Pathogenesis of Tuberculosis

1. Introduction

2. Causative Organism

3. Transmission

• Route: Inhalation of airborne droplet nuclei (1–5 μm) from an individual with active pulmonary TB
• Infectious dose: As few as 1–3 bacilli can initiate infection
• Target: Alveolar macrophages in the distal airspaces (lower lobe upper segment / upper lobe lower segment)

4. Pathogenesis — Step-by-Step Sequence

Fig 11.34: Sequence of events in primary pulmonary tuberculosis — Robbins & Kumar Basic Pathology

Phase A: Before Activation of Cell-Mediated Immunity (First 3 weeks)

Step 1 — Entry into Macrophages

• Inhaled bacilli are engulfed by alveolar macrophages via receptor-mediated phagocytosis
• Key receptors: mannose receptor (binds mycobacterial cell wall mannose residues), complement receptor 3 (CR3/CD11b) (binds C3b-opsonized bacteria), and scavenger receptors
• Dendritic cells are also infected and carry organisms to draining lymph nodes

Step 2 — Intracellular Survival and Replication

• M. tuberculosis arrests phagosomal maturation and blocks phagolysosome fusion
• Mechanism: The bacterium recruits host protein coronin to the phagosome membrane → coronin activates the phosphatase calcineurin → inhibits phagosome-lysosome fusion
• Result: Bacteria replicate unchecked within phagocytic vacuoles, protected from lysosomal microbicidal mechanisms
• During these first 3 weeks, bacilli proliferate in alveolar macrophages and air spaces → bacteremia with seeding of multiple organs
• Clinically: most patients are asymptomatic or have a mild flu-like illness

Step 3 — Innate Immune Recognition (PAMPs & TLRs)

• Mycobacterial lipoarabinomannan (LAM) → binds TLR2
• Unmethylated CpG nucleotides → bind TLR9
• These interactions trigger production of pro-inflammatory cytokines, initiating the bridge to adaptive immunity

Phase B: Adaptive (Cell-Mediated) Immunity (From ~3 weeks)

Step 4 — Antigen Presentation and Th1 Differentiation

• Infected dendritic cells migrate from the lung to draining hilar lymph nodes
• Mycobacterial antigens are presented to CD4+ T cells via MHC class II
• Macrophages secrete IL-12 and IL-18 → drive differentiation of naïve CD4+ T cells into Th1 cells
• TLR2 stimulation by mycobacterial ligands promotes IL-12 production

Step 5 — Th1-Mediated Macrophage Activation and Bacterial Killing

Importance of TNF: Patients on anti-TNF therapy (rheumatoid arthritis, IBD) have markedly increased risk of TB reactivation.

Step 6 — Granuloma Formation (The Hallmark Lesion)

• IFN-γ activates macrophages → transform into epithelioid histiocytes (large, pale, eosinophilic cells with abundant cytoplasm)
• Epithelioid cells aggregate into a granuloma; some fuse to form Langhans giant cells (peripheral horseshoe/arc arrangement of nuclei) or foreign-body giant cells
• Caseous necrosis develops at the center — a creamy white, cheese-like material representing liquefied cell debris and a hypersensitivity reaction
• Granulomas are surrounded by a collar of lymphocytes and fibroblasts

Step 7 — Tuberculin (Delayed Hypersensitivity)

• The same Th1 response produces delayed-type hypersensitivity (Type IV)
• Detectable by the tuberculin skin test (Mantoux/PPD) or IGRA (in-vitro IFN-γ release assay)
• A positive test signals T-cell sensitization — NOT necessarily active disease
• Tuberculin conversion appears at ~3–8 weeks post-infection
• Loss of tuberculin positivity in an infected patient is an ominous sign of waning immunity

5. Primary Tuberculosis (Ghon Complex)

• Progressive fibrosis → calcification (Ranke complex)
• Organisms become latent (dormant in macrophages for decades)
• No further disease unless immunity wanes

• Occurs in overtly immunocompromised patients (HIV+ with CD4 <200, severe malnutrition, infants)
• Resembles acute lobar pneumonia — lower lobe consolidation, hilar lymphadenopathy, pleural effusion
• May progress to miliary TB (hematogenous dissemination) or tuberculous meningitis

6. Latent TB

• After primary infection, viable but non-replicating organisms persist in macrophages (especially in the lung apex — higher oxygen tension favors dormancy)
• Patient is asymptomatic, non-infectious
• Lifetime risk of reactivation: ~5–10% in immunocompetent individuals
• Risk rises to 10–16% per year in HIV-infected patients

7. Secondary (Post-primary / Reactivation) Tuberculosis

Fig 8.27: Natural history and spectrum of TB — Robbins, Cotran & Kumar Pathologic Basis of Disease

• Occurs in a previously sensitized host: either reactivation of latent infection or exogenous reinfection
• Due to preexisting hypersensitivity, the bacilli elicit a prompt, intense tissue response — rapid walling off of the focus
• Location: Classically the apex of the upper lobe (high O₂ tension favors bacterial growth)
• Regional lymph nodes are less prominently involved (unlike primary TB) due to rapid hypersensitivity response

Key Differences: Primary vs. Secondary TB

8. Host Susceptibility Factors

9. Summary of Key Cytokines and Molecules

10. Summary Flow Chart

Inhalation of M. tuberculosis
         ↓
Alveolar macrophage phagocytosis
(Mannose receptor + CR3)
         ↓
Phagolysosome fusion blocked (coronin/calcineurin)
Unchecked intracellular replication
         ↓ (first 3 weeks)
Bacteremia → seeding of organs (asymptomatic/flu-like)
         ↓
Dendritic cells migrate to hilar lymph nodes
Antigen presentation (MHC II) to CD4+ T cells
         ↓
IL-12/IL-18 → Th1 differentiation
         ↓
IFN-γ → macrophage activation
 • iNOS → NO          → mycobacterial killing
 • Autophagy          → intracellular clearance
 • Phagolysosome      → maturation restored
         ↓
TNF + chemokines → epithelioid histiocytes
         → Granuloma + caseous necrosis
         ↓
OUTCOME:
   95% → Ghon complex → fibrosis/calcification (Ranke) → Latent TB
   5%  → Progressive primary TB → Miliary TB / Meningitis
         ↓ (years later, if immunity wanes)
   Secondary TB → Apical cavitation → Active disease

Key Points for 15-Mark Exam

1. Virulence mechanism = phagolysosome fusion block via coronin-calcineurin pathway
2. Central cytokine = IFN-γ (from Th1 cells) — activates macrophages to kill bacilli
3. Tissue damage = same immune response (Th1 hypersensitivity) that protects also causes caseous necrosis
4. Ghon complex = Ghon focus + lymphangitis + hilar lymphadenopathy (triad)
5. Ranke complex = healed, calcified Ghon complex
6. 95% rule = 95% of primary infections are contained and become latent
7. Reactivation = upper lobe apex, rapid hypersensitivity response, cavitation
8. TNF antagonists → reactivation of latent TB (clinically important)
9. HIV → loss of CD4+ Th1 cells → absent granulomas → disseminated, progressive disease
10. Tuberculin positivity = evidence of sensitization (not disease); tuberculin negativity in infected patient = ominous sign of failing immunity