Journal of Clinical Immunology

, Volume 30, Issue 1, pp 17–23 | Cite as

Rheumatic Fever and Rheumatic Heart Disease: Cellular Mechanisms Leading Autoimmune Reactivity and Disease




Rheumatic fever (RF) is an autoimmune disease caused by the gram-positive bacteria Streptococcus pyogenes that follows a nontreated throat infection in susceptible children. The disease manifests as polyarthritis, carditis, chorea, erythema marginatum, and/or subcutaneous nodules. Carditis, the most serious complication, occurs in 30% to 45% of RF patients and leads to chronic rheumatic heart disease (RHD), which is characterized by progressive and permanent valvular lesions. In this review, we will focus on the genes that confer susceptibility for developing the disease, as well as the innate and adaptive immune responses against S. pyogenes during the acute rheumatic fever episode that leads to RHD autoimmune reactions.


The disease is genetically determined, and some human leukocyte antigen class II alleles are involved with susceptibility. Other single nucleotide polymorphisms for TNF-alpha and mannan-binding lectin genes were reported as associated with RF/RHD. T cells play an important role in RHD heart lesions. Several autoantigens were already identified, including cardiac myosin epitopes, vimentin, and other intracellular proteins. In the heart tissue, antigen-driven oligoclonal T cell expansions were probably the effectors of the rheumatic heart lesions. These cells are CD4+ and produced inflammatory cytokines (TNFα and IFNγ).


Molecular mimicry is the mechanism that mediated the cross-reactions between streptococcal antigens and human proteins. The elucidation of chemokines and their receptors involved with the recruitment of Th1, Th2, and Th17 cells, as well as the function of T regulatory cells in situ will certainly contribute to the delineation of the real picture of the heart lesion process that leads to RHD.


S. pyogenes M protein T cells T cell receptor cytokines heart tissue proteins autoimmunity 



Acute rheumatic fever


Rheumatic fever


Rheumatic heart disease


Human leukocyte antigens


Tumor necrosis factor


Mannan-binding lectin


Single nucleotide polymorphism


T cell receptor


T cell receptor beta-chain variable region


Antigen-presenting cell






T regulatory cells



We acknowledge all of the people at the Heart Institute (InCor), School of Medicine from the University of Sao Paulo that contributed to the scientific data published elsewhere and described in this review. This work was supported by grants from “Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)” and “Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)”.


