MOLECULAR MIMICRY IN CHAGAS’ DISEASE
Molecular mimicry of host antigens by parasite antigens has been found to gener-ate autoantibodies that are found in chronic T. cruzi infection (See table 12.2). Autoim-mune pathogenesis by molecular mimicry requires breakdown in tolerance of the immune system to self-antigens. A break-down in tolerance could occur in response to chronic T. cruzi infection or because of the polyclonal lymphocyte proliferative response that occurs early after infection. Although many molecular mimicry epit-opes have been described, only a few have been shown to correlate with disease in chronic T. cruzi infection.
For example, high levels of antibod-ies to rodent endocardium, blood vessels, and interstitium (EVI) have been found in the sera of T. cruzi–infected individu-als and the mammalian host and were absorbed by epimastigote antigens, thus demonstrating cross-reactivity. However, these EVI antigens shown to be directed against α-galactose epitopes were spe-cific for murine laminin and not human laminin. Furthermore, anti-EVI antibodies (α-galactose/laminin) or other autoanti-bodies have not been shown to transfer disease to noninfected animals.
Perhaps more interesting (in terms of the organs infected) has been a protein found on the surface of trypomastigotes in asso-ciation with the flagellum, Fl-160. This pro-tein molecularly mimics myenteric plexus and peripheral neurons. These antibodies are found in 30 percent of individuals with chronic Chagas’ disease; yet, they do not appear to correlate with disease activity in these patients. In addition, T-cell responses to this protein have not been seen in indi-viduals with Chagas’ disease, and passive transfer of these immune T-cells was not consistently effective.
Another peptide of interest has been the ribosomal Po protein (R13 peptide), which has been shown to cross-react with a functional protein on human B1-adenergic receptors. Antibodies to this receptor via immunization with the R13 peptide have led to electrocardiographic (ECG) changes in mice that are similar to those seen in chronic Chagas’ carditis but no changes in digestive symptoms have been noted.
Antibodies to an interesting T. cruzi protein called B13 is seen in the sera of all patients with chronic Chagas’ cardio-myopathy and this antibody cross-reacts with human cardiac myosin but in only 17 percent of asymptomatic individu-als. Furthermore, T cells directed to both B13 and myosin have been detected in biopsy specimens from persons with chronic Chagas’ cardiomyopathy. These results suggest that antibody and T cells directed to cardiac myosin may be patho-genic in chronic Chagas’ cardiomyopathy. However, in animal models transfer of anti-body and T cells directed to myosin have not been reported to lead to pathogenic changes. Perhaps the mouse model may not be correct and as in rheumatic fever the introduction of myosin in the Lewis rat may be a better animal model.
Figure 12.8 Relative magnitude of immune response mediators and parasite burden during acute Trypanosoma cruzi infection in the mouse. Adapted with permission from Buckner FS, Van Voorhis WC. Immune response to Trypanosoma cruzi: control of infection and pathogenesis of Chagas’ disease. In: Cunningham MW, Fujinami RS, eds. Effects of Microbes on the Immune System. Philadelphia, PA: Lippincott-Raven Press; 2000:5 69–591.