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  1. 1. CLASSIFICATION & IMMUNOPATHOLOGY OF LEPROSY Moderator- Dr Ram singh meena sir Presenter- Dr Teja ram
  2. 2. INTRODUCTION • Caused by Mycobacterium leprae. • It is highly contagious, but its morbidity is low • Affects mainly the skin and peripheral nerves. • Diagnosis is established based on skin and neurologic examination of the patient. • Early diagnosis is very important. • The timely and proper implementation of treatment will prevent sequelae and physical disabilities.
  3. 3. NEED FOR CLASSIFICATION • To know variation in the disease presentation, its course, prognosis and complication. • The correct classification helps to decide the treatment options. • The frequency and the type of leprosy reaction also become clear. • The infectivity of a case and its epidemiological importance can also be determined. • A uniform classification helps in communication with the other workers, sharing the ideas on a common platform and the comparison of data becomes more clear and realistic.
  4. 4. • Leprosy may be classified based upon • Bacteriological, • Immunological, • Clinical or Histopathological • Parameters individually or by using a correlated combination of these. • Bacteriological Criteria: BI is a measure of the density of the organisms • Immunological Criteria :CMI against M. leprae, is measured indirectly by lepromin testing and the patients classified as lepromin positive (good immunity) to lepromin negative (poor immunity) on a standard scale.
  5. 5. • Histopathological Criteria : • It is most definitive criteria for defining the different entities. • The interpretations are not influenced by external factors, are less prone to the subjective errors . • However, it is not practicable to apply them universally over a large leprosy population. • Clinical Criteria : Based on the clinical features is the easiest to apply . Clinical features can be identified with some training by even a health worker in the field.
  6. 6. Classifications of leprosy 1. Pre-Manila classifications a) Danielssen & Boeck (1847) • 1) Elephantiasis graecorum tuberosa • 2) Elephantiasis anesthetosa • 3) Mixta b) Danielssen & Boeck (1848) 1) Nodular 2) Anesthetic c) Hansen & Looft (1895) 1) Tuberose (nodular) and 2) Maculoanesthetic d) Neisser (1903) 1) Lepra tuberosa 2) Lepra cutanae 3) Lepra nervosum
  7. 7. 2. The Strassbourg classification (1923) : based on location of bacilli in various tissue of the body. 1. Skin leprosy 2. Nerve lepros 3. Mixed 3. The Manila classification (1931): • International system of classification for the first time use • This formed basis of future classifications 4. The Cairo classification (1938) 5. The Pan American classification (1946) 6. The Havana classification (1948) 7. WHO expert committee (1952)
  8. 8. 8. The Madrid classification (1953) 9. The Indian classification (1955) 10. Ridley-Jopling classification (1966) 11. The New IAL classification (1981) 12. Job & Chacko classification 13. WHO classification (1982) 14. WHO classification (1988) 15. WHO classification based on the number of lesions (1998) 16. Classification under NLEP, India (2009)
  9. 9. CLASSIFICATION PREMANILA NODULAR ANAESTHETIC MANILA 1931 CUTANEOUS NEURAL MIXED CAIRO 1938 Cutaneous' replaced by the term 'lepromatous' and neural' was retained Disadvantages. Use of the term 'neural', because nerves are affected in both types. Neuromacular simple Neuromacular tuberculoid Neuroanesthetic PANAMERICAN 1946 Based on histological grounds. term neural was replaced by the tuberculoid. Disadvantages. Use of the term Uncharacteristic leprosy Tuberculoid leprosy Lepromatous leprosy Uncharacteristic leprosy HAVANA 1948 Uncharacteristic' was replaced by 'indeterminate' Tuberculoid leprosy Lepromatous leprosy Indeterminate leprosy
  10. 10. RECOMMENDATION OF THE W.H.O EXPERT COMMITTEE 1952 Recommended adding a borderline group to the three types accepted at Havana. Therefore, leprosy was divided into four main classes: 1. Lepromatous leprosy 2. Tuberculoid leprosy 3. Borderline leprosy 4. Indeterminate leprosy
  11. 11. The Madrid classification (1953) Two types : Definite and typical clinical entities 1. Lepromatous type (L) • Macular • Diffuse • Infiltrated • Nodular • Neuritic, pure (?) 2. Tuberculoid type (T) • Macular (Tm) • Minor tuberculoid (micropapuloid) (Tt) • Major tuberculoid (plaques, annular lesion etc.) (TT) • Neuritic, Pure (Tn) Two Groups’ were less distinct, nontypical entities 3. Indeterminate group (I) • Macular (Im) • Neuritic type (In) 4. Borderline (Dimorphous) group(B) • Infiltrated • (Others?) The major problem with this classification was that the pure neuritic type was included in I, L and T groups.
