The outermost layer of skin, the epidermis, is composed of four layers – a basal layer of proliferating keratinocytes, a spinous layer, a granular layer, and the stratum corneum, a brick and mortar structure, composed of dense layers of corneocytes resulting from the differentiation of keratinocytes in the epidermal layers below. These cells are held together by tight junctions, which restrict circulation of large molecules or pathogens through the skin. Tight junctions are formed by transmembrane proteins (notably Claudin-1 to 24) held together by scaffolding proteins (including zonulae occludens Z0–1 to 3). A growing body of evidence suggests that skin barrier dysfunctions promote the development and severity of AD [8
]. Recently, impaired epidermal expression of claudin-1 has been reported in non-lesional skin of AD patients compared to psoriasis patients and non-atopic controls with a concomitant association with disease severity [9
]. Claudin-1 deficient mice suffer from severe dehydration and skin barrier dysfunction, assessed by measuring increased trans-epidermal water loss (TEWL), and die shortly after birth [10
Over 30 studies have reported positive associations between polymorphisms in skin barrier genes and AD [11
]. A number of the barrier genes are localized on chromosome 1 in a cluster called the epidermal differentiation complex (EDC) and include filaggrin (FLG), loricrin, and involucrin. Most of the genetic studies relate to FLG, a keratinocyte gene that encodes profilaggrin, a large molecule composed of a dozen filaggrin repeats and a major component of keratohyaline granules, that characterize the granular layer of the epidermis [12
]. A growing number of rare mutations have been described in the numerous repeats of the FLG gene, most of which differ between European and Asian populations [13
]. Most studies are not powered to detect rare variants within a specific population, hampering an accurate estimate of the real prevalence of these filaggrin mutations in AD patients and non-atopic skin diseases. While filaggrin mutations are important contributors to AD, anecdotal evidence indicates that filaggrin loss-of-function mutations do not necessarily lead to AD. Despite being generally associated with more severe AD, carriers of these filaggrin mutations can outgrow the disease [14
] suggesting that breakdown in the skin barrier is not sufficient for the development of AD.
Profilaggrin is dephosphorylated and cleaved by serine proteases, that in turn are tightly regulated, most notably by the serine peptidase inhibitor Kazal type 5 (SPINK5). Mutations in SPINK5 have been associated with AD in several studies [11
Mice with a natural mutation in their filaggrin gene develop dry a scaly skin a few days after birth but this phenotype subsides as they start growing fur. These so called “flaky tail (ft)” mice have a frameshift point mutation in their FLG gene resulting in an abnormal profillagrin polypeptide that is not cleaved to generate filaggrin [16
]. Filaggrin is involved in the collapse of the keratin cytoskeleton resulting in the formation of the cornified layers that help maintain hydration and possibly also skin pH. One of the earliest features of AD is dry skin, resulting in increased trans-epidermal water loss (TEWL) and in impaired protection against environmental pathogens and molecules (irritants, endotoxins, allergens) [16
]. As the ft mice age, they start developing clinical feature of AD like erythema, pruritic lesions and edema as well as increased blood IgE levels [18
]. Interestingly, the nature of the immune responses evolves with time, starting with elevated skin levels of Th17 associated cytokines (IL-6, IL-17A and IL-23). Several months later, skin levels of Th2 cytokines (IL-4 and IL-13) started increasing whereas IFNγ levels remained unchanged. The filaggrin mutation in the ft mice occurred spontaneously resulting from a mutation in the matted (ma) gene located close by. After these ft mice were backcrossed until the ma mutation was lost, increased skin inflammation dominated by eosinophils could still be observed [16
]. Increased sensitization to ovalbumin, an allergen which usually fails to induced an immune response when applied to intact wild type skin, was observed in OVA exposed filaggrin deficient mice [16
]. The nature of the environmental factors leading to the early Th17 response and the mechanisms behind the emergence of a Th2 response still need to be addressed.
Skin barrier removal by tape stripping has been recently shown to polarize skin dendritic cells to promote a Th2 response upon allergen exposure [20
]. Interestingly, damaging the skin by tape stripping increased skin levels of TSLP and the resulting Th2 response was dependent on TSLP signaling [20
]. Together these data suggest that skin barrier dysfunction is an important contributor to the development of AD.