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Rheumatic Fever: How S. pyogenes-Primed Peripheral T Cells Trigger Heart Valve Lesions
aHeart Institute (InCor), School of Medicine, University of São Paulo, São Paulo, Brazil bInstitute for Immunology Investigation, Millennium Institute, São Paulo, Brazil cClinical Immunology and Allergy, Department of Clinical Medicine, University of São Paulo, School of Medicine, São Paulo, Brazil
Address for correspondence: Luiza Guilherme, Laboratório de Imunologia, Instituto do Coração (HC-FMUSP), Av. Dr. Eneas de Carvalho Aguiar, 44 - 9 andar., 05403-000 São Paulo, SP, Brazil. Voice: +55-11-3069-5901; fax: +55-11-3069-5953. luizagui{at}usp.br
The pathogenesis of rheumatic fever (RF) is related to autoimmune humoral and cellular responses against human tissues triggered by Streptococcus pyogenes. CD4+ T cells are the ultimate effectors of chronic heart lesions in rheumatic heart disease (RHD). Heart-infiltrating CD4+ T cell clones are able to recognize heart tissue and streptococcal antigens by molecular mimicry. The streptococcal M5(81-103) region, an immunodominant region, was recognized by both intralesional and peripheral T cell clones (62% and 38%, respectively). Peripheral T lymphocytes from Brazilian patients with severe RHD preferentially recognized the M5(81-96) peptide, in the context of HLA-DR7+ and DR53+ molecules. HLA-DR7 seems to be related to the development of multiple valvular lesions in RHD patients from different countries. In addition, the fact that peripheral and intralesional T cells recognized the M5(81-103) region points to this region as one of the streptococcal triggers of autoimmune reactions in RHD. T cell repertoire analysis from peripheral and intralesional T cell lines derived from RHD patients showed several oligoclonal expansions of BV families. Major expansions were found in the heart lesions, suggesting that such T cell populations preferentially migrate from the periphery to the heart. Some cross-reactive intralesional T cell clones displayed the same T cell receptor (TCR) BVBJ and CDR3 sequences, showing a degenerate pattern of antigen recognition. Heart tissue-infiltrating cells from myocardium and valvular tissue produced TNF-
 , IFN- , IL-10, and IL-4, whereas few cells from valvular tissue produced IL-4, showing that the lack of regulation in the valves could be responsible for the permanent and progressive valvular lesions.
Key Words: autoimmune disease • rheumatic fever • M protein • heart tissue proteins • molecular mimicry • T lymphocytes • T cell receptor • cytokines This article has been cited by other articles:
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