**4.1.4 Accessory cells (Dendritic cells and macrophages)**

236 Psoriasis

mouse, gave rise to creation of psoriatic plaque characterized by diffuse keratinocyte expression of CD1d, CD161+ T cells infiltration and marked presence of mRNA for IFN-c

In line with these data, it seems that constitutive CD1d expression on prepsoriatic skin keratinocytes represents a primary prerequisite that ensures their contact with the CD161 molecule on NKT cells. This interaction might also represent one of the critical events in the triggering of psoriasis as CD1d-bearing keratinocytes can present endogenous (self) or exogenous (bacterial, viral) glycolipids to NKT-cells. Consequently to the recognition of glycolipid antigens, NKT cells produce large amounts of IFN-c which induces stronger keratinocyte expression of CD1d; in this way the pathogenic mechanism of psoriatic plaques

Numerous studies have addressed the issue of NKT cells in the lesional skin of psoriasis patients and a constant result evidenced by independent groups of investigators is that CD161+ T cells appear in greater numbers in lesional skin of patients with psoriasis than in normal healthy skin and/or prepsoriatic skin (Bonish et al., 2000; Cameron et al., 2002;

However, Curry group shown a greater frequency of CD161+ T cells yet in the prepsoriatic skin in comparison with the normal skin, suggesting that certain immune response dysregulations exists in the uninvolved skin and creates a milieu, promoting the psoriatic

A flow cytometric analysis of psoriatic tissue-infiltrating T cell demonstrated the presence of CD3+ cells expressing also CD16, CD56, CD158b, CD94 or NKG2A and CD4–CD8–, the majority of these is a subset of NKT cells (Liao et al., 2006). In addiction a recent study (Zhao et al., 2008) confirmed that NKT cells as well as CD1d molecules were increased within

The supposed pathogenic role of NKT cells in psoriasis is also supported by the effects of different pharmacological treatments, that decreases NKT cell numbers in psoriatic plaques, in particular the clinical efficacy of betamethasone dipropionate (Bovenschen et al., 2007; Vissers et al., 2004b, 2008;) and similarly of alefacept that induce an improvement in plaque severity accompanied by significant reductions of dermal CD94+ and CD161+ (Bovenschen

In general, these data strongly indicate that lesional CD94+ and CD161+ NKT cells actively participate in the development and/or maintenance of psoriatic lesions, but the relative relevance of each of these subsets remains elusive. However, it might be hypothesized that epidermal NKT cells play a major pathogenic role due to their direct interaction with CD1d+ keratinocytes and the resulting hyperproliferation while the dermal component of NKT cells participates in the immune response through the interaction with CD1d-bearing dermal

Likewise other Th1-mediated autoimmune diseases, psoriasis is associated with decreased numbers of circulating NKT cells (Cameron et al., 2003; Koreck et al., 2002; van der Vliet et al., 2001;); Koreck reported that decreased percentage of NKT cells population in blood of psoriasis patients tended to be even lower in those with frequently relapsing (Koreck et al., 2002). Moreover, different systemic therapy regimens resulted in the recovery of these cells,

and IL-15 (Nickoloff et al., 2000).

is not only initiated but also maintained.

Curry et al., 2003; Vissers et al., 2004a).

lesions onset (Curry et al., 2003).

dendritic cells and monocytes.

psoriatic skin.

et al., 2007).

DCs are involved in the development of tolerance (Steinman et al., 2003) and are the unique professional antigen-presenting able to take up antigen in the tissue they reside in and to migrate to the draining lymph nodes; here activate naive T cells, generating specific T-cell responses (Teunissen, 2005).

In the peripheral tissues DCs receive all kinds of microenvironment signals, that influence the their maturation process, determining the phenotype and function of mature DCs and their type 1 type 2 polarizing potential. In case of risk (e.g. infection, cancer), DCs will transform into strong stimulatory antigen presenting cells, whereas under non pathological steady-state conditions DCs do not reach full maturation and they will present self-peptides MHC complexes in the presence of insufficient costimulatory molecules, inducing T-cell anergy or expansion of regulatory T cells (peripheral tolerance). If this delicate balance of immune reactivity vs. tolerance is broken, chronic inflammatory diseases, like psoriasis, may develop.

In the absence of pathogenic substances, stress signals from neighbouring cells (e.g. necrotic cells) can activate DCs enabling them to stimulate naive T cells (Gallucci et al., 1999). In relation to this, Krueger has expressed an remarkable view concerning traumatic injuries (breaches in the basement membrane and disruption of desmosome connections between adjacent keratinocytes) caused by migrating T cells and DCs in the epidermis, that are possibly involved in the development of psoriasis lesions (J. G. Krueger, 2002). Keratinocytes will respond to these defects by overproduction of cytokines, among others TNF-a, a key cytokine to induce DC migration/maturation.

