Which is the least important in

pathogenesis of psoriasis?
A. IL 12
B. IL 23
C. IL 17
D. IL22
Which of these hasnt been
implicated in the pathogenesis of
psoriasis?
A. Staph aureus
B. Chlamydia spp.
C. Candida albicans
D. Bordetella pertussis
How do antimalarials exacerbate
psoriasis?
A. Transglutaminase inhibition
B. IMP depletion
C. cAMP depletion
D. Nitric oxide inhibition
Which of the following is false?
A. Canthelicidin levels increase in psoriatic plaques
B. TLR 1 has been implicated in pathogenesis of
psoriasis
C. Frequency of psoriasis in HIV patients remains
unchanged compared to normal population
D. Vit D3 analogues act at multiple steps in
pathogenesis of psoriasis



Presenter Dr. Gagandeep Singh
Moderator- Dr. Amit Dhawan
Etiology
Intrinsic factors
External factors

Pathogenesis

Evidence supporting genetic
factors
+ve family history- 35-90 % of patients, series dependent
Lomholts classic epidemiological study -Faroe Islands
(1963), more than 10 000 inhabitants, incidence of psoriasis
much greater amongst first-and second degree relatives of
sufferers
German survey- probability of diseased child
both parents affected 41 %
single parent 14%
sibling 6%
Danish Twin registry and Farther & Nall concordance
analysis in twins
monozygotic 82/141 + similar clinical features
dizygotic 31/155
Linkage analysis family pedigrees - polygenic
Henseler and Christophers

TYPE I TYPE II
Hereditary Sporadic
Strongly HLA associated
(particularly HLA-Cw6)
HLA
Unrelated
Early onset Late onset
More likely to be severe Usually mild
Haplotypes
Association with certain HLA-types
HLA-Cw6
HLA-B13
HLA-B17
HLA-Bw57
HLA-DR4

PSORS1 in the MHC region on chromosome 6 (6p21)
associated with most cases of psoriasis.




GENETIC LOCI LINKED TO
PSORIASIS

PSORS1 6p21.3
PSORS2 17q25
PSORS3 4q3235
PSORS4 1cenq21
PSORS5 3q21
PSORS6 19p13q13
PSORS7 1p3534
PSORS8 16q1213
PSORS9 4q3134
PSORASI 16q12

Psoriasis, an inherited disease
If you have psoriasis, what is the risk to:
Your unrelated neighbor? About 2%
Your sibling? 15-20%
Your identical twin? 65-70%
Your child? 20%- one parent
75%- both parents

Trauma - Koebnerisation
Physical
Chemical
Surgical
Infective
Inflammatory insults
TGF-1 is released by keratinocytes upon injury or
infection
714 days after injury
Reverse Koebners
Tendency to have early onset and early relapse
Infection
Streptococcal infection is strongly
associated with guttate and chronic plaque
type of psoriasis HLA-Cw6
HIV - severe psoriasis
psoriatic arthropathy
poor prognosis
frequency unchanged
Disease exacerbation has been linked with skin and/or gut
colonization by
Staphylococcus aureus
Malassezia
Candida albicans- dendritic cells produce IL-23 when
stimulated by infection with Candida albicans, and this
event is mediated by dectin-1, a C-type lectin receptor
Toll-like receptor (TLR) 4 signaling induced by
lipopolysaccharide from Bordetella pertussis

The role, if any, of viruses (papillomaviruses, HIV, and
endogenous retroviruses) present in lesional skin is at
present unknown
Drugs exacerbating psoriasis
Drug aggravated or drug induced
Beta blockers beta 2 mediated cAMP depletion
Lithium- IMP depletion
Antimalarials- Transglutaminase inhibition
Steroid withdrawal
NSAIDS
ACE Inhibitors
Tetracyclines
Interferons
Terbinafine
Benzodiazapines
Digoxin