  12. 12. The Indian classification (1955) Almost similar to the Madrid classification, but maculoanesthetic and pure neuritic were kept as separate categories. The classification was kept simple for field workers. 1. Lepromatous (L) 2. Tuberculoid (T) 3. Maculoanesthetic (MA) 4. Polyneuritic (P) 5. Borderline (B) 6. Indeterminate (I)
  13. 13. Ridley-Jopling classification (1966) • The main advantage It is based on bacteriological, immunological, histopathological and clinical features of leprosy. • For these reasons, this classification has been widely accepted. • The main drawback is that there is no specific place for the indeterminate and pure neuritic leprosy in the spectrum. 1. Tuberculoid leprosy (TT) 2. Borderline tuberculoid leprosy (BT) 3. Mid-borderline leprosy (BB) 4. Borderline lepromatous leprosy (BL) 5. Lepromatous leprosy (LL)
  14. 14. • The New IAL classification (1981) MA Leprosy was merged with T 1. Lepromatous (L) 2. Tuberculoid (T) 3. Polyneuritic (P) 4. Borderline (B) 5. Indeterminate (1) WHO classification (1982) Base on Bacterial index 1. Paucibacillary leprosy (BI<2+) 2. Multibacillary leprosy (BI≥2+)
  15. 15. WHO classification (1988) . • Categorized into PB or MB leprosy depending upon Slit-skin smears • All the patients with demonstrable acid fast bacilli in SSS without any reference to bacterial index were to be categorized as multibacillary 1. Paucibacillary leprosy: It included only smear negative cases belonging to • Indeterminate (I), tuberculoid (TI), • and borderline tuberculoid (BT) cases as classified under Ridley-Jopling classification and • Indeterminate (I), and tuberculoid (T) cases under Madrid classification 2. Multibacillary leprosy: included all • Mid-borderline, borderline lepromatous , and lepromatous under Ridley-Jopling classification • Borderline (B) and lepromatous (L) cases under the Madrid classification • Any other smear positive case
  16. 16. WHO classification based on the number of lesions (1998) • Based upon the total number of leprosy lesions in the patient and categorized into PB and MB types . • If skin smear facilities are available or any patient, the smear positive cases should be placed in multibacillary type irrespective of the number of lesions. • With the use of this classification, some MB cases may wrongly be classified into PB types resulting in under treatment. • Paucibacillary single lesion leprosy (SLPB); • Paucibacillary leprosy (2-5 skin lesions); • Multibacillary leprosy- six or more skin lesions and , also, all smear positive cases. • WHO 2017
  17. 17. Classification under National Leprosy Eradication Programme, India (2009) • Number of nerves involved also consideration along with the skin lesion count. • If skin smear is positive, irrespective of number of skin and nerve lesions, the disease is classified as MB leprosy; • But if skin smear is negative it is classified on the basis of the number of skin and nerve lesions.