  1. 1.
    Dajani AS, Ayoub E, Bierman FZ, et al. Guidelines for the diagnosis of rheumatic fever: Jones criteria, 1992 uptade. JAMA. 1992;268:2069–73.CrossRefGoogle Scholar
  2. 2.
    Carapetis JR, Mulholland SAC, EK WM. The global burden of group A streptococcal disease. Lancet Infect Dis. 2005;5:685–94.CrossRefPubMedGoogle Scholar
  3. 3.
    Guilherme L, Ramasawmy R, Kalil J. Rheumatic fever and rheumatic heart disease: genetics and pathogenesis. Scand J Immunol. 2007;66:199–207.CrossRefPubMedGoogle Scholar
  4. 4.
    Stanevicha V, Eglite J, Sochnevs A, Gardovska D, Zavadska D, Shantere R. HLA class II associations with rheumatic heart disease among clinically homogeneous patients in children in Latvia. Arthritis Res Ther. 2003;5:R340–6.CrossRefPubMedGoogle Scholar
  5. 5.
    Hernandez-Pacheco G, Flores-Dominguez C, et al. Tumor necrosis factor-alpha promoter polymorphisms in Mexican patients with rheumatic heart disease. J Autoimmun. 2003;21:59–63.CrossRefPubMedGoogle Scholar
  6. 6.
    Ramasawmy R, Fae KC, Spina G, et al. Association of polymorphisms within the promoter region of the tumor necrosis factor-alpha with clinical outcomes of rheumatic fever. Mol Immunol. 2007;44:1873–8.CrossRefPubMedGoogle Scholar
  7. 7.
    Jack DL, Klein NJ, Turner MW. Mannose-binding lectin: targeting the microbial world for complement attack and opsonophagocytosis. Immunol Rev. 2001;180:86–99.CrossRefPubMedGoogle Scholar
  8. 8.
    Messias Reason IJ, Schafranski MD, Jensenius JC, Steffensen R. The association between mannose-binding lectin gene polymorphism and rheumatic heart disease. Hum Immunol. 2006;67:991–8.CrossRefPubMedGoogle Scholar
  9. 9.
    Schafranski MD, Pereira-Ferrari L, Scherner D, Messias-Reason IJ. High-producing MBL2 genotypes increase the risk of acute and chronic carditis in patients with history of rheumatic fever. Mol Immunol. 2008;45(14):3827–31.CrossRefPubMedGoogle Scholar
  10. 10.
    Ramasawmy R, Spina G, Faé KC, Perreira AC et al. Association of mannosebinding lectin gene polymorphism but not of mannose-binding serine protease-2 with chronic severe aortic regurgitation of rheumatic etiology. Clinical and Vaccine Immunology. 2008;15(6):932-6.CrossRefPubMedGoogle Scholar
  11. 11.
    Cunningham MW. Pathogenesis of group A streptococcal infections. Clin Microbiol Rev. 2000;13:470–511.CrossRefPubMedGoogle Scholar
  12. 12.
    Guilherme L, Kalil J, Cunningham MW. Molecular mimicry in the autoimmune pathogenesis of rheumatic heart disease. Autoimmunity. 2006;39(1):31–9.CrossRefPubMedGoogle Scholar
  13. 13.
    Lehmann PV, Forsthuber T, Miller A, Sercarz EE. Spreading of T cell autoimmunity to cryptic determinants of an autoantigen. Nature. 1992;359:155–7.CrossRefGoogle Scholar
  14. 14.
    Raizada V, Williams RC Jr, Chopra P, et al. Tissue distribution of lymphocytes in rheumatic heart valves as defined by monoclonal anti-T cell antibodies. Am J Med. 1983;74:90–6.CrossRefPubMedGoogle Scholar
  15. 15.
    Kemeny E, Grieve T, Marcus R, Sareli P, Zabriskie JB. Identification of mononuclear cells and T cell subsets in rheumatic valvulitis. Clin Immunol Immunopathol. 1989;52:225–37.CrossRefPubMedGoogle Scholar
  16. 16.
    Guilherme L, Weidebach W, Kiss MH, Snitcowsky R, Kalil J. Association of human leukocyte class II antigens with rheumatic fever or rheumatic heart disease in a Brazilian population. Circulation. 1991;83:1995–8.PubMedGoogle Scholar
  17. 17.
    Galvin JE, Hemric ME, Ward K, Cunnimgham M. Cytotoxic monoclonal antibody from rheumatic carditis reacts with human endothelium: implicxations in rheumatic heart disease. J Clin Invest. 2000;106:217–24.CrossRefPubMedGoogle Scholar
  18. 18.
