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

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Abstract

Introduction

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.

Discussion

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).

Conclusion

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.

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Abbreviations

ARF:

Acute rheumatic fever

RF:

Rheumatic fever

RHD:

Rheumatic heart disease

HLA:

Human leukocyte antigens

TNF:

Tumor necrosis factor

MBL:

Mannan-binding lectin

SNP:

Single nucleotide polymorphism

TCR:

T cell receptor

TCR-BV:

T cell receptor beta-chain variable region

APC:

Antigen-presenting cell

IL:

Interleukin

IFN:

Interferon-gamma

Tregs:

T regulatory cells

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Acknowledgments

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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Correspondence to Luiza Guilherme.

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Guilherme, L., Kalil, J. Rheumatic Fever and Rheumatic Heart Disease: Cellular Mechanisms Leading Autoimmune Reactivity and Disease. J Clin Immunol 30, 17–23 (2010). https://doi.org/10.1007/s10875-009-9332-6

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  • DOI: https://doi.org/10.1007/s10875-009-9332-6

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