Mimicry in recognition of cardiac myosin peptides by heart-intralesional T cell clones from rheumatic heart disease.
Molecular mimicry between Streptococcus pyogenes Ags and human proteins has been considered as a mechanism leading to autoimmune reactions in rheumatic fever and rheumatic heart disease (RHD). Cardiac myosin has been shown as a putative autoantigen recognized by autoantibodies of rheumatic fever patients. We assessed the human heart-intralesional T cell response against human light meromyosin (LMM) and streptococcal M5 peptides and mitral-valve-derived proteins by proliferation assay. Cytokines induced by LMM peptides were also evaluated. The frequency of intralesional T cell clones that recognized LMM peptides was 63.2%. Thirty-four percent of T cell clones presented cross-reactivity with different patterns: 1) myosin and valve-derived proteins; 2) myosin and streptococcal M5 peptides; and 3) myosin, valve-derived proteins and M5 peptides. In addition, several LMM peptides were recognized simultaneously showing a multiple reactivity pattern of heart-infiltrating T cells. Inflammatory cytokines (IFN-gamma and TNF-alpha) were predominantly produced by heart-infiltrating T cells upon stimulation with LMM peptides. The alignment of LMM and streptococcal M5 peptides showed frequent homology among conserved amino acid substitutions. This is the first study showing the cellular response by human heart-infiltrating T cells against cardiac myosin epitopes in RHD patients. The high percentage of reactivity against cardiac myosin strengthens its role as one of the major autoantigens involved in rheumatic heart lesions. T cell reactivity toward myosin epitopes in RHD patients may also trigger the broad recognition of valvular proteins with structural or functional similarities.
Faé
Kellen C
KC
Heart Institute (Instituto do Coração) University of São Paulo, School of Medicine, Avenida Dr. Eneas de Carvalho Aguiar, 44-9o andar, 05403-000 São Paulo, Brazil.
da Silva
Danielle Diefenbach
DD
Oshiro
Sandra E
SE
Tanaka
Ana C
AC
Pomerantzeff
Pablo M A
PM
Douay
Corinne
C
Charron
Dominique
D
Toubert
Antoine
A
Cunningham
Madeleine W
MW
Kalil
Jorge
J
Guilherme
Luiza
L
D000595:Amino Acid Sequence; D001426:Bacterial Proteins / Q000737:chemistry / Q000276:immunology / Q000378:metabolism*; D024722:Cardiac Myosins / Q000378:metabolism*; D002460:Cell Line; D002999:Clone Cells; D003429:Cross Reactions / Q000276:immunology; D016207:Cytokines / Q000378:metabolism; D018984:Epitopes, T-Lymphocyte / Q000737:chemistry / Q000276:immunology; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D018716:Molecular Mimicry; D008969:Molecular Sequence Data; D015879:Myosin Subfragments / Q000378:metabolism; D010446:Peptide Fragments / Q000378:metabolism*; D012214:Rheumatic Heart Disease / Q000276:immunology / Q000378:metabolism* / Q000473:pathology*; D017386:Sequence Homology, Amino Acid; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism*
D001426:Bacterial Proteins; D016207:Cytokines; D018984:Epitopes, T-Lymphocyte; D018836:Inflammation Mediators; D015879:Myosin Subfragments; D010446:Peptide Fragments; D024722:Cardiac Myosins