Epidermal layers of the skin include, the stratum corneum, stratum lucidum, stratum granulosum, stratum spinosum, and stratum basale. The structure of these layers is demonstrated in [9
]. Until recently, the outermost layer of the dermis was relatively ignored as a factor in the development of atopic dermatitis. In the epidermis there are multiple components important to barrier function. These components include claudin, desmoglein, filaggrin, ceramide, and proper control of proteases (). When properly functioning, this layer prevents water loss and provides a barrier to epidermal invasion of allergens and bacteria.
Layers forming the protective epidermal barrier.
Functions of epidermal barrier components and possible protective role in prevention of atopic march.
Each corneocyte in the stratum corneum is held together by tight junctions and scaffolding proteins. Claudins are a family of proteins that are important components of the tight junctions between corneocytes that help to maintain the skin barrier. Claudin-deficient patients have aberrant formation of tight junctions that cause disruption of the bioelectric barrier [10
]. Claudins are an essential component controlling the paracellular barrier flow of molecules in the intercellular space between the cells of an epithelium. These tight junctions help prevent moisture loss through this layer of the skin as well as block access through the skin of external environmental allergens. Claudin expression in atopic dermatitis patients has been inversely correlated to increased TH
2 biomarker expression [10
]. This suggests that claudin may help inhibit immune exposure to allergic stimuli.
Similar tight junction dysfunction has been found in desmoglein transgenic mice. Desmogleins play a role in the formation of desmosomes that promotes cell-to-cell tight junction adhesion in the stratum corneum. Mice without desmoglein were ultimately found to die from dehydration presumably due to increased transepidermal water loss mediated by lack of corneocyte adhesion [11
A different genetic knock-out mouse model of atopic dermatitis examined the relationship between scaffolding proteins and skin barrier function. Scaffolding proteins are required to overlaying tight junction linked corneocytes with cross-linked proteins and lipids to form an effective epidermal barrier. Loss of epidermal scaffolding proteins such as involucrin, envoplakin, and periplakin is associated with alterations in epidermal barrier function such as filaggrin and desmoglein-1 processing with formation of an abnormal cornified epidermal envelope [12
]. Immune regulatory dysfunction after disruption of scaffolding proteins was associated with increased CD4+
T cell infiltration and lack of gamma delta+ T cells. This association suggests that an abnormal epidermal layer may contribute to the allergic inflammatory process associated with atopic dermatitis.
Another factor allowing proper function of the epidermis is the control of the on or off activity of skin proteases. SPINK is a protein that inhibits serine protease action in the skin. The SPINK gene is absent in Netherton's syndrome. This syndrome is characterized by severe atopic dermatitis, scaling, and an elevated serum IgE [13
]. In this potentially lethal disease, lack of SPINK results in uncontrolled serine protease elastase-2 activity. Increased protease activity negatively alters filaggrin and lipid (ceramide) processing thereby decreasing skin barrier function. It has been suggested that barrier function in populations with SNP alterations of SPINK5 may lead to increased susceptibility to asthma [14
Increased protease functioning also occurs in atopic dermatitis patients. Allergens such as dust mite, cockroach and mold can activate serine proteases, adversely affecting the epidermal barrier [15
]. In fact, dust mite and cockroach allergens themselves can be proteolytically active and stimulate the serine protease pathway thereby decreasing skin barrier function [16
Filaggrin is an important protein found in lamellar bodies of stratum granulosum corneocytes. When these granules are released they become a vital component of the extracellular matrix of the stratum corneum. Mutations of the filaggrin gene have been associated with ichthyosis vulgaris and persistent atopic dermatitis [18
]. Filaggrin gene defects may exist in as many as 50% of atopic dermatitis patients [20
]. Meta-analysis of filaggrin polymorphism data has identified a genetic alteration in filaggrin as a significant risk for development of atopic dermatitis [22
]. The results of filaggrin gene mutations are striking as several studies have demonstrated that the severity of atopic dermatitis correlates with the number of filaggrin gene defects [23