**4. Immune response**

Although the initial event triggering a psoriatic lesion is still unknown many factors have been shown to play a role in the pathogenesis of psoriasis: physical trauma, infections, stress, drugs, alcohol and smoking can all trigger an initial episode of psoriasis in individuals with genetic predisposition (Bowcock & J. G. Krueger, 2005).

This initial trigger activates dendritic cells, favoring their migration to skin-draining lymph nodes, where antigen-specific T cells (primed by DCs) differentiate into effector T cells,

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

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

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

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

Although the initial event triggering a psoriatic lesion is still unknown many factors have been shown to play a role in the pathogenesis of psoriasis: physical trauma, infections, stress, drugs, alcohol and smoking can all trigger an initial episode of psoriasis in

This initial trigger activates dendritic cells, favoring their migration to skin-draining lymph nodes, where antigen-specific T cells (primed by DCs) differentiate into effector T cells,

regulation of psoriasis, contributing to disease pathogenesis.

individuals with genetic predisposition (Bowcock & J. G. Krueger, 2005).

pathogenesis.

responses.

on NK and NKT cells.

**4. Immune response** 

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

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**).

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

The Role of Immune Response and the Impact of Biological Drugs in Psoriasis Patients 235

inflammatory skin lesions but also a form of destructive arthritis. This evidence suggested that alteration in the epidermal Jun-pathway may be sufficient to induce inflammatory reactions in the skin as well as in the joints. At the skin level these mice showed typical hallmarks of psoriasis: hyperkeratosis, enlarged blood vessels, infiltration of T cells and

The most intriguing aspect was the examination of the T cells role in development of psoriasis in a genetic model: upon deletion of JunB and c-Jun proteins in Rag2-deficient mice (mice deficient of T/B cells), skin changes like in psoriasis were still induced, though they were milder. These data suggest a minor role for T cells in the etiology of psoriasis-form skin inflammation, and that primary alterations in KCs were sufficient to drive psoriasisform changes in the mice skin. But before stating that KCs instigate psoriasis in humans, the relevance of this model must be discussed further. A recent study (Haider et al., 2006) showed that the JunBwas expression increased in psoriatic plaques instead of decreased/deleted as in the Zenz mouse model, suggesting a role for JunB as a

The ongoing discussion about the primary instigator of psoriasis reflects the complexity of this disease and the still elusive interplay between KCs and immune cells in driving

This problem was further addressed in a another mouse model, in which STAT-3 was constitutively activated in basal KCs under the control of the keratin 5 promoter (K5.Stat3C) (Sano et al., 2005). As in human psoriatic plaques, induced lesions of K5.Stat3C mice shown a considerable number of CD4+ T and CD8+ T cells in the epidermis. For psoriasis development, this model required both activated STAT-3 in KCs and activated T cells in the dermis and epidermis of the transgenic rodents, suggesting the theory that KCs and T cells

Early studies in psoriasis (Jablonska, 1986), in which the initial (pre-pinpoint) lesions were studied histologically,indicated that the primary abnormality in a developing lesion of psoriasis is the perivascular accumulation of neutrophils as well as their epidermis invasion (Kogoj phenomenon). Next, these neutrophils accumulations lead to microscopically detectable microabscesses (Munro abscesses). In many patients with psoriasis, these micropustules may enlarge and become clinically visible as sterile 2–3-mm pustules. In some patients, pustules are the primary visible abnormality, often on an erythematous base.

The presence of neutrophils must be important for the formation of psoriatic skin lesions, in fact agranulocytosis has been reported to result in the remission of psoriasis (Toichi et al., 2000). Next, neutrophils can contribute to the hyperproliferation of keratinocytes by the

The potential role of cells expressing NK receptors in psoriatic skin was firstly proposed by Nickoloff (Nickoloff et al., 1999b); in further experiments, he showed that a CD94+/CD161+ NKT cell line (isolated from a psoriatic patient) injected in prepsoriatic skin of a SCID

neutrophils, and up-regulation of pro-inflammatory cytokines.

transcriptional activator of disease-related genes in psoriatic KCs.

effects of human leucocyte-derived elastase (Rogalski et al., 2002).

could act together in psoriasis pathogenesis.

**4.1.2 Neutrophilic granulocytes** 

**4.1.3 Natural killer T cells** 

psoriasis.

Th1 and Th17 pro-inflammatory cytokines mediate keratinocyte hyperproliferation and trigger a 'vicious cycle' of inflammation. IL-23 secreted principally by keratinocytes, dendritic cells and macrophages is critical for maintenance of Th17 function. Low levels of anti-inflammatory cytokines released by Th2 and Tregs potentially counteract but cannot balance the effects of Th1/Th17 cytokines.

From the foregoing it is clear that the contribution of both innate and adaptive immune responses are important in mediating the inflammatory psoriasis cascade (Gaspari, 2006) (**Figure 1**).
