RECENT ADVANCES IN THE

PATHOPHYSIOLOGY OF
PSORIASIS
DR. MIKHIN GEORGE THOMAS
 PSORIASIS
• Common , chronic, disfiguring, inflammatory and proliferative condition
of the skin, in which both genetic and environmental influences play a
critical role.
 HISTORY
• Ancient biblical records 2000 BC

• Corpus hippocraticum

• Galen

• “Psora”= to itch
• Robert Willan- ‘On cutaneous
diseases’ published in 1808

• Ferdinand von Hebra -1841

Incidence : 0.5% to 12%

Equal gender predisposition

Bimodal peak : 2nd decade or

5th/6th
GENETIC FACTORS

• 1ST AND 2 ND DEGREE RELATIVES

• one parent affected - 14%
• both parents - 41%
• one sibling - 6%
• no parent or sibling affected - 2%
• HLA- Cw6
• HLA- B13,B17,Bw16
• HLA – genetic and epidemiological guideposts in psoriasis
• B 13, Bw57, Bw 16-EARLY ONSET(<40y)
• Bw 17 –higher family incidence
• A2, B 27- LATE ONSET
• Cw6-exacerbation following strep infection
• B13 –milder, more reversible disease
• B 27- psoriatic sacroiliitis

• Bw 38- psoriasis and distal arthritis

20 potential loci on 15
chromosomes
PSORS 1-9
PSORS1
Best established locus : PSORS1 in
MHC region of chromosome 6
HLA – Cw6 allele in PSORS1 :
type1 psoriasis
RISK FACTORS & MODIFYING
FACTORS
• KOEBNER PHENOMENON
• SEASONAL VARIATIONS
• PREGNANCY
• EMOTIONAL STRESS
• INFECTIONS
• DRUGS
• SUNLIGHT
• ALCOHOL & SMOKING
• OBESITY
Beta-blockers A delayed type hypersensitivity reaction, an immune Both cardioselective and non-
mediated response and a decrease in intraepidermal cardioselective drugs have been
implicated but the frequency is higher
cAMP and a consequent increase in epidermal cell
with the latter. Also with topical timolol,
turnover reported to induce psoriasis .
DRUGS

Lithium Acts directly by blocking cell differentiation and Provokes or induces chronic plaque
leading to dysregulation of inflammatory psoriasis, localized or generalized
cytokines and indirectly by ↓ cAMP levels pustular psoriasis and even psoriatic
erythroderma
Antimalarials May trigger psoriasis by inhibiting the enzyme Do not induce psoriasis although they are
transglutaminase known to trigger psoriasis in 18% of
patients
NSAIDs Inhibit the cyclo-oxygenase pathway, leading to accumulation of leukotrienes and hence
may exacerbate psoriasis

Tetracyclines May provoke psoriasis either by inhibiting cAMP or by inducing Koebner’s phenomenon
due to their photosensitizing potential
• angiotensin-converting • calcium-channel blockers
enzyme inhibitors • granulocyte-colony stimulating
factor
• interferons • potassium iodide
• digoxin • penicillin
• progesterone
• clonidine
• morphine
• carbamazepine • acetazolamide
• Valproic acid
HIV INFECTION

• Exacerbation or initial manifestation

• Loss of regulatory T cells and increased activity of CD8
T cells
• Remit in terminal stage
• Alter the course and severity
• Combination of genetic and environmental factors
PATHOPHYSIOLOGY OF PSORIASIS
EVOLUTION….

Psoriasis was primarily a disease of epidermal hyperproliferation and

increased cell turn over time - glycine - 14C
• Increase in the proliferating cell compartment in the basal and suprabasal
layers
• Length of these layers-three folds by enlarged dermal papillae
• 4 days
CELL CYCLE KINETICS
• Abnormal keratinocyte differentiation
rather than proliferation

• Alteration in cytokeratin expression of

the psoriatic epidermis compared to
the normal skin

• A down regulation of cytokeratins K1

& K10 and an upregulation of K6 &
K10
ROLE OF CYCLIC NUCLEOTIDES

• Cyclic AMP has been implicated as a modulator of

cellular growth and differentiation
• Defect in adenyl cyclase-c AMP cascade
• Increase c-AMP: c- GMP ratio
• Accelerated cell division, incomplete division,
glycogen buildup in the epidermis
• Based on observations of psoriasiform lesions being
caused by beta blockers and NSAIDS.
 POLYAMINES

