Pathogenesis of Atopic Dermatitis and Psoriasis: Focus on the Epidermal Differentiation Complex

Abstract

Loss-of-function mutations in the FLG gene (encoding the epidermis-specific protein filaggrin) were recently shown to be associated with atopic dermatitis in several populations. These findings have challenged the dogma that atopic dermatitis is primarily an immune-mediated disease, and suggest skin barrier deficiency as a major cause. Similarly, psoriasis was until recently regarded as a T-cell driven disease caused by (auto)immune mechanisms. This view is supported by clinical data, and several genetic studies have identified risk factors associated with a function in adaptive immunity such as HLA-Cw6. Analysis of the PSORS4 region on chromosome 1q, however, has recently identified the deletion of late cornified envelope (LCE) genes LCE3B/C as novel psoriasis genes with a considerable population attributable risk. Because these genes are expressed in epithelial cells and not by the immunocytes, these findings have changed our view on psoriasis. The mechanism by which loss of LCE3B/C genes predisposes to psoriasis is unclear as both genes are not expressed in normal skin but appear to be induced upon skin barrier disruption or inflammation. We hypothesize that psoriasis could be the result of an interplay of immunological mechanisms and deficient repair of skin barrier integrity. Altogether, these findings demonstrate that in addition to immune mechanisms, genetic variation of skin barrier genes contribute to major skin diseases such as atopic dermatitis and psoriasis.