ETIO-PATHOGENESIS AND

PATHOLOGY OF LEPROSY
• Leprosy, also known as Hansen's disease, is a
chronic infectious disease caused
by Mycobacterium leprae, a microorganism
that has a predilection for the skin and nerves.
Though nonfatal, leprosy is one of the most
common causes of nontraumatic peripheral
neuropathy worldwide.
• Mycobacterium leprae, the causative agent of
leprosy, was discovered by G. H. Armauer
Hansen in Norway in 1873.
 Mycobacterium leprae
• M. leprae, an acid-fast bacillus is a major human
pathogen. In addition to humans, leprosy has
been observed in nine-banded armadillo and
three species of primates. The bacterium can also
be grown in the laboratory by injection into the
footpads of mice.
• Mycobacteria are known for their notoriously
slow growth. With the doubling time of 14
days, M. leprae has not yet been successfully
cultured in vitro
 M. lepromatosis
• M. lepromatosis is a newly identified
mycobacterium which is described to cause
disseminated leprosy whose significance is still
not clearly understood.
 Transmission
• Two exit routes of M. leprae from the human
body often described are the skin and the
nasal mucosa. Lepromatous cases show large
numbers of organisms deep in the dermis.
• Fairly large numbers of M. leprae were found
in the superficial keratin layer of the skin of
lepromatous leprosy patients, suggesting that
the organism could exit along with the
sebaceous secretions.
 Transmission
• While the lepra bacillus of Hansen is generally
conceded to be the specific cause of the disease.
• The skin and the upper respiratory tract are most
likely, recent research increasingly favours the
respiratory route.
• The theory of direct hereditary transmission is
practically disproved.
• The precise manner in which leprosy is acquired
is as yet unsettled.
 Incubation Period
• Measuring the incubation period in leprosy was difficult
because of the lack of adequate immunological tools and
slow onset of the disease.
• The minimum incubation period reported is as short as a
few weeks and this is based on the very occasional
occurrence of leprosy among young infants.
• The maximum incubation period reported is as long as 30
years, or over, as observed among war veterans known to
have been exposed for short periods in endemic areas but
otherwise living in nonendemic areas.
• It is generally agreed that the average incubation period is
between three and ten years.
 Risk Factors
• Those living in endemic areas with poor
conditions such as inadequate bedding,
contaminated water, and insufficient diet, or
other diseases that compromise immune
function are at highest risk for acquiring M.
leprae infection.
• People that live in close contact with patients
who have untreated, active, predominately
multibacillary leprosy and people living in
countries with endemic leprosy are at an
increased risk of infection.
 HIV and Leprosy
• Unlike TB, HIV infection has not been reported to
increase susceptibility to leprosy, impact on
immune response to M. leprae, or to have a
significant effect on the pathogenesis of neural or
skin lesions to date.
• On the contrary, initiation of antiretroviral
treatment has been reported to be associated
with activation of subclinical M. leprae infection
and exacerbation of existing leprosy lesions likely
as part of immune reconstitution inflammatory
syndrome.
 Leprosy during pregnancy and puerperium

• Depression of Cell mediated immunity (CMI)

