Rheumatic fever: how S. pyogenes-primed peripheral T cells trigger heart valve lesions.
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-alpha, IFN-gamma, 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.
Guilherme
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Laboratório de Imunologia, Instituto do Coração (HC-FMUSP), School of Medicine, University of São Paulo, Av. Dr. Eneas de Carvalho Aguiar, 44-9 andar., 05403-000 São Paulo, SP, Brazil. luizagui@usp.br
Faé
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Oshiro
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Tanaka
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Pomerantzeff
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Kalil
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D000942:Antigens, Bacterial / Q000502:physiology; D015551:Autoimmunity; D001425:Bacterial Outer Membrane Proteins / Q000502:physiology; D002352:Carrier Proteins / Q000502:physiology; D016207:Cytokines / Q000096:biosynthesis; D006801:Humans; D012213:Rheumatic Fever / Q000209:etiology* / Q000276:immunology; D012214:Rheumatic Heart Disease / Q000209:etiology* / Q000276:immunology; D013297:Streptococcus pyogenes / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*
D000942:Antigens, Bacterial; D001425:Bacterial Outer Membrane Proteins; D002352:Carrier Proteins; D016207:Cytokines; C014689:streptococcal M protein