**2. Filaggrin and atopic dermatitis**

#### **2.1 Filaggrin mutation and atopic dermatitis**

Filaggrin protein is localized in the granular layers of the epidermis. Profilaggrin, a 400-kDa polyprotein, is the main component of keratohyalin granules (Candi, et al., 2005, Listwan & Rothnagel, 2004). In the differentiation of keratinocytes, profilaggrin is dephosphorylated and cleaved into 10-12 essentially identical 27-kDa filaggrin molecules, which aggregates in the keratin cytoskeleton system to form a dense protein-lipid matrix in humans (Candi, et al., 2005). This structure is thought to prevent epidermal water loss and impede the entry of external stimuli, such as allergens, toxic chemicals, and infectious organisms. Therefore, filaggrin is a key protein in the terminal differentiation of the epidermis and in skin-barrier function (Gan, et al., 1990).

The genetic contribution of *FLG* loss-of-function mutations to AD is now well established. *FLG* mutation was first identified in ichthyosis vulgaris (IV), a common keratinizing disorder (Irvine &McLean, 2006). In 2006, Palmer et al. first identified two such mutations within the *FLG* gene, which strongly predispose to AD as well as IV (Palmer, et al., 2006). Since then, several additional studies have confirmed this association and discovered other mutations within this gene that predispose to AD. To date, approximately 40 loss-offunction *FLG* mutations have been identified in IV and/or AD in European and Asian populations. (Brown, et al., 2008, Marenholz, et al., 2006, Nomura, et al., 2007, Rodriguez, et al., 2009, Sandilands, et al., 2006, Sandilands, et al., 2007). Major differences exist in the spectra of *FLG* mutations observed between different ancestral groups, and each population is likely to have a unique set of *FLG* mutations (Osawa, et al., 2011).

disease phenotype in AD; (2) both the clinically uninvolved skin sites and the skin cleared of inflammation continue to display significant barrier abnormalities; (3) emollient therapy comprises effective ancillary therapy; and (4) specific replacement therapy which targets the prominent lipid abnormalities that account for barrier abnormality in AD, not only corrects the permeability-barrier abnormality but also comprises an effective anti-inflammatory

The evidence for a primary structural abnormality of the SC in AD is derived from a recently discovered link between the incidence of AD and loss-of-function mutations in the gene encoding filaggrin (*FLG*). Genetic studies have shown a strong association between AD and this mutation (Jin, et al., 2009). Moreover, there is a dose-response relationship between *FLG* deficiency and disease severity, such that patients with double-allele or compound heterozygote mutation in *FLG* display more severe and earlier-onset AD and an increased propensity for AD to persist into adulthood (Brown, et al., 2008, Irvine &McLean, 2006). This rapidly growing body of work has led to a paradigm shift in conception of AD pathogenesis, with increasing weight being placed on the role of a primary barrier abnormality that then precipitates downstream causing immunologic abnormalities as

Based on these findings, it is assumed that mice that have a genetic defect in barrier function will provide a model of AD closer to the human disease than models provided by epidermal sensitization with allergens or haptens or by transgenic overexpression of cytokines in the skin or disruption of immune genes, and that these mice will have an advantage over NC/Nga mice in which the genetic defect is not known. Application of the knowledge gained from existing mouse models of AD to mice with genetic defects in skin barrier function should

Filaggrin protein is localized in the granular layers of the epidermis. Profilaggrin, a 400-kDa polyprotein, is the main component of keratohyalin granules (Candi, et al., 2005, Listwan & Rothnagel, 2004). In the differentiation of keratinocytes, profilaggrin is dephosphorylated and cleaved into 10-12 essentially identical 27-kDa filaggrin molecules, which aggregates in the keratin cytoskeleton system to form a dense protein-lipid matrix in humans (Candi, et al., 2005). This structure is thought to prevent epidermal water loss and impede the entry of external stimuli, such as allergens, toxic chemicals, and infectious organisms. Therefore, filaggrin is a key protein in the terminal differentiation of the epidermis and in skin-barrier

The genetic contribution of *FLG* loss-of-function mutations to AD is now well established. *FLG* mutation was first identified in ichthyosis vulgaris (IV), a common keratinizing disorder (Irvine &McLean, 2006). In 2006, Palmer et al. first identified two such mutations within the *FLG* gene, which strongly predispose to AD as well as IV (Palmer, et al., 2006). Since then, several additional studies have confirmed this association and discovered other mutations within this gene that predispose to AD. To date, approximately 40 loss-offunction *FLG* mutations have been identified in IV and/or AD in European and Asian populations. (Brown, et al., 2008, Marenholz, et al., 2006, Nomura, et al., 2007, Rodriguez, et al., 2009, Sandilands, et al., 2006, Sandilands, et al., 2007). Major differences exist in the spectra of *FLG* mutations observed between different ancestral groups, and each population

provide us with AD models that closely mimic human disease (Jin, et al., 2009).

is likely to have a unique set of *FLG* mutations (Osawa, et al., 2011).

therapy for AD (Elias, et al., 2008).

proposed (Elias, et al., 2008).

function (Gan, et al., 1990).

**2. Filaggrin and atopic dermatitis** 

**2.1 Filaggrin mutation and atopic dermatitis** 

Typically atopic manifestations follow a certain sequence, called the atopic march, beginning with AD in early infancy, followed by food allergy, asthma and the development of allergic rhinitis (Illi, et al., 2004). The association of *FLG* mutation with atopic march has been reported in cases involving pediatric asthma (Muller, et al., 2009), peanut allergy (Brown, et al., 2011), atopic asthma (Poninska, et al., 2011), allergic rhinitis (Poninska, et al., 2011) and nickel allergy (Novak, et al., 2008).

In addition, epidemiological studies have identified extremely significant statistical association between *FLG* mutation and AD. Intriguingly, these mutations are highly associated with several characteristics in AD patients, such as reduced level of natural moisturizing factor (NMF) in the SC (Kezic, et al., 2008), increased incidence of dry and sensitive skin (Sergeant, et al., 2009), clinical severity and barrier impairment (Nemoto-Hasebe, et al., 2009), allergen sensitization and subsequent development of asthma associated with eczema (Weidinger, et al., 2008), and serum levels of IgE (Wang, et al., 2011). On the other hand, several studies failed to identify an effect of *FLG* mutations on AD, such as skin conditions assessed by clinical scoring of AD and measurement of TEWL in a French population (Hubiche, et al., 2007). A similar lack of association was reported in contact allergy (Carlsen, et al., 2011) and pediatric eczema (O'Regan, et al., 2010).

As the conceptual framework underlying AD moves from solely immunological to epidermal barrier defects, the role of filaggrin and its putative mechanisms in priming AD have come under closer scrutiny. *FLG* mutations are postulated to have wide-ranging downstream biological effects, which include altered pH of SC, cutaneous microflora and aberrant innate and adaptive immune responses (O'Regan &Irvine, 2010).
