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In recent years, different genes and proteins have been highlighted as potential biomarkers for psoriasis, one of the most common inflammatory skin diseases worldwide. However, most of these markers are not only psoriasis-specific but also found in other inflammatory disorders. We performed an unsupervised cluster analysis of gene expression profiles in 150 psoriasis patients and other inflammatory skin diseases (atopic dermatitis, lichen planus, contact eczema, and healthy controls). We identified a cluster of IL-17/tumor necrosis factor-α (TNFα)-associated genes specifically expressed in psoriasis, among which IL-36γ was the most outstanding marker. In subsequent immunohistological analyses, IL-36γ was confirmed to be expressed in psoriasis lesions only. IL-36γ peripheral blood serum levels were found to be closely associated with disease activity, and they decreased after anti-TNFα-treatment. Furthermore, IL-36γ immunohistochemistry was found to be a helpful marker in the histological differential diagnosis between psoriasis and eczema in diagnostically challenging cases. These features highlight IL-36γ as a valuable biomarker in psoriasis patients, both for diagnostic purposes and measurement of disease activity during the clinical course. Furthermore, IL-36γ might also provide a future drug target, because of its potential amplifier role in TNFα- and IL-17 pathways in psoriatic skin inflammation.

In human patients, a wide range of mutations in keratin (K) 5 or K14 lead to the blistering skin disorder epidermolysis bullosa simplex. Given that K14 deficiency does not lead to the ablation of a basal cell cytoskeleton because of a compensatory role of K15, we have investigated the requirement for the keratin cytoskeleton in basal cells by inactivating the K5 gene in mice. We report that the K5 Ϫ/Ϫ mice die shortly after birth, lack keratin filaments in the basal epidermis, and are more severely affected than K14 Ϫ/Ϫ mice. In contrast to the K14 Ϫ/Ϫ mice, we detected a strong induction of the wound-healing keratin K6 in the suprabasal epidermis of cytolyzed areas of postnatal K5 Ϫ/Ϫ mice. In addition, K5 and K14 mice differed with respect to tongue lesions. Moreover, we show that in the absence of K5 and other type II keratins, residual K14 and K15 aggregated along hemidesmosomes, demonstrating that individual keratins without a partner are stable in vivo. Our data indicate that K5 may be the natural partner of K15 and K17. We suggest that K5 null mutations may be lethal in human epidermolysis bullosa simplex patients. INTRODUCTIONKeratin (K) intermediate filaments (IFs) belong to a gene family that is organized into two subfamilies, coding for type I (K9 -20) and type II keratins (K1-8). At least one member of each family is necessary to form heterodimeric IFs. In epidermis, keratins display a complex expression pattern that is widely assumed to reflect the structural requirements of distinct epidermal compartments (Fuchs and Cleveland, 1998).The major keratins in the basal layer of stratified epithelia are K5, K14, and K15 (Fuchs and Green, 1978, 1980;Moll et al., 1982;Leube et al., 1988;Lloyd et al., 1995). In wound healing or in hyperproliferative disorders, the keratin pair K6 and K16 is transiently expressed in the suprabasal layers instead of K1, K2e, and K10 (for review, see McGowan and Coulombe, 1998). The functional significance of the highly patterned expression profile of keratins is still poorly understood, but evidence is accumulating that they have distinct functions in epidermis (Paladini and Coulombe, 1999).The structural function of keratins was elucidated by the discovery of point mutations in human epidermal keratin genes (Corden and McLean, 1996), preceded by studies on transgenic mice expressing mutant keratin subunits . These mutations cause a number of inherited human skin disorders such as epidermolysis bullosa simplex (EBS) (Bonifas et al., 1991;Coulombe et al., 1991;Lane et al., 1992;Rothnagel et al., 1995;Corden and McLean, 1996). The characteristic feature of EBS is epidermal blistering resulting from cytolysis of basal keratinocytes. On the basis of these observations, it was suggested that the overall function of epidermal keratins was to provide the reinforcement of the epidermis and the maintenance of cellular integrity under mechanical and thermal stress. Several mice carrying null or dominant keratin mutations that affect epidermal integrity have added further support to t...

Here, we present data of a gene expression profiling approach to apply the diagnostic value and pathological significance of this method in different inflammatory skin diseases, using whole skin biopsies. Initially, SAGE was performed to identify frequent tags differentially expressed in various skin diseases. On the basis of these results, a new skin pathology-oriented PIQOR microarray was designed. Lichen planus (LP) was chosen as a model disease to evaluate this system. Controls included healthy skin, atopic dermatitis (AD), and psoriasis (Pso). Gene expression analyses using the topic-defined microarray followed by unclassified clustering was able to discriminate LP from AD and Pso. Genes significantly expressed in LP included type I IFN inducible genes and a specific chemokine expression pattern. The CXCR3 ligand, CXCL9, was the most significant marker for LP. In situ hybridization and immunohistochemistry confirmed the results and revealed that keratinocytes are type I IFN producers in LP skin lesions. Our results show that gene expression profiling using a skin-specific microarray is a reliable method to identify patients with LP in the chosen context and reflect recent models concerning the pathogenesis of this disease. Gene expression profiling might complement the diagnostic spectrum in dermatology and may provide new pathogenetic insights.

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