• Putrescine, spermidine, spermine

• Important in the regulation of cell proliferation
• Increased levels in psoriasis ; increased activity of ornithine
decarboxylase
• Treatment with PUVA, retinoids, topical corticosteroids.
 ARACHIDONIC ACID
METABOLISM
• PG s- stimulate epidermal DNA synthesis, dilate cutaneous vessels,
inflammatory reactions
• In psoriatic skin : an endogenous suppression of COX pathway
• Increased levels of leukotrienes and 12- HETE
• Diversion of arachidonic acid to lipoxygenase pathway- leukotrienes
• LTB4- most potent chemotactic agent
• Increased number of chemotactic factors, increased response of
PMNL-accumulation in lesional epidermis
NEUROPEPTIDES

• Vasoactive intestinal peptide- IL 6, IL 8

• Substance P
VITAMIN D

• VDR are expressed in all viable layers

• Increased expression in psoriasis
• Accelerated proliferation and incomplete differentiation
• CALCITRIOL – inhibits IFN, IL 6, IL 8
• Decreased phagocytosis, generation of ROS
PSORIASIS ….

A T -CELL MEDIATED AUTO

IMMUNE CHRONIC
INFLAMMATORY DISEASE
CELLULAR COMPONENTS
IN PSORIASIS

• T cells
• Dendritic cells
• Monocytes and macrophages
• Neutrophils
.
• Antigen specific rather than superantigen mediated

• CD 4 and CD 8 subsets

• Cutaneous lymphocyte antigen-ligand for e –selectin-selectively

expressed on skin capillaries-access to skin
• CD 8 in epidermis, CD4 in upper dermis
• Interferon γ rich in psoriatic lesions
• IL -23 and IL- 17, along with IL- 22-chronic inflammation
• IL- 23- dermal inflammation and epidermal hyperplasia
• Impaired inhibitory function-IL6 rich tissue environment
• NATURAL KILLER T CELLS
• T cell receptor
• CD16,CD 56,CD 57,CD94,CD161
• IFN-γ, IL- 4, IL- 2, IL 5, IL- 10, IL 13, IL
17,TNF- α
• NATURAL KILLER CELLS
• IFN- γ
• Bridge between innate and acquired
• Regulated in part by KIR (killer immunoglobulin like receptors)-
associated with psoriasis and psoriatic arthritis
• DENDRITIC CELLS
• Believed to play a central role : antigen
presenting cells
• High numbers in lesional skin
• Increased numbers of dermal
dendritic cells and Langerhans cells

•PLASMACYTOID DENDRITIC
CELLS

Produce large amounts of IFN- α

• MAST CELLS
• Mast cell degranulation
• increased numbers in
lesional skin
• Major source of IL- 17
• MACROPHAGES
• CD 11c- , CD 1a+,CD 68+
• Involved in generating fenestrations in the
basement membrane
• NEUTROPHILS
• Found late in disease
IMMUNOPATHOLOGY OF
PSORIASIS

• Innate and adaptive immunity

• Initiating inflammation, amplifying an immune

response, shaping nature of immune response
• T cell activation by presentation of antigen by APC in the lymph nodes
• Keratin epitopes cross reacting with bacterial antigen
• Denatured peptide epitopes boosted by bacterial and viral infection
• Activated APC travel to the lymph nodes, where they interact with naïve
T cells
1) T CELL ACTIVATION

• BINDING: CD8/CD4 through their TCR, bind to MHC class II

• CO-STIMULATION: connection of DC and T cells stabilized

by LFA-1 and ICAM-1---immunological synapse

• T CELL DIFFERENTIATION : towards the Th1 subtype

2) T CELL BINDING TO ENDOTHELIUM
• Memory T cells reenter the circulation into the epidermis and dermis

• At the level of endothelium, there is interaction between the CLA

receptors on their surface and P and E selectins

• IFN is the key cytokine that activates signal transducer and activator of
transcription 1 (stat1).
• TNF : key cytokine and key regulator of maturation of dc cells and is
responsible for proliferation of resident T cells in unaffected skin
3) T CELL REACTIVATION

• After second exposure to antigen- keratinocytes act as APC under

influence of IFN-γ- differentiation of memory T cells into effector T cells
with release of IL 2 , IFN-γ and TNF- α.

