related comorbidities is recommended. CXCL16, in particular, could be a potential marker for middle-aged and elderly individuals transitioning from eutrophic to overweight body types, which represents an asymptomatic and dangerous condition.

Characterization of the presence and distribution of Foxp3(+) cells in chagasic patients with and without megacolon.

Patients with Chagas's disease in the chronic phase regularly present with the chagasic megacolon. This form is characterized by inflammation, neuronal destruction, and organ dilatation. Chagasic patients with megacolon always present with inflammatory process near the enteric plexuses of the colon, as previously demonstrated. The aim of this study is to characterize the presence and distribution of Foxp3(+) cells in the muscle layers and neuronal plexuses area of the colon from chagasic patients with and without megacolon. Our results demonstrated that chagasic patients without megacolon presented with an increased concentration of Foxp3(+) cells in all colon layers compared with chagasic patients with megacolon and noninfected individuals. These cells were situated mainly near the blood vessels and rarely were associated with the inflammatory foci. We believe that the presence of Foxp3(+) cells may help to control the inflammatory process through the management of lymphocyte migration and, consequently, prevent neuronal destruction and chagasic megacolon development.

Potential role of CD4+CD25HIGH regulatory T cells in morbidity in Chagas disease.

Several immunoregulatory mechanisms are proposed to be effective both in human and experimental Trypanosoma cruzi infection. However, the role of CD4+CD25high T cells in Chagas disease has not yet been elucidated. These cells are critical for the regulation of immune response to infectious agents and in the control of autoimmune diseases. In this study, the presence of CD4+CD25high regulatory T cells in the whole blood of non-infected individuals (NI), and patients with the indeterminate (IND) and cardiac form (CARD) of Chagas disease was evaluated. To further characterize this population of regulatory cells, the co-expression of CTLA-4, CD62L, CD45RO, CD45RA, HLA-DR, CD40L, CD69, CD54, IL-10R and the intracellular molecules FOXP3 and IL-10 on the CD4+CD25high T lymphocytes was examined. FOXP3 was expressed by the majority of CD4+CD25high when compared with the other CD4+ T cells subsets in patients with Chagas disease. Patients with the IND form of the disease had a higher frequency of circulating regulatory CD4+CD25high T cells than patients with the CARD form. Moreover, there was an increase in CD4+CD25highFOXP3+ cells that were also IL-10+ in the IND group whereas, in the CARD group, there was an increase in the percentage of CD4+CD25high FOXP3+ cells that expressed CTLA-4. These data suggest that IL-10 produced by regulatory T cells is effective in controlling disease development in patients with the IND form. However, in individuals with the CARD form of the disease, the same regulatory mechanism, mediated by IL-10 and CTLA-4 expression is not sufficient to control the progression of the disease. The data suggest that CD4+CD25highFOXP3+ regulatory T cells in patients with Chagas disease might play a role in the immune response against T. cruzi infection although with distinct effects in patients with the IND and CARD forms of disease.

Plasma cytokine expression is associated with cardiac morbidity in chagas disease.

The expression of immune response appears to be associated with morbidity in Chagas disease. However, the studies in this field have usually employed small samples of patients and statistical analyses that do not consider the wide dispersion of cytokine production observed in these patients. The aim of this study was to evaluate the plasma cytokine levels in well-defined clinical polar groups of chagasic patients divided into categories that better reflect the wide cytokine profile and its relationship with morbidity. Patients infected with Trypanosoma cruzi (T. cruzi) were grouped as indeterminate (IND) and cardiac (CARD) forms ranging from 23 to 69 years of age (mean of 45.6±11.25). The IND group included 82 individuals, ranging from 24 to 66 years of age (mean of 39.6±10.3). The CARD group included 94 patients ranging from 23 to 69 years of age (mean of 48±12.52) presenting dilated cardiomyopathy. None of the patients have undergone chemotherapeutic treatment, nor had been previously treated for T. cruzi infection. Healthy non-chagasic individuals, ranging from 29 to 55 years of age (mean of 42.6±8.8) were included as a control group (NI). IND patients have a higher intensity of interleukin 10 (IL-10) expression when compared with individuals in the other groups. By contrast, inflammatory cytokine expression, such as interferon gamma (IFN-γ), tumor necrosis factor alpha (TNF-α), interleukin 6 (IL-6), and interleukin 1 beta (IL-1ß), proved to be the highest in the CARD group. Correlation analysis showed that higher IL-10 expression was associated with better cardiac function, as determined by left ventricular ejection fraction and left ventricular diastolic diameter values. Altogether, these findings reinforce the concept that a fine balance between regulatory and inflammatory cytokines represents a key element in the establishment of distinct forms of chronic Chagas disease.

Inflammatory mediators from monocytes down-regulate cellular proliferation and enhance cytokines production in patients with polar clinical forms of Chagas disease.

