Note: Harsh Mohan's Textbook of Pathology is not available in this library's collection. The content below is drawn primarily from Robbins, Cotran & Kumar Pathologic Basis of Disease (the equivalent international pathology standard) and supplemented with Park's Textbook of Preventive & Social Medicine and other authoritative sources. The pathological concepts are identical to what Harsh Mohan covers.

Leprosy (Hansen Disease) - Pathology

Definition and Epidemiology

• Despite low communicability, ~200,000 new infections/year globally
• Endemic in Southeast Asia, East Africa, and Brazil
• M. leprae cannot be cultured in vitro; proliferates best at 32-34°C (temperature of human skin)
• Transmitted via human respiratory secretions; rare zoonotic transmission from armadillos

Pathogenesis

• Disseminates via blood but replicates primarily in cool tissues (skin, extremities)
• Virulence is based on cell wall properties; bacterial lipid PGL-1 is critical for host cell invasion
• Inhibits mitochondrial energy metabolism to evade immune response
• Secretes no exotoxins
• BCG immunization confers some cross-protection (similar enough to M. tuberculosis)

• In lepromatous leprosy, antibodies form immune complexes that can cause erythema nodosum, vasculitis, and glomerulonephritis

Classification

Ridley-Jopling Classification (Immuno-histological spectrum)

Note: The neuritic (pure neural) type has no skin lesions and does not fit into the Ridley-Jopling scheme - it is recognized in the Indian classification separately.

WHO Classification (for control programs)

Morphology / Histopathology

Tuberculoid Leprosy (Paucibacillary)

• Localized flat, red skin lesions that enlarge with irregular shapes
• Indurated, elevated, hyperpigmented margins with depressed pale centers (central healing)
• Skin lesions are anesthetic (loss of sensation)
• Asymmetric involvement of large peripheral nerves

• Well-formed epithelioid cell granulomas closely resembling tuberculosis (sarcoid-like granulomas)
• Granulomas enclose and destroy small peripheral nerve twigs
• Langhans giant cells may be present
• Bacilli are almost never found (paucibacillary) - reflects strong T-cell immunity
• Nerves show granulomatous destruction → skin anesthesia, muscle atrophy, chronic ulcers
• Facial nerve involvement → paralysis of eyelids → keratitis and corneal ulceration
• Can result in: contractures, paralyses, autoamputation of digits

Lepromatous Leprosy (Multibacillary)

• Symmetric skin thickening: macular, papular, or nodular lesions on face, ears, wrists, elbows, knees
• Coalescence of nodular lesions → leonine facies (lion-like face)
• Most skin lesions are hyposthetic or anesthetic
• Nasal lesions: persistent inflammation, bacilli-laden discharge
• Symmetric peripheral nerve invasion (ulnar, peroneal nerves)
• Testes destruction → sterility

• Large aggregates of lipid-laden foamy macrophages called:
  • Lepra cells (= Virchow cells / foam cells)
  • Filled with masses ("globi") of acid-fast bacilli
• Minimal lymphocytic inflammation around nerves (unlike tuberculoid)
• Lymph nodes: bacteria-filled foamy macrophages in paracortical (T-cell) areas with reactive germinal centers
• Spleen: aggregates in red pulp
• Liver: macrophage aggregates

Comparative Summary Table

Lepra Reactions

1. Type 1 (Reversal reaction): Occurs in borderline leprosy (BT, BB, BL); upgrading reaction due to sudden increase in cell-mediated immunity; existing lesions become inflamed
2. Type 2 - Erythema Nodosum Leprosum (ENL): Occurs in LL/BL; immune complex-mediated (Type III hypersensitivity); painful erythematous nodules, fever, systemic inflammation; can cause vasculitis and glomerulonephritis

Key Staining

• Ziehl-Neelsen (ZN) / Wade-Fite stain: Demonstrates acid-fast bacilli in lepromatous leprosy
• In tuberculoid leprosy, bacilli are not demonstrable on staining

Note: Harsh Mohan's Textbook of Pathology is not in this library's collection. The content below is drawn from Robbins, Cotran & Kumar Pathologic Basis of Disease, Harrison's Principles of Internal Medicine 22e, Goldman-Cecil Medicine, and Dermatology 5e - all of which carry the same pathological concepts that Harsh Mohan covers on this topic. The immunopathology of leprosy is a well-established framework consistent across all major pathology textbooks.

Classification and Immunopathology of Leprosy

Overview: The Immunological Spectrum Concept

"The histopathologic changes in nerve and skin - and thus the type of leprosy that develops - depend on the immunologic resistance of the person infected, in particular on the cell-mediated immune response to the bacillus and its antigens."

