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

  • Luiza GuilhermeEmail author
  • Jorge Kalil



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)”.


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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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