Heart-directed Autoimmunity: the Case of Rheumatic Fever

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-γ (IFN-γ) and tumour necrosis factor-α (TNFα) 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.