Immunoregulatory networks in human Chagas disease

Abstract

Chagas disease, caused by the infection with Trypanosoma cruzi, is endemic in all Latin America. Due to the increase in population migration, Chagas disease has spread worldwide and is now considered a health issue not only in endemic countries. While most chronically infected individuals remain asymptomatic, approximately 30% of the patients develop a potentially deadly cardiomyopathy. The exact mechanisms that underlie the establishment and maintenance of the cardiac pathology are not clear. However, there is consistent evidence that immunoregulatory cytokines are critical for orchestrating the immune response and thus influence disease development or control. While the asymptomatic (indeterminate) form represents a state of balance between the host and the parasite, the establishment of the cardiac form represents the loss of this balance. Analysis of data obtained from several studies has led to the hypothesis that the indeterminate form is associated with an anti-inflammatory cytokine profile, represented by high expression of IL-10, while cardiac form is associated with a high production of IFN-gamma and TNF-alpha in relation to IL-10, leading to an inflammatory profile. Here, we discuss the immunoregulatory events that might influence disease outcome, as well as the mechanisms that influence the establishment of these complex immunoregulatory networks.

Keywords: Chagas disease; Trypanosoma cruzi; cytokines; immunoregulation; neuroendocrine; pathology.

Figure 1

Cytokines play a key role in the orchestration of the immune response: the yin/yang of immunoregulation. This figure depicts the involvement of cytokines, produced by specific cell populations, in the development of Chagas disease. Upon infection, it is important to produce inflammatory cytokines such as IFN-gamma and TNF-alpha, which will activate macrophages to kill the intracellular parasites. However, these cytokines favor the establishment of an inflammatory environment that, if not controlled, may lead to tissue destruction and, thus, the establishment of the cardiac clinical form. On the other hand, if the initial inflammatory environment is controlled by the expression of anti-inflammatory cytokines such as IL-10, this may lead to a balanced response, and the maintenance of the indeterminate clinical form. Several studies have shown that TNF-alpha and IL-10 are mainly produced by monocytes/macrophages, although CD4+ and CD4−CD8−T cells also express these cytokines. IFN-gamma and IL-17 are mainly produced by CD4+ T cells, but CD8+ and CD4−CD8− T cells also express significant percentages of these cytokines. While patients with both clinical forms express inflammatory and anti-inflammatory cytokines, the predominance of an inflammatory environment is observed in cardiac patients, whereas an anti-inflammatory environment is predominantly observed in indeterminate patients.

Figure 2

The crosstalk between the HPA-axis, nervous and immune systems. Neuroendocrine hormones, neuropeptides and cytokines produced by immune and neuroendocrine cells are recognized by common receptors expressed in both systems. The released neuroendocrine mediators act on immune cells influencing their function. In turn, molecules produced and released by immune cells, such as cytokines and neuropeptides, affect the response of neuroendocrine system. VIP and substance P influence the expression of immunoregulatory cytokines. While an increase in VIP and decrease in substance P lead to a modulatory cytokine environment, decrease in VIP and increase in substance P lead to an inflammatory cytokine environment, which are associated with the different clinical forms of Chagas disease.