Autoimmunity in Chagas disease cardiopathy: biological relevance of a cardiac myosin-specific epitope crossreactive to an immunodominant Trypanosoma cruzi antigen.

Abstract

Heart tissue destruction in chronic Chagas disease cardiopathy (CCC) may be caused by autoimmune recognition of heart tissue by a mononuclear cell infiltrate decades after Trypanosoma cruzi infection. Indirect evidence suggests that there is antigenic crossreactivity between T. cruzi and heart tissue. As there is evidence for immune recognition of cardiac myosin in CCC, we searched for a putative myosin-crossreactive T. cruzi antigen. T. cruzi lysate immunoblots were probed with anti-cardiac myosin heavy chain IgG antibodies (AMA) affinity-purified from CCC or asymptomatic Chagas disease patient-seropositive sera. A 140/116-kDa doublet was predominantly recognized by AMA from CCC sera. Further, recombinant T. cruzi protein B13--whose native protein is also a 140- and 116-kDa double band--was identified by crossreactive AMA. Among 28 sera tested in a dot-blot assay, AMA from 100% of CCC sera but only 14% of the asymptomatic Chagas disease sera recognized B13 protein (P = 2.3 x 10(-6)). Sequence homology to B13 protein was found at positions 8-13 and 1442-1447 of human cardiac myosin heavy chain. Competitive ELISA assays that used the correspondent myosin synthetic peptides to inhibit serum antibody binding to B13 protein identified the heart-specific AAALDK (1442-1447) sequence of human cardiac myosin heavy chain and the homologous AAAGDK B13 sequence as the respective crossreactive epitopes. The recognition of a heart-specific T. cruzi crossreactive epitope, in strong association with the presence of chronic heart lesions, suggests the involvement of crossreactivity between cardiac myosin and B13 in the pathogenesis of CCC.

Ergosterol biosynthesis and drug development for Chagas disease

“…Several studies have implicated autoimmunity as a primary factor leading to the persistent inflammation associated with chronic Chagas disease pathology including chronic Chagas' cardiomyopathy (Cunha-Neto et al 1995, Kalil & Cunha-Neto 1996. This hypothesis was based on the apparent absence of the parasite in the characteristic inflammatory lesions of the heart and gastrointestinal tract coupled with the presence of "anti-self" antibody responses in Chagas disease patients; the latter is postulated to result from molecular mimicry between parasite antigens and a host's cellular components (Cunha-Neto et al 1995, Kalil & Cunha-Neto 1996. According to such a hypothesis, after the parasite triggers the autoimmune response in the host, its persistence does not play a pivotal role in the pathogenesis of the disease, and even successful antiparasitic treatment may not lead to an improvement in the clinical outcome of the patients.…”

“…Although the role of T. cruzi in the pathology and treatment of the acute phase of Chagas disease is widely accepted (Brener & Gazzinelli 1997, Bahia-Oliveira et al 2000, Kirchhoff et al 2004, the parasite's influence on the pathogenesis of chronic Chagas disease has been the subject of controversies for decades (Cunha-Neto et al 1995, Kalil & Cunha-Neto 1996, Tarleton & Zhang 1999, Tarleton 2001.…”

The treatment of Chagas disease patients with nitroderivative is unsatisfactory

“…Furthermore, an effective chemotherapy for the infection is also highly desirable because it would curtail parasitemia in reservoir hosts, thus preventing peridomestic insect-vector dissemination of the infection in endemic areas. Meanwhile, we believe that chemotherapy of T. cruzi infections with nitroderivative compounds should not be recommended because of the observation of results reported by LAURIA-PIRES et al 32 , as follows: 1) severe side effects preclude patients older than 20 years of age from complying with full treatment prescribed by physicians; 2) lack of clinical findings showing a benefit of treatment with nitroderivatives; 3) lymphoproliferative tumors, such as those described in Chagas patients undergoing heart transplant and benznidazole therapy, can be produced experimentally in rabbits and mice upon injection of either nifurtimox or benznidazole at the dose used to treat human Chagas disease patients, and 4) eradication of the infection appears to be required, in view that decreasing parasitemias did not abrogate humoral and cell-mediated immune responses associated with autoimmunity 15 , and pathogenesis in Chagas disease patients, but this result cannot be achieved by administration of nitroderivatives 32 . …”

Chagas disease cardiomyopathy: current concepts of an old disease

“…In particular, antibodies crossreactive with cardiac myosin heavy chain and the T. cruzi protein B13 are more frequent in sera from CCC than in indeterminate Chagas disease patients (CUNHA- NETO et al, 1995). CD4+ T cell clones derived from an endomyocardial biopsy sample taken from a CCC patient crossreactively recognized T. cruzi protein B13 and cardiac myosin, but not actin (CUNHA- .…”