**4. Conclusion**

20 Psoriasis

differentiation and function of the epidermis (Heidenreich et al., 2009). Consequently, VEGF over-expression in psoriasis might contribute to the epidermal changes observed in this disease. Although immune cells are also able to secrete VEGF, the findings of VEGF overexpression in psoriatic epidermis together with the data reported from the transgenic animals strongly suggest that VEGF derived from epidermal keratinocytes acts as a key cytokine driving angiogenesis in psoriasis and as a central paracrine growth factor

The expression of CD1d by normal human skin and its pronounced over-expression in psoriatic skin lesions is well documented (Bonish et al., 2000) as well as the presence of NK-T cells in the epidermis of acute and chronic psoriatic plaques (Nickoloff & Wrone-Smith, 1999; Nickoloff et al., 2000). A hallmark of NK-T cells is their expression of certain C-type lectin NK cell receptors (NKRs)4 such as CD94 and CD161. Classical NK-T cells may plan an immunoregulatory role for recognition of both self and foreign antigens and are implicated in the pathogenesis of autoimmune and inflammatory diseases like psoriasis. An important clue to the function of NK-T cells is provided by their interaction with professional antigen presenting cells (APCs) via CD1d (Huang et al., 1999). CD1d has some similarities in structure to the major histocompatibility complex class II (MHC II) molecules. While initially CD1d was believed to bind and present peptide antigens to T cells (Castano et al., 1995), more recent studies highlight its ability to present glycolipids and GPI-linked proteins (Huang et al., 1999). NK-T cells can become activated in a CD1drestricted fashion with subsequent proliferation and cytokine production, including IFN-γ and IL-4. Keratinocytes in vitro and in vivo synthesize and express CD1d, which is capable of triggering CD161+ NK-T cells to produce high levels of IFN-γ, but not IL-4. The stimulation by CD1d of T cells bearing NK receptors preferentially induces a cytokine switch to IFN-γ (Arase et al., 1996, 1997). Moreover, the differential induction of IFN-γ production, but not IL-4, after the NK-T cell clones recognized CD1d on keratinocytes has potentially important implications for psoriasis. Not only is there over-expression of CD1d by psoriatic epidermal keratinocytes and the presence of NK-T cells bearing CD94 and CD161, but the cytokine IFN-γ has been shown to trigger psoriatic lesions (Fierlbeck et al., 1990). Therefore a positive feedback loop could be established in skin due to the presence of NK-T cells being activated to produce IFN-γ upon contact with CD1d-positive keratinocytes, leading to further CD1d expression and subsequent NK-T cell release of more IFN-γ. The lack of a proliferative response by NK-T cells to CD1d keratinocytes is also consistent with the general number and distribution of CD94- and CD161-positive NK-T cells in psoriasis. Thus, the NK-T cells are never observed in tight clusters or in very large numbers as might be expected if they were undergoing a local proliferative response; rather, they are found as more evenly distributed single cells throughout a psoriatic plaque. In normal human skin CD1d is generally restricted to the outermost keratinocyte layers in the stratum granulosum just beneath the lipid-rich stratum corneum. In addition to epidermal keratinocytes, CD1d is detected on upper dermal dendritic cells, endothelium, eccrine ducts, acrosyringium, and the pilo-sebaceous unit, except for the dermal papillae and hair matrix cells. In psoriatic plaques CD1d expression was increased compared with that in normal and symptomless skin, beginning in the supra-basilar layer and extending to the outermost keratinocytes immediately beneath the

contributing to the pathology seen in psoriasis.

**3.3.2 Keratinocytes and C1d** 

The pathogenesis of psoriasis is considered to be an immunologically mediated process that takes place upon a favourable genetic background. According to this view, the presence of a yet unknown (auto)-antigen causes the generation of effector T-cells that infiltrate the skin and initiate the inflammatory process. Over its course, cutaneous infiltration of various immune cell populations and, subsequently, an activation of numerous immune and tissue cells in the skin takes place. Two fundamentally different cell types interact in the formation of a psoriatic lesion: epidermal keratinocytes and mononuclear leukocytes. Whereas keratinocytes might be viewed only as bystander cells in terms of immune activation, it is more likely that they are active participants in the recruitment and activation of leukocytes in psoriatic lesions: the interplay between keratinocytes and immune cells can be considered the main feature of the psoriasis pathogenesis. In facts whatever the sequence of events that leads to the induction of the mentioned cytokines and mediators in epidermal keratinocytes, it is highly likely that they significantly contribute to the typical changes observed in psoriatic lesions; cytokine or growth factor secretion by epidermal keratinocytes can be sufficient to recruit immune cells into the skin and induce a hyperplastic epidermis with hyperkeratosis and reproduce features of psoriatic disease. Regulation of the inflammatory events initiated or perpetuated by keratinocytes could so represent an important strategy for the treatment of psoriasis and other chronic inflammatory skin diseases.

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**3** 

**Wound Repair Studies Reveal** 

Chee Ren Ivan Lam1, Ming Jie Tan1, Yan Yih Goh1, Mark Boon Yang Tang2 and Nguan Soon Tan1

*1School of Biological Sciences, Nanyang Technological University, Nanyang Drive* 

Psoriasis, a chronic relapsing inflammatory skin disease with a disturbing global incidence of approximately 2%, is an afflicting and disfiguring skin disease with high morbidity (Lomholt, 1964). The disease is characterized by the well-demarcated erythematous plaques with silvery white scales and a predilection for body areas such as the elbows, knees, umbilicus and lumbar area (Schön & Boehncke, 2005). In contrast to normal skin, the dermal vasculature in psoriasis dermis is dramatically increased with large, tortuous blood vessels, accounting for the erythematous appearance or redness of the affected skin regions/psoriatic plaques (Nestle et al, 2009). In addition, the psoriatic epidermis is significantly thickened and acanthotic, due to hyperproliferative keratinocytes with an approximate seven-fold increase in the number of dividing cells in the basal and suprabasal epidermal layers (Castelijns et al, 2000). Keratinocytes of the psoriatic skin are prematurely differentiated, as evident in the incomplete cornification of the stratum corneum, characterized by the retention of nuclei (i.e., parakeratosis) and the loss of the granular layer. The stratum corneum of psoriasiform skin is also thickened (i.e., hyperkeratosis). This heavy disruption of epidermal differentiation and skin barrier homeostasis coupled with altered levels of intercellular adhesion molecules result in the widespread scaling of psoriatic lesions (Christensen et al, 2006). While psoriasis primarily affects the epidermis, the disease has a strong immunopathological basis, with the psoriatic skin being significantly infiltrated with immune cells. Notably, this immune infiltrate has a characteristic distribution and is composed mainly of dendritic cells and macrophages in the dermis, neutrophils in the epidermis and T cells in both layers. Another immunologic feature of the disease is its extracutaneous manifestation of an arthritic condition, which affects approximately 5% of the population and approximately 20% of psoriasis patients (Zachariae et al, 2002; Hueber & McInnes, 2007). However, the direct involvement of the skin and immune system in psoriasiform features complicates and confounds studies of psoriasis. Therefore, despite the detailed documented pathological observations of psoriasis and the vast research efforts aimed at understanding the disease, a key question remains

unanswered: is psoriasis provoked by an epidermal or an immunological trigger?

**1. Introduction** 

**New Insights to Psoriasis** 

*2National Skin Centre* 

*Singapore* 

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