• Harrison's Principles of Internal Medicine 22e

A. Classifications of Leprosy

1. Ridley-Jopling Classification (1966) - THE STANDARD

• An early/pre-classification form is recognized: Indeterminate Leprosy (IL) - the earliest sign, characterized by infiltration by lymphocytes alone, with no granuloma formed yet
• TT and LL are the stable "polar" types - they show little change over time
• BT, BB, BL are unstable - can shift toward either pole, especially if untreated; BB is the most immunologically unstable and short-lived, mostly progressing toward LL if untreated
• The neuritic (pure neural) type - recognized in the Indian classification - has no skin lesions and does not fit into the Ridley-Jopling scheme

2. Indian Classification (Most used in field programs in India)

3. Madrid Classification

4. WHO Classification (for treatment/field use)

• PB corresponds broadly to: Indeterminate, TT, BT
• MB corresponds broadly to: BB, BL, LL

B. Immunopathology of Leprosy

The Fundamental Principle

Immunopathology at the Tuberculoid Pole (TT)

• IL-2, IFN-γ (Type II IFN), IL-12, IL-15, IL-17, TNF-α
• Th17 cellular response
• Activated M1 macrophages (classically activated)

• Dendritic cells recognize M. leprae via complement receptor → upregulate MHC class II + CD40L → produce IL-12
• IL-12 drives Th0 → Th1 differentiation
• IFN-γ activates macrophages → transform into epithelioid cells
• Epithelioid cells cluster to form well-organized granulomas with Langhans giant cells
• CD4+ T cells predominate in lesions; CD8+ cytotoxic T cells also participate
• TLR1 and TLR2 are strongly expressed on monocytes/dendritic cells → robust innate response
• Lepromin test: POSITIVE (delayed hypersensitivity reaction at 3-4 weeks = Mitsuda reaction)
• Bacilli are eliminated/controlled → paucibacillary disease
• Antibody production is LOW

• Granulomas destroy peripheral nerve twigs → anesthesia, muscle wasting, trophic ulcers
• High CMI = nerve destruction but low bacterial burden

Immunopathology at the Lepromatous Pole (LL)

• IL-4, IL-5, IL-10, IL-13, IL-22, TGF-β
• Type I IFNs (IFN-α, IFN-β) predominate (instead of type II IFN-γ)
• FOXP3+ regulatory T cells, CD8+ suppressor T cells
• Suppressed M2 macrophages (alternatively activated - foamy phenotype)

• Weak Th1 response → macrophages are not effectively activated
• Macrophages engulf bacilli but cannot kill them → bacilli proliferate intracellularly
• Macrophages become lipid-laden foamy macrophages = Lepra cells (Virchow cells)
• Lepra cells are packed with masses of bacilli called "globi"
• TLR1 and TLR2 expression is WEAK → poor innate activation
• M. leprae PGL-1 (cell wall lipid) actively suppresses T-cell responses and IFN-γ production
• M. leprae also inhibits mitochondrial energy metabolism to evade the immune response
• Lepromin test: NEGATIVE (anergy - no CMI to the bacillus)
• Bacilli proliferate unchecked → multibacillary disease
• Antibody production is HIGH but non-protective; antibodies are against PGL-1 antigen

• Minimal inflammation around nerves despite massive bacterial invasion
• Symmetric nerve damage due to direct invasion by bacilli
• Immune complex deposition → Type III hypersensitivity features (vasculitis, glomerulonephritis, ENL)

Immunopathology of Borderline Types

• BT: resembles TT but subepidermal grenz zone present; satellite lesions / pseudopodia; 3-10 lesions
• BB: annular lesions with "Swiss cheese" appearance (punched-out inner edge, ill-defined outer edge); most unstable, mostly progresses to LL if untreated
• BL: numerous copper-hued round/oval macules, symmetrical; moderate bacillary load

Genetic Susceptibility (Immunogenetics)

• HLA-DR2 and HLA-DR3 (MHC class II genes) influence which end of the spectrum a patient develops
• Susceptibility to tuberculoid leprosy mapped to chromosome 10p13
• SNPs in TNF-α and IL-10 genes have been identified
• Innate immunity genes: NRAMP1, TLR2, MICA, TNF-α, MRC1
• Adaptive immunity genes: HLA, TAP2, VDR, PTPN22

Nerve Damage Mechanism

• Binds to G domain of laminin alpha-2 chain on the Schwann cell-axon surface via a 21-kDa histone-like protein
• Invasion of Schwann cells and axons → demyelination + axonal degeneration
• In TT: nerve destruction by granuloma (immune-mediated)
• In LL: nerve destruction by direct bacillary invasion with minimal inflammation

Summary Comparison Table