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. 1995 Apr 11;92(8):3541–3545. doi: 10.1073/pnas.92.8.3541

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

E Cunha-Neto 1, M Duranti 1, A Gruber 1, B Zingales 1, I De Messias 1, N Stolf 1, G Bellotti 1, M E Patarroyo 1, F Pilleggi 1, J Kalil 1
PMCID: PMC42203  PMID: 7536937

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.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Berneman A., Ternynck T., Avrameas S. Natural mouse IgG reacts with self antigens including molecules involved in the immune response. Eur J Immunol. 1992 Mar;22(3):625–633. doi: 10.1002/eji.1830220303. [DOI] [PubMed] [Google Scholar]
  2. Cossio P. M., Diez C., Szarfman A., Kreutzer E., Candiolo B., Arana R. M. Chagasic cardiopathy. Demonstration of a serum gamma globulin factor which reacts with endocardium and vascular structures. Circulation. 1974 Jan;49(1):13–21. doi: 10.1161/01.cir.49.1.13. [DOI] [PubMed] [Google Scholar]
  3. Cunningham M. W., McCormack J. M., Talaber L. R., Harley J. B., Ayoub E. M., Muneer R. S., Chun L. T., Reddy D. V. Human monoclonal antibodies reactive with antigens of the group A Streptococcus and human heart. J Immunol. 1988 Oct 15;141(8):2760–2766. [PubMed] [Google Scholar]
  4. Dale J. B., Beachey E. H. Sequence of myosin-crossreactive epitopes of streptococcal M protein. J Exp Med. 1986 Nov 1;164(5):1785–1790. doi: 10.1084/jem.164.5.1785. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Geysen H. M., Rodda S. J., Mason T. J., Tribbick G., Schoofs P. G. Strategies for epitope analysis using peptide synthesis. J Immunol Methods. 1987 Sep 24;102(2):259–274. doi: 10.1016/0022-1759(87)90085-8. [DOI] [PubMed] [Google Scholar]
  6. Gorza L., Mercadier J. J., Schwartz K., Thornell L. E., Sartore S., Schiaffino S. Myosin types in the human heart. An immunofluorescence study of normal and hypertrophied atrial and ventricular myocardium. Circ Res. 1984 Jun;54(6):694–702. doi: 10.1161/01.res.54.6.694. [DOI] [PubMed] [Google Scholar]
  7. Gruber A., Zingales B. Trypanosoma cruzi: characterization of two recombinant antigens with potential application in the diagnosis of Chagas' disease. Exp Parasitol. 1993 Feb;76(1):1–12. doi: 10.1006/expr.1993.1001. [DOI] [PubMed] [Google Scholar]
  8. Harrington W. F., Rodgers M. E. Myosin. Annu Rev Biochem. 1984;53:35–73. doi: 10.1146/annurev.bi.53.070184.000343. [DOI] [PubMed] [Google Scholar]
  9. Higuchi M. L., De Morais C. F., Pereira Barreto A. C., Lopes E. A., Stolf N., Bellotti G., Pileggi F. The role of active myocarditis in the development of heart failure in chronic Chagas' disease: a study based on endomyocardial biopsies. Clin Cardiol. 1987 Nov;10(11):665–670. doi: 10.1002/clc.4960101113. [DOI] [PubMed] [Google Scholar]
  10. Houghten R. A. General method for the rapid solid-phase synthesis of large numbers of peptides: specificity of antigen-antibody interaction at the level of individual amino acids. Proc Natl Acad Sci U S A. 1985 Aug;82(15):5131–5135. doi: 10.1073/pnas.82.15.5131. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Kabat E. A. Heterogeneity and structure of antibody-combining sites. Ann N Y Acad Sci. 1970 Feb 13;169(1):43–54. doi: 10.1111/j.1749-6632.1970.tb55978.x. [DOI] [PubMed] [Google Scholar]
  12. Kerner N., Liégeard P., Levin M. J., Hontebeyrie-Joskowicz M. Trypanosoma cruzi: antibodies to a MAP-like protein in chronic Chagas' disease cross-react with mammalian cytoskeleton. Exp Parasitol. 1991 Nov;73(4):451–459. doi: 10.1016/0014-4894(91)90069-9. [DOI] [PubMed] [Google Scholar]
  13. Khoury E. L., Diez C., Cossio P. M., Arana R. M. Heterophil nature of EVI antibody in Trypanosoma cruzi infection. Clin Immunol Immunopathol. 1983 May;27(2):283–288. doi: 10.1016/0090-1229(83)90078-8. [DOI] [PubMed] [Google Scholar]
  14. Laemmli U. K. Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature. 1970 Aug 15;227(5259):680–685. doi: 10.1038/227680a0. [DOI] [PubMed] [Google Scholar]