Clonidine
Amiodarone
Quinidine
Gold

TNF alpha inhibitors

Imiquimod

Fluoxetine

Cimetidine

Gemfibrozil
Sunlight
Generally beneficial
May provoke
40% -history of polymorphic light eruption (PLE) with
psoriasis as a secondary phenomenon
severely photosensitive psoriasis
predominantly female
distinct from PLE
HLA-Cw6
family history
early age of onset
Smoking


First study linking 1985
3 out of 4 studies have implicated increased risk
esp. in CPP
More in women.
Polymorphonuclear cells- altered by smoking.
Keratinocytes possess nicotinic cholinergic
receptors which stimulate calcium influx and
accelerate cell differentiation.
Oxidative tissue damage
Clinical and experimental derm.2005




Alcoholism

Young & middle aged.
Increased infection and trauma.
Decreased therapeutic compliance.
Metabolic & immunological effect
1. Suppression of cell-mediated immunity.
2. Enhancement of mitogen driven
lymphocyte proliferation.
3. Up-regulation of pro-inflammatory
cytokine.
Stress and Psoriasis
Psychoneuroimmunology : emotional states can
alter immune responses in body.

Onset and increased severity closely related to
stress.

Psychoneural Hypothesis : stressful life events
increase substance P influence inflammation
( endogenous Koebnerisation )

Decreased compliance and self care

IJD 2005


Diet, Metabolism & Psoriasis
Association with metabolic syndrome and
hypocalcemia
Fasting periods, low energy diets and vegetarian
diets improved symptoms.
Diets rich in PUFA from fish oil beneficial
Influence the eicosanoid profile
Patients with antigliadin antibodies improve on a
gluten-free diet.
Vitamin D exhibits anti proliferative and immuno
regulatory effects.
BJD 2005
Metabolic syndrome &
psoriasis
The National Health and Nutrition Examination
Survey, 2003-2006
prevalence of metabolic syndrome
40% among psoriasis cases
23% among controls
2008 US census data, the projected number of patients
with psoriasis aged 20 to 59 years with the metabolic
syndrome was 2.7 million
most common feature- abdominal obesity
hypertriglyceridemia
low levels of HDL
Overlapping inflammatory pathways and genetic
susceptibility
Dose-response relationships between more severe
psoriasis and higher prevalence of metabolic syndrome
components
Number of common inflammatory markers are often
increased in patients e.g. C-reactive protein, interleukin
(IL)-6, tumour necrosis factor (TNF)-
Increased homocysteine levels
Inflammation shown to be a key factor in atherogenesis
Psoriasis is an inflammatory disease that is associated with
atherosclerosis, similar to the association of atherosclerosis
and systemic lupus erythematosus and rheumatoid
arthritis.
Pregnancy
Th-2 cytokine mediated down-regulation of the
immune response by virtue of its anti-inflammatory
and antagonizing effects on the Th-1 cytokines
improves psoriasis.

Th-1 cytokines (IL-2, IFN,TNF- alpha) are elevated in
early postpartum leading to exacerbation of the
disease activity.


History
Prior to 1980s biochemical hypothesis ; defect
presumed to be at keratinocyte level
Post cyclosporine immunopathogenesis; T cell
mediated
Current hypothesis-
POLYGENIC INFLAMMATORY EPITHELIAL
DISEASE
Innate immune system- epidermis
Adaptive immune system- T cells
Evidence for T cell mediation
Early influx of T cells into expanding lesions
Strong association with the MHC, particularly HLA-Cw6
Ablative (albeit temporary) effect of anti-T-cell therapy
Increased antigen presentation in psoriatic plaques
Anecdotal evidence of development of psoriasis after
syngenic bone marrow transplant
Change in phenotype to lesional psoriatic skin in non-
lesional psoriatic skin transplanted on to severe combined
immunodeficient mice and injected with autologous T cells
? Antigen-specific response
?? nature of the antigen involved

