Pathogenesis of Rheumatic Heart Disease

1. The Triggering Event: GAS Pharyngitis

• GAS undergoes phagocytosis by neutrophils, macrophages, and dendritic cells at the pharyngeal mucosa
• Processed antigens activate both humoral (B cell/antibody) and cellular (CD4+ T cell) arms of the adaptive immune system
• A latent period of 2-3 weeks follows the infection before symptoms of ARF appear - this delay reflects the time needed to generate a full adaptive immune response; by this point, streptococci are completely absent from the lesions

2. Molecular Mimicry: The Core Mechanism

3. Antibody-Mediated Valvular Injury

1. Cross-reactive IgG antibodies bind to the valvular endothelium and basement membrane, particularly targeting laminin and cardiac myosin epitopes
2. Antibody binding triggers complement activation and Fc receptor engagement on macrophages, generating an inflammatory signal
3. This upregulates expression of adhesion molecules, particularly VCAM-1 (vascular cell adhesion molecule-1) on the valvular endothelium
4. VCAM-1 interacts with VLA-4 (very late activation antigen-4) expressed on CD4+ T lymphocytes, facilitating their extravasation into valve tissue
5. Additional molecules upregulated include ICAM, P-selectin, and several chemokines: CCL3/MIP-1α (myocardium), CCL1/I-309 and CXCL9/Mig (valvular tissue)
6. T cells infiltrating the valve migrate predominantly along CXCL9/Mig chemokine gradients

4. T Cell-Mediated Injury

• Intralesional T cell clones from valve tissue of RHD patients show 63.2% reactivity against human light meromyosin (LMM) peptides - the major cardiac myosin autoantigen
• 34% of these T cell clones show cross-reactivity patterns: myosin + valve proteins; myosin + streptococcal M5 peptides; or all three
• CD4+ T cells activated by myosin epitopes can also trigger broad recognition of valvular proteins with structural similarity (bystander activation)
• Within the Aschoff body, cytokines from stimulated T cells lead to macrophage activation - producing the characteristic Anitschkow cells

5. The Aschoff Body (Pathognomonic Lesion)

• Central zone of fibrinoid necrosis
• Surrounded by lymphocytes (primarily T cells), scattered plasma cells
• Anitschkow cells (pathognomonic): plump activated macrophages with abundant cytoplasm and nuclei showing centrally condensed chromatin in a slender, wavy ribbon pattern - the "caterpillar cells"
• Aschoff bodies can occur in any of the three cardiac layers during ARF, hence pancarditis

6. Acute Rheumatic Carditis - Layer by Layer

• Valvular involvement (valvulitis) follows myocarditis
• The mitral and aortic valves are most severely affected due to the higher mechanical stress they endure

7. Progression to Chronic RHD

1. Aschoff bodies are replaced by fibrous scar in chronic disease
2. Valve leaflets become permanently thickened and retracted
3. Commissural fusion narrows the valve orifice
4. Chordae tendineae thicken, shorten, and fuse
5. Neovascularization occurs in the leaflets (normally avascular)
6. Calcification superimposes on fibrosis, creating the classic "fishmouth" or "buttonhole" stenosis of the mitral valve

• Upregulated: vimentin, lumican, apolipoprotein-A1
• Downregulated: collagen-VI, haptoglobin-related protein, prolargin, biglycan, cartilage oligomeric matrix protein

8. Valve Distribution and Consequences

• Left atrial dilation → atrial fibrillation → mural thrombus formation → systemic emboli
• Pulmonary venous hypertension → pulmonary congestion → right ventricular hypertrophy and failure

9. Mechanism Summary (Flowchart)

GAS pharyngitis
       ↓
Innate immune activation (macrophages, dendritic cells, neutrophils)
       ↓
Antigen presentation → CD4+ T cell & B cell activation
       ↓
MOLECULAR MIMICRY
  ├── Antibodies: GAS carbohydrate (N-acetylglucosamine) ↔ laminin, myosin
  ├── T cells: GAS M protein ↔ cardiac myosin LMM, valve proteins
       ↓
Antibodies bind valve endothelium → complement activation
→ VCAM-1/VLA-4 upregulation → CD4+ T cell infiltration
       ↓
T cell cytokines (IFN-γ, TNF, IL-17) → macrophage activation → Aschoff bodies
       ↓
Fibrinoid necrosis of valve → verrucae (acute phase)
       ↓
Repeated episodes of ARF → organizing inflammation → fibrosis
       ↓
Commissural fusion + chordal shortening + calcification
       ↓
CHRONIC RHD: Mitral/aortic stenosis & regurgitation

Key Points

• The mechanism is autoimmune, not direct bacterial invasion; organisms are absent from cardiac lesions at the time of symptoms
• Only pharyngeal GAS (not skin) triggers ARF - the pharynx's lymphoid environment is uniquely permissive for the cross-reactive immune response
• Genetic susceptibility determines who among infected individuals develops ARF (estimated 3-6% of the population is susceptible)
• The deforming fibrotic lesions result from healing and scarring after acute inflammation, explaining why repeated episodes cause cumulative valve damage
• Secondary prophylaxis with penicillin to prevent recurrent GAS pharyngitis is the most effective intervention to halt progression