Sub-clinical disease may become overt
Established disease may worsens
Deterioration of nerve function
• Regaining of CMI - First six months of puerperium
Increased incidence of lepra reaction
• New born
Weigh less than baby of healthy mothers
High risk of getting infected with leprosy
 Genetic Determinants of Host
Response
• Human genetic factors influence the
acquisition of leprosy and the clinical course
of disease.
• Single-nucleotide polymorphism (SNP)
association studies showed a low
lymphotoxin-α (LTA)-producing allele as a
major genetic risk factor for early onset
leprosy.
 Genetic Determinants
• Other Single-nucleotide polymorphism SNPs
to be associated with disease and/or the
development of reactions in several genes,
such as vitamin D receptor (VDR), TNF-α, IL-
10, IFN-γ, HLA genes, and TLR1 .
 Genetic Determinants
• Linkage studies have identified polymorphic
risk factors in the promoter region shared by
two genes: PARK2 and PACRG.
• A study also suggests that NOD2 genetic
variants are associated with susceptibility to
leprosy and the development of reactions
(type I and type II).
 Infectious Agent
• Leprosy is cause by infection with an
intercellular pathogen known
as Mycobacterium leprae.
• M. leprae is a strongly acid-fast, rod-shaped
bacterium. It has parallel sides and rounded
ends, measuring 1-8 microns in length and
0.2-0.5 micron in diameter, and closely
resembles the tubercle bacillus.
Acid fast staining showing M. lerpae bacilli
• Besides humans, the only known reservoir is
the armadillo. It is thought that they are a
good host for Mycobacterium leprae because
of their low body temperature.
Picture of a Nine banded Armadillo
 Vector
• It is uncertain whether or not insects can act
as a vector for M. leprae.
 Pathogenesis:
M. Leprae

Enters Transient Bacillemia

Schwann cells, cooler places (Cutaneous nerves &

Peripheral nerves trunks of limbs and face)

Strong Immunological Response Weak immunological Response

M. Leprae multiply in Schwann

Nerves only: Pure Neural Leprosy cells or
Escape to skin: Skin lesions appear Engulfed Histiocytes – wandering
Lesions may heal spontaneously Macrophages
Affect other organs in the body
Insight Into B Lymphocytes & Plasma Cells

• Schwann cells (SCs) are a major target for

infection by M. leprae leading to injury of the
nerve, demyelination, and consequent disability.
• Binding of M. leprae to SCs induces
demyelination and loss of axonal conductance.
• Several studies have been performed on the
involvement of T cells in leprosy and more
recently have focused on genetic factors and
innate immune response.
• The clinical demonstration of the disease is
determined by the quality of host immune
response.
• Th1-type immune response helps to kill the
bacteria, but hosts are encroached upon when
Th2-type response is predominant.
• The bacteria have affinity to the peripheral
nerves and are likely to cause neuropathy. M.
leprae/laminin-alpha2 complexes bind to
alpha/beta dystroglycan complexes expressed on
the Schwann cell surface.
• It has been shown that M. leprae can invade SCs by a
specific laminin-binding protein of 21 kDa in addition
to PGL-1.
• PGL-1, a major unique glycoconjugate on the M.
leprae surface, binds laminin-2, which explains the
predilection of the bacterium for peripheral nerves.
• Mycobacterium leprae-induced demyelination is a
result of direct bacterial ligation to neuregulin receptor,
ErbB2 and Erk1/2 activation, and subsequent MAP
kinase signaling and proliferation.
• Macrophages are one of the most abundant
host cells to come in contact with
mycobacteria.
• Phagocytosis of M. leprae by monocyte-
derived macrophages can be mediated by
complement receptors CR1 (CD35), CR3
(CD11b/CD18), and CR4 (CD11c/CD18) and is
regulated by protein kinase.
 Pathogenesis contd
M. Leprae