Evidence of an antigen-specific response
(i) limited clonality of infiltrating T cells
(ii) persistence of T-cell clones in plaques over several
years
(iii) identical T-cell clones in tonsils and skin of patients
with Streptococcus-associated psoriasis
Key events
T cell activation-
accumulation of inflammatory cells, particularly
neutrophils and T lymphocytes

Epidermal hyperproliferation & loss of
differentiation

Angiogenesis-
dilatation and proliferation of dermal blood vessels
34
DERMIS
STRATUM
BASALE
STRATUM
SPINOSUM
STRATUM
GRANULOSUM
STRATUM
CORNEUM
Proliferation
Immaturity
Neutrophil
accumulation
Disorganized N
O
R
M
A
L
P
S
O
R
I
A
S
I
S
SENSITISATION PHASE
DCs process and present antigens, development of skin
infiltrating effector memory Th17 and T1 cells .Is not
accompanied by any skin alterations.

SILENT PHASE

EFFECTOR PHASE
(i) skin infiltration of immune cells
(ii) immune cell activation in the skin and
(iii) keratinocyte response

IL-17A

signaling activates both the nuclear factorB and mitogen-activated
protein kinase intracellular pathways

has pleiotropic effects, but its main effect is recruitment and
activation of neutrophils

able to directly inhibit apoptosis of neutrophils in inflamed tissues

also enhances angiogenesis and mediates tissue remodeling by
stimulating the production of angiogenic factors and matrix
metalloproteases

synergizes with TNF- to enhance inflammation,
causing the release of IL-6, TNF-, and IL-1





IL 22
induces keratinocyte hyperproliferation in vitro and in
vivo; this effect is mediated through Stat3 signaling

also stimulates keratinocytes to secrete antimicrobial
peptides

causes keratinocytes to produce matrix
metalloproteinase 1, which is involved in tissue
remodeling


Transcription defects in psoriasis
large number of alterations of cytokine and growth factor
profiles within psoriasis - genetic aberration in psoriasis is quite
basic- proximal to the common element in the cascade of
inflammatory events that lead to a lesion of psoriasis
Defect in transcription regulatory elements associated with one
or more cytokines (or growth factors). This mutation could occur
(1) in the regulatory element itself;
(2) in the receptor, which binds both ligand and regulatory
element;
(3) in the ligand (cytokine or growth factor); or
(4) in a gene responsible for the control of proliferation that is
under the influence of the sites mentioned in 1, 2, and 3

