Autoimmunity in Chronic Chagas Disease: A Road of Multiple Pathways to Cardiomyopathy?

Abstract

Chagas disease (CD), a neglected tropical disease caused by the protozoan Trypanosoma cruzi, affects around six million individuals in Latin America. Currently, CD occurs worldwide, becoming a significant public health concern due to its silent aspect and high morbimortality rate. T. cruzi presents different escape strategies which allow its evasion from the host immune system, enabling its persistence and the establishment of chronic infection which leads to the development of chronic Chagas cardiomyopathy (CCC). The potent immune stimuli generated by T. cruzi persistence may result in tissue damage and inflammatory response. In addition, molecular mimicry between parasites molecules and host proteins may result in cross-reaction with self-molecules and consequently in autoimmune features including autoantibodies and autoreactive cells. Although controversial, there is evidence demonstrating a role for autoimmunity in the clinical progression of CCC. Nevertheless, the exact mechanism underlying the generation of an autoimmune response in human CD progression is unknown. In this review, we summarize the recent findings and hypotheses related to the autoimmune mechanisms involved in the development and progression of CCC.

Keywords: Chagas disease; autoantibodies; autoimmunity; bystander activation; chronic Chagas disease; complement system; mimicry.

Figure 1

Overview on the natural history of CD, development of cardiomyopathy and its autoimmunity pathophysiological mechanisms. (A) Natural history of CD: the acute phase of Trypanosoma cruzi infection is oligosymptomatic and characterized by high parasitemia, which starts to decrease after 4 weeks. During the chronic phase (6–8 weeks), the parasitemia remains low and some patients (30–40%) might develop Chagas-related symptoms, especially cardiomyopathy. The parasite invades and differentiates in cardiomyocytes, leading to a fibrosis condition and consequently dysrhythmia, myocardial thinning, and cardiac hypertrophy. (B) Direct mechanisms associated with the cardiomyocyte damage: myocytolysis (cell lysis after amastigote differentiate into trypomastigote); toxic molecules produced by the parasite; microvascular changes induced by the parasite (cardiac hypoperfusion); disruption of immune regulation mechanisms in B cell (represented by X); constant presence of T. cruzi antigens triggers T cell-mediated damage and DTH process; autoimmunity (represented by the antibodies in the right). (C) Autoimmunity pathways in chronic CD: T. cruzi presents different escape strategies which enable its evasion from CS activation, allowing its entry in phagocytes, persistence, and the establishment of chronic infection which lead to the development of CCC. The potent immune stimuli generated by T. cruzi persistence (here represented by TNF, IFN-γ, ROS, NO, iNOS production by phagocytic cell) may result in tissue damage and inflammatory response through bystander activation and molecular mimicry. Bystander activation is caused by the exposure of both host and parasite intracellular proteins resulting in potent immune stimuli due to the release of self-antigens that induces the production of autoantibodies. Molecular mimicry occurs when there are structural similarities between T. cruzi-specific molecule and host-molecule, triggering T-cell activation. Specific antibodies from B cells can participate in ADCC mechanism on target cells. Neutrophil, eosinophil, and NK cell interact with these antibodies via CD16 (Fc receptor) and release lytic molecules like enzymes, perforins, or TNF on the target cells, independent of the CS. Moreover, CS activation and constant evasion strategies from T. cruzi could damage the host tissues through MAC formation. Abbreviations: CD, Chagas disease; DTH, delayed-type hypersensitivity; CCC, chronic Chagas cardiomyopathy; CP, classical pathway; LP, lectin pathway; AP, alternative pathway; CS, complement system; TNF, tumor necrosis factor; IFN-γ, interferon; ROS, reactive oxygen species; NO, nitric oxide; iNOS, inducible nitric oxide synthase; ADCC, antibody-dependent cell-mediated cytotoxicity; MAC, membrane attack complex; NK, natural killer cell.