• T cell activation without antigen presentation -microbial agents and heat

shock proteins can activate toll like receptors, leading to production of
cytokines and T cell activation.
4) CYTOKINE PRODUCTION

• By various effector cells- TNF and IFN, increases the expression of

adhesion molecules ICAM-1 and E selectin and VCAM- 1 and
promotes synthesis of other proinflammatory cytokines.
Cytokines in the pathogenesis
of psoriasis

Cytokine/Growth
factor Role in psoriasis

TNF-α
Stimulation of keratinocytes to produce IL-8, ICAM-1, TGF-α, β-defensins, .
Enhancement of pro-inflammatory cytokine secreting capacity of Macrophage.
Stimulation of endothelial cell to secrete VEGF.
Increased keratinocyte proliferation.
IFN-γ
Antiproliferative effect on normal keratinocyte in-vitro.
Induction of ICAM-1 expression on keratinocytes and endothelial cells, influencing the trafficking of T
lymphocytes into lesional epidermis.
Stimulation of APC activity and TNF-α release by phagocytes and up regulation of TNF-α receptors

GM-CSF
Increases keratinocyte proliferation and activates neutrophils.
It also stimulates migration and proliferation of endothelial cells.
IL-1 Induction of E-selectin, VCAM-1, ICAM-1 on keratinocytes . These fibroblast-derived factors
in turn stimulate keratinocyte proliferation and differentiation.
IL-2 Is a growth factor and chemo-attractant for T cells
Induces T cell cytotoxicity.
Stimulates NK cell activity.
High doses of IL-2 may induce psoriasis in predisposed patients.

IL-6 Enhances the activation, proliferation, and chemotaxis of T lymphocytes in

dermal infiltrate. Proliferation and activation of B cells and macrophages.
Stimulation of keratinocyte proliferation in vitro.

IL-8 Migration of neutrophils and T Cells in to epidermis

Activation and proliferation of T lymphocytes and stimulation of angiogenesis.
IL-12 Enhances T cell activation and differentiation stimulating the type 1 T cell
maturation pathway.
EGF family Expression of TGF-α and amphiregulin is increased in psoriasis.
Increased EGF/TGFα receptors in psoriatic epidermis.
TGF-α induces IL-1, and has mitogenic and angiogenic properties.
DEVELOPMENT OF LESIONS
:HISTOPATHOLOGY

• UNINVOLVED SKIN
• Subclinical morphological and biochemical changes,
lipid biosynthesis
• Changes in stratum corneum
• Changes in levels of phospholipids, free α amino
acids, hydrolytic cells ,dehydrogenases
• Histochemical parakeratosis
INITIAL LESION

• Pinhead sized macule

• Epidermis- spongiosis with focal loss of granular layer
• Upper dermis -marked edema, mononuclear infiltrate
• Vessels-dilated and surrounded by infiltrate
DEVELOPING LESIONS

• 50% increase in epidermal thickening

• Increased number of mast cells, dermal macrophages, increased mast
cell degranulation
• Increased dermal T cells
• Centre of lesion-marginal zone-inc band like epidermal thickening,
capillary proliferation, parakeratosis, perivascular infiltrate without
exudation into epidermis
• Rete ridges begin to develop
MATURE LESION
• Uniform elongation of rete ridges
• Hypogranulosis
• Thinning of suprapapillary epidermis
• Camel foot appearance of rete ridges
• Lymphocytes and neutrophils in the epidermis
• Squirting papillae
• Munro’s microabscess
• Spongiform pustule of Kogoj
• Collections of serum
RECENT CONCEPTS

Emerged from genetic, genomic and

cellular information from basic studies and
from clinical studies of selective immune
targeting drugs.
Psoriasis results from interplay between genetic
susceptibility, skin barrier defect and
dysregulation of innate and adaptive immunity.
GENETICS
• CORNEODESMOSIN (CDSN) gene, encodes a
protein expressed in differentiated keratinocytes

• SINCE PSORS1 HARBORS BOTH THE CDSN

GENE AND HLA-C-*06– ADAPTIVE
IMMUNITY AND DEFECTIVE BARRIER
FUNCTION ARE INVOLVED
• Homozygous missense mutation in the IL36RN gene encoding for
IL-36 receptor antagonist : unregulated secretion of inflammatory
cytokines and an increased predisposition to develop generalized
pustular psoriasis.

• NLR/CATERPILLAR (nucleotide binding domain) family of genes-

encode important mediators of innate immunity.

• Concerned with maintaining epidermal barrier function and

initiating pathogenic responses to environmental microbes.
• NLR products can be divided into those with N-terminal coiled-coil
structures and those with N-terminal Toll like receptors (TLR)/IL-1
receptor domains.
•
• NLR gene products - Nod 1, Nod 2 and IPAF proteins
•
• Intracellular recognition of bacterial components and regulation of
chemokine secretion and defensin release.
Gene/Locus Function
Genes associated with adaptive immunity

HLA C or MHC gene Present antigens to naïve T cells

IL-23R or IL-23 receptor subunit Maturation of T cells

IL-12B Maturation of T cells

ERAP1 (Endoplasmic reticulum aminopeptidase 1) Trimming of peptide antigens for binding to MHC1

