Heart-directed autoimmunity: the case of rheumatic fever

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.