  18. 18. 1. Paucibacillary (PB) • Skin lesions - 1-5 lesions • Peripheral nerve involvement - No nerve or only one nerve with or without 1-5 lesions • Skin smears - Negative at all sites 2. Multibacillary (MB) • Skin lesions – 6 and above • Peripheral nerve involvement - More than one nerve irrespective of the number of skin lesions • Skin smears - Positive at any site
  19. 19. ETIOPATHOGENESIS M. leprae, was identified by Norwegian physician Gerhard Armauer Hansen in 1873. Therefore, it is also called Hansen’s bacillus. • class Schizomycetes • order Actinomycetales • family Mycobacteriaceae • genus Mycobacterium It is a straight or slightly curved rod, with rounded ends, measuring 1.5-8 microns in length by 0.2-0.5 micron in diameter. In smears, stains red with carbol fuchsin using the Ziehl-Neelsen (ZN) stain, acid-alcohol resistant because of mycolic acid.
  20. 20. • Arranged in parallel chains, just like cigarettes in a pack, forming the globi. • M. leprae infects mainly macrophages and Schwann cells. • It has never been grown in artificial media. • Reproduction (about 12-14 days) in the foot pads of mice. • 27 ºC and 30 ºC. • Cooler areas preferred skin, peripheral nerves, testicles, and upper airways, and lower visceral involvement. • Immune privilege sites- scalp, axilla, groin, transverse band of skin over lumbosacral area, midline back.
  21. 21. Ultrastructural characteristics
  22. 22. IMMUNOPATHOLOGY • Ability of the host to develop different degrees of cellular immune response to M. leprae, led to the spectral concept of the disease. • The first barrier to infection with M. leprae is innate immunity, represented by the integrity of epithelia, secretions, and surface immunoglobulin A(IgA). • In addition, natural killer (NK) cells, cytotoxic T lymphocytes, and activated macrophages.
  23. 23. Genes involved in the immuno-pathogenesis of leprosy 1. MHC genes 2. Cytokine genes 3. Low molecular weight Proteases 2 and 7 4. Transporters associated with peptide loading 1 and 2 5. Protein tyrosine phosphatase non-receptor type 22 6. Single-nucleotide polymorphism involving lymphotoxin-a, VIT D receptor (VDR), TNF-a, IL-10, IFN-Y, HLA genes, and TLR1
  24. 24. • leprosy patients may have different MHC patterns with HLA variability. • The spectrum of disease at one end • little or no bacillary proliferation, • positive lepromin reaction and • epithelioid granulomas. • Other end • .Bacillary proliferation, • lepromatous or foam cell granulomas and • negative lepromin reaction. • The dual response of macrophages and monocytes to leprosy bacilli may be responsible for the clinico-pathological bipolarity of leprosy
  25. 25. Key steps in the immunopatho-genesis of leprosy 1. The portal of entry for M. leprae is via the nose and then it spreads to the skin and nerves via the circulation. 2.Invasion and multiplication in dermal lymphatics and vascular cells play a major role in the hematogenous spread. 3. M. leprae invades peripheral nerves via blood vessels of the perineurium.
  26. 26. 4. The clinical phenotype depends on the immunological response mounted by the host. 5. In tuberculoid leprosy the monocytes destroy the organism completely, whereas in lepromatous leprosy, microvacuolated monocytes (phagocytes) with bacillary debris may persist. 6. The specific response in Th1 or Th2 is dependent on the cytokines/chemokines that are released after the mycobacterial lipoproteins are recognized by the Toll- like receptors on innate immune cells following uptake of M leprae by the dendritic cells. conti.
  27. 27. 7. TLR1 and TLR2 activation leads to Th1-type cytokines, and Th2-type cytokines are associated with inhibition of this activation. monocytes and DCs in TT lesions have a stronger expression of TLR1 and TLR2 as compared with LL lesions. 8. The CD4/CD8 T-cell ratio is 2:1 in tuberculoid leprosy lesions, leading to a Th1-like profile with secretion of pro-inflammatory cytokines IL-2, IFN-y, TNF and IL-12 that induce strong CMI and phagocytic activity. 9. In lepromatous leprosy there is weak CMI, but strong humoral response, CD4/CD8 ratio is 1: 2, and Th2-like profile characterized by anti-inflammatory cytokines IL-4 and IL-10. conti.
