This document discusses recent advances in the pathophysiology of psoriasis. It begins by providing background on psoriasis as a chronic inflammatory skin condition influenced by both genetic and environmental factors. It then covers the genetic factors and risk factors involved, including specific HLA alleles. The pathophysiology involves both the innate and adaptive immune system, with an overview of the cellular components like T cells, dendritic cells, and cytokines involved. It discusses recent concepts around the interplay between genetic susceptibility, skin barrier defects, and immune dysregulation. Key genes associated with both adaptive and innate immunity as well as skin barrier function are highlighted.

1. RECENT ADVANCES IN THE
PATHOPHYSIOLOGY OF
PSORIASIS
DR. MIKHIN GEORGE THOMAS

2. PSORIASIS
• Common , chronic, disfiguring, inflammatory and proliferative condition
of the skin, in which both genetic and environmental influences play a
critical role.

3. HISTORY
• Ancient biblical records 2000 BC
• Corpus hippocraticum
• Galen
• “Psora”= to itch

5. • Robert Willan- ‘On cutaneous
diseases’ published in 1808
• Ferdinand von Hebra -1841

6. Incidence : 0.5% to 12%
Equal gender predisposition
Bimodal peak : 2nd decade or
5th/6th

7. 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

8. • 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

9. 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

10. RISK FACTORS & MODIFYING
FACTORS
• KOEBNER PHENOMENON
• SEASONAL VARIATIONS
• PREGNANCY
• EMOTIONAL STRESS
• INFECTIONS
• DRUGS
• SUNLIGHT
• ALCOHOL & SMOKING
• OBESITY

11. Beta-blockers
A delayed type hypersensitivity reaction, an immune Both cardioselective and nonmediated response and a decrease in intraepidermal
cAMP and a consequent increase in epidermal cell
turnover
cardioselective drugs have been
implicated but the frequency is higher
with the latter. Also with topical timolol,
reported to induce psoriasis .
Lithium
Acts directly by blocking cell differentiation and
leading to dysregulation of inflammatory
cytokines and indirectly by ↓ cAMP levels
Provokes or induces chronic plaque
psoriasis, localized or generalized
pustular psoriasis and even psoriatic
erythroderma
Antimalarials
May trigger psoriasis by inhibiting the enzyme
transglutaminase
Do not induce psoriasis although they are
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
DRUGS

12. • angiotensin-converting
enzyme inhibitors
• interferons
• digoxin
• clonidine
• carbamazepine
• Valproic acid
• calcium-channel blockers
• granulocyte-colony stimulating
factor
• potassium iodide
• penicillin
• progesterone
• morphine
• acetazolamide

13. 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

14. PATHOPHYSIOLOGY OF PSORIASIS

15. 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

16. CELL CYCLE KINETICS

17. •
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

18. 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.

19. 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.

20. 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

22. NEUROPEPTIDES
• Vasoactive intestinal peptide- IL 6, IL 8
• Substance P

23. 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

24. PSORIASIS ….
A T -CELL MEDIATED AUTO
IMMUNE CHRONIC
INFLAMMATORY DISEASE

25. CELLULAR COMPONENTS
IN PSORIASIS
• T cells
• Dendritic cells
• Monocytes and macrophages
• Neutrophils
.

26. • 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

27. • 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

28. • 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

29. • 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

30. • 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

31. • MAST CELLS
• Mast cell degranulation
• increased numbers in
lesional skin
• Major source of IL- 17

32. • MACROPHAGES
• CD 11c- , CD 1a+,CD 68+
• Involved in generating fenestrations in the
basement membrane
• NEUTROPHILS
• Found late in disease

33. IMMUNOPATHOLOGY OF
PSORIASIS
• Innate and adaptive immunity
• Initiating inflammation, amplifying an immune
response, shaping nature of immune response

34. • 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

35. 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

36. 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

37. 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.

38. 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.

39. 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.

40. 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.
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.
EGF family

41. 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

42. 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

43. 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

44. 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

48. RECENT CONCEPTS
Emerged from genetic, genomic and
cellular information from basic studies and
from clinical studies of selective immune
targeting drugs.

49. Psoriasis results from interplay between genetic
susceptibility, skin barrier defect and
dysregulation of innate and adaptive immunity.

51. 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

52. • 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 genesencode important mediators of innate immunity.
• Concerned with maintaining epidermal barrier function and
initiating pathogenic responses to environmental microbes.

53. • 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.

54. Gene/Locus
Function
Genes associated with adaptive immunity
HLA C or MHC gene
IL-23R or IL-23 receptor subunit
Present antigens to naïve T cells
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
helicase C domain),
MDA5
Rig like helicases, involved in recognition of RNA viruses

55. 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
protein 19)
Inhibition of demethylase activity to activate NFκB
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

56. STREPTOCOCCUS
• Guttate psoriasis - tonsillar Streptococcus pyogenes
• Disease exacerbation - skin and/or gut colonization by Staphylococcus aureus,
Malassezia and Candida albicans
• Streptococcal superantigens.

57. • 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

58. • 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

59. • Tonsillectomy may improve chronic psoriasis
• Palatine tonsils generate effector T cells - recognize
keratin determinants in the skin

60. 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.

61. • 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

62. 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.

63. IMMUNOLOGY
presence of
TNF-α,
TGF-β and IL-6
Th1, Th2, Th17 or T
regulatory cells
presence of TGFβ and IL-6
Th17 cells
Naïve T cells

65. • 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

66. ABNORMAL KERATINISATION
Increased exp of
CSDN, small proline
rich proteins, cystatin
A, transglutaminase- I
Aberrant formation of
cornified envelope
Abnormal
keratinization
Decreased expression of
loricin, fillagrin
• Inc TEWL
• Dec exp of
aquaporins in str
corneum and str
spinosum

67. ROLE OF SKIN BARRIER
Deletions of LCE3B and LCE3C genes
incomplete barrier repair after minor trauma
penetration of various antigens
induces inflammatory response

68. 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

69. • 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

70. +

71. Solving the tough jigsaw!!!