Role of Trypanosoma cruzi Autoreactive T Cells in the Generation of Cardiac Pathology

Abstract

Chagas disease, caused by Trypanosoma cruzi, affects several million people in Central and South America. About 30% of chronic patients develop cardiomyopathy probably caused by parasite persistence and/or autoimmunity. While several cross-reactive antibodies generated during mammal T. cruzi infection have been described, very few cross-reactive T cells have been identified. We performed adoptive transfer experiments of T cells isolated from chronically infected mice. The results showed the generation of cardiac pathology in the absence of parasites. We also transferred cross-reactive SAPA-specific T cells and observed unspecific alterations in heart repolarization, cardiac inflammatory infiltration, and tissue damage.

Pathogenesis of Chagas' Disease: Parasite Persistence and Autoimmunity

“…On the one hand, active immunization with a parasitic subcellular antigen produces discrete inflammatory lesions (416), but a documentation of clinical manifestations and cardiomegaly has not been not obtained (Table 4). On the other hand, the passive transfer of immunocompetent donor cells renders small, focal lymphocytic infiltrates in the heart of the syngeneic recipient but no gross lesion (152,153). Furthermore, reports showing the passive transfer of autoimmune heart lesions are consistently challenged because parasite persistence among donor immune system cells from chagasic patients has not been ruled out.…”

“…On the other hand, multiple genes that regulate the host's susceptibility and resistance to T. cruzi may not be involved directly in autoimmunity (311,332). Thus, whether inflammatory infiltrates are driven by a T. cruzi antigen or by antigen-independent autoimmunity remains controversial (152,227). Moreover, the treatment of infections with a trypanocidal drug reduces cardiac myosin-specific delayed-type reactions and antibody production, but the curtailment of the T. cruzi infection does not diminish the prospects for autoimmunity in Chagas' disease (182,183).…”

“…The microscopic examination of the tissues revealed small, focal inflammatory infiltrates in the heart of the immunized rabbit. The results suggest that crossreactive antigens in the heart may induce inconspicuous lymphocytic infiltrates, because the immunization of rabbits with (152). The production of lesions in the absence of active T. cruzi infection in mice immunized with cross-reacting shed acutephase antigen (SAPA), a parasite acute-phase immunodominant antigen emulsified with CFA, was attempted, but tissue damage remained unclear because target heart cell lysis and the gross cardiomyopathy of Chagas' disease were not demonstrated (152).…”

“…Second, the gross lesions typical of Chagas' disease were not produced (40,199 (73,209). One such mechanism is molecular mimicry, a situation in which an antigen-specific T or B cell's anti-self response can be initiated in the presence of a pathogen (83,132,152,153). Accordingly, a cross-reaction of parasite antigen-stimulated immunocompetent cells against a self-protein with putative similar amino acid motifs or threedimensional epitopes is required to trigger the rejection of a self-tissue.…”

“…However, the clinical and pathological manifestations of the disease have not been obtained by conventional immunizations with wild or with recombinant T. cruzi antigens (386), and therefore, the origin of the autoimmunity in Chagas' disease is unresolved. This explains the necessity to reproduce experimentally the clinical and pathological gross lesions and the microscopic rejection of the target cells in in vivo myocarditis in a parasite-free model system, which cannot be obtained by the injection of antigens into laboratory animals (40,119,152,311,324,344,400,401,417). Within this context, the challenge is to demonstrate that LkDT and VkDT are triggers of the genetically driven autoimmune inflammatory cardiomyopathy in human Chagas' disease.…”