    Roberts S, Kosanke S, Dun TS, et al. Pathogenic mechanism in rheumatic carditis: focus on valvular endothelium. J Infect Diseases. 2001;183:507–11.CrossRefGoogle Scholar
  19. 19.
    Fae KC, da Silva DD, Oshiro SE, et al. Mimicry in recognition of cardiac myosin peptides by heart-intralesional T cell clones from rheumatic heart disease. J Immunol. 2006;176:5662–70.PubMedGoogle Scholar
  20. 20.
    Guilherme L, Oshiro SE, Fae KC, Cunha-Neto E, et al. T cell reactivity against streptococcal antigens in the periphery mirrors reactivity of heart-infiltrating T lymphocytes in rheumatic heart disease patients. Infect Immun. 2001;69:5345–51.CrossRefPubMedGoogle Scholar
  21. 21.
    Yoshinaga M, Figueiroa F, Wahid MR, Marcus RH, Suh E, Zabriskie JB. Antigenic specificity of lymphocytes isolated from valvular specimens of rheumatic fever patients. J Autoimmun. 1995;8:601–13.CrossRefPubMedGoogle Scholar
  22. 22.
    Cunningham MW. T cell mimicry in inflammatory heart disease. Mol Immunol. 2004;40:1121–7.CrossRefPubMedGoogle Scholar
  23. 23.
    Ellis NM, Li Y, Hildebrand W, Fischetti VA, Cunningham MW. T cell mimicry and epitope specificity of cross-reactive T cell clones from rheumatic heart disease. J Immunol. 2005;175:5448–56.PubMedGoogle Scholar
  24. 24.
    Lievremont JP, Rizzuto R, Hendershot L, BiP MJ. A major chaperone protein of the endoplasmic reticulum lumen, plays a direct and important role in the storage of the rapidly exchanging pool of Ca2+. J Biol Chem. 1997;272:30873–9.CrossRefPubMedGoogle Scholar
  25. 25.
    Little E, Ramakrishnan M, Roy B, Gazita G, Lee AS. The glucose-regulated proteins (GRP78 and GRP94): functions, gene regulation, and applications. Crit Rev Eukaryot Gene Expr. 1994;4:1–18.PubMedGoogle Scholar
  26. 26.
    Nigam SK, Goldberg AL, Ho S, Rohde MF, Bush KT, Sherman M. A set of endoplasmic reticulum proteins possessing properties of molecular chaperones includes Ca(2+)-binding proteins and members of the thioredoxin superfamily. J Biol Chem. 1994;269:1744–9.PubMedGoogle Scholar
  27. 27.
    Guilherme L, Dulphy N, Douay C, Coelho V, Cunha-Neto E, et al. Molecular evidence for antigen-driven immune responses in cardiac lesions of Rheumatic Heart Disease patients. Int Immunol. 2000;12:1063–74.CrossRefPubMedGoogle Scholar
  28. 28.
    Faé K, Kalil J, Toubert A, Guilherme L. Heart-infiltrating T cell clones from a rheumatic heart disease patient display a common TCR usage and a degenerate antigen recognition pattern. Mol Immunol. 2004;40(14–15):1129–35.CrossRefPubMedGoogle Scholar
  29. 29.
    Guilherme L, Faé K, Oshiro SE, Kalil J. (2005) Molecular pathogenesis of rheumatic fever and rheumatic heart disease. Exp Rev Mol Immunol (7):1–15. On line access. doi:  10.1017/S146239940501015X
  30. 30.
    Guilherme L, Cury P, Demarchi LM, et al. Rheumatic heart disease: proinflammatory cytokines play a role in the progression and maintenance of valvular lesions. Am J Pathol. 2004;165:1583–91.PubMedGoogle Scholar
  31. 31.
    Ivanov II, Mckenzie BS, Zhou L, Tadokoro CE, et al. The orphan nuclear receptor RORgammat directs the differentiation program of proinflammatory IL-17+ T helper cells. Cell. 2006;126:1121–33.CrossRefPubMedGoogle Scholar
  32. 32.
    Annunziato F, Cosmi L, Santarlasci V, Maggi L, et al. Phenotypic and funcational features of human Th17 cells. J Exp Med. 2007;204(8):1849–61.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  1. 1.Heart Institute (InCor)School of Medicine, University of São PauloSão PauloBrazil
  2. 2.Clinical Immunology and Allergy DivisionUniversity of São PauloSão PauloBrazil
  3. 3.Institute for Immunology InvestigationINCT- National Institute of Science and Technology, CNPqSão PauloBrazil
  4. 4.Heart Institute (InCor)São PauloBrazil

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