Rheumatic fever pathophysiology

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Monish Thuvooru Muthu Kalyanaraman, M.B.B.S[2]

Pathophysiology

Acute rheumatic fever (ARF) is an immune-mediated (autoimmune) multisystem sequela of superficial group A Streptococcus (GAS; Streptococcus pyogenes) infection, not a result of direct bacterial invasion of target organs. It arises 2–4 weeks after pharyngitis or skin infection in genetically susceptible hosts whose immune systems have been primed by prior streptococcal exposure.[1]

The mechanisms that inform diagnosis, prognosis, and secondary prevention include repeated-infection priming, molecular mimicry and neo-antigen generation, the antibody-then-T-cell cascade producing valvulitis, two-phase evolution of carditis, chemokine-driven fibrosis, and host genetic susceptibility. Clinical Jones criteria, echocardiographic findings, and treatment protocols are addressed in their dedicated microchapters and are referenced here only for mechanistic context.

Trigger and host priming

  • The initiating event is a superficial GAS infection. Pharyngitis is the classic and best-established trigger; skin infection (impetigo/pyoderma) is increasingly recognized as a trigger or early-life priming exposure, particularly in high-burden Indigenous and Pacific populations.[1]
  • Repeated infections appear necessary to prime the immune system for loss of self-tolerance. This represents an update from the older single-infection model and is supported by epidemiologic and serologic data.[1]
  • Only a subset of untreated children develop ARF, and only a minority of those progress to rheumatic heart disease (RHD), implicating host genetic susceptibility as a necessary co-factor.[2]

Immune activation and molecular mimicry

After GAS adheres to and invades pharyngeal or skin epithelium, neutrophils, macrophages, and dendritic cells phagocytose bacteria and present antigen to T cells. Both B cells (producing IgM, IgA, IgG) and CD4+ T cells are activated.[1]

Molecular mimicry is the prevailing hypothesis: streptococcal antigens structurally resemble human proteins, generating cross-reactive antibodies and T cells. The two most-implicated streptococcal antigens are the surface M protein and the group A carbohydrate epitope N-acetyl-β-D-glucosamine (GlcNAc).[3][4]

  • M protein and cardiac myosin are both α-helical coiled-coil molecules; cross-reactive T cells recognize both. Because myosin is absent from valves, cross-reactivity with valvular laminin and collagen is invoked to explain valvulitis.[5][4]
  • Autoantibody reactivity is broad and evolves via epitope spreading. IgG3 is elevated in ARF, and the anti–M-protein response is IgG3-polarized.[6]

Neo-antigen (anti-collagen) theory

A complementary mechanism posits that GAS penetrates the epithelial basement membrane, where an octapeptide motif on M protein (PARF) binds the CB3 region of type IV collagen, rendering it immunogenic and inducing anti–type IV collagen antibodies and systemic inflammation. These antibodies may cross-react with type I collagen in the valve.[3]

The molecular-mimicry and neo-antigen theories are not mutually exclusive and may act sequentially, consistent with the presence of both anti-myosin/laminin and anti-collagen antibodies in rheumatic carditis.[3]

Valvular injury cascade (rheumatic carditis)

The mechanistic sequence that produces valve damage proceeds as follows:

  1. Antibody deposition and endothelial activation — Cross-reactive (antiendothelial) antibodies bind valve endothelium and up-regulate vascular cell adhesion molecule-1 (VCAM-1).[5]
  2. T-cell infiltration — VCAM-1 permits CD4+ T cells (expressing integrin α4β1/VLA-4) to adhere and extravasate into the valve. CD4+ cells predominate over CD8+ in the inflamed valve.[5]
  3. Cytokine-mediated damage — Infiltrating T cells and macrophages generate a Th1 (and Th17) response with IFN-γ, TNF-α, and IL-17, driving valve breakdown.[4]
  4. Epitope spreading — Tissue breakdown liberates endogenous antigens (collagen, laminin, myosin, tropomyosin) that recruit further autoreactive T cells, amplifying and perpetuating injury across successive episodes.[7]

