Trypanosoma cruzi: Immune Response and Functional Heart Damage Induced in Mice by the Main Linear B-Cell Epitope of Parasite Ribosomal P Proteins

Motrán, Claudia Cristina; Cerbán, Fabio M.; Rivarola, Walter; Iosa, Daniel; Cima, Elsa Vottero de

doi:10.1006/expr.1998.4255

Cited by 21 publications

(17 citation statements)

References 35 publications

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“…In parallel with this humoral response, electrocardiographic changes such as prolonged PQ and QRS segments and intraventricular conduction disturbances, which are typical findings in Chagas' disease patients, were observed in all R13-immunized mice. In addition to the anti-R13 response, the sera from the immunized mice contained autoantibodies able to bind to mouse and human 38-kDa heart antigen (14). This antigen would be a P0, the largest protein from the P family, which has an apparent molecular mass of 38 kDa, in agreement with the results obtained by Hines et al (11), who described antibodies against ribosomal 38-kDa antigen by assaying the immunization with Artemia salina ribosomes.…”

Section: Introductionsupporting

confidence: 71%

“…Previously, we showed that the immunization of BALB/c mice with R13 coupled to a carrier protein (OVA) was able to induce specific and anti-heart reactive antibodies as well as to generate heart functional alterations (14). These anti-R13 antibodies, unlike spontaneous anti-P autoantibodies occurring in SLE, were directed toward the region of the R13 peptide which contains the amino acid substitution (EE-EDDD).…”

Section: Introductionmentioning

confidence: 98%

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Characterization of Autoantibodies Generated in Mice by Immunization with the C-Terminal Region ofTrypanosoma cruziRibosomal P1 and P2 Proteins

Motrán

Cerbán

Rivarola

et al. 1999

Clinical Immunology

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Section: Introductionsupporting

confidence: 71%

Section: Introductionmentioning

confidence: 98%

Characterization of Autoantibodies Generated in Mice by Immunization with the C-Terminal Region ofTrypanosoma cruziRibosomal P1 and P2 Proteins

Motrán

Cerbán

Rivarola

et al. 1999

Clinical Immunology

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“…3B). The size of this antigen is different from the sizes of other published cross-reactive antigens, including B13 (8), ribosomal proteins (12,29), Cha (15), cruzipain (13), and Fl-160 (41). We have attempted to do searches for A/J mouse alpha heavychain cardiac myosin homologs in T. cruzi DB but have found only unknown-clone sequences with low scores (smallest sum probability, Ͻ10 Ϫ7 ).…”

Section: Discussionmentioning

confidence: 69%

A Cardiac Myosin-Specific Autoimmune Response Is Induced by Immunization withTrypanosoma cruziProteins

et al. 2004

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Trypanosoma cruzi is the protozoan parasite that causes Chagas' heart disease, a potentially fatal cardiomyopathy prevalent in Central and South America. Infection with T. cruzi induces cardiac myosin autoimmunity in susceptible humans and mice, and this autoimmunity has been suggested to contribute to cardiac inflammation. To address how T. cruzi induces cardiac myosin autoimmunity, we investigated whether immunity to T. cruzi antigens could induce cardiac myosin-specific autoimmunity in the absence of live parasites. We immunized A/J mice with a T. cruzi Brazil-derived protein extract emulsified in complete Freund's adjuvant and found that these mice developed cardiac myosin-specific delayed-type hypersensitivity (DTH) and autoantibodies in the absence of detectable cardiac damage. The induction of autoimmunity was specific since immunization with extracts of the related protozoan parasite Leishmania amazonensis did not induce myosin autoimmunity. The immunogenetic makeup of the host was important for this response, since C57BL/6 mice did not develop cardiac myosin DTH upon immunization with T. cruzi extract. Perhaps more interesting, mice immunized with cardiac myosin developed T. cruzi-specific DTH and antibodies. This DTH was also antigen specific, since immunization with skeletal myosin and myoglobin did not induce T. cruzi-specific immunity. These results suggest that immunization with cardiac myosin or T. cruzi antigen can induce specific, bidirectionally cross-reactive immune responses in the absence of detectable cardiac damage.Trypanosoma cruzi is the protozoan parasite that causes Chagas' heart disease (CHD), a potentially fatal cardiomyopathy resulting in dilated tissue. Approximately 16 million people are infected with this protozoan parasite, and 120 million are at risk of infection in Central and South America (28). CHD develops in roughly one-third of T. cruzi-infected individuals as an acute or chronic myocarditis of variable degree (reviewed in reference 39). Among the various mechanisms invoked to explain the pathogenesis of CHD, autoimmunity is one that both has been supported by much experimental evidence and has received much criticism. There is no doubt that autoimmunity results from chronic T. cruzi infection of humans and experimental animals. The questions are (i) whether this autoimmunity is pathogenic and (ii) by what mechanism(s) autoimmunity is induced. The debate surrounding this issue is long-standing (reviewed in references 17, 22, 39, and 40).T. cruzi infection induces humoral and cellular autoimmunity to a diverse set of autoantigens (reviewed in references 17 and 22), including cardiac myosin. Myosin-specific autoimmunity is induced in both humans (8) and experimental models (24) upon T. cruzi infection. In previous work (24), it was found that within weeks of infection, A/J mice acutely infected with T. cruzi developed severe myocarditis accompanied by myosinspecific delayed-type hypersensitivity (DTH) and antibody production. Autoimmunity to cardiac myosin has also been rep...