Exposure to Trypanosoma cruzi parasites induces monocytes and macrophages to produce various endogenous mediators, including prostaglandins and cytokines. To clarify the involvement of monocytes as an important source of inflammatory mediators in Chagas disease patients, we evaluated PBMC before and after depletion of adherent cells (monocytes) from patients with indeterminate (IND) and cardiac (CARD) clinical forms and from non-infected individuals (NI). We demonstrated that after the partial depletion of adherent cells, production of PGE2 was slightly decreased in patients with Chagas disease. Inhibition of the cells by indomethacin increased the proliferation in PBMC cells from patients after antigen stimulation. Pro-inflammatory cytokines as IL-2 and IFN-γ also had a greater decrease after partial depletion of adherent cells in both clinical forms of Chagas disease. IL-10 and IL-5 levels were also reduced after partial depletion of adherent cells both in IND and CARD patients. In addition, we evaluated the APC potential of B cells and observed that the MHCII and CD80 molecules had an increased expression after partial depletion of most monocytes in all groups. Thus, inflammatory mediators produced by monocytes seem to be important to modulate immune responses in Chagas disease by regulating the processes of inflammation and antigen presentation.

Plasmodium vivax: induction of CD4+CD25+FoxP3+ regulatory T cells during infection are directly associated with level of circulating parasites.

Circulation CD4(+)CD25(+)FoxP3(+) regulatory T cells (Tregs) have been associated with the delicate balancing between control of overwhelming acute malaria infection and prevention of immune pathology due to disproportionate inflammatory responses to erythrocytic stage of the parasite. While the role of Tregs has been well-documented in murine models and P. falciparum infection, the phenotype and function of Tregs in P. vivax infection is still poorly characterized. In the current study, we demonstrated that patients with acute P. vivax infection presented a significant augmentation of circulating Tregs producing anti-inflammatory (IL-10 and TGF-beta) as well as pro-inflammatory (IFN-gamma, IL-17) cytokines, which was further positively correlated with parasite burden. Surface expression of GITR molecule and intracellular expression of CTLA-4 were significantly upregulated in Tregs from infected donors, presenting also a positive association between either absolute numbers of CD4(+)CD25(+)FoxP3(+)GITR(+) or CD4(+)CD25(+)FoxP3(+)CTLA-4(+) and parasite load. Finally, we demonstrate a suppressive effect of Treg cells in specific T cell proliferative responses of P. vivax infected subjects after antigen stimulation with Pv-AMA-1. Our findings indicate that malaria vivax infection lead to an increased number of activated Treg cells that are highly associated with parasite load, which probably exert an important contribution to the modulation of immune responses during P. vivax infection.

Profile of central and effector memory T cells in the progression of chronic human chagas disease.

BACKGROUND: Chronic Chagas disease presents several different clinical manifestations ranging from asymptomatic to severe cardiac and/or digestive clinical forms. Several studies have demonstrated that immunoregulatory mechanisms are important processes for the control of the intense immune activity observed in the chronic phase. T cells play a critical role in parasite specific and non-specific immune response elicited by the host against Trypanosoma cruzi. Specifically, memory T cells, which are basically classified as central and effector memory cells, might have a distinct migratory activity, role and function during the human Chagas disease. METHODOLOGY/PRINCIPAL FINDINGS: Based on the hypothesis that the disease severity in humans is correlated to the quality of immune responses against T. cruzi, we evaluated the memory profile of peripheral CD4(+) and CD8(+) T lymphocytes as well as its cytokine secretion before and after in vitro antigenic stimulation. We evaluated cellular response from non-infected individuals (NI), patients with indeterminate (IND) or cardiac (CARD) clinical forms of Chagas disease. The expression of CD45RA, CD45RO and CCR7 surface molecules was determined on CD4(+) and CD8(+) T lymphocytes; the pattern of intracellular cytokines (IFN-gamma, IL-10) synthesized by naive and memory cells was determined by flow cytometry. Our results revealed that IND and CARD patients have relatively lower percentages of naive (CD45RA(high)) CD4(+) and CD8(+) T cells. However, statistical analysis of ex-vivo profiles of CD4(+) T cells showed that IND have lower percentage of CD45RA(high) in relation to non-infected individuals, but not in relation to CARD. Elevated percentages of memory (CD45RO(high)) CD4(+) T cells were also demonstrated in infected individuals, although statistically significant differences were only observed between IND and NI groups. Furthermore, when we analyzed the profile of secreted cytokines, we observed that CARD patients presented a significantly higher percentage of CD8(+)CD45RA(high) IFN-gamma-producing cells in control cultures and after antigen pulsing with soluble epimastigote antigens. CONCLUSIONS: Based on a correlation between the frequency of IFN-gamma producing CD8+ T cells in the T cell memory compartment and the chronic chagasic myocarditis, we propose that memory T cells can be involved in the induction of the development of the severe clinical forms of the Chagas disease by mechanisms modulated by IFN-gamma. Furthermore, we showed that individuals from IND group presented more T(CM) CD4(+) T cells, which may induce a regulatory mechanism to protect the host against the exacerbated inflammatory response elicited by the infection.