Another exciting point to mention is the observation that DC development is also affected by mutual interaction with NKT cells (Taniguchi et al., 2003): weak responses by NKT cells to glycolipid CD1d complexes can be enhanced by DC-derived IL-12, resulting in upexpression of IFN-c by NK T cells. This interaction may be relevant in psoriasis.

DCs are numerous in the dermal part of psoriasis skin and many of them exhibit an activated phenotype (CD80+, CD83+, CD86+ and DC-LAMP+) (Abrams et al., 2000; Teunissen, 2005) and may be an important source of TNF-a (Nickoloff et al., 1991; Zhou et al., 2003).

Recent evidences from different genetic mouse models show that also the macrophages can contribute to T-cell-mediated and epidermis-mediated psoriasis-form skin inflammation

The Role of Immune Response and the Impact of Biological Drugs in Psoriasis Patients 239

(Abrams et al., 1999). This agent blocks T cell co-stimulation mediated by DCs without directly deplete T cells. Its effectiveness indicated that continuing T cell co-stimulation is required to sustain psoriasis disease activity, including the excessive infiltration of T cells and DCs into the skin (Abrams et al., 2000). All these clinical results confirmed that lesion-

Additional evidence highlighting the implication of T cells in psoriasis pathogenesis have been reviewed (Nestle et al., 2009) including the appearance of clonal T cells in psoriatic lesions (Menssen et al., 1995); the development of psoriasis-form phenotype within symptomless psoriatic skin after transplantion onto the xenotransplantation AGR 129 mouse model again underlines the importance of epidermal T cells in psoriasis genesis (Conrad et

Also, based on the findings that expansion of skin resident T cells is important in psoriasis progress in the xenotransplantation AGR mouse model, the function of tissue-specific factors in activation and expansion of resident T cells has been further explored (Conrad et al., 2007). T cells need to pass through the dermo-epidermal junction in order to go into the epidermis and collagen fibrils are an essential part of the dermo-epidermal junction. The most important basement membrane collagen is collagen IV and long-term activation of T cells results in the expression of a receptor for collagen IV, the heterodimeric integrin . It has been shown that epidermal accumulation of + Th1 and Tc1 cells correlate with psoriasis development. Blocking with a neutralizing Moab prevents epidermal T cell accumulation and subsequent psoriasis development in the xenotransplantation AGR mouse model. expression can act as a checkpoint for entry of T cells into epidermis with + epidermal T cells potentially playing an important role in psoriatic lesion

In conclusion, targeting of these integrins may offer new and effective therapeutic

The IL-23/Th17 pathway is an exciting area in psoriatic pathology (**Figure1**) because it has led to the development of promising innovative treatments which specifically target this pathway (D'Elios et al., 2010). The development, characterization and function of Th17 cells and the role of IL-23 in Th17-cell dependent chronic inflammation in psoriasis have been recently reviewed (Di Cesare et al., 2009). Briefly, IL-23 is a heterodimeric cytokine (Oppmann et al., 2000) composed of the subunits IL-23p19 and IL-12p40 (an IL-12 subunit). Intradermal injection of IL-23 in mice resulted in the development of a psoriasis-form phenotype with histopathological features (Chan et al., 2006). IL-23 can mediate epidermal hyperplasia, acanthosis, hyperparakeratosis and orthohyperkeratosis by way of TNF-, IL-20R2 and IL-22 (Chan et al., 2006; Zheng et al., 2007). These data are supported by findings in humans including an mRNA over-expression of IL-23p19 and IL-12p40 seen in psoriatic skin lesions, compared to uninvolved skin. Further other results indicate that IL -23 production occurs at inflammatory skin sites and is mediated by tissue-resident and/or

The pathogenic role of IL-23 in psoriasis is strongly supported by the clinical findings that anti-TNF- agents can reduce IL-23p19 and IL-12p40 mRNA levels also the reduction of IL-

recruited immune cells, such DCs and KCs (Piskin et al., 2006).

associated T cells are central to sustaining disease activity in psoriasis.

al., 2007).

formation.

approaches in psoriasis.

**4.2.2 The IL-23/Th17 pathway** 

and in particular the data from the CD18hypo PL/J psoriasis mouse model demonstrate (Wang et al., 2009) that the psoriasis-form inflammatory skin disorder critically depends on an appropriate activation of macrophages, with ample release of TNF-a.