Innate immunity, Vitamin D &
Psoriasis
A significant component of the innate immune system is a
group of antimicrobial peptides (defensins, cathelicidins,
e.g. LL-37)
Transcription factor - vitamin D receptor
Recent studies have shown that clinical response of
psoriasis to 1,25-dihydroxyvitamin D
3
is correlated
with the vitamin D receptor mRNA expression level
Journal of Investigative Dermatology (1999) 104 patients -
A significant association between vitamin D receptor
genotypes and the mean age at onset was observed
Effect Study type
Topical treatment with calcitriol or analogs
(calcipotriol) exerts antiproliferative and
differentiation-inducing effects in epidermal
keratinocytes of lesional psoriatic skin.
Immunohisto-chemical in situ analysis of
psoriatic skin
In dendritic cells, calcitriol suppresses expression
of MHC II molecules and of costimulatory
molecules including CD40, CD80 and CD86.
Production of IL-10 is stimulated and production
of IL-12 is inhibited, leading to a suppression of T-
cell activation.
In vitro experiments
Vitamin D analogs suppress IgE-production and
IgE-mediated cutaneous reactions.
In vitro experiments
Calcitriol induces the expression of the CCR-10
receptor on the surface of T-cells, which leads to a
migration of these T-cells towards CCL-27-
expressing epidermal keratinocytes.
In vitro experiments
Physiological concentrations of 1,25-
dihydroxyvitamin D
3
generate in keratinocytes
apoptosis-resistance against ceramides, ultraviolet
radiation and tumor necrosis factor (TNF). In
contrast, pharmacological concentrations of 1,25-
dihydroxyvitamin D
3
(10
6
M) induce apoptosis.
In vitro experiments
T helper 17 cells, produce IL-17. These Th17 cells
accumulate in some sites of inflammation, such as
psoriasis
may contribute to LL-37 production, as well as apoptosis of
keratinocytes in the thickening skin of psoriasis plaques
DNA is released from keratinocytes in psoriatic skin
This host DNA binds the antimicrobial peptide LL-37
The LL-37/DNA complex mimics bacterial DNA and
triggers the Toll-like receptors (TLR) on the surface of
immune cells, dendrocytes, to activate NFkB, the
transcription factor controlling inflammation
Caveolin-1 is a key structural and functional protein for
plasmalemmal invaginations termed caveolae
loss of caveolin-1 within epidermal keratinocytes may
contribute to the development and/or progression of the
psoriatic phenotype
KC have inherent defects in intracellular signalling which
could be usefully targeted to allow the development of
more effective therapies
peroxisome proliferator-activated receptors, the notch
receptor and defects in calcium and other ion transporting
proteins may contribute to impairment in the ability of
psoriatic KC to differentiate
Adipokines & psoriasis
? Missing link between psoriasis & comorbidities
Levels of adiponectin & leptin found to be increased in
psoriasis & psoriatic arthritis
Correlates with increased burden of skin & joint
inflammation and with Th 17 cytokines
Future implications ?
levels of IL-22 could be used as a diagnostic &
prognostic marker for psoriasis, as these levels
correlate with disease severity
if IL-22 was found to be the major circulating factor
that induces keratinocyte proliferation, targeting this
molecule would be a therapeutic strategy for
individuals with psoriasis
if IL-22 was the main inducer of Stat3 in psoriatic
keratinocytes, this cell-signaling molecule would also
be an attractive target for therapeutic development
monoclonal antibodies directed against p40 have produced
striking clinical results in psoriasis patients. These
promising phase 2 studies have led to large-scale,ongoing
phase 3 trials in patients with moderate-to-severe psoriasis.
Although these drugs were initially developed to target IL-
12, many scientists now believe that blocking the biologic
activity of IL-23 is the main mechanism for the clinical
activity of anti-p40 monoclonal antibody therapy in
psoriasis.
Is blocking IL-23 aloneby using monoclonal antibodies
directed against p19is sufficient to improve psoriasis?
Psoriatic arthritis
10-15 % of patients with psoriasis
CD8+ T cell driven
3 main affected sites
1) Enthesis
2) Synovium of peripheral synovial
joints
3) Spine & sacroiliac joints

Stages of pathogenesis
1. Genetic predisposition
2. Triggering of T cells
3. Overt joint inflammation &
injury
HLA Associations

B27
B38
B39
B13
B57
Cw6
Psors1
Inheritance may simulate incomplete
penetrance or recessive mode
Pediatric psoriatic arthritis-
2 subsets-
11-12 years
2-4 years
predominantly female
Lower association with HLA B27 & Cw6
Positive ANA
Chronic anterior uveitis


BIOLOGICAL MECHANISM CLINICAL STATUS
Etanercept Anti TNF alpha Approved
Infliximab Anti TNF alpha Approved
Adalimumab Anti TNF alpha Approved
Elefacept Anti LFA3 fusion protein Approved
Efalizumab Anti CD11A Approved
Ustekinumab Anti IL12/23 Approved
Secukinumab Anti IL17 Phase III
Anti p40 Anti p40 (IL 23 subunit) Phase III
Humax CD4 Anti CD4 Phase II
CTLA4Ig Anti CD28 & CD152 Phase II
CNTO-1275 Anti IL126 Phase II
Onercept Anti TNFbp17 Phase II
Bibliography

Rooks textbook of dermatology
Fitzpatricks dermatology in general medicine
Bolognias dermatology
Articles from IJD, IADVL, BJD