The role of interleukin 17-mediated immune response in Chagas disease: High level is correlated with better left ventricular function

Abstract

Interleukin 17A (IL-17A) has been associated with protective rather than pathogenic response in Chagas disease (ChD). However, it is not established whether or not IL-17A-mediated immune response is correlated with patient’s left ventricular (LV) function in ChD. To address this question we have gathered cardiac functional parameters from ChD patients and analysed the possible relationship between their plasma IL-17A levels and LV function. Plasma IL-17A levels were measured by BD Cytometric Bead Array (CBA) in 240 patients with positive specific serology for Trypanosoma cruzi (T. cruzi) grouped as indeterminate (IND) and Chagas cardiomyopathy (CARD) forms. The levels of IL-17A in ChD patients were compared with 32 healthy individuals, mean age of 39 years, 50% male, that were also included as a control group (non-infected [NI]). The overall mean age of ChD patients was 46 years and 52% were male. The IND group included 95 asymptomatic patients, with ages ranging from 27 to 69 years (mean of 43 years), and 42.1% of them were male. The CARD group included 145 patients, which 58.6% were male, with ages ranging from 23 to 67 years (mean of 49). The IND group presented substantially higher levels of IL-17A, median of 26.16 (3.66–48.33) as compared to both the CARD group, median of 13.89 (3.87–34.54) (P <0.0001), and the NI group, median of 10.78 (6.23–22.26) (P <0.0001). The data analysis demonstrated that the IND group comprises a significantly greater proportion (P <0.001) of high IL-17A producers (52.6%, 50 of 95 subjects) than do the other groups. A significant direct correlation was verified between IL-17A levels and cardiac function expressed by LV ejection fraction (LVEF), LV diastolic diameter (LVDd), and body surface area (BSA)-indexed LVDd as well as ratio of the early diastolic transmitral flow velocity to early diastolic mitral annular velocity (E/e’) in both groups. We demonstrated that plasma IL-17A levels has an accurate sensitivity and specificity to predict heart failure in serology-positive patients and might be a useful parameter to distinguish patients with or without cardiac impairment. This study indicates a consistent relationship between high expression of IL-17A and better LV in human chronic ChD. Our data raise the possibility that IL-17A plays an important immunomodulatory role in the chronic phase of ChD and might be involved in protection against myocardial damage.

Mucosal Heterologous Prime/Boost Vaccination Induces Polyfunctional Systemic Immunity, Improving Protection Against Trypanosoma cruzi

“…We believe that multifunctional T-cell priming would be a desirable attribute for a T-cell-based vaccine against T. cruzi considering that it involves not only a higher effector function but also a greater long-term memory potential, as single positive cells are associated with terminal effector T lymphocytes (54). Interestingly, monofunctional responses have been observed in T. cruzi chronically infected patients (55) and a higher functionality has been observed in patients with less severe forms of chronic Chagas cardiomyopathy (24,56), as well as in T. cruzi-infected children (55), a stage of life where parasitic cure by drug treatment is possible. In the murine model, the functionality of CTL responses during the chronic phase is essential for controlling parasite burden (57), and improving it through active immunotherapy or drug combination therapy, though challenging, seems an attractive area of research.…”

“…However, there is plenty of data showing the beneficial effect of IL-17 immunity in T. cruzi infection in humans and mice. High levels of this cytokine were detected in patients with better cardiac function in the indeterminate form of the disease (24,25) or after benznidazole treatment (26). Besides, many experimental studies in mice have found a protective effect of IL-17 by inhibiting an otherwise exaggerated proinflammatory response (27), controlling myocarditis (28), promoting CD8 Tcell priming (29), and even showing more protection than Th1 cells (30).…”

Vasoactive intestinal peptide degradation might influence Interleukin-17 expression in cardiac chagasic patients

“…Their results demonstrated that cardiac patients presented a lower intensity of IL-17 expression by total lymphocytes and a lower frequency of circulating T helper 17 cells. Another study evaluating the expression of IL-17 in plasma samples of Chagas patients 15 observed that a significant frequency of indeterminate patients presented high levels of IL-17A, whereas most of the cardiac patients expressed low plasma levels of this cytokine. Thus, the authors have shown that low and high IL-17A producers were observed in both groups.…”

“… 14 , correlating IL-17 expressing cells and cardiac function in chagasic patients, demonstrated that chagasic cardiac patients presented a lower intensity of expression of IL-17 by total lymphocytes and that a higher cellular expression of IL-17 was associated with better cardiac function. Similarly, another study suggests a relationship between high plasma expression of IL-17A and a better cardiac function in chronic human Chagas disease 15 . However, studies relating IL-17 and the best prognosis in Chagas disease fail in explaining the mechanism by which this cytokine would improve cardiac function.…”

New Insights into the Immunobiology of Mononuclear Phagocytic Cells and Their Relevance to the Pathogenesis of Cardiovascular Diseases

“…The fact that the treatment of macrophages with IL-17A plus IFN-γ is more efficient to eliminate the parasite compared with single-cytokine stimulation, might explain the higher mortality ratio in IL23p19KO and IL-17AKO mice even though the Th1 immune response, measured by IFN-γ production and the iNOS expression, is not impaired during the infection in both KO mice ( 52 ). Finally, correlation analysis in Chagas disease patients demonstrates that high IL-17 serum levels are associated with better cardiac function ( 54 – 56 ).…”