Antibodies to ribosomal P proteins ofTrypanosoma cruziin Chagas disease possess functional autoreactivity with heart tissue and differ from anti-P autoantibodies in lupus

Abstract

Anti-P antibodies present in sera from patients with chronic Chagas heart disease (cChHD) recognize peptide R13, EEEDDDMGFGLFD, which encompasses the C-terminal region of the Trypanosoma cruzi ribosomal P1 and P2 proteins. This peptide shares homology with the Cterminal region (peptide H13 EESDDDMGFGLFD) of the human ribosomal P proteins, which is in turn the target of anti-P autoantibodies in systemic lupus erythematosus (SLE), and with the acidic epitope, AESDE, of the second extracellular loop of the ␤ 1 -adrenergic receptor. Anti-P antibodies from chagasic patients showed a marked preference for recombinant parasite ribosomal P proteins and peptides, whereas anti-P autoantibodies from SLE reacted with human and parasite ribosomal P proteins and peptides to the same extent. A semi-quantitative estimation of the binding of cChHD anti-P antibodies to R13 and H13 using biosensor technology indicated that the average affinity constant was about 5 times higher for R13 than for H13. Competitive enzyme immunoassays demonstrated that cChHD anti-P antibodies bind to the acidic portions of peptide H13, as well as to peptide H26R, encompassing the second extracellular loop of the ␤ 1 adrenoreceptor. Anti-P antibodies isolated from cChHD patients exert a positive chronotropic effect in vitro on cardiomyocytes from neonatal rats, which resembles closely that of anti-␤ 1 receptor antibodies isolated from the same patient. In contrast, SLE anti-P autoantibodies have no functional effect. Our results suggest that the adrenergicstimulating activity of anti-P antibodies may be implicated in the induction of functional myocardial impairments observed in cChHD.

Parasitological cure of Chagas disease: is it possible? Is it relevant?

“…2 -Current knowledge seems to indicate that eradication of T. cruzi from infected human patients and animals may be prerequisite to arrest the evolution of the disease and to avert its irreversible long-term consequences (Andrade et al 1991, 1996, Viotti et al 1994, Docampo & Schmuñis 1997, Kaplan et al 1997, Andrade & Zicker 1997, Urbina 1999. Thus, specific chemotherapeutic approaches should play an essential role in the successful clinical outcome of this parasitic disease.…”

“…Moreover, several lines of evidence show that some of the antibodies previously implicated in Chagas disease pathogenesis (Cunha-Neto et al 1995) could be more a consequence than a cause of tissue lesions (Levin 1996). Antibodies against the parasite's ribosomal P proteins cross-react with the host's ribosomal P proteins but also with the cardiac β 1 receptor (Rosenbaum et al 1994, Kaplan et al 1997) and have been implicated in chagasic cardiomyopathy (Rosenbaum et al 1994); however, it has recently been shown that these antibodies differ from classical auto-antibodies present in diseases such as lupus erythematosus, being specific for the parasite's antigens and having low affinity for the human antigens (Kaplan et al 1997).…”

The pathogenesis of Chagas' disease: when autoimmune and parasite-specific immune responses meet

“…The production of autoantibodies against beta1 and beta2-adrenoreceptors correlated with primary electrical cardiac abnormalities (Chiale et al 1995). It was also demonstrated that sera from chronic chagasic individuals interfere with electric and mechanical activities of embryonic myocardial cells in vitro (Costa et al 2000, Kaplan et al 1997 and affect cardiac electrogenesis and conduction when perfused in the rabbit heart (de Oliveira et al 1997). These alterations in heart-cell function seem to result from the binding of antibodies to β-adrenergic and M2-cholinergic receptors on the myocardial cell surface (Costa et al 2000, de Oliveira et al 1997, Kaplan et al 1997.…”

“…It was also demonstrated that sera from chronic chagasic individuals interfere with electric and mechanical activities of embryonic myocardial cells in vitro (Costa et al 2000, Kaplan et al 1997 and affect cardiac electrogenesis and conduction when perfused in the rabbit heart (de Oliveira et al 1997). These alterations in heart-cell function seem to result from the binding of antibodies to β-adrenergic and M2-cholinergic receptors on the myocardial cell surface (Costa et al 2000, de Oliveira et al 1997, Kaplan et al 1997. Thus, by stimulating the production of autoantibodies against certain self-antigens, T. cruzi infection may cause disturbances in heart cell functions, which may lead to complications associated with CChC.…”

Prevalencia de autoanticuerpos contra receptores autonómicos en pacientes panameños con cardiopatía chagásica crónica y con otras formas de cardiopatía

“…Se postula que estos autoanticuerpos podrían generarse como consecuencia del mimetismo molecular que ocurre durante la infección con T. cruzi. Al respecto, se ha observado que las regiones C terminales de las proteínas ribosómica de T. cruzi pueden interactuar con los epítopos presentes tanto en los receptores betaadrenérgicos como en los muscarínicos (16)(17)(18).…”