Mechanisms underlying rheumatic heart disease immune-mediated pathogenesis: T-cell responses, cytokine networks, and immune dysregulation as drivers of valvular injury.

Acute rheumatic fever is an immune-mediated sequela of Streptococcus pyogenes (group A Streptococcus) infection, presenting with fever, arthritis, chorea, rash, and, crucially, carditis. Without effective secondary prophylaxis and care, acute rheumatic fever can progress to chronic rheumatic heart disease, a leading yet under-recognised cause of cardiovascular morbidity and death that disproportionately affects children and young adults aged 5-24 years in low-resource settings. Robust evidence implicates the role of antigenic mimicry-particularly between streptococcal M protein and cardiac or myocardial matrix proteins-together with dysregulated immune control in driving valvular injury. In this Review, we discussed mechanisms of rheumatic heart disease immunopathogenesis, highlighting the roles of T-cell responses, chemokine-guided recruitment to valves, cytokine dysregulation, endothelial activation, and stromal remodelling. We also analysed limitations of existing data and delineate strategies to develop experimental models, identify biomarkers, and define immunomodulatory targets that can inform earlier diagnosis, enhanced secondary prevention, and rational therapeutic strategies.