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

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 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 be confirmed in two independent studies (Hubiche et al. 2007; Weidinger et al. 2008). *SPINK5* gene mutations are linked the with AD, when maternally inherited (Walley et al. 2001; Kato et al. 2003; Nishio et al. 2003; Weidinger et al. 2008). It is worth noting that the association was weaker than in the case of *FLG* mutations, in part, owing to a high prevalence in the control population. In a separate study on a French population, an association between *SPINK5* and AD was not found; however, there was an association between carriers and raised IgE serum levels (Hubiche et al. 2007)). The association of *SPINK5* mutations with raised IgE serum levels and with other atopic conditions, such as asthma, led to the suggestion that they are risk factors for general atopy (Walley et al. 2001; Nishio et al. 2003). In addition to *SPINK5*, a mutation has been identified in the *CSTA* gene encoding the cysteine protease inhibitor, cystatin A, which associates with AD. The cystatin A gene maps to chromosome 3q21, which has been identified as a major susceptibility locus for AD (Lee et al. 2000).