Carditis occurs in more than 50% of first ARF episodes and is typically a pancarditis that almost always includes valvulitis (inflammation of the valvular endocardium).[5] Subclinical carditis—echocardiographic valvulitis without auscultatory findings—has a weighted pooled prevalence of approximately 17% (95% CI 11.9–21.6%; range across studies 0–53%) and provides the mechanistic rationale for echocardiographic screening.[8][9]

Chemokines, fibrosis, and chronic remodeling

  • CXCL9 and CXCL10 are elevated in ARF/RHD and recruit CXCR3+ T cells to the heart; circulating CXCR3+ cells fall as they home to valve tissue, providing direct evidence of T-cell trafficking to the valve.[1][6]
  • TGF-β drives fibrotic remodeling and neovascularization; neovascularization grants immune cells greater valve access in later episodes. Tenascin C links inflammation to fibrosis.[1][7]
  • Damage concentrates in the left-sided (mitral > aortic) valves, which endure the highest pressure gradients and have limited repair capacity, explaining the anatomic distribution of clinical disease.[1]

Two-phase evolution of carditis and progression to RHD

  • Exudative phase (first 2–3 weeks): interstitial edema, cellular infiltration, collagen fragmentation, and fibrinoid deposition.[10]
  • Proliferative phase (months to years): formation of Aschoff bodies—the pathognomonic lesion, consisting of central fibrinoid necrosis surrounded by T lymphocytes, plasma cells, and activated macrophages (Anitschkow cells), found chiefly in the myocardium.[10][1]
  • The conduction system is rarely structurally involved; the common PR prolongation is functional/inflammatory rather than a fixed lesion.[10]
  • Chronic RHD is the cumulative product of one or more episodes of carditis: repeated inflammation causes fibrosis, leaflet thickening/calcification, commissural fusion, and chordal shortening/fusion, producing mitral regurgitation (acute/early) and, over years, mitral stenosis.[5][11]
  • Progression to RHD depends on severity of initial carditis, number of recurrences, and adherence to secondary penicillin prophylaxis—the biologic basis for long-term secondary prevention.[10][11]

Genetic and host susceptibility

  • Twin studies estimate ARF heritability near 60%; children of parents with RHD have approximately 2.9-fold higher risk even when raised apart.[7]
  • Genome-wide association studies implicate HLA class II alleles (varying by population) and immune-gene loci including CTLA4, FCGR2A, FCN1–3, IL10, IL1RN, MBL2, TLR2, TNF, and TGFB1. The FCN (ficolin) and MBL2 loci converge on lectin-pathway complement activation. The RHDGen study replicated an IGH locus association and identified a novel chromosome-11 locus in Black African individuals.[4]
  • Sex predilection: RHD is predominantly a disease of women (approximately 80% of cases). Prothymosin-α (ProTα), linked to estrogen-receptor-α–associated CD8+ cytotoxicity, has been proposed as a contributor.[4]

Areas of uncertainty and controversy

  • Molecular mimicry remains a hypothesis rather than proven causation; the pathophysiologic link between GAS and ARF is under active investigation.[1]
  • The role of group A carbohydrate has been questioned because of the quality of antigens used in older studies.[1]
  • Animal models are imperfect: the Lewis rat model most often produces myocarditis rather than valvulitis, raising validity concerns.[1]
  • Superantigen involvement is unresolved: TCR Vβ-skewing has been inconsistent across studies, and direct evidence for a superantigen role in ARF/RHD is currently lacking.[12]
  • Emerging models frame ARF/RHD as mechanistically distinct stages—early valvulitis driven by systemic inflammation and high-titer autoantibodies versus chronic valve-intrinsic pathology sustained by tissue remodeling and local T-cell dysregulation—with therapeutic implications.[13]

Clinical implications of pathophysiology

  • ARF is a delayed autoimmune sequela (2–4 weeks post-infection), not an active bacterial infection of the heart or joints; antibiotics eradicate residual GAS but do not treat the ongoing immune injury.
  • No disease-specific biomarker or diagnostic test exists; diagnosis remains clinical (Jones criteria). No immunomodulatory therapy has been proven to halt ongoing immune injury or prevent progression to RHD; current management is limited to symptom control and GAS eradication, and corticosteroid/IVIG data remain non-definitive.[1][9][6]
  • Subclinical carditis is common enough that a normal cardiac examination does not exclude valvulitis; echocardiography is required for detection.
  • Aschoff bodies are pathognomonic but represent a myocardial/proliferative-phase finding and are not a real-time diagnostic tool.
  • Recurrence drives cumulative valve damage and progression to RHD. The priming/recurrence biology is the rationale for long-term secondary antibiotic prophylaxis.

