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.

• Ancient biblical records 2000 BC

• Corpus hippocraticum

• Galen

• “Psora”= to itch

HISTORY

• 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

• KOEBNER PHENOMENON

• SEASONAL VARIATIONS

• PREGNANCY

• EMOTIONAL STRESS

• INFECTIONS

• DRUGS

• SUNLIGHT

• ALCOHOL & SMOKING

• OBESITY

RISK FACTORS & MODIFYING FACTORS

DRUGS

Beta-blockers A delayed type hypersensitivity reaction, an immune mediated response and a decrease in intraepidermal cAMP and a consequent increase in epidermal cell turnover

Both cardioselective and non-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

• angiotensin-converting enzyme inhibitors

• interferons

• digoxin

• clonidine

• carbamazepine

• Valproic acid

• calcium-channel blockers

• granulocyte-colony stimulating factor

• potassium iodide

• penicillin

• progesterone

• morphine

• acetazolamide

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. A direct keratinocyte mitogen, which mediates angiogenesis

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

• 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

DEVELOPING LESIONS

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

Genes associated with innate immunity

Regulation of T-cell activation

IFIH1 (Interferon induced helicase C domain), MDA5

Rig like helicases, involved in recognition of RNA viruses

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)

Genes associated with skin barrier function

Inhibition of demethylase activity to activate NF-κB

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 26

Involved in gap junction formation

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.

Naïve T cells

presence of TNF-α,TGF-β and IL-6

presence of TGF-β and IL-6

Th1, Th2, Th17 or Tregulatory cells

Th17 cells

IMMUNOLOGY

• 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 keratinization

Increased exp of CSDN, small proline

rich proteins, cystatin A, transglutaminase- I

Decreased expression of loricin, fillagrin

Aberrant formation of cornified envelope

• Inc TEWL• Dec exp of

aquaporins in str corneum and str spinosum

ABNORMAL KERATINISATION

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!!!