1. ^*Department of Dermatology, University Hospital of Zurich, Zurich, Switzerland
2. ^†Department of Immunology, MD Anderson Cancer Center, University of Texas, Houston, Texas, USA

Psoriasis is a common chronic-relapsing immune-mediated pathology involving skin and joints of genetically predisposed individuals (^{Nickoloff and Nestle, 2004;Schon and Boehncke, 2005}), which potentially shares disease pathways with other chronic inflammatory diseases such as rheumatoid arthritis and inflammatory bowel disease (^{Davidson and Diamond, 2001}). The pathogenesis of psoriasis is dependent on activation and expansion of lesional and/or circulating T cells culminating in a psoriasiform angiogenic tissue reaction and epidermal hyperplasia (^{Boyman et al, 2004}). Based on the analysis of infiltrating cell types, their secreted products, and genetic signatures present in lesional skin, psoriasis is regarded as a type-1 tissue reaction with a prominent role for T cell-derived interferon (IFN)- (^{Nestle et al, 1994;Lew et al, 2004}). Given that environmental factors such as mechanical stress and infections of the skin represent a common trigger for disease relapses, much effort has been devoted to understanding the link between these unspecific stimuli and the pathogenic T cell cascade leading to psoriasis. Recent evidence suggests that type-1 IFN, a class of cytokines produced at early stages of the innate immune response to pathogens, may represent the missing link.

Type I IFN contain various family members (IFN- subtypes, -, -, -, -, -, -), the most abundant and best-studied being IFN- and -. Although IFN-/ can be produced by virtually all cells of the human organism, plasmacytoid dendritic cells (PDC), or "natural IFN-producing cells" (NIPC) have the unique ability to produce up to 1000-fold more IFN-/ than any other cell type (^{Liu et al, 2001}). IFN-/ share a heterodimeric receptor composed of IFNAR1 and IFNAR2. Ligand binding leads to receptor dimerization, auto-phosphorylation of Janus kinases (JAK), recruitment and phosphorylation of signal transducer and activator of transcription (STAT-1, STAT-2, STAT-3, STAT-4 in some cell types), translocation of STAT homo- and heterodimers into the nucleus, and induced expression of a large numbers of IFN-stimulated genes (ISG), including IFN regulatory factor (IRF)-7, protein kinase (PKR) and myxovirus-resistance (Mx) protein (^{Theofilopoulos et al, 2005}). IRF-7 is of special importance since it has been recently shown to be the master regulator of the IFN-/ mediated immune response (^{Honda et al, 2005}). Through the induction of ISG, IFN-/ exhibits a unique pleiotropy of biological effects primarily aimed at a cellular state of antiviral defense, encompassing growth inhibition and immunomodulation (^{Theofilopoulos et al, 2005}). Immunomodulatory effects include upregulation of MHC class I, NK cell activation, and most importantly activation of myeloid dendritic cells.

Although never convincingly demonstrated, a potential involvement of IFN-/ in the pathogenesis of psoriasis has been previously suggested by the following observations: (i) the induction of psoriasis after injection of recombinant IFN- (^{Funk et al, 1991}), (ii) the presence of an activated IFN-/ signaling pathway in keratinocytes (^{van der Fits et al, 2004}), and (iii) the development of psoriasiform inflammation in IRF-2 knockout mice (^{Hida et al, 2000}). A functional role of IFN-/ in the initiation of psoriasis has been demonstrated very recently (^{Nestle et al, 2005}). This study showed that IFN- was not elevated in fully established psoriatic plaques but was transiently produced at very early stages of psoriasis development (^{Boyman et al, 2004}) and represented a key innate event leading to the expansion of pathogenic T cells and to their activation into effectors mediating the development of the psoriatic lesion (^{Nestle et al, 2005}).

In this issue, Wessel Eriksen et al provide a link between IFN- produced during psoriasis development and the T cell effector functions in psoriasis. IFN--induced signaling was shown to be increased and prolonged in psoriatic T cells at the level of STAT activation. Increased IFN- signaling led to increased STAT binding, IFN- production, and inhibition of T cell growth. Interestingly, in addition to an increased STAT-1 and STAT-2 activation, Wessel Eriksen et al (2005) also show enhanced STAT-3 activation in psoriatic T cells which complements recent data on the role of activated STAT-3 in psoriatic keratinocytes (^{Sano et al, 2005}). Wessel Eriksen et al further demonstrate increased STAT-4 activation linking IFN- sensitivity of psoriatic T cells and generation of lesional Th-1 responses (^{Kaplan et al, 1996}). The response to IFN- was specific since STAT responses to other cytokines were not altered.

How can we integrate the findings of Wessel Eriksen et al in the current view of the pathogenesis of psoriasis? An integrated view is depicted in Figure 1. In uninvolved skin of psoriatic patients there is an increased number of PDC (^{Nestle et al, 2005}). Innate activation of PDC to produce IFN- drives "quiescent" resident T cells in uninvolved psoriatic skin into activated pathogenic effectors. This may occur indirectly through the induction of myeloid DC activation/maturation as suggested for SLE (^{Blanco et al, 2001}). In line with this scenario, myeloid dermal DC in psoriatic skin are activated and have the ability to stimulate autoreactive Th-1 cells (^{Nestle et al, 1994}). Additional indirect effects of IFN- on T cells include (i) the enhanced survival and expansion of T cells through induction of IL-15 (^{Zhang et al, 1998}) and (ii) an increased cross-presentation of tissue specific (auto-) antigens by lesional DC (^{Le Bon et al, 2003}). Wessel Eriksen et al suggest that IFN- may also act directly through activation of IFN- sensitive lesional T cells. Furthermore, increased STAT-4 activation in psoriatic T cells links IFN- sensitivity and generation of lesional Th-1 responses. These findings further strengthen the emerging concept that IFN- is an early innate master cytokine in autoimmune diseases including psoriasis and raise several important questions. What causes the increased IFN--sensitivity in psoriatic T cells? Is there a genetic component related to increased IFN- sensitivity? Is the primary defect in psoriasis rather an aberrant activation of the IFN- pathway as a consequence of the recruitment and the activation of PDC in psoriatic skin? The molecular definition of ligands activating lesional PDC as well as factors involved in the generation and differentiation of lesional pathogenic T cells may provide important clues to answer these questions. How does IFN- compare to TNF-, a validated target for psoriasis (^{Chaudhari et al, 2001;Boyman et al, 2004})? In contrast to TNF-, IFN- production in psoriasis is a transient event occurring early during the psoriatic disease process and is mainly confined to one cell type, dermal PDC. It will be therefore of particular interest to test inhibitors of IFN- and its signaling pathways as prophylactic and therapeutic agents in psoriasis. Thus, we suggest a spatial and temporal view of psoriasis development, in which PDC-derived IFN- represents an early and tightly regulated upstream event preceding Th-1 mediated autoimmune inflammation, induced by IFN- sensitive autoreactive T cells.

Figure 1.

Interferon (IFN)- links innate and adaptive immunity leading to the development of psoriasis. A spatial and temporal view of psoriasis development in which IFN- production represents an early and transient event during the psoriatic disease process and is confined to activated plasmacytoid dendritic cells (PDC) (innate immunity). Innate activation of PDC may result from the release of skin-derived products upon skin injury or infection. IFN- stimulates the pathogenic T cell cascade (adaptive immunity) indirectly by promoting the activation and maturation of myeloid dendritic cells (MDC) or by direct stimulation of IFN--sensitive pathogenic T cells, leading to Th1-mediated inflammation and the development of the psoriatic epidermal hyperproliferation.

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