Common pitfalls

  • Attributing ARF to direct streptococcal infection of the heart or joints (it is immune-mediated).
  • Assuming a single sore throat is sufficient to cause ARF—repeated priming infections are implicated.
  • Overlooking skin infection as a trigger or priming exposure, especially in high-burden populations.
  • Equating a normal auscultatory examination with absence of carditis (thereby missing subclinical valvulitis).
  • Interpreting the histologic presence of Aschoff bodies as evidence of active, clinically detectable disease at a specific point in time.

References

  1. ↑ 1.00 1.01 1.02 1.03 1.04 1.05 1.06 1.07 1.08 1.09 1.10 1.11 Zühlke L, Beaton A, Engel M, et al. Acute rheumatic fever and rheumatic heart disease. Nature Reviews Disease Primers. 2026;12(1):7. doi:10.1038/s41572-026-00685-y.
  2. ↑ Pandian NG, Kim JK, Arias-Godinez JA, et al. Recommendations for the Use of Echocardiography in the Evaluation of Rheumatic Heart Disease: A Report From the American Society of Echocardiography. Journal of the American Society of Echocardiography. 2023.
  3. ↑ 3.0 3.1 3.2 Dougherty S, Okello E, Mwangi J, Kumar RK. Rheumatic Heart Disease: JACC Focus Seminar 2/4. Journal of the American College of Cardiology. 2023.
  4. ↑ 4.0 4.1 4.2 4.3 4.4 Small AM, Yutzey KE, Binstadt BA, et al. Unraveling the Mechanisms of Valvular Heart Disease to Identify Medical Therapy Targets: A Scientific Statement From the American Heart Association. Circulation. 2024.
  5. ↑ 5.0 5.1 5.2 5.3 5.4 Carapetis JR, Beaton A, Cunningham MW, et al. Acute rheumatic fever and rheumatic heart disease. Nature Reviews Disease Primers. 2016;2:15084. doi:10.1038/nrdp.2015.84.
  6. ↑ 6.0 6.1 6.2 Middleton FM, McGregor R, Lorenz N, et al. CXCR3 is associated with T-cell-induced heart damage in acute rheumatic fever. Nature Communications. 2026.
  7. ↑ 7.0 7.1 7.2 Watkins DA, Beaton AZ, Carapetis JR, et al. Rheumatic Heart Disease Worldwide: JACC Scientific Expert Panel. Journal of the American College of Cardiology. 2018.
  8. ↑ Gewitz MH, Baltimore RS, Tani LY, et al. Revision of the Jones Criteria for the Diagnosis of Acute Rheumatic Fever in the Era of Doppler Echocardiography: A Scientific Statement From the American Heart Association. Circulation. 2015;131(20):1806-18. doi:10.1161/CIR.0000000000000205.
  9. ↑ 9.0 9.1 Hirani K, Rwebembera J, Webb R, et al. Acute Rheumatic Fever. Lancet. 2025;405(10495):2164-2178. doi:10.1016/S0140-6736(25)00185-0.
  10. ↑ 10.0 10.1 10.2 10.3 Lahiri S, Sanyahumbi A. Acute Rheumatic Fever. Pediatrics in Review. 2021.
  11. ↑ 11.0 11.1 Kumar RK, Antunes MJ, Beaton A, et al. Contemporary Diagnosis and Management of Rheumatic Heart Disease: A Scientific Statement From the American Heart Association. Circulation. 2020.
  12. ↑ Tuffs SW, Dufresne K, Rishi A, Walton NR, McCormick JK. Novel insights into the immune response to bacterial T cell superantigens. Nature Reviews Immunology. 2024.
  13. ↑ Yeow S, Frost H, Porrello ER, Steer A, Voges HK. Valve Biology and Rheumatic Heart Disease Pathogenesis. Nature Cardiovascular Research. 2026.
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