Chagas’ Disease and the Autoimmunity Hypothesis

Abstract

SUMMARY The notion that the pathology of Chagas’ disease has an autoimmune component was initially based on the finding of circulating antibodies binding heart tissue antigens in patients and mice chronically infected with Trypanosoma cruzi. Later, T lymphocytes reactive with heart or nerve tissue antigens were found in chagasic mice and patients, extending the concept to include cell-mediated immunity. However, there is disagreement about whether the observed immunologic autoreactivities are triggered by T. cruzi epitopes and then affect host tissue antigens by virtue of molecular mimicry or are elicited by host antigens exposed to lymphocytes after tissue damage caused by the parasite. There is also disagreement about the relevance of immunologic autoreactivities to the pathogenesis of Chagas’ disease because of the lack of reproducibility of some key reports supporting the autoimmunity hypothesis, conflicting data from independent laboratories, conclusions invalidated by advances in our understanding of the immunologic mechanisms underlying cell lysis, and, last but not least, a lack of direct, incontrovertible evidence that cross-reacting antibodies or autoreactive cells mediate the typical pathologic changes associated with human Chagas’ disease. The data and views backing and questioning the autoimmunity hypothesis for Chagas’ disease are summarized in this review.

Induction of antibodies reactive to cardiac myosin and development of heart alterations in cruzipain-immunized mice and their offspring

“…Although there is certain controversy about the involvement of the immune response induced by the T. cruzi in the tissue damage [5], there is also evidence supporting it. One question to be elucidated is whether the presence of the parasite is essential to induce cardiac injury or whether the immune response induced by a single parasite antigen may promote heart damage.…”

“…Electrocardiographic alterations such as intraventricular conduction disturbances and sinus bradycardia are the most frequent findings in murine and human Chagas' disease [2][3][4]. Immune mechanisms have been suggested to be involved in the pathogenesis, although other hypotheses have been proposed [5]. In fact, sera from T. cruziinfected mice or humans react to heart or skeletal muscle and other self antigens [5][6][7][8].…”

“…Immune mechanisms have been suggested to be involved in the pathogenesis, although other hypotheses have been proposed [5]. In fact, sera from T. cruziinfected mice or humans react to heart or skeletal muscle and other self antigens [5][6][7][8]. Cell-mediated immune response against the heart and nerve tissue antigens has also been reported as being involved in the pathogenesis of this disease [9,10].…”

Significant association between the skewed natural antibody repertoire ofXid mice and resistance toTrypanosoma cruzi infection

“…Surviving mice enter a chronic phase, and develop a characteristic inflammatory process suggested to have autoimmune component [2][3][4][6][7][8][9]. In most mouse strains, parasite infection induces an extensive polyclonal lymphocyte activation, with a predominantly nonspecific immune response and increased levels of antibodies displaying NAb features [37].…”

“…T. cruzi infection induces an intense polyclonal activation of all lymphocyte classes, with hypergammaglobulinemia and general immunosuppression of responses towards unrelated antigens [2,3]. Several reports suggest that chronic-phase pathology results from autoimmune mechanisms, which in turn may be triggered by the polyclonal lymphocyte activation characteristic of acute infection [1,2,4,5], although a direct causality has, as yet, not been established [6,7]. Molecular mimicry of various host molecules by parasite antigens has been shown [8,9].…”