Influência do metabolismo do ATP extracelular na sinalização purinérgica em linfócitos e plaquetas de pacientes com a forma indeterminada da doença de chagas

Abstract

Trypanosoma cruzi infection causes Chagas disease (CD), a chronic inflammatory disease. The most infected individuals present no apparent morbidity, consistent with the indeterminate form of Chagas disease (IFCD). Although parasite-related factors may influence the clinical progress of disease, factors such as immune and inflammatory responses of host have a fundamental participation in the dynamic of pathology. The cellular immune response is closely associated with the presence of a tissue inflammatory infiltrate, which is composed by mononuclear cells that proliferate and produce pro- and anti-inflammatory cytokines. The inflammatory reaction triggered by T. cruzi infection is maintained by persistence of parasite in the host, and produces systemic effects, including microvascular changes. The puricergic signaling system plays an important role in the modulatiib of immune and inflammatory responses as well as vascular thrombosis by adenine nucleotides (ATP, ADP and AMP) and their derivative nucleoside adenosine. These signaling molecules are released from cells such as lymphocytes and platelets in response to damage or cell stimulation by the action of pathogens. The effects of adenine nucleotides and adenosine are promoted through the agonism of specific purinergic receptors and controlled by an enzymatic complex located on the cell surface. The aim of this study was to evaluate the influence of purinergic signaling in the regulation of microvascular dysfunction triggered by infection and in the adaptive immune response induced by the host through ectoenzymes activities involved in the metabolism of ATP in lymphocytes and platelets of patients IFCD. It was observed a decrease in both E-NTPDase and E-ADA activities, representing an adaptive consequence of host to a low antigenic stimulation during the latent phase of disease. Therefore, low concentrations of extracellular ATP would lead the induction of a Th2 response that would protect the host from an intense Th1 response, while high concentrations of extracellular adenosine would be responsible for anti-inflammatory and immunosuppressive effects. It was not observed any change in E-NTPDase expression when compared with the control group, demonstrating that its decreased activity may be a result of some tridimencional alteration of the enzyme itself. In platelets of IFCD patients, there was an increase in E-NPP and E-5 -NT activities and a decrease in E-ADA activity, which could be related to tromboregulatory effects by nucleotides degradation as well as formation and preservation of extracellular adenosine levels, in view of its vasodilator and cardioprotective roles. The decreased platelet aggregation observed in IFCD patients probably occurred due to antiaggregating action of adenosine. In conclusion, the purinergic system ectoenzymes, which are responsible for ATP metabolism, contribute in tromborregulation and modulation of host immune responses during the indeterminate form of the disease.