**3. Genetics of psoriasis**

230 Psoriasis

Psoriasis is thought to be a complex condition resultant by a combination of genetic and environmental factors. The acute forms of psoriasis, guttate and generalized pustular psoriasis (von Zumbusch psoriasis), are both associated with infections (typically bhaemolytic streptococcal or a viral infection). Other triggering factors which may elicit psoriasis in predisposed individuals include trauma (Koebner phenomen) (Eyre & G. G. Krueger, 1984), HIV infection (Reveille et al., 1990), psychogenic stress (Gupta et al., 1989) and definite drugs (e.g. lithium, beta-blockers, interferons and high dose corticosteroids)

Histological examination of psoriatic plaques reveals hyperproliferation of keratinocytes (Kcs) with parakeratosis, increased angiogenesis and dermal infiltration of immune cells, predominantly T cells, neutrophils, macrophages and dendritic cells (DCs) (**Figure 1**)

Fig. 1. Psoriatic skin lesions evolution. Different stimuli (e.g. infections, etc.) can trigger an initial episode of psoriasis in genetically predisposed individuals. After starting, the earliest events driving the inflammatory eruption are the secretion of INF- from pDCs (plasmacytoid dendritic cells) and the production of TNF- by immune cells of both innate and adaptive response. Large amounts of IFN- induce activation of the local immune effector cells that secrete pro-inflammatory cytokines. TNF- is a very active cytokine of the inflammatory infiltrate and is principally secreted by activated macrophages (M), dermal DCs, keratinocytes and T cells. The elevated levels of TNF- lead to the maturation of DCs into forceful APCs (antigen presenting cells) and, with other cytokines, up-regulates the expression of endothelial E-selectin and ICAM-1 attracting further CLA+ T cells in the skin. Also, the panel of cytokines released by T cells contributes to the stimulation of epidermal keratinocytes and is at least, in some measure, responsible for typical psoriasis skin changes. They induce the

expression of ICAM-1, CD40 and MHC-II and trigger keratinocyte hyper-proliferation.

**2. Pathogenesis** 

(Abel et al., 1986).

(Nestle et al., 2009; Nickoloff et al. 2007b).

Family studies have shown that psoriasis has a strong genetic component although the inheritance pattern is still unclear. 71 % of patients with childhood psoriasis have a positive family history (Morris et al., 2001) and analysis of concordance rates in twin studies show a threefold increased risk of psoriasis in monozygotic twins compared to dizygotic twins (Brandrup et al., 1978; Pisani & Ruocco, 1984).

At least ten chromosomal loci have been identified showing statistically significant evidence for linkage to psoriasis (PSORS 1-10). However, the only region that has consistently been identified in genetic screens of families with psoriasis is the major-histocompatibility complex (MHC) region on chromosome 6 named PSORS1 (Capon et al., 2008; Nair et al., 2006), that is responsible for up to 50 % of genetic susceptibility to psoriasis. Within PSORS1 the human leukocyte antigen-C (HLA-C) gene which is the strongest candidate gene for psoriasis , precisely its allele HLACw6 (HLA-Cw\*0602) the predominant risk allele (Nair et al., 2006): individuals with this allele have a 10-20-fold increased risk of developing psoriasis (Mallon et al., 1999).

HLA-Cw6 positive and negative psoriasis patients may exhibit distinctive clinical phenotypes (Henseler & Christophers, 1985): guttate psoriasis is mostly confined to HLA-Cw6+ patients meanwhile psoriatic nail disease, palmoplantar pustulosis and psoriatic arthritis are more common in HLA-Cw6- patients (Fan et al., 2007; Gudjonsson et al., 2006). Furthermore, partial or total remission during pregnancy is much more frequent in HLA-Cw\*0602+ women (Gudjonsson et al., 2006).

Despite this strong association, the functional role of HLA-Cw6 remains unknown; as far as we know HLACw6 may exert its effect through the specific or the innate immune system (Figure 2): HLA-Cw6 may act via the adaptive immune system by its antigen presenting capacity and the fact that guttate psoriasis (sturdily associated with HLA-Cw6) is triggered by streptococcal pharyngitis (J. C. Prinz, 2001), supports this hypothesis. HLA-Cw6 may also exert an innate immune response via its interaction with KIRs (killer immunoglobulin-

The Role of Immune Response and the Impact of Biological Drugs in Psoriasis Patients 233

which then traffic to the skin where they induce – in concert with other cells, especially dermal DCs – the creation of a primary psoriatic plaque. During this step some T cells and DCs start to infiltrate the epidermis, where stimulating KCs support the typical epidermal

Epidermal keratinocytes are able to recruit and activate T cells and most T cells infiltrating psoriatic skin are divided into Th1 (CD4+) and T cytotoxic 1 (Tc1; CD8+) subsets (J. G. Krueger, 2002). Two further T cell subtypes, Th17 cells (McKenzie et al., 2006) and regulatory T cells (Treg) (Sugiyama et al, 2005) have been identified as important contributors to the pathogenesis of autoimmune diseases such as psoriasis (**Figure 3**).

changes (Bowcock & J. G. Krueger, 2005).

Fig. 3. Role of CD4 T cell subtypes in psoriasis.

like receptors) of natural killer (NK) and natural killer T (NKT) cells, which are implicated, in psoriasis pathogenesis (Nickoloff, 1999a). KIRs recognize different types of HLA-C molecules leading to either an overall activating or inhibitory immune response. KIRs have been associated with psoriasis and PsA (Martin et al., 2002). HLA-Cw6 is a natural ligand for KIR2DL1 (an inhibitory receptor) and it is possible that interaction between HLA-Cw6 and PaKIR2DL1 would lead to aberrant function of lymphoid cells in psoriasis pathogenesis.

Fig. 2. Hypothetical regulating role of HLA-Cw6 in both specific and innate immune responses.

HLA-Cw6 expressed on APCs can trigger specific immune responses by presentation of processed antigen to the TCR of CD8+ T cells. Also, innate immune response can be elicited by interaction of HLA-Cw6 with its natural Killer immunoglobulin-like receptors expressed on NK and NKT cells.

A new psoriasis susceptibility gene ZNF313/RNF114, which may regulate T cell activation through ubiquitin ligase activity, has been identified (Capon et al., 2008). All these data further supports the concept that multiple gene products share a role in the immune regulation of psoriasis, contributing to disease pathogenesis.
