**6. Conclusion**

58 Atopic Dermatitis – Disease Etiology and Clinical Management

Interestingly, the inhibitory of activity of LEKTI-1 depends on the pH, too, which might enhance proteolytic deregulation, when the epidermal pH is elevated. Moreover, Zn2+ inhibits KLK5 (Debela et al. 2007). This might have clinical consequences, when Zink levels are low as in acrodermatits enteropathica. The exfoliation and inflammation observed in this

PARs represent seven membrane-spanning G-protein coupled receptors, which are activated by serine proteases, which cleave a 'tethered' receptor-activating ligand at the Nterminus (Steinhoff et al. 2005). To date, four PARs (PAR1-4) have been characterized. PAR-1, PAR-3 and PAR-4 are activated by thrombine, and PAR-2 by trypsin and chymotrypsin. In human skin, PAR-2 is abundantly expressed by keratinocytes (Steinhoff et al. 1999), where it plays a role in regulating permeability barrier homeostasis, inflammation, pruritus, pigmentation, and wound healing upon activation by various endogenous and exogenous serine proteases. Whereas during skin-inflammation, PAR-2 is activated by neutrophil elastase and mast cell tryptase, upon infection or skin barrier defects proteases originating from certain bacteria, house dust mites, cockroaches or parasites can activate this receptor (Shpacovitch et al. 2007). Activation by *Propionibacterium acnes* protease causes induction of certain proinflammatory proteins, matrix metalloproteinases and antimicrobial peptides,

**5. Epidermal serine proteases and their inhibitors in atopic dermatitis** 

Filaggrin defect and the KLK-PAR2-TSLP axis, seem to be crucial for inducing AD.

To date, there is no evident point demonstrating that either intrinsic or extrinsic signals are promoting cutaneous allergic-type inflammation in AD. The fact that only 37–50% of patients with *Ichthyosis vulgaris* develop atopic manifestations (Kuokkanen 1969; Smith et al. 2006), supports the notion that in NS in which all patients develop allergic manifestations, additional mechanisms to primary skin barrier defect have a key role in immune response polarization toward a Th2 response. Since serine protease activity is elevated in AD patients (Voegeli et al. 2009), one might speculate that similar mechanisms are involved in AD as in ND. It was reported recently that KLK11 and KLK7 are elevated in lesions of AD patients (Voegeli et al. 2011). Some genetic studies have suggested that proteases and inhibitors are involved in the genetic predisposition of AD patients. In a case–control study on 103 AD patients and 261 matched controls, a significant association was found between a 4-bp insertion in the 3′-untranslated region of the *KLK7* gene, encoding KLK7 and AD (Vasilopoulos et al. 2004)). This association of the 4-bp insertion mutation with AD could not

Our understanding of the pathogenesis of Atopic Dermatitis has increased by the discovery of pro-filaggrin (*FLG*) mutations as the major predisposing factor of AD and the genodermatose Netherthon Syndrom, which shows similarities to AD. *FLG* mutations lead to decreased or missing filaggrin, which leads to dry skin as its cleavage and processing product, the skin moisturizing factor, is decreased. The skin barrier defect leads to increases antigen penetration, which finally leads to specific sensitization and allergic inflammation. Here we have learnt from the ND model that missing LEKT-1 leads to increased KLK activity, which activate PAR-2, thus resulting in increased thymic stromal lymphopoetin (TSLP) (Briot et al. 2009). TSLP finally leads to a Th2 imbalance. Therefore, both events, the

disease might be a result of decreased KLK5 inhibitions.

**4. Protease-activated receptors (PARs)** 

including hCAP18/LL-37 (Lee et al. 2010).

Until today the complex pathogenesis of AD is not fully understood. But there is more and more evidence that epidermal proteases and their inhibitors are involved in the pathogenesis of AD. Their expression can be altered by genetic mutations and their activity is influenced by environmental factors like the pH, which is increased in AD patients (Sparavigna et al. 1999). Taken together there seems to exist a feedback regulation system important for skin barrier homeostasis in AD especially for kallikrein activity involving filaggrin mutations, PAR2 and LEKTI expression Tanaka 2011. It will be interesting to see whether inhibition of elevated protease activity will improve severity of AD lesions. Clinical trials are currently on their way with promising preliminary results (http://clinicaltrial.gov).
