Antimicrobial Peptides and Diseases 51 Skin Diseases

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5.1.1 Psoriasis

The identification of various antimicrobial peptides from lesional skin of patients with the common chronic inflammatory skin disease psoriasis might explain the phenomenon that these patients suffer from significantly fewer skin infections than expected (Henseler and Christophers 1995). Psoriatic scale extracts are known to contain a broad spectrum of antimicrobial peptides when compared with healthy stratum corneum proteins (Harder and Schröder 2005) and several of these proteins, like hBD-2 (Harder et al. 1997), -3 (Harder et al. 2001), psoriasin (Madsen et al. 1991; Gläser et al. 2005), and calprotectin (Clohessy and Golden 1995), were originally characterized in psoriasis patients.

An enhanced expression of lysozyme in lesional skin of psoriasis patients was documented by immunohistochemical analysis (Gasior-Chrzan et al. 1994). Upregulation of the human cathelicidin gene was shown in inflammatory skin disorders like psoriasis, whereas in normal skin no induction was found (Frohm et al. 1997). By in situ hybridization and immunohistochemistry, the transcript and the peptide was located in keratinocytes throughout the epidermis of the inflammatory regions and LL-37 was detected in partially pure fractions derived from psoriatic scales by immunoblotting (Frohm et al. 1997). A strong cytoplas-mic staining of antimicrobial ALP was reported in the suprabasal keratinocytes in lesional psoriatic epidermis whereas only weak expression was found in the stratum granulosum of healthy skin (Wingens et al. 1998). Strong induction of NGAL in the epidermis of psoriasis patients was also identified and the protein was confined to spatially distinct subpopulations of keratinocytes underlying areas of parakeratosis (Mallbris et al. 2002). High expression of hBD-2 in psoriasis was confirmed by in situ hybridization and immunohistochemistry in lesional psoriatic keratinocytes (Liu et al. 1998; Huh et al. 2002). RT-PCR, immunoblotting and immunohistochemical analysis revealed enhanced mRNA- and protein expression of hBD-2, -3 and LL-37 in lesional psoriatic skin (Ong et al. 2002; Nomura et al. 2003).

As yet, it is not clear which factors are responsible for the induction of these antimicrobial peptides in psoriasis. A likely endogenous inducer might be proin-flammatory cytokines like TNF-a and/or IL-1ß which are known to be elevated in psoriasis lesions (Gearing et al. 1990). Another candidate might be IL-22 (Wolk et al. 2004) which is critically involved in the IL-23-dependent activation of IL-17 (Zheng et al. 2007). IL-22-producing TH17-lymphocytes are believed to represent important immune cells in psoriasis (Liang et al. 2006). As yet it is not clear whether bacterial PAMs are also important trigger factors for the induction of antimicrobial peptides in psoriasis.

5.1.2 Atopic Dermatitis

Atopic dermatitis (AD) represents another common inflammatory skin disease often associated with an increased infection rate with bacteria, especially S. aureus. In contrast to psoriasis, hBD-2, -3 and LL-37 expression was shown not to be increased in acute and chronic lesions from patients suffering from this disease (Ong et al. 2002; Nomura et al. 2003) when compared with psoriasis. Elevated amounts of Th2 cytokines present in atopic skin are suggested to inhibit the expected induced expression of antimicrobial peptides in the inflamed skin; and it was shown that IL-4 and IL-13 are able to suppress the cytokine-mediated induction of hBD-2 and -3 (Ong et al. 2002; Nomura et al. 2003). Using primary kerati-nocytes from atopic dermatitis patients, it was recently shown that the deficiency in hBD-3 expression is an acquired defect and that neutralizing the Th2 cytokine milieu in skin explants from this patients resulted in augmentation of the innate immune response(Howell et al. 2006). These data suggest that the low expression of antimicrobial peptides may contribute to the increased susceptibility of skin infection in patients with AD. Representing the first skin disease in which a diminished production of antimicrobial proteins correlates with an increased occurrence of skin infections, one can speculate that other recurrent skin infections may also be associated with a dysregulation of antimicrobial proteins.

5.1.3 Other Skin Diseases and Infections

In contrast to AD and in addition to psoriasis, increased levels of antimicrobial proteins were also found in other inflammatory skin diseases and skin infections. For example, in acne vulgaris intense hBD-2 immunoreactivity was shown in the lesional and perilesional epithelium, indicating that upregulated beta-defensins may be involved in the pathogenesis of this disease (Chronnell et al. 2001). Induced expression of hBD-2 was also associated with superficial folliculitis (Oono et al. 2003) and in tinea pedum (Kawai et al. 2006). In viral skin infections the expression of LL-37 was found to be increased in keratinocytes of patients with Condyloma acuminata and Verrucae vulgares, suggesting a role of LL-37 in cutaneous infections caused by papillomavirus (Conner et al. 2002).

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