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* Heart Institute (Instituto do Coração) University of São Paulo, School of Medicine, São Paulo, Brazil;
Institute for Immunology Investigation, Millenium Institute, São Paulo, Brazil;
Assistance Publique-Hôpitaux de Paris, Centre d’Investigations Biomédicales, Laboratoire d’Immunologie et Histocompatibilité, Institut National de la Sante et de la Recherche Medicale Unité 662, Université Paris VII, Institut Universitaire d’Hématologie, Hôpital Saint Louis, Paris, France;
Department of Microbiology and Immunology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104; and
¶ Clinical Immunology and Allergy, Department of Clinical Medicine, University of São Paulo, School of Medicine, São Paulo, Brazil
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-
and TNF-
) 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.
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