Immunology of psoriasis

Nikhil Yawalkar

Department of Dermatology

Inselspital Bern

Aetiopathogenesis of psoriasis

Genetic factors

Environmental factors

e.g. streptococci

Defects in

epidermal function,

innate/acquired immunity

Pathological hallmarks of psoriasis

Abnormal differentiation and hyperproliferation of keratinocytes

Infiltration of inflammatory cells

Increased dermal blood vessels

• Previous hypothesis (pre 1990)

- Primary activation of keratinocytes

- Subsequent release of cytokines and antigen-independent activation of T cells

• Current understanding (post 1990)

- Persistent T-cell stimulation (antigen?) which drives abnormal keratinocyte proliferation

Where is the primary defect?

- Alteration of transcription factors in keratinocytes

- Exaggerated innate immune response

(DC, macrophages, IFNs, TNF , IL-12/IL-23)

Boyman et al. J Exp Med. 2004;199: 731

Role of T cells in psoriasis

CD3

Day 56

Xenotransplantation models:

- AGR-/- xenograft model1

non-lesional human skin engrafted onto AGR129 mice

spontaneous development of psoriatic phenotype

• Infiltrate:

- memory-effector T cells

CD4 DC, macrophages

CD8 keratinocytes

Krueger JG. J Am Acad Dermatol 2002; 46: 1

Nickoloff et al. J Invest Dermatol. 1998; 110, 459-460

Role of T cells in psoriasis

CD4 > CD8

CD8 > CD4

• T cells are activated - CD69, CD25, HLA-DR

CD 69

TCR

TCR

TCR

T cell TCR

TCR

• clonal T cell expansions

- antigen-specific stimulation

Putative antigen(s) ?

• -haemolytic streptococci can trigger psoriasis

• Superantigens stimulate a skin-homing

molecule (CLA) on T cells

• T cells cross-react with epitops which are

common to streptococcal M protein and

keratins 1,2

1.Gudjonsson et al. Clin Exp Immunol 2004; 135:1

2. Baker et al. Scand J Immunol 2003; 58: 335

TCR

TCR

TCR

T cell TCR TCR

DC

Signal 1: Antigen

Innate immunity is critical for T cell activation

Signal 2:

- Co-stimulatory molecules

- Adhesion molecules

CD28

CD2

LFA1

CD80

LFA3

ICAM1

Signal 3:

- Cytokines (IL-2, IL-12, IL-23,…)

T cell

• Psoriatic skin is highly infiltrated by

dendritic cells (DC)

Abrams et al. J Exp Med. 2000; 192: 681

Lowes et al. PNAS. 2005; 102: 19057

Zaba et al J Invest. Dermatol 2009;129:79

- plasmacytoid DC (BDCA-2)

- myeloid DC (CD11c, BDCA-1-)

Innate immunity in psoriasis

DC

- plasmacytoid DC (BDCA-2)

- myeloid DC (CD11c)

Activation of DC and production of cytokines

IFN-

TNF- , IL-12, IL-23

IL-23

IL-12 IFN

TNF

„stress“

infection, trauma

„danger signals“

cytokines, HSP, LL-37

+ antigen ?

Day 0

Day 35

Anti-BDCA-2

Key cytokines in psoriasis: IFN

- Psoriasis is inhibited by anti–BDCA-2

- fully restored by the addition of

recombinant human IFN-

Xenotransplantation models:

- AGR-/- xenograft model1

Nestle et al. J Exp Med. 2005; 202: 135

Anti-BDCA-2 + IFN

• Enhanced expression in

- skin

- joints

- serum (correlates with activity)

• Produced by multiple cells

- DC, macrophages

- T cells

- mast cells

- keratinocytes, endothelial cells

Key cytokines in psoriasis: TNF

Key cytokines in psoriasis: TNF

TNF

Stimulation of

cytokines/ chemokines

Keratinocyte activation

Adhesion molecules

Neovascularisation Recruitment of further

leucocytes

Modulation of key cytokines

TNF

Etanercept, ENBREL

Adalimumab, HUMIRA

Infliximab, REMICADE

• TNF Antagonists

before Remicade on Remicade since 3 years

TNF Antagonists

IL-12 IL-23

Lee et al. Exp Med. 2004; 199:125

Yawalkar et al. J Dermatol Science 2009; 54: 99

Key cytokines in psoriasis: IL-12 and IL-23

1. Blauvelt A. J Invest Dermatol. 2008;128: 1064

• IL-12 and IL-23 bind to specific receptors on T cells and natural

killer cells

• Strongly influence T cell differentiation and activation

IL-12 and IL-23 are heterodimers with a

common p40 subunit

IL-12 and IL-23 drive development of Th1

and Th17 cells

Th 1

Th17

IL-12

IL-23

IFN , TNF

IL-17, IL-22,

TNF

Th17 Th17

Th1

Th1

DC

Th1 cytokines drive inflammatory

processes in the psoriatic plaque

Th1

IFN

TNF

Adapted from: Lowes MA, et al. Dermatol Clin. 2004; 22:349

iNOS (NO)

IL-8

MIG, IP-10

VEGF

MHC Class II

ICAM-1

VCAM-1

Keratinocyte and endothelial cell activation

Neovascularisation

T cell influx

Neutrophil influx

Vasodilation

Th17 cytokines drive inflammation and

keratinocyte hyperplasia in the psoriatic plaque

Th17

IL-17

IL-22

TNF

Aggarwal S, Gurney AL. J Leukoc Biol. 2002; 71:1

Monocyte and

neutrophil recruitment

Neovascularisation

Vasodilatation

T cell influx

Keratinocyte

hyperplasia

MCP-1

Gro-

IL-8

G-CSF

GM-CSF

IL-6

PGE2

ICAM-1

VCAM-1

Modulation of key cytokines

Ustekinumab, STELARA®

Briakinumab, ABT-874

• Anti-IL-12/Il-23 p40

Images courtesy of the PHOENIX 2 Investigators

week 12 week 52

Ustekinumab, STELARA

before Stelara

• Activation of DC and T cells

Summary:

Key steps in the immunopathogenesis

Th17

Th1

IL-12

IL-23

• Perpetuation of inflammation

• Stimulation of keratinocytes

• Neovascularisation

• Recruitment of further leucocytes

IFN

TNF