TNF-α Important pro inflammatory cytokine involved in psoriasis

IL-23A/STAT2 or IL-23, subunit p19 Regulation of T-cell activation

IL-23A, α-subunit p19 Regulation of T-cell activation

Genes associated with innate
immunity
IFIH1 (Interferon induced Rig like helicases, involved in recognition of RNA viruses
helicase C domain),
MDA5
TNFAIP3 (Tumour necrosis
factor-α induced protein 3)/
A20
TNF-α inducible zinc-finger protein that
temporarily limits immune response by
inhibiting
NF-κB signalling

FBXL19 (F-box and leucine rich repeat Inhibition of demethylase activity to activate NF-
protein 19) κB
Genes associated with skin barrier function

LCE3B and LCE3C Barrier of skin function

CDSN Component of cornified envelope

DEFB cluster or β-defensins Antimicrobial and chemotactic function

GJB2 (Gap junction protein β2) , connexin Involved in gap junction formation
26
STREPTOCOCCUS

• Guttate psoriasis - tonsillar Streptococcus pyogenes

• Disease exacerbation - skin and/or gut colonization by Staphylococcus aureus,
Malassezia and Candida albicans
• Streptococcal superantigens.
• However, psoriatic lesions are characterized by an oligoclonal T cell
expansion, which points towards an antigen-specific T cell response.

• STREPTOCOCCAL M PROTEIN MAY BE THIS ANTIGEN, DUE TO

ITS MIMICRY WITH TYPE 1 KERATIN
• Streptococcal peptidoglycan is more likely to
be the candidate than M protein

• Strong proinflammatory immunogen

• Genes encoding the peptidoglycan recognition

receptors are located within the linkage sites
associated with psoriasis
• Tonsillectomy may improve chronic psoriasis

• Palatine tonsils generate effector T cells - recognize

keratin determinants in the skin
KOEBNER PHENOMENON

• The time interval between injury and onset of psoriasis : 3 days to 2 years.

• Disease severity

• more in unstable or flaring disease.

• Epidermal cell injury and dermal inflammation to produce KP.

• The onset of KP may be a two step process :

1. inflammatory response
2. nonspecific inflammation initiates

• The production of inflammatory mediators-cytokines

(specially IL-23), stress proteins (mainly nerve growth factor
and basic fibroblastic growth factor), adhesion molecules and
autoantigens.

• Disease-specific reactions- T cells, autoantibodies, and

immune deposits
EXPERIMENTAL MODELS

The transgenic mouse model suggests that human skin (perhaps

as influenced by fundamental genetic alterations in psoriasis)
can serve not only as a long term reservoir of pathogenic
immune cells, but also frank growth and expansion of skin
homing memory T cells can occur exclusively within the skin.
Hence, the skin can potentially function as a surrogate of
formal lymphoid tissue, at least for expansion of already
differentiated skin homing T cells.
IMMUNOLOGY

presence of Th1, Th2, Th17 or T

TNF-α, regulatory cells
TGF-β and IL-6

Naïve T cells

presence of TGF- Th17 cells

β and IL-6
• Dermal γδ T cells amplify adaptive immunity by release
of IL 17
• INCREASED IL -6 : decreased T cell regulatory activity
• AMP’s are overexpressed------stimulus for plasmacytoid
dendrites—secrete TYPE 1 IFN
• AUTOINFLAMMATORY CASCADE
ABNORMAL KERATINISATION

Increased exp of
CSDN, small proline
rich proteins, cystatin
A, transglutaminase- I • Inc TEWL
• Dec exp of
Aberrant formation of
aquaporins in str
cornified envelope
Abnormal corneum and str
keratinization spinosum

Decreased expression of
loricin, fillagrin
ROLE OF SKIN BARRIER

Deletions of LCE3B and LCE3C genes

incomplete barrier repair after minor trauma

penetration of various antigens

induces inflammatory response

TREATMENT OF PSORIASIS

DRUGS KEY IMMUNOLOGIC STEP INHIBITED

• Methotrexate Decreases IL-22 levels

• Cyclosporine Decreases IL-15 mediated rise in IL-17 levels

• Infliximab, Etanercept, TNF-α inhibition

Adalimumab, Golimumab, Certolizumab
• Alefacept blocking the interaction b/w LFA 3 and CD2
• Efalizumab : T cell inhibition by preventing
interaction between LFA-1 and ICAM-1
• Abatacept : T cell inhibition by inhibiting
the binding of CD28 to CD80/CD86
• Ustekinumab : Anti IL 12/23 antibodies
• Briakinumab, Apilimod
• Secukinumab, Ixekizumab :IL17/
IL17R*inhibitors
+
Solving the tough jigsaw!!!