Psoriasis is caused by an interaction between genetic and environmental factors that lead to immune system dysfunction and skin barrier defects. Genes associated with immune response pathways and skin barrier proteins contribute to psoriasis risk. When environmental triggers like infections or stress occur in genetically predisposed individuals, they activate immune cells that drive inflammation and rapid skin cell growth. This involves both innate and adaptive immune responses, particularly from T cells. Ongoing research aims to further elucidate these pathogenic mechanisms to identify new treatment targets.

1. D R V R U S H A L I S A L V E
PATHOGENESIS OF
PSORIASIS

2. INTRODUCTION
 Psoriasis is a chronic inflammatory papulosquamous
disease characterized by multiple remissions and
relapses
 For long, it was believed to be primarily a disorder of
keratinization
 In the past decade researchers have come up with
new factors that may be involved in the pathogenesis
of disease, but they have failed to establish a
pathogenetic model that incorporates all the factors

3.  Currently, the most accepted hypothesis is that
psoriasis is an immune-mediated inflammatory skin
disease that manifests in a genetically predisposed
person exposed to certain environmental agents or
triggers
 This view has been reinforced by the efficacy of
various immunomodulatory agents in the treatment
of psoriasis

5. Environmental factors
• Infections
• Drugs
• Alcohol/smoking
• Psychological stress
Genetic factors
• PSORS1 locus
• Other genes
Activation of
APCs
Activation and
proliferation
of T cells
Keratinocyte
proliferation
Psoriasis

6. OVERVIEW
 Genetic factors
 Environmental factors
 Adaptive and innate immunity
 Impaired skin barrier

7. ROLE OF GENETIC FACTORS
 If only one parent has psoriasis, then the risk for the
child developing psoriasis is 16% which increases to
a 50% chance if both parents have psoriasis. Twin
pair analysis has revealed 72% concordance among
monozygotic twins
 Due to genomic imprinting, men are more likely than
women to transmit psoriasis to the offspring
 Psoriasis has been associated with many HLA
haplotypes

8.  At least nine candidate loci have been identified:
6p (PSORS1), 17q25 (PSORS2), 4q34 (PSORS3),
1q21 (PSORS4), 3q21 (PSORS5), 19p13 (PSORS6),
1p32 (PSORS7), 16q (PSORS8) and 4q31 (PSORS9)
 A few non-major histocompatibility complex
(MHC) susceptibility loci have also been identified
 Strongest signal was found at the HLA-C locus with
a 206% elevated risk of psoriasis
 Strong association of HLA-A2, B8, and B17
antigens with psoriasis

9.  PSORS1 is present in the HLA Class I region of
chromosome 6p and accounts for 35-50% of heritability
of the disease. HLA-Cw06 is the most likely
susceptibility gene in the PSORS1 region, the
association reflects the role of the adaptive immune
response in psoriasis
 The locus also harbours the corneodesmosin (CDSN)
gene, which encodes a protein expressed in
differentiated keratinocytes and is considered a genetic
risk factor for psoriasis development
 Since it harbours both the CDSN gene and HLACw*06,
it is quite possible that both adaptive immunity and
defective barrier function are involved in the
pathogenesis of psoriasis

10. HLA-Cw6
 Earlier onset of disease
 Extensive plaques
 Nail involvement
 Recurrent clinical course
 More likely to experience koebner’s phenomenon
 More likely to experience remission during
pregnancy

11.  Significant associations have also been found in gene
regions involving specific inflammatory pathways,
namely, IL-23 signaling modulation of Th2 immune
responses (IL-4 and IL-13), and nuclear factor (NF)
κB signaling
 The NLR/CATERPILLAR (nucleotide binding
domain) family of genes encode important mediators
of innate immunity and are concerned with
maintaining epidermal barrier function and
initiating pathogenic responses to environmental
microbes

14. ROLE OF ENVIRONMENTAL FACTORS
 Several factors, such as physical trauma,
psychological stress, drugs and infections, may
trigger the disease
 These triggers are probably most relevant in patients
with a genetic predisposition to developing psoriasis

17. KOEBNER’S PHENOMENON
 The time interval between injury and onset of psoriasis
varies from 3 days to 2 years
 The factors that contribute to Koebnerisation include
season (seen more frequently in winter than in summer)
and disease severity (more in unstable or flaring disease).
 Trauma has to cause both epidermal cell injury and
dermal inflammation

18.  The first step is of nonspecific inflammation, which
initiates the production of inflammatory mediators,
including cytokines (specially IL-23), stress proteins
(mainly nerve growth factor and basic fibroblastic
growth factor), adhesion molecules and autoantigens
 The second step is characterized by disease-specific
reactions, by T cells, B cells, autoantibodies, and
immune deposits under the restriction of genetic
backgrounds.
 LCE3B and LCE3C genes are also induced after minor
skin trauma and deletion of these proteins leads to
incomplete barrier repair after minor trauma which in
turn causes penetration of various antigens and
induction of inflammatory response

19. ROLE OF MICROORGANISMS
 Guttate psoriasis may be preceded by tonsillar
Streptococcus pyogenes infection
 Exacerbation has been linked with skin and/or gut
colonization by Staphylococcus aureus, Malassezia
and Candida albicans
 Super antigens of streptococci, staphylococci,
candida, streptococcal M protein, streptococcal
peptidoglycan have been implicated

20. ROLE OF ADAPTIVE AND INNATE IMMUNITY
 Activated T cells are believed to be the primary
modulators in the pathogenesis
 The earlier concept of psoriasis being solely a
T-helper (Th1) mediated disorder has been replaced
by the concept of combined Th1 and Th17 mediated
inflammatory disease
 Psoriasis is more aptly considered as the outcome of
complex interactions within various subsets of
T-cells instead of being a disease caused by a single
subset.

