title: Heart-directed autoimmunity: the case of rheumatic fever.
abstract: Molecular mimicry was proposed as a potential mechanism for streptococcal sequelae leading to rheumatic fever (RF) and rheumatic heart disease (RHD). CD4(+)infiltrating T cells are able to recognize streptococcal M peptides and heart tissue proteins. We analyzed the M5 peptide- and heart-specific responses, cytokine profile and T cell receptor (TCR) BV usage from peripheral and heart-infiltrating T cell lines and clones from patients across the clinical spectrum of ARF/RHD. The patient with ARF displayed a higher frequency of mitral valve infiltrating T cell clones reactive against M5: 1-25, 81-103 and 163-177 regions and several valve-derived proteins than the post-RF and chronic RHD patient (67%; 20% and 27%, respectively). The presence of oligoclonal BV families indicative of oligoclonal T cell expansion among mitral valve-derived T cell lines was increased in the chronic RHD patient. Furthermore, mitral valve T cell lines from all patients produced significant amounts of inflammatory cytokines interferon-gamma (IFN-gamma) and tumour necrosis factor-alpha (TNFalpha) in response to M5(81-96) peptide, with the highest production attained by the chronic RHD patient. These data are consistent with an important role for M5 peptide and host antigen-driven, T1-type CD4(+)T cells in the pathogenesis of RHD and heart lesion progression after recurrence of the streptococcal infection.
authors.affiliation: Heart Institute-InCor, University of São Paulo, School of Medicine, São Paulo, Brazil. luizagui@usp.br
authors.forename: L
authors.initials: L
authors.lastname: Guilherme
authors.forename: E
authors.initials: E
authors.lastname: Cunha-Neto
authors.forename: A C
authors.initials: AC
authors.lastname: Tanaka
authors.forename: N
authors.initials: N
authors.lastname: Dulphy
authors.forename: A
authors.initials: A
authors.lastname: Toubert
authors.forename: J
authors.initials: J
authors.lastname: Kalil
mesh_terms: D000293:Adolescent; D000595:Amino Acid Sequence; D015551:Autoimmunity / Q000276:immunology*; D002648:Child; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis; D016753:Interleukin-10 / Q000096:biosynthesis; D015847:Interleukin-4 / Q000096:biosynthesis; D008297:Male; D008969:Molecular Sequence Data; D009206:Myocardium / Q000276:immunology*; D012214:Rheumatic Heart Disease / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
chemical_list: D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D015847:Interleukin-4; D007371:Interferon-gamma