  15. Levin M. J., Mesri E., Benarous R., Levitus G., Schijman A., Levy-Yeyati P., Chiale P. A., Ruiz A. M., Kahn A., Rosenbaum M. B. Identification of major Trypanosoma cruzi antigenic determinants in chronic Chagas' heart disease. Am J Trop Med Hyg. 1989 Nov;41(5):530–538. doi: 10.4269/ajtmh.1989.41.530. [DOI] [PubMed] [Google Scholar]
  16. Margossian S. S., Lowey S. Preparation of myosin and its subfragments from rabbit skeletal muscle. Methods Enzymol. 1982;85(Pt B):55–71. doi: 10.1016/0076-6879(82)85009-x. [DOI] [PubMed] [Google Scholar]
  17. Neu N., Beisel K. W., Traystman M. D., Rose N. R., Craig S. W. Autoantibodies specific for the cardiac myosin isoform are found in mice susceptible to Coxsackievirus B3-induced myocarditis. J Immunol. 1987 Apr 15;138(8):2488–2492. [PubMed] [Google Scholar]
  18. Neu N., Rose N. R., Beisel K. W., Herskowitz A., Gurri-Glass G., Craig S. W. Cardiac myosin induces myocarditis in genetically predisposed mice. J Immunol. 1987 Dec 1;139(11):3630–3636. [PubMed] [Google Scholar]
  19. Rizzo L. V., Cunha-Neto E., Teixeira A. R. Autoimmunity in Chagas' disease: specific inhibition of reactivity of CD4+ T cells against myosin in mice chronically infected with Trypanosoma cruzi. Infect Immun. 1989 Sep;57(9):2640–2644. doi: 10.1128/iai.57.9.2640-2644.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Schuler G. D., Altschul S. F., Lipman D. J. A workbench for multiple alignment construction and analysis. Proteins. 1991;9(3):180–190. doi: 10.1002/prot.340090304. [DOI] [PubMed] [Google Scholar]
  21. Smith S. C., Allen P. M. Myosin-induced acute myocarditis is a T cell-mediated disease. J Immunol. 1991 Oct 1;147(7):2141–2147. [PubMed] [Google Scholar]
  22. Teixeira A. R., Cunha Neto E., Rizzo L. V., Silva R. Trypanocidal nitroarene treatment of experimental Trypanosoma cruzi infection does not prevent progression of chronic-phase heart lesions in rabbits. J Infect Dis. 1990 Dec;162(6):1420–1420. doi: 10.1093/infdis/162.6.1420. [DOI] [PubMed] [Google Scholar]
  23. Teixeira A. R., Teixeira M. L., Santos-Buch C. A. The immunology of experimental Chagas' disease. IV. Production of lesions in rabbits similar to those of chronic Chagas' disease in man. Am J Pathol. 1975 Jul;80(1):163–180. [PMC free article] [PubMed] [Google Scholar]
  24. Tibbetts R. S., McCormick T. S., Rowland E. C., Miller S. D., Engman D. M. Cardiac antigen-specific autoantibody production is associated with cardiomyopathy in Trypanosoma cruzi-infected mice. J Immunol. 1994 Feb 1;152(3):1493–1499. [PubMed] [Google Scholar]
  25. Towbin H., Staehelin T., Gordon J. Electrophoretic transfer of proteins from polyacrylamide gels to nitrocellulose sheets: procedure and some applications. Proc Natl Acad Sci U S A. 1979 Sep;76(9):4350–4354. doi: 10.1073/pnas.76.9.4350. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Van Voorhis W. C., Schlekewy L., Trong H. L. Molecular mimicry by Trypanosoma cruzi: the F1-160 epitope that mimics mammalian nerve can be mapped to a 12-amino acid peptide. Proc Natl Acad Sci U S A. 1991 Jul 15;88(14):5993–5997. doi: 10.1073/pnas.88.14.5993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Zicker F., Smith P. G., Netto J. C., Oliveira R. M., Zicker E. M. Physical activity, opportunity for reinfection, and sibling history of heart disease as risk factors for Chagas' cardiopathy. Am J Trop Med Hyg. 1990 Nov;43(5):498–505. doi: 10.4269/ajtmh.1990.43.498. [DOI] [PubMed] [Google Scholar]
  28. Zingales B., Andrews N. W., Kuwajima V. Y., Colli W. Cell surface antigens of Trypanosoma cruzi: possible correlation with the interiorization process in mammalian cells. Mol Biochem Parasitol. 1982 Aug;6(2):111–124. doi: 10.1016/0166-6851(82)90069-x. [DOI] [PubMed] [Google Scholar]
  29. dos Santos R. R., Rossi M. A., Laus J. L., Silva J. S., Savino W., Mengel J. Anti-CD4 abrogates rejection and reestablishes long-term tolerance to syngeneic newborn hearts grafted in mice chronically infected with Trypanosoma cruzi. J Exp Med. 1992 Jan 1;175(1):29–39. doi: 10.1084/jem.175.1.29. [DOI] [PMC free article] [PubMed] [Google Scholar]

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