Pathogenesis of Tuberculosis — Comprehensive MD Exam Answer (15 Marks)

I. INTRODUCTION

1. Transmission and initial infection
2. Innate immune response (and bacterial evasion)
3. Adaptive immunity and granuloma formation
4. Outcomes: latency vs. active disease (primary and secondary/reactivation TB)

II. TRANSMISSION

• MTB is transmitted person-to-person via aerosolized droplet nuclei (1–5 μm in diameter) generated by coughing, sneezing, or talking by an individual with active pulmonary TB.
• Particles of this size bypass mucociliary defenses and reach the terminal alveoli.
• Infectiousness depends on: severity of cough (promoted by sulfolipids in the mycobacterial cell envelope) and bacterial burden. Cavitary lesions, containing 10⁷–10⁹ bacilli, are the most infectious.
• On average, one infectious person infects 3–10 contacts per year; in household exposure, 25–50% of contacts become infected.

Goldman-Cecil Medicine, p. 3251

III. INNATE IMMUNE PHASE — EARLY EVENTS

Step 1: Alveolar macrophage uptake

• Inhaled bacilli are phagocytosed by alveolar macrophages via pattern recognition receptors (PRRs), including toll-like receptors (TLR-2, TLR-4, TLR-9), mannose receptors, and complement receptors (CR3/Mac-1).
• MTB is taken up into a phagosome.

Step 2: Immune evasion within the macrophage

• Despite uptake, MTB survives and replicates within the macrophage, killing it eventually, and is then taken up by newly recruited macrophages — amplifying infection.

Step 3: Recruitment of inflammatory cells

• Over days, monocyte-derived macrophages, interstitial macrophages, and neutrophils are recruited to the site.
• However, these also fail to control MTB replication, allowing further dissemination.
• Infected dendritic cells travel to draining lymph nodes and present MTB antigens, initiating adaptive immunity.

Goldman-Cecil Medicine, p. 3251; Robbins Pathologic Basis of Disease, p. 353

IV. ADAPTIVE IMMUNE PHASE — GRANULOMA FORMATION

T-cell priming

• The interval from initial infection to a positive tuberculin skin test (TST) or IGRA is 2–8 weeks — this delay allows MTB to disseminate largely unhindered.
• MTB antigens are presented by dendritic cells → prime and expand antigen-specific CD4+ Th1 T cells.
• IL-12 (from macrophages/DCs) drives Th1 differentiation.
• Activated Th1 cells secrete IFN-γ → the critical cytokine that activates macrophages to upregulate bactericidal capacity (increased production of reactive oxygen species, reactive nitrogen intermediates/nitric oxide via iNOS, and lysosomal enzymes).
• TNF-α is essential for granuloma formation and maintenance.

Granuloma formation — the histopathologic hallmark

• Center: Epithelioid macrophages (modified macrophages with abundant pale cytoplasm) and Langhans-type multinucleate giant cells (nuclei arranged in horseshoe or peripheral pattern)
• Surrounding zone: CD4+ and CD8+ T lymphocytes
• Outer rim: Fibroblasts and collagen

• The center of the granuloma undergoes caseous necrosis — a distinctive cheese-like, pale, firm necrosis, unique to TB (and few other granulomatous infections).
• Unlike liquefactive necrosis (pus), caseous material is semi-solid and contains dead cells, lipids from bacilli, and proteinaceous debris.
• Caused by a combination of: delayed-type hypersensitivity (DTH) reaction and direct cytotoxic T-cell activity.
• The caseous center is relatively hypoxic and acidic — inimical to MTB replication — but may also harbor dormant bacilli.

Critical point for exams: Patients on TNF-α inhibitors (e.g., infliximab for RA) fail to form and maintain granulomas → highest pharmacological risk for TB reactivation. Similarly, HIV infection (CD4 depletion) → poorly organized or absent granulomas → progressive/disseminated TB.

Goldman-Cecil Medicine, p. 3251; Robbins & Kumar Basic Pathology, p. 476

V. OUTCOMES AFTER PRIMARY INFECTION

Exposure to MTB
       ↓
Innate immune clearance (~few individuals)
       ↓ (most)
Primary TB infection
       ↓
Adaptive immunity develops (2–8 weeks)
       ↓
95% → Controlled → Latent TB infection
  5% → Progressive primary TB (immunocompromised, infants, elderly)
       ↓ (latent)
~10% lifetime risk of reactivation → Secondary/Reactivation TB

VI. PRIMARY TUBERCULOSIS — MORPHOLOGY

Ghon Focus

• In a previously unexposed individual, inhaled bacilli implant in the distal airspaces of the lower upper lobe or upper lower lobe, close to the pleura.
• A 1–1.5 cm gray-white area of consolidation with central caseous necrosis forms → this is the Ghon focus.