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“…In mice immunized with recombinant TcP2␤, only antibodies from mice recognizing the C terminus are able to exert a chronotropic effect on spontaneously beating neonatal myocytes. This may be correlated with electrocardiogram modifications that occur after immunization with recombinant maltose-binding protein fusion TcP2␤ or R-13 coupled to bovine albumin or egg albumin as previously described (19,28) and with the presence of antiadrenoreceptor autoantibodies in chagasic cardiomyopathy. A monoclonal antibody specific for the TcP2␤ C terminus is currently under investigation to determine the fine specificity of the epitope and its role after in vivo transfer.…”

Section: Discussionmentioning

confidence: 69%

Modulation of Cardiocyte Functional Activity by Antibodies againstTrypanosoma cruziRibosomal P2 Protein C Terminus

et al. 2000

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Antibodies against the Trypanosoma cruzi ribosomal P2␤ protein (TcP2␤) have been associated with the chronic cardiac pathology of Chagas' disease in humans. Using synthetic peptides spanning the entire TcP2␤ molecule, we investigated their epitope recognition by antibodies from mice chronically infected with T. cruzi and from mice immunized with two recombinant TcP2␤s. We found clear differences in epitope recognition between antibodies from T. cruzi-infected mice and mice immunized with two different recombinant TcP2␤s associated with different schedules of immunization. Major epitopes recognized by antibodies from mice immunized with recombinant glutathione S-transferase (GST) or histidine (Hist) fusion TcP2␤ (GST-TcP2␤ or HistTcP2␤) are located in the central and hinge regions of the molecule. Nevertheless, mice immunized with Hist-TcP2␤ were also able to elicit antibodies against the TcP2␤ C terminus, a region which is highly conserved in both T. cruzi and mammal ribosomal P proteins. Strikingly, antibodies from infected animals recognized only the TcP2␤ C terminus. By using these antisera with distinct profiles of epitope recognition, it could be shown that only C terminus-specific antibodies were able to increase the beating frequency of cardiomyocytes from neonatal rats in vitro by selective stimulation of the ␤1-adrenergic receptor. Thus, antibodies against the TcP2␤ C terminus elicited in the absence of infection are able to modulate a functional activity of host cells through a molecular mimicry mechanism.

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Trypanosoma cruzi: Immune Response and Functional Heart Damage Induced in Mice by the Main Linear B-Cell Epitope of Parasite Ribosomal P Proteins

Cited by 21 publications

References 35 publications

Characterization of Autoantibodies Generated in Mice by Immunization with the C-Terminal Region ofTrypanosoma cruziRibosomal P1 and P2 Proteins

Characterization of Autoantibodies Generated in Mice by Immunization with the C-Terminal Region ofTrypanosoma cruziRibosomal P1 and P2 Proteins

A Cardiac Myosin-Specific Autoimmune Response Is Induced by Immunization withTrypanosoma cruziProteins

Modulation of Cardiocyte Functional Activity by Antibodies againstTrypanosoma cruziRibosomal P2 Protein C Terminus

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