21. Damage associated molecular patterns
(DAMP) pathogen associated molecular
patterns (PAMP)
TLR and NOD like receptors
activation of keratinocytes and
epidermal innate immune system
TNF-α, IL-8 and IL-1β
defective skin barrier repair
(increased expression
of keratins 6 and 17, and the LCE3)
sustained exposure to PAMPs
Maturation of APCs
migrate to the local lymph nodes where
they interact
with naïve T-cells

22. Naïve T cells
Activated Th 17
TGF-β and IL-6
Enter the circulation and extravasate
through the endothelium to the sites of inflammation
Th1-Th2-Th17 imbalance
Dendritic cells and
macrophages, γδ T cells
IL-23
IL-17 IL-22
increase in levels of pro-
inflammatory cytokines like
S-100, A7, β-defensins
and lipocalin
epidermal
acanthosis and
abnormal
keratinocyte
differentiation
promote keratinocytes to
produce CXC-chemokines
and CCL-20
Attract neutrophils to
the site inflammation
Th22
TNF-α, IL-6 and
CCL20

23. ANGIOGENESIS
 Keratinocytes are thought to be a major source of
pro-angiogenic cytokines (VEGF, IL-8) but the
precise mechanism for angiogenesis in psoriasis is
still unknown
 Although it may not be the primary event in the
pathogenesis of psoriasis, understanding the
pathways leading to angio-proliferation may help in
finding novel antipsoriatic drugs
 Vitamin D analogues, retinoids, and cyclosporine all
possess anti-angiogenic activity

24. endothelial cells
swell and become activated
developing psoriatic plaque
migrate, sprout, and lay down a BM
with pericytes for structural support to
form novel
vessel networks.
Widening of the intercellular
spaces, and dermal blood vessels dilate
easier for leukocytes to migrate into
the skin

25. IMPAIRED SKIN BARRIER
 The skin acts as a two-way barrier to prevent the
inward or outward passage of water and electrolytes.
 The barrier is largely situated in the epidermis,
isolated epidermis being as impermeable as whole
skin, whereas once the epidermis is removed the
residual dermis is almost completely permeable
 A two-compartment model of the stratum corneum
as a barrier is currently accepted, in which protein-
rich cells, the corneocytes, are embedded within a
continuous lipid-rich matrix

26.  The abnormal keratinization is seen as an increased
expression of early differentiation markers such as CDSN
and small proline rich proteins, cystatin A and
transglutaminase 1, and decreased expression of late
differentiation markers such as loricrin and filaggrin.
 This leads to aberrant formation of the cornified
envelope that in turn affects the barrier capacity of the
skin.
 This manifests as increased transepidermal water loss,
which is directly proportional to the clinical severity.
 The expression of aquaporins, a family of water
transporting proteins present in the plasma membrane of
the stratum corneum and the stratum spinosum, is
decreased in lesional and perilesional skin in psoriasis

27. Psoriatic lesions are characterized by
increased levels of β-defensin
lower incidence of
skin infections in psoriatic plaques,
potent proinflammatory activity
high β-defensin copy numbers
increase the
intensity of inflammatory response to
minor stimuli
Koebner’s phenomenon
Cathelicidin LL-37 is
overexpressed in inflammed skin
in psoriasis
binds to extracellular self-
DNA released from dying cells,
and converts self-DNA
into a potent stimulus for
plasmacytoid dendritic cells
secrete type I interferons
and trigger an auto-inflammatory
cascade

30. CONCLUSION
 Psoriasis therapy has evolved as our understanding
of the basic science has developed.
 Further characterising the key genomic, immune and
microbiomic pathways involved will help to identify
novel disease mechanisms and novel therapeutic
targets
 Three way interactions between adaptive immunity,
innate immunity and skin barrier defect may best
explain the pathophysiology of psoriasis

31. MCQs

32. Gene most implicated in psoriasis?
a) HLA B7
b) HLA Cw6
c) HLA DQA1
d) Non MHC genes

33. Methotrexate acts by?
a) Decreasing IL17 levels
b) Inhibiting TNF alpha
c) Decreasing IL 22
d) Decreasing IL 23

34. NSAIDs exacerbate psoriasis by?
a) Decreasing cAMP
b) Accumulation of leukotrienes
c) Inhibiting transglutaminase
d) None of the above

35. PSORS stands for?
a) Psoriasis sensitivity
b) Psoriasis stability
c) Psoriasis susceptibility
d) Psoriasis severity

36. Psoriasis is-
a) Th1 mediated
b) Th17 mediated
c) Th22 mediated
d) All of the above