**2. Pathogenesis**

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) (Abel et al., 1986).

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

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.

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; Torti & Feldman, 2007).

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