Primary role of barrier dysfunction in the pathogenesis of atopic dermatitis

Abstract

Based upon the efficacy of recently developed biologics, the pathogenesis of atopic dermatitis (AD) is being attributed once again to the prominent inflammation that occurs in this disorder. Yet, molecular genetics has clearly shown that the aetiology of AD can be attributed to mutations in stratum corneum structural proteins that impact epidermal barrier function, while inflammation instead emerges as a downstream consequence of a sustained, barrier-driven cytokine cascade. Although several different mutations that compromise barrier function are associated with AD, all of these mutations compromise either the contents or secretion of epidermal lamellar bodies. Therapies directed at specific immune participants, though effective temporarily, inevitably are followed by "rebound flares," just as occur following glucocorticoid therapy. While occlusive moisturizers dampen inflammation, they do not address the underlying lipid biochemical abnormality in AD, which can be corrected more specifically with topical, physiologic lipid-based forms of barrier repair therapy (BRT). Accordingly, BRT has been shown to be as effective as topical, mid-potency steroids for the treatment of moderate-to-severe paediatric AD.

On the relevance of an in vitro reconstructed human epidermis model for drug screening in atopic dermatitis

“…Most importantly, current therapies usually aim to decrease cutaneous inflammation and alleviate pruritus, but fail to correct the underlying barrier defects driving the process. [1,2] To meet this need, intense research is being performed to develop specific strategies to restore epidermal integrity. In this search for