slide is review about leprosy and recent articles

1. CLASSIFICATION &
IMMUNOPATHOLOGY OF LEPROSY
Moderator- Dr Ram singh meena sir
Presenter- Dr Teja ram

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. 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. • 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. • 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. 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. 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. 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. 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. 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. 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. 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. 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. • 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. 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. 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. 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. 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. 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. • 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. Ultrastructural characteristics

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. 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. • 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. 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. 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. 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. 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.

30. 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

31. 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.

33. 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.

34. 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

36. 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.

37. 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

38. 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

39. 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

40. 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.

41. 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.

42. 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.

43. 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.

44. 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.

46. 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,

47. 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.

48. 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.

51. THANK YOU