  28. 28. 10. A polyclonal B-cell response and autoantibodies production with no effect on M. leprae results in formation of immune complexes. 11. The borderline forms are immunologically unstable, shifts between the two polar forms occur; causing reactions that are a feature of the borderline states. conti.
  29. 29. Tuberculoid lesions Lepromatous lesions • Predominance of T helper (CD4+) • CD4:CD8 ratio of 2:1, the same ratio found in blood • CD4+ cells in tuberculoid lesions express the phenotype memory-T cells (CD45R0+) • Predominance of the population of T CD8+ lymphocytes with CD4:CD8 ration of 1:2 • most CD8+ cells belong to the CD28- phenotype, suggesting that they are T-suppressor cells • cytokines involved • interferon-gamma (IFN-γ), interleukin-2 (IL-2), and TNF-α. • Suppressor cytokines of macrophage activity • interleukin-4 (IL-4), interleukin-5 (IL-5), and IL-10 • Th1 pattern • enhancers of cell-mediated immunity and reduced proliferation of M. leprae. • Th2 pattern • Contribute to the stimulation of B lymphocytes, with increased humoral immune response and production of antibodies • IL-7 and IL-12 - growth and differentiation factors of T cells • IL-13 seems to play a role in the immunosuppression of lepromatous lesions. • In type 1 reaction, sudden influx of CMI and T CD4+ cells and production of IL-1, TNF-α, IL-2, and IFN-γ in the lesions, Th1 response pattern. • In ENL, immune complexes reaction, characterized by increased IL-6, IL-8, and IL-10 in the lesions, suggesting Th2 response
  30. 30. Divergent macrophage pathways for antimicrobial activity versus phagocytosis • Toll like receptor (TLR) induced IL-15 triggers ↓ • Upregulation of the Vit D receptor (VDR) and CYP27b1. ↓ • CYP27b1 converts inactive 25D3 to active 1, 25 D3 which can then ↓ • Bind the to VDR and initiate transcription of cathelicidin and in conjunction with IL-1, ↓ • Results in Defensin beta 4 production. ↓ • Cathelicidin initiates autophagy and autophagolysosomal fusion resulting in the killing of mycobacteria.
  31. 31. Phagocytic pathway • IL-10 induces ↓ • A scavenger receptor program ↓ • Resulting in enhanced phagocytosis of mycobacteria and oxidized lipid ↓ • Resulting in foam cell formation and microbial persistence. • IL-10 and IL-4 can suppress TLR expression.
  32. 32. SCHWANN CELL (SC) • Initial Target: Laminin a2 -> PGL 1 of M. leprae binds to it • Laminin a2 seen in Schwann cell, Striated muscle, Placenta • H1p/LBP21-> potentiates interaction of M. leprae with SC • SC processes antigen & presents it through MHC - II • CD4+ T Cells then get activated & releases ILs-> leads to • Macrophage activation -> kills bacteria • Concurrent nerve demyelination occurs due to inflammatory events
  33. 33. MECHANISM OF ENTRY INTO NERVE • SC membrane has laminin 2 and a laminin 2 receptor (a-dystroglycan) • Laminin 2 has a G domain on the a2 chain • PGL-1 of M. leprae binds to this domain. • This PGL-Laminin-2 complex interacts with a-dystroglycan, leading to uptake of M. leprae. • Laminin binding protein 21 (LBP21) of M. leprae also binds to a-DG on SC membrane, leading to its entry.
  34. 34. Important innate immune cells Macrophages: • Role in immune response to M. leprae • Phagocytic and antimicrobial function • M1 M ↑ in TT spectrum: Antimicrobial • M2 M ↑ in LL spectrum: Phagocytic • Cytokine release modulates the adaptive Th response
  35. 35. Dendritic cells (DC) •Professional antigen presenting cells; release proinflammatory cytokines • Marked deficit in LL • Activation and maturation of DCs inhibited by M. leprae • PGL-I impairs DC maturation and activation
  36. 36. Keratinocytes • ↑ ICAM expression in TT • Upregulation of human beta-defensins 2 and 3 on stimulation with M. leprae • Major producer of CXCL-10 in TT • Present M. leprae to CD4+ T cells
  37. 37. PGL-1 • It is a major glycolipid antigen of M. leprae. • Is unique to M. leprae. • It is part of lipid capsule. • Accounts for 2% of mass of bacilli • Has an antigenically distinct trisaccharide linked to phenol, which is linked to 29C phthiocerol, which are attached 2 mycoserosic acids.
