Antibodies against the carboxyl-terminal end of the Trypanosoma cruzi ribosomal P proteins are pathogenic.
Sera from patients with chronic Chagas heart disease recognize the carboxyl-terminal regions of the Trypanosoma cruzi ribosomal P proteins defined by B cell epitopes P013 (EDDDDDFGMGALF) and R13 (EEEDDDMGFGLFD) corresponding to the T. cruzi ribosomal P0 (TcP0) and P2beta (TcP2beta) proteins, respectively. It has been hypothesized that both epitopes may induce antibodies that cross-react and stimulate the beta1-adrenoreceptor. However, no proof as to their pathogenicity has been obtained. We investigated the consequences of immunizing mice with either TcP0 or TcP2beta proteins. Of 24 immunized animals, 16 generated antibodies against the carboxyl-terminal end of the corresponding protein, 13 of which showed an altered ECG (P<0.001, 81%). Immunization with TcP0 induced anti-P013 antibodies that bind to and stimulate cardiac G-protein-coupled receptors and are linked to the induction of supraventricular arrhythmia, repolarization, and conduction abnormalities as monitored by serial electrocardiographic analysis. In contrast, immunization with TcP2beta generated anti-R13 antibodies with an exclusive beta1-adrenergic-stimulating activity whose appearance strictly correlated with the recording of supraventricular tachycardia and death. These findings demonstrate that anti-P antibodies are arrhythmogenic in the setting of a normal heart, since no inflammatory lesions or fibrosis were evident to light microscopic examination.
López Bergami
P
P
Laboratorio de Biologia Molecular de la Enfermedad de Chagas, Instituto de Investigaciones en Ingeniería Genética y Biología Molecular (INGEBI), 1428, Buenos Aires, Argentina.
Scaglione
J
J
Levin
M J
MJ
D000409:Alanine / Q000235:genetics; D000595:Amino Acid Sequence; D000818:Animals; D000913:Antibodies, Protozoan / Q000276:immunology*; D000917:Antibody Formation; D019556:COS Cells; D002352:Carrier Proteins / Q000235:genetics; D002598:Chagas Cardiomyopathy / Q000097:blood / Q000276:immunology / Q000503:physiopathology; D003001:Cloning, Molecular; D004562:Electrocardiography; D018604:Epitope Mapping; D005982:Glutathione Transferase / Q000235:genetics; D006339:Heart Rate / Q000502:physiology; D006801:Humans; D007114:Immunization; D007074:Immunoglobulin G / Q000097:blood; D058619:Maltose-Binding Proteins; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D016296:Mutagenesis; D009206:Myocardium / Q000166:cytology / Q000276:immunology; D015800:Protozoan Proteins; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology; D012269:Ribosomal Proteins / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D014349:Trypanosoma cruzi / Q000235:genetics / Q000276:immunology*
D000913:Antibodies, Protozoan; D002352:Carrier Proteins; D007074:Immunoglobulin G; C064601:L12E protein, Trypanosoma cruzi; D058619:Maltose-Binding Proteins; D015800:Protozoan Proteins; D011993:Recombinant Fusion Proteins; D012269:Ribosomal Proteins; D005982:Glutathione Transferase; D000409:Alanine