Epidermal Barrier Function in Atopic Dermatitis

Filaggrin Mutations and Exogenous Factors in AD Contribute to Epidermal Barrier Dysfunction

There has been a large focus on the role of genetic abnormalities leading to defects in key structural components of the epidermal barrier. Perhaps the best example of this is a loss of function mutation in the filaggrin gene, which encodes for the filament aggregating protein (FLG), found in up to 60% of AD patients.^[12] While there are various other candidate genes that lead to increased susceptibility, including KLK7, SPINK5, and CSTA, FLG remains by far the most prominent.^[14] Although filaggrin is certainly one of the most important single genes involved in AD susceptibility, inherent redundancy in the epidermal differentiation complex with several other similar genes may mitigate the negative effect of filaggrin mutations and explain the incomplete penetrance in AD. As such, patients carrying a mutation in the FLG gene display a wide spectrum of disease, ranging from mildly dry skin to more severe manifestations of ichthyosis vulgaris.^[15] Moreover, since only 44% of AD patients carry the heterozygous mutation and 76% of homozygous or compound heterozygous FLG mutation carrying patients suffer from AD,^[16] this further implicates the role of other genes and the environment in disease pathogenesis. Nevertheless, complete absence of FLG, either as a homozygous mutation or a compound heterozygote mutation, clearly disrupts the epidermal barrier, as all of these patients to date have been shown to present with a clinical picture of ichthyosis vulgaris.^[17,18]

Filaggrin normally assists in cytoskeletal aggregation and formation of the cornified cell envelope (CCE), providing additional strength and structure. It is required for normal lamellar body formation and content secretion. Furthermore, as corneocytes mature and start losing water, FLG dissociates from the CCE and is processed into acidic metabolites acting as osmolytes that help to retain hydration and keep the pH below the threshold required for the activation of Th2-inducing endogenous serine proteases.^[9] Therefore, a FLG mutation contributes to a disrupted epidermal barrier, increased water loss, and inflammation. There are also many exogenous factors that can exacerbate barrier dysfunction, specifically soaps and surfactants in detergents that accelerate corneocyte and lipid degradation. Several antigens, including those from cockroaches, Staphylococcus aureus, dust mites, and scabies induce endogenous proteolytic activity, cleaving corneodesmosomal proteins and filaggrin, thus contributing further to the cycle of inflammation and pruritus.^[1]

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