Ghon Complex (Primary Complex)

• Bacilli travel via lymphatics to regional (hilar) lymph nodes → these also undergo caseous necrosis.
• The triad of: Ghon focus + lymphangitis + hilar lymphadenopathy = Ghon complex (also called the primary complex).
• In 95% of immunocompetent individuals: the Ghon complex undergoes progressive fibrosis and calcification → Ranke complex (visible on radiograph as calcified parenchymal and nodal lesions).
• Despite hematogenous seeding of other organs during this phase, no distant lesions typically develop.

Robbins & Kumar Basic Pathology, p. 476; Goldman-Cecil Medicine, p. 3251

Histology

• Caseating granulomas: Epithelioid macrophages + Langhans giant cells + peripheral lymphocytes + central caseous necrosis.
• Non-caseating granulomas may also occur in early or contained lesions.
• In immunocompromised hosts: sheets of macrophages filled with bacilli, no granulomas (anergic pattern).

VII. LATENT TB INFECTION

• Most often, adaptive immunity controls but does not eradicate the bacilli.
• Organisms remain viable but dormant within granulomas (particularly in macrophages).
• TST/IGRA positive; chest X-ray may be normal or show calcified Ranke complex.
• Lifetime reactivation risk: ~10% (half in the first 2 years; significantly higher in HIV+).

VIII. SECONDARY (REACTIVATION) TUBERCULOSIS

Mechanism of reactivation

• Waning immunity (aging, malnutrition, HIV, diabetes, immunosuppressive drugs, silicosis, malignancy) allows dormant bacilli to reactivate.
• In high-prevalence areas, exogenous reinfection may also cause secondary TB.
• Because the host is already sensitized, the adaptive immune response (DTH) is rapid and brisk — producing more tissue destruction and less lymph node involvement than primary TB.

Classic sites

• Apex of the upper lobes (Simon foci — seeded during primary bacteremia; high oxygen tension favors MTB growth).
• Both lungs may be involved; apical distribution is characteristic.

Progression and cavitation

1. Apical lesion: caseating granuloma → central caseous necrosis.
2. Caseous material liquefies (due to proteolytic enzymes from activated macrophages).
3. Liquefied material drains into a bronchus → cavity formation (the hallmark of secondary TB).
4. Cavities have: inner necrotic wall (rich in bacilli, up to 10⁹/cavity) → highly infectious when coughed up.
5. Erosion into bronchial vessels → hemoptysis.

Consequences of cavity formation

• Bronchogenic spread: Bacilli enter the bronchial tree → spread to other lung segments → tuberculous bronchopneumonia.
• Pleural spread: Direct extension → tuberculous pleuritis/empyema.
• Hematogenous dissemination: Erosion into blood vessels → miliary TB (multiple small lesions, 1–3 mm, in many organs, resembling millet seeds).
• Lymphatic spread: Hilar/mediastinal adenopathy (less prominent than in primary TB).

IX. COMPLICATIONS AND EXTRAPULMONARY SPREAD

Miliary TB

• Hematogenous dissemination → seeding of liver, spleen, bone marrow, kidneys, meninges, adrenals.
• Microscopically: numerous small caseating granulomas.
• Most dangerous in immunocompromised and infants.

X. ROLE OF HYPERSENSITIVITY IN TB PATHOGENESIS

1. Protective immunity (Th1/IFN-γ/TNF-α axis): Contains infection, forms granulomas, prevents dissemination.
2. Immunopathology (Type IV/DTH hypersensitivity): The same activated macrophages and cytotoxic T cells that kill bacilli also cause tissue destruction — caseation, cavitation, and fibrosis.

Koch phenomenon: Re-inoculation of a sensitized host causes a rapid, localized necrotic reaction — evidence that TB tissue damage is immune-mediated (DTH), not purely bacterial.

• Loss of hypersensitivity (tuberculin-negative in known MTB-infected patient) = ominous sign of fading immunity → harbinger of severe disseminated disease.

Robbins & Kumar Basic Pathology, p. 476

XI. SUMMARY FLOW CHART

Inhalation of MTB droplet nuclei (1–5 μm)
          ↓
Alveolar macrophage phagocytosis
          ↓
MTB evades phagolysosome fusion → survives intracellularly
          ↓
Hematogenous + lymphatic dissemination (before adaptive immunity)
          ↓
DCs → hilar lymph nodes → CD4+ Th1 priming (2–8 weeks)
          ↓
IFN-γ + TNF-α → macrophage activation + granuloma formation
          ↓
Caseating granuloma → Ghon complex
          ↓
[95%] Fibrosis/calcification → Ranke complex → Latent TB
[5%] Progressive primary TB → miliary TB, meningitis
          ↓ (from latency, ~10% lifetime)
Reactivation (apical upper lobe) → cavitation → bronchogenic spread

XII. KEY EXAM POINTS (Quick Recall)

• Robbins, Cotran & Kumar Pathologic Basis of Disease (Robbins Pathology 10th Ed.)
• Robbins & Kumar Basic Pathology (11th Ed.)
• Goldman-Cecil Medicine (International Edition, 2-Vol Set), pp. 3250–3251