In human psoriasis, the number of epithelium-lining macrophages was reported to increase in lesional skin. These macrophages can play a role in the regulation of epidermal proliferation and differentiation (van den Oord & de Wolf-Peeters, 1994); also vigorous interactions between macrophages and keratinocytes (Djemadji-Oudjiel et al., 1996) may be involved in the psoriasis pathogenesis (van den Oord & de Wolf-Peeters, 1994).

Macrophages, under different conditions, secrete various pro-inflammatory cytokines: TNF- , IL-1b, IFN-, IL-6, IL-10, IL-12, and IL-18, (Willment et al., 2003) and notably, in a recent study CD68+ macrophages were identified as important TNF-source in human psoriasis and upon treatment with anti-TNF- antibody macrophage levels decreased in the plaque psoriasis, with clinical psoriasis resolution (Marble et al., 2007). In according to this finding, it is also showed that CD68+ macrophages as important TNF- source in human psoriatic skin, which had distinctly decreased number and TNF- concentration following bath-PUVA therapy (Wang et al., 2009). This was also found in a T-cell-independent mouse model, with an increase of TNF- in macrophages (Stratis et al., 2006).

Based on literature data, an emerging model of psoriasis pathogenesis in humans suggests that dermal macrophages, activated by T-cell cytokines, produce large amounts of TNF-, leading to skin changes (Clark & Kupper, 2006).

### **4.2 Dysfunction of the adaptive immune response cells**

Until the 1990s, psoriasis was thought to be a disease of disordered keratinoctye proliferation and differentiation (G. G. Krueger et al., 1984) and epidermal hyperplasia was the most prominent clinical and histological feature. For this reason, the old psoriasis treatments using antimetabolites including methotrexate which limit epidermal hyperproliferation. However, successive evidence from clinical studies and, experimental models support the theory that psoriasis is a T cell-mediated inflammatory skin disease (Lew et al., 2004) affecting genetically predisposed individuals and the epidermal hyperplasia is an effect of cellular immune infiltration.

#### **4.2.1 Role of T cells**

The first evidence resulting in psoriasis being widely considered as a T cell mediated autoimmune disease came from the success in the psoriasis treatment of T cell-targeted therapies such as cyclosporine (Baker et al., 1987), tacrolimus (Jegasothy et al., 1992) or CD4 specific monoclonal antibodies (Moabs) (J. Prinz et al., 1991).

A pivotal study involved the testing of IL-2-diphtheria-toxin fusion protein in psoriasis patients (S. L. Gottlieb et al., 1995). This agent selectively depleting activated T cells that express IL-2 receptors from psoriasis skin lesions and resulted in clinical remission of psoriasis vulgaris.

Subsequently, administration of another fusion protein, cytotoxic T-lymphocyte antigen 4 (CTLA4)-antibody, was shown to reverse the clinical and cellular features of psoriasis (Abrams et al., 1999). This agent blocks T cell co-stimulation mediated by DCs without directly deplete T cells. Its effectiveness indicated that continuing T cell co-stimulation is required to sustain psoriasis disease activity, including the excessive infiltration of T cells and DCs into the skin (Abrams et al., 2000). All these clinical results confirmed that lesionassociated T cells are central to sustaining disease activity in psoriasis.

Additional evidence highlighting the implication of T cells in psoriasis pathogenesis have been reviewed (Nestle et al., 2009) including the appearance of clonal T cells in psoriatic lesions (Menssen et al., 1995); the development of psoriasis-form phenotype within symptomless psoriatic skin after transplantion onto the xenotransplantation AGR 129 mouse model again underlines the importance of epidermal T cells in psoriasis genesis (Conrad et al., 2007).

Also, based on the findings that expansion of skin resident T cells is important in psoriasis progress in the xenotransplantation AGR mouse model, the function of tissue-specific factors in activation and expansion of resident T cells has been further explored (Conrad et al., 2007). T cells need to pass through the dermo-epidermal junction in order to go into the epidermis and collagen fibrils are an essential part of the dermo-epidermal junction. The most important basement membrane collagen is collagen IV and long-term activation of T cells results in the expression of a receptor for collagen IV, the heterodimeric integrin . It has been shown that epidermal accumulation of + Th1 and Tc1 cells correlate with psoriasis development. Blocking with a neutralizing Moab prevents epidermal T cell accumulation and subsequent psoriasis development in the xenotransplantation AGR mouse model. expression can act as a checkpoint for entry of T cells into epidermis with + epidermal T cells potentially playing an important role in psoriatic lesion formation.

In conclusion, targeting of these integrins may offer new and effective therapeutic approaches in psoriasis.