Nerves Skin Other organs

In MB leprosy
Cutaneous Periph. Nerve
nerves Trunk

Loss of Sensory loss Macule Face

Sensation Weak/ Papule Eyes
Secretions of Paralysed
Nodule Testes
Cutan. glands Muscles
Infiltration Kidney
Vasomotor function Loss of
sweating / Bone
Hair follicles hairs
 TYPE 1 (REVERSAL) REACTIONS
• A T1R is characterised by the development of
acute inflammation in skin lesions or nerves or
both. Borderline leprosy is a strong risk factor
for the occurrence of T1Rs 4 but individuals
with polar forms of leprosy may also
experience T1Rs.
 TYPE 1 (REVERSAL) REACTIONS
• T1Rs are frequently recurrent and this can
lead to further nerve damage. Skin lesions
become acutely inflamed and oedematous
and may ulcerate.
• Oedema of the hands, feet and face can also
be a feature of a reaction but systemic
symptoms are unusual.
 TYPE 1 (REVERSAL) REACTIONS
• Acute neuritis if not treated rapidly and
adequately leads to permanent loss of nerve
function causing peripheral sensory and/or
motor neuropathy.
• Skin lesions develop scaling in the chronic
phase of T1R and may then mimic psoriasis,
dermatophyte infections and cutaneous T-cell
lymphoma.
PATHOLOGY OF TYPE 1 (REVERSAL)
REACTIONS
• T1Rs are delayed hypersensitivity reactions.
The dermatopathological features of acute
T1R are oedema, increased number of
lymphocytes in the dermis and loss of normal
granuloma organisation. As time passes there
is an increase in the number of Langhans’
giant cells.
• M. leprae antigens have been demonstrated in
the nerves and skin of patients experiencing
T1Rs, localised to Schwann cells and
macrophages.
• M. leprae infection may lead to the expression
of MHC II on the surface of the cells. This may
give rise to antigen presentation which
triggers CD4 lymphocyte killing of the infected
cell which is mediated by cytokines such as
tumour necrosis factor (TNF).
• T1Rs appear to be mediated via Th1
lymphocytes and cells from reactional lesions
express the pro-inflammatory cytokines
interferon gamma (IFN-γ) and interleukin 12
(IL-12).
 ERYTHEMA NODOSUM
LEPROSUM / T2Rs
• ENL or type 2 reaction is a serious, difficult to
manage immunological complication of
borderline lepromatous (BL) and lepromatous
leprosy (LL). The majority of patients with ENL
go on to develop several episodes over many
years, as multiple acute episodes or chronic
ENL.
 ERYTHEMA NODOSUM
LEPROSUM / T2Rs
• The cutaneous manifestation of ENL is
widespread crops of erythematous, inflamed
nodules and papules, which may be superficial
or deep.
 ERYTHEMA NODOSUM
LEPROSUM / T2Rs
• Ulcerated, necrotic, pustular and bullous
forms have also been reported. Some nodules
may persist as a chronic painful panniculitis
leading to fibrosis and scarring.
 PATHOLOGY OF T2Rs
• The inflammatory infiltrate in ENL is situated
in the dermis and the subcutis. The
predominant cell type is the neutrophil.
Eosinophils and mast cells may also be
present.
• Skin biopsies performed show fewer
neutrophils and increasing numbers of
lymphocytes, plasma cells and histiocytes,
representing a chronic inflammatory infiltrate.
 PATHOLOGY OF T2Rs
• Immune complexes are important in the
pathogenesis of ENL as demonstrated by the
presence of complexes of complement and M.
leprae antigen in cutaneous lesions.
 PATHOLOGY OF T2Rs
• There is evidence of a cell mediated immune
response in the pathogenesis of ENL. The
major T cell subtype in ENL is the CD4+ cell in
contrast to lepromatous leprosy where CD8+
cells predominate.
• TNF and IL-6 have been shown to be present
in skin lesions of ENL.
PRESENTATION
OF
LEPROSY
 Pathogenesis: Skin Lesions
Leprosy Lesions Exclude Leprosy

•One/ Few/ Many •Present since birth

•Small/ Large •Black / dark red / De-
pigmented
•Hypo- pigmented / reddish/ pale /
coppery •Itches
•Ill defined / well defined margins •Appears disappears suddenly
•Dry/ wrinkled / granular to shiny soft •Painful
succulent
•Scaly
•Sweating +/-
•Shows any seasonal variation
•Hairs – sparse/ fragile / absent
•Macule/ Papule/ nodular
 Nerve involvement
Stage I Stage II

•Incomplete / complete paralysis of

• Thickening of nerve trunk recent
origin
•Loss of sweating
• Pain & tingling along the •Loss of sensibility
nerve trunk
•Muscle weakness/ Paralysis

• Tenderness along the Stage III

course of nerve trunk •Complete Nerve Paralysis for 1 year/
more

• No evidence of loss of
nerve function •Recovery of Nerve function not
possible
Commonly affected Nerves
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