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<p>For decades, the pathogenesis of Acute Rheumatic Fever and Rheumatic Heart Disease has been primarily attributed to autoimmune activation in genetically predisposed children, triggered by molecular mimicry between Group A Streptococcus antigens and cardiac tissue components. Recent evidence reveals that immune priming generates complement-fixing and non-complement-fixing cross-reactive antibodies, initiating inflammatory cascades. Tissue-infiltrating neutrophils, T lymphocytes, macrophages, and neutrophil extracellular traps (NETs) critically contribute to rheumatic carditis immunopathology. These effectors damage endothelium, release acute-phase reactants, facilitate infiltration, exposing autoantigens, and promoting epitope spreading. All the three complement pathways emerge as key inflammatory amplifiers enhancing NET formation (NETosis) via PAD4-mediated histone citrullination, depositing on NET scaffolds, stabilizing them and perpetuating tissue injury. Dysregulated complement-NET interactions drive progression from acute inflammation to chronic valvular fibrosis. Circulating biomarkers such as cell-free DNA, MPO-DNA complexes, and complement fragments may indicate disease activity. Emerging therapeutic strategies include PAD4 inhibition, DNase-based NET clearance, and complement modulation.</p> Graphical Abstract <p></p>

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Neutrophil Extracellular Traps and Complement Pathways: The Missing Links in Acute Rheumatic Fever and Rheumatic Heart Disease Pathogenesis

  • 期刊论文

  • 发表日期：

    2026年2月5日

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  • Saligrama Ramegowda Kalpana,
  • Rudrapatna Subramanyam Jayshree

摘要

For decades, the pathogenesis of Acute Rheumatic Fever and Rheumatic Heart Disease has been primarily attributed to autoimmune activation in genetically predisposed children, triggered by molecular mimicry between Group A Streptococcus antigens and cardiac tissue components. Recent evidence reveals that immune priming generates complement-fixing and non-complement-fixing cross-reactive antibodies, initiating inflammatory cascades. Tissue-infiltrating neutrophils, T lymphocytes, macrophages, and neutrophil extracellular traps (NETs) critically contribute to rheumatic carditis immunopathology. These effectors damage endothelium, release acute-phase reactants, facilitate infiltration, exposing autoantigens, and promoting epitope spreading. All the three complement pathways emerge as key inflammatory amplifiers enhancing NET formation (NETosis) via PAD4-mediated histone citrullination, depositing on NET scaffolds, stabilizing them and perpetuating tissue injury. Dysregulated complement-NET interactions drive progression from acute inflammation to chronic valvular fibrosis. Circulating biomarkers such as cell-free DNA, MPO-DNA complexes, and complement fragments may indicate disease activity. Emerging therapeutic strategies include PAD4 inhibition, DNase-based NET clearance, and complement modulation.

Graphical Abstract