LEPROSY

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LEPROSY

• Robert L. Modlin, M.D.
• Professor, Division of Dermatology, Department of
  Microbiology, Immunology and Molecular Genetics
• David Geffen School of Medicine at UCLA
• Boyer (MBI) 536
• x56214
• rmodlin_at_mednet.ucla.edu

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LEPROSY

• a disease of skin and nerves caused by the
  intracellular bacterium Mycobacterium leprae.
• discovered by Hansen in 1874, hence it is also
  known as Hansen's disease.

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REASONS TO STUDY LEPROSY

• the disease itself
• affects approximately one million people
  worldwide.
• health and economic burden on developing
  countries.
• targeted by World Health Organization for
  eradication.
• M. leprae is resistant to some antibiotic
  therapies (dapsone).
• need for a vaccine.
• clinical model for studying immunoregulation in
  humans.

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PREVALENCE OF LEPROSY

• a disease of developing countries.
• several hundred cases in Los Angeles, all
  immigrants.
• new cases in Louisiana and Texas, perhaps related
  to armadillo exposure.

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THE SPECTRUM OF LEPROSY
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IMMUNOLOGIC REACTIONS IN LEPROSY

• LEPROMIN OR MITSUDA REACTIONS
• 3 wk response to intradermal challenge with M.
  leprae
• organized granulomas
• standard measure of DTH in leprosy
• REVERSAL REACTIONS
• clinical upgrading, reduction in number of
  bacilli
• naturally occuring DTH response
• ERYTHEMA NODOSUM LEPROSUM
• no upgrading or clearance of bacilli
• immune complex deposition

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SKIN TESTING

• Patients are challenged with intradermal
  injection of M. leprae.
• Fernandez reaction - present at 48 hours.
• Mitsuda reaction
• occurs at three weeks.
• characterized by the presence of granulomas
  (organized collections of lymphocytes and
  macrophages).
• positive in tuberculoid patients, negative in
  lepromatous patients.

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DIAGNOSIS OF LEPROSY

• ONE OF THE FOLLOWING
• nerve deficit
• acid fast bacilli

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CLINICAL SIGNS OF LEPROSY

• eyebrow alopecia (hair loss)
• enlarged earlobes
• broadening of the nose
• swelling of the fingers
• subtle papulonodular changes in pt at risk
• hypopigmentation

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TUBERCULOID LEPROSY

• clinical
• elevated, sharply marginated plaques
• decreased sensitivity to stimulation
• histopathology
• organized granulomas (a core of macrophages with
  a surrounding ring of lymphocytes)
• multi-nucleated giant cells
• acid fast negative
• Mitsuda reaction positive

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LEPROMATOUS LEPROSY

• clinical
• disseminated nodules
• diffuse infiltration and thickening of skin
• histopathology
• disorganized granulomas
• foamy macrophages (they are foamy due to
  secreted lipids from the intracellular bacteria)
• few lymphocytes
• many bacilli on acid fast stain
• Mitsuda reaction negative

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REVERSAL REACTION

• definition clinically upgrading response from
  the lepromatous to the tuberculoid pole
• clinical
• new erythematous, sharply marginated lesions
• nerve trunk palsies
• histopathology
• organized granulomas
• bacilli rare
• Mitsuda test positive
• thought to be a DTH reaction to M. leprae

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ERYTHEMA NODOSUM LEPROSUM

• definition nodular lesions with systemic signs
  developing in lepromatous patients.
• clinical
• fever, chills, anorexia, malaise
• subcutaneous tender nodules, arthritis, orchitis,
  iritis
• histopathology
• occurs in subcutaneous fat
• polys infiltrate on top of lepromatous histology
• Mitsuda test negative
• due to immune complex deposition

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LUCIO'S REACTION

• clinical
• hemorrhagic infarcts occurring in patients with
  diffuse non-nodular lepromatous leprosy.
• histopathatholgy
• ischemic necrosis due to endothelial
  proliferation and thrombosis.
• Mitsuda test negative.

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MANAGEMENT

• combination chemotherapy dapsone, rifampin and
  clofazamine.
• antiinflammatory for reactions steroids,
  thalidomide.
• supportive care, eyes, hands, feet (to prevent
  tissue injury related to neurologic deficit).

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EPIDEMIOLOGY

• incubation period 1-20 years.
• leprosy is one of the least contagious contagious
  diseases (Guiness Book of Records).
• most individuals exposed develop protective
  immunity, do not get disease. Only a small
  percentage exposed get the disease.
• portal of entry thought to be related to
  nasopharyngeal secretion or contact of skin
  wounds with bacilli in soil.

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RISK FACTORS

• genetic predisposition as to getting or not
  getting leprosy linked to chromsome 6q25 (Mira et
  al, Nature Genetics 2003).
• if you get leprosy
• HLA-DR 2 (15), 3 associated with tuberculoid
  form.
• HLA-DQ 1 associated with lepromatous form.
• other factors poverty, living in an endemic
  area, living in the same house with a patient.

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THE ENEMY M. LEPRAE

• an intracellular organism
• gram positive
• acid fast positive
• replication rate in vivo 10-12 days
• globi masses of bacilli in tissue macrophages,
  1010 bacilli/g of tissue
• cannot be grown in the laboratory

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GROWING M. LEPRAE

• 1962. Mouse foot pad model permits testing of
  antibiotic susceptibility.
• 1971. Nine banded armadillo.
• low body temperature 70F.
• 40 of armadillos in parts of Louisiana and Texas
  are naturally infected.
• Patients in these areas as well as Mexico have
  armadillo contact racing armadillos, skinning
  armadillos and eating armadillos.

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GROWING M. LEPRAE

• 1985. Lepromatous-like disease in the monkey.
• 1985. Some M. leprae genes have been cloned and
  recombinant proteins produced.
• 2001. M. leprae genome sequenced. Gene deletion
  and decay have eliminated many important
  metabolic activities.

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STRUCTURE OF M. LEPRAE CELL ENVELOPE
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THE SPECTRUM OF LEPROSY
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CYTOKINE PATTERNS IN LEPROSY LESIONS
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PATTERNS OF LYMPHOKINE PRODUCTION
Cytokine conc. (pg/ml)
8000
IFN-?
IL-4
6000
4000
2000
0
Type 1
Type 2
Type 1
Type 2
CD4
CD8
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T-CELL CYTOKINE PATTERNS
Th2
Th1
CROSS-REGULATION
IL-2
LYMPHOTOXIN
IL-4 IL-10 IL-13
IL-5
IFN-?
IL-10
....
MACROPHAGE ACTIVATION
CTL
MACROPHAGE SUPPRESSION
B-CELL STIMULATION
EOSINOPHIL RESPONSES
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TOLL-LIKE RECEPTORS AND HOST DEFENSE
lipoproteins
LPS
CpG DNA
dsRNA
flagellin
TLR2
TLR4
TLR9
TLR3
TLR5
NF-kB pathway
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Gene chips or microarrays it is now possible to
simultaneously analyze 30,000 genes!!
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GENE EXPRESSION DATA CAN BE USED FOR DIAGNOSIS,
CLASSIFICATION AND PREDICTION OF OUTCOME
Prinicpal Component Analysis
Heirarchical Clustering
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IMMUNE RESPONSE GENES IN L-LEP LESIONS
T-Lep
L-Lep
TGFb1 IL-5 latent TGFb binding protein-2 SIGLEC7 C
D47 PLAB STAT6 SIRP-1a LIR-7/ILT-1 LIR-4/ILT-6 LIR
-3/ILT-5 LIR-8/ILT?? FcER1, gamma
(FcRg) FcgRIIa FHR-3 IL-2 receptor,
gamma macrophage scavenger receptor MX1 IFNa
receptor 1 TLR5 CD14 chitinase 1 CD59 plexin 1
Anti-inflammatory/Th2
Inhibitory receptors
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L-LEP LESIONS ARE CHARACTERIZED BY HIGH
EXPRESSION OF LIR RECEPTORS
T-Lep
L-Lep
SIRP-1a LIR-7/ILT-1 LIR-4/ILT-6 LIR-3/ILT-5 LIR-8/
ILT?? FcER1, gamma (FcRg) FcgRIIa

• LIRs (Leukocyte Immunoglobulin-like Receptors)
• Members of the Ig superfamily
• Primarily expressed on monocytes
• Functions are largely unknown

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LIR-7 IN LEPROSY
MACROPHAGE

• LIR-7 activation blocks TLR-induced antimicrobial
  activity.

....

• LIR-7 activation on monocytes shifts production
  from IL-12 towards IL-10 blocking a Th1 response.

IL-12

• LIR-7 activation may contribute to susceptibility
  to disseminated infection.

T-cell
IFN-?
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Possibilities

• Gene chips (microarrays) represent a powerful
  tool for identifying genes which predict an
  immune response.
• LIR-7 represents a new anti-inflammatory pathway
  in the treatment of skin disease.

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"A map of the world without utopia on it is not
worth glancing at." Oscar Wilde