Transcript LEPROSY - University of California, Los Angeles

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
[email protected]
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.
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.
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.
THE SPECTRUM OF LEPROSY
TUBERCULOID
LEPROMATOUS
SKIN LESIONS
BACILLI
CELL-MEDIATED IMMUNITY
ANTIBODIES
NERVE DAMAGE
IMMUNOLOGIC REACTIONS IN LEPROSY
LEPROMIN


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OR MITSUDA REACTIONS
3 wk response to intradermal challenge with M. leprae
organized granulomas
standard measure of DTH in leprosy
REVERSAL


clinical upgrading, reduction in number of bacilli
naturally occuring DTH response
ERYTHEMA
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
REACTIONS
NODOSUM LEPROSUM
no upgrading or clearance of bacilli
immune complex deposition
SKIN TESTING
Patients
are challenged with intradermal
injection of M. leprae.
Fernandez reaction - present at 48 hours.
Mitsuda reaction
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

occurs at three weeks.
characterized by the presence of granulomas
(organized collections of lymphocytes and
macrophages).
positive in tuberculoid patients, negative in
lepromatous patients.
DIAGNOSIS OF LEPROSY
ONE
OF THE FOLLOWING:
 nerve deficit
 acid fast bacilli
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
TUBERCULOID LEPROSY
clinical
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
elevated, sharply marginated plaques
decreased sensitivity to stimulation
histopathology
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organized granulomas (a core of macrophages with a
surrounding ring of lymphocytes)
multi-nucleated giant cells
acid fast negative
Mitsuda
reaction positive
LEPROMATOUS LEPROSY
clinical


disseminated nodules
diffuse infiltration and thickening of skin
histopathology

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
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
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
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
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.
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).
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.
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.
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
GROWING M. LEPRAE
 1962.
Mouse foot pad model permits testing of
antibiotic susceptibility.
 1971. Nine banded armadillo.
 low body temperature 70°F.
 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.
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.
STRUCTURE OF M. LEPRAE CELL ENVELOPE
THE SPECTRUM OF LEPROSY
TUBERCULOID
LEPROMATOUS
SKIN LESIONS
BACILLI
CELL-MEDIATED IMMUNITY
ANTIBODIES
NERVE DAMAGE
CYTOKINE PATTERNS IN LEPROSY LESIONS
PATTERNS OF LYMPHOKINE PRODUCTION
Cytokine conc. (pg/ml)
8000
IFN-
IL-4
6000
4000
2000
0
Type 1 Type 2
CD4
Type 1
CD8
Type 2
T-CELL CYTOKINE PATTERNS
Th2
Th1
CROSS-REGULATION
IL-2
IFN-
LYMPHOTOXIN
IL-12
IL-10
IL-4
IL-10
IL-13
IL-5
....
bLP
MACROPHAGE
ACTIVATION
CTL
EOSINOPHIL
MACROPHAGE
B-CELL
SUPPRESSION STIMULATION RESPONSES
TOLL-LIKE RECEPTORS AND HOST DEFENSE
lipoproteins
TLR2
LPS
TLR4
dsRNA
flagellin
TLR3
TLR5
CpG DNA
TLR9
NF-kB pathway
Immunomodulatory Genes
Influence adaptive
response
T cells
Tissue Injury
Direct antimicrobial
response
RIP
Cell Mediated
Immunity
Apoptosis
Septic
Shock
GENE EXPRESSION IN LEPROSY LESIONS
Bleharski JR et al, Science 301: 1527-1530, 2003
T-lep L-lep
Gene chips or
microarrays: it is now
possible to
simultaneously
analyze 30,000 genes!!
low
high
Relative expression
GENE EXPRESSION DATA CAN BE USED FOR DIAGNOSIS,
CLASSIFICATION AND PREDICTION OF OUTCOME
Heirarchical Clustering
Prinicpal Component Analysis
Original T4 T3 T1 T5 T2 L3 L2 L1 L5 T6 L4
Corrected T4 T3 T1 T5 T2 L3 L2 L1 L5 L6 L4
Principal component value
T-leppatients
patients
T-lep
0.6
T1 T2 T3 T4
T6 T4
T5 T5
0.4
0.2
0
-0.2
-0.4
-0.6
L1 L2
L3 L4
L1 L2
L3 L4
L5 L5
L6
L-leppatients
patients
L-lep
IMMUNE RESPONSE GENES IN L-LEP LESIONS
T-Lep
Anti-inflammatory/Th2
Inhibitory receptors
L-Lep
TGFb1
IL-5
latent TGFb binding protein-2
SIGLEC7
CD47
PLAB
STAT6
SIRP-1a
LIR-7/ILT-1
LIR-4/ILT-6
LIR-3/ILT-5
LIR-8/ILT??
FcER1, gamma (FcRg)
FcRIIa
FHR-3
IL-2 receptor, gamma
macrophage scavenger receptor
MX1
IFNa receptor 1
TLR5
CD14
chitinase 1
CD59
plexin 1
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 (FcR)
FcgRIIa
LIRs (Leukocyte Immunoglobulin-like Receptors)
• Members of the Ig superfamily
• Primarily expressed on monocytes
• Functions are largely unknown
LIR-7 IN LEPROSY
MACROPHAGE

LIR-7 activation blocks TLRinduced antimicrobial
activity.
LIR-7
RIP
....
bLP
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LIR-7 activation on
monocytes shifts production
from IL-12 towards IL-10
blocking a Th1 response.
LIR-7 activation may
contribute to susceptibility to
disseminated infection.
IL-12
IL-10
T-cell
IFN-
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.
"A map of the world without
utopia on it is not worth
glancing at."
Oscar Wilde