Epidermal Barrier Dysfunction in Atopic Dermatitis

Abstract

Atopic dermatitis (AD) is a multifactorial, heterogenous disease that arises as a result of the interaction between both environmental and genetic factors. Changes in at least three groups of genes encoding structural proteins, epidermal proteases, and protease inhibitors predispose to a defective epidermal barrier and increase the risk of developing AD. Loss-of-function mutations found within the FLG gene encoding the structural protein, filaggrin, represent the most significant genetic factor predisposing to AD identified to date. Enhanced protease activity and decreased synthesis of the lipid lamellae lead to exacerbated breakdown of the epidermal barrier. Environmental factors, including the use of soap and detergents, exacerbate epidermal barrier breakdown, attributed to the elevation of stratum corneum pH. A sustained increase in pH enhances the activity of degradatory proteases and decreases the activity of the lipid synthesis enzymes. The strong association between both genetic barrier defects and environmental insults to the barrier with AD suggests that epidermal barrier dysfunction is a primary event in the development of this disease. Our understanding of gene-environment interactions should lead to a better use of some topical products, avoidance of others, and the increased use and development of products that can repair the skin barrier.

Epidermal tight junctions in health and disease

“…Recent evidence suggests that both features are due in part to an epidermal barrier defect. 91,92 The theory is that a leaky barrier promotes immunologic responsiveness to allergens. 93 A critical aspect of the barrier theory is that even nonlesional or clinically "unaffected" AD skin is compromised, thus suggesting that the epidermal barrier defect precedes the development of the clinical manifestations.…”

Filaggrin Genotype in Ichthyosis Vulgaris Predicts Abnormalities in Epidermal Structure and Function

“…The increased pH in FLGdeficient SC could also impact SC function by altering TJ function and by favoring corneodesmosome proteolysis, which could further compromise barrier function. 33 Therefore, we assessed the expression and localization of TJ proteins in FLG-deficient skin biopsies compared to wildtype and heterozygous skin. Whereas in control skin, a clear staining at the cell-cell borders of the uppermost living layers was observed for both occludin and ZO-1 ( Figure 7, A and B), staining was reduced with a more cytoplasmic pattern in heterozygous skin biopsies ( Figure 7, C and D) and was almost completely lost in FLG-deficient skin ( Figure 7, E and F).…”

Structure and Mechanical Properties of Soft Tissues during Selected Pathological Processes

“…The existing research agrees that the lipid structures help in preventing water loss and penetration in substances readily soluble. As a result, it can be suggested that mentioned compounds are responsible for skin elasticity and make everything is packed so tightly as it is possible [24]. All of the processes mentioned above lead to increase of Young modulus of the tissue over the time [1,15].…”