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Heart-directed autoimmunity: the case of rheumatic fever
L Guilherme1, E Cunha-Neto, A C Tanaka
1Heart Institute-InCor, University of São Paulo, School of Medicine, São Paulo, Brazil. luizagui@usp.br
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.
Insights
Molecular mimicry involving streptococcal M5 peptides and CD4(+) T cells drives rheumatic heart disease (RHD). Heart-infiltrating T cells recognize M5 peptides, contributing to RHD pathogenesis and progression.
Area of Science:
- Immunology
- Cardiology
- Infectious Diseases
Background:
- Rheumatic fever (RF) and rheumatic heart disease (RHD) are potential sequelae of streptococcal infections.
- Molecular mimicry, where microbial antigens resemble host antigens, is a proposed mechanism for RF/RHD.
- CD4(+) T cells play a role in recognizing both streptococcal M peptides and cardiac tissue proteins.
Observation:
- Heart-infiltrating T cell clones from acute RF patients showed higher reactivity to M5 peptide regions and valve proteins compared to post-RF and chronic RHD patients.
- Oligoclonal T cell expansion, indicated by T cell receptor (TCR) BV usage, was elevated in mitral valve T cell lines from chronic RHD patients.
- Mitral valve T cell lines from all patients produced inflammatory cytokines like interferon-gamma (IFN-γ) and tumor necrosis factor-alpha (TNF-α) in response to M5 peptide.
Findings:
- A higher frequency of T cell clones reactive to specific M5 peptide regions and heart valve proteins was observed in acute rheumatic fever (ARF) patients.
- Chronic RHD patients exhibited increased oligoclonal T cell expansion in heart-infiltrating T cell lines.
- Significant production of inflammatory cytokines IFN-γ and TNF-α by heart-infiltrating T cells in response to M5 peptide was detected across patient groups, notably higher in chronic RHD.
Implications:
- These findings support a crucial role for M5 peptide and host antigen-driven T1-type CD4(+) T cells in the pathogenesis of RHD.
- The study suggests that streptococcal M5 peptide-specific T cell responses contribute to heart lesion progression, especially after recurrent streptococcal infections.
- Understanding these immune mechanisms could lead to targeted therapies for preventing or managing RHD.