**1. Introduction**

Psoriasis is a chronic immune-mediated skin disease with a intricate pathogenesis and a strong genetic background (Nickoloff et al., 2007a), that affects approximately 1–3% of the worldwide population, with an equal sex distribution (Stern et al., 2004). The main type of psoriasis is chronic plaque psoriasis (Cpp) accounting for approximately 85–90% of all cases. The Cpp is characterized by erythematous scaly plaques, usually on elbows, knees, scalp and buttocks. Plaque size can diverge from minimal to the involvement of the entire skin surface (erythrodermic psoriasis) (C. E. Griffiths et al., 2007; Nestle et al., 2009). Other forms of psoriasis comprise guttate psoriasis, inverse, palmoplantar and generalized pustular psoriasis (C. E. Griffiths & Barker, 2007; Nestle et al., 2009).

The concept of psoriasis as "the disease of healthy people" has long been surpassed, nowadays we know that during the time course of this disease, as a consequence of dysregulated immunity and ensuing inflammation, certain conditions may appear at somewhat unpredictable time points in a progressive fashion; these so-called comorbidities, although targeting different organs, share common pathogenetic factors. They often become manifest years after the onset of skin manifestations and are often observed in severe forms of psoriasis.

Psoriatic Arthritis (PsA) is traditionally included among common co-morbidities, even if it should be rather considered a component of the clinical spectrum of psoriatic disease. PsA involves peripheral joints, the axial skeleton, sacroiliac joints, nails and enthuses, and is frequently associated with psoriatic skin lesions. The prevalence of PsA ranges from 5 to 40% among psoriatic patients lesions (D. D. Gladman, 2009; Nograles et al., 2009).

Recently, co-morbidities like cardiovascular disease, obesity and metabolic syndrome have been found to be associated with psoriasis, raising the idea that psoriasis might not be only a skin disorder (Gerdes & Mrowietz, 2009; Kimball et al., 2008a; Menter et al., 2008).

Psoriasis patients suffer also from considerable psychological and financial burdens resulting in a significantly impaired quality of life (Rapp, et al., 1999); likewise traditional systemic psoriasis therapies (methotrexate [MTX], cyclosporin A, retinoids or PUVA therapy) have a potential for long-term toxicity and cannot always provide plenty disease improvement (Pathirana et al., 2009; Smith et al., 2009). Thus, the development of agents efficiently targeting key steps in the pathogenesis of psoriasis and co-morbidities is clearly an important goal.

The Role of Immune Response and the Impact of Biological Drugs in Psoriasis Patients 231

The increased dermis vascularity is driven by angiogenic factors, such as VEGF (vascular endothelial growth factor ), highly present in psoriasis plaques (Detmar et al., 1994). Also, the interaction between VEGF and the angiopoietin/Tie signaling pathway is modulated by TNF-a (Tumour necrosis factor-a), that together with interleukin 12 (IL-12) and IL-23 are well known to be crucial immunological mediators in psoriasis. (Holash et al., 1999; Kuroda et al., 2001). Whereas IL-12 induces Th1 (T helper 1) differentiation and thus increases the production of TNF-a, IL-23 stimulates primarily Th17 cells, which secrete most importantly pro-inflammatory cytokines such as IL-17 and IL-22 (Nestle et al., 2009; Toichi et al., 2006;

Increased concentrations of TNF-a and IL-12/IL-23 have been found as in psoriatic skin (Nestle et al., 2009) as in the synovial fluid and tissue of patients with PsA (FitzGerald & Winchester , 2009; Ritchlin et al, 1998). Their role in psoriasis genesis is highlighted by the successful treatment of psoriasis by agents blocking these cytokines (Boker et al., 2007; Mössner et al., 2008; Scalon et al., 2009). In addition, polymorphisms of IL-23 receptor gene and gene encoding the shared p40 subunit of IL-12 and IL-23 have been linked to psoriasis

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

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

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

Furthermore, partial or total remission during pregnancy is much more frequent in HLA-

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-

patients (Fan et al., 2007; Gudjonsson et al., 2006).

development (Elder et al., 2010; Hüffmaier et al., 2009; Nestle et al., 2009).

Torti & Feldman, 2007).

**3. Genetics of psoriasis** 

(Mallon et al., 1999).

(Brandrup et al., 1978; Pisani & Ruocco, 1984).

arthritis are more common in HLA-Cw6-

Cw\*0602+ women (Gudjonsson et al., 2006).