  38. 38. PGL-1 (contd.) • Specific IgM antibodies develop to it, more at lepromatous spectrum. • Antigen specificity resides in terminal sugars, which has been exploited for serodiagnosis. • Helps in entry and colonization within phagocytes. • Once inside phagocytes, it can scavenge ROS and helps the bacteria survive intracellularly.
  39. 39. REACTIONAL STATES • Leprosy reactions result from changes in the immune balance between the host and M. leprae. • Such reactions are acute episodes that primarily affect the skin and nerves, being the main cause of morbidity and neurological disability. • They may occur during the natural course of the disease, throughout treatment or after it. • They are classified into two types: type 1 reaction and type 2 reaction.
  40. 40. TYPE 1 REACTION • Delayed-type hypersensitivity reactions. • It M/C occurs in the immunologically unstable borderline forms of leprosy (BT, BB & BL) • Expression of MHC II on the surface of the infected cells leading to antigen presentation resulting in cell damage mediated by CD4 lymphocytes through cytokines such as TNF alfa. • Th1 response ensues and pro-inflammatory cytokines, such as IFN-Y, IL-12, IL- 8, monocyte chemoattractant protein (MCP)1 • And inducible nitric oxide synthase (iNOS), are expressed in the lesions.
  41. 41. Conti. T1R • Rise in serum TNF-a levels is observed 4-8 weeks prior to T1R, highlighting the key role of TNF-a in leprosy immunopathogenesis. • A microsatellite polymorphism in the tlr2 gene have been found to predispose to an increased frequency of T1R; • Increase in Tregs during T1R. It perform the role of controlling the exacerbated CMI seen in T1R with beneficial consequences for the host • On the other hand, Tregs to be depleted in T2R. The unregulated inflammation may cause extensive clinical manifestations associated with widespread tissue damage.
  42. 42. cont T1R • Th17, an increase in T2R is consistently and in T1R variably • The cytokine much higher levels in T1R skin lesions than T2R lesions, • T1R is a hyperimmune response characterized by a selective increase of CD4+ IFN- gama producing cells resulting in the clearing of bacilli and concomitant tissue damage,
  43. 43. TYPE 2 REACTION • T2R is immune complex mediated affects patients with BB, BL, and LL forms . • It is initiated by the release of mycobacterial antigens, resulting in immune complex formation and activation of complement pathway and mononuclear cells releasing cytokines mediating tissue damage. • Monocytes also play a significant role in leprosy reactions and associated tissue damage.
  44. 44. conti.T2R • It is possible that T-cell activation leading to cytokine-mediated killing of bacilli may release pathogen-related antigens which then bind to existing antibodies to create immune complexes. • There are reports of increased absolute neutrophil count, in ENL. • IFN-y is the hallmark cytokine for T2R.
  45. 45. THANK YOU

Hinweis der Redaktion

  • The cell wall attached to the plasma membrane is composed of peptidoglycans bound to branched chain polysaccharides, consisting of arabinogalactans, which support mycolic acids, and lipoarabinomannan(LAM),
    . Lipoarabinomannan (a major lipoglycan of the cell wall envelope)—resistance to oxidative metabolites;
    2. Mycolic-acid glycolipids, wax D, and trehalose dimycolate (cord factor)—granuloma formation and adjuvant activity;
    3. Sulfatides—inhibition of phagolysosome fusion.

    The capsule, the outermost structure, has lipids, especially phthiocerol dimycocerosate and phenolic glycolipid (PGL-1), which has a trisaccharide bound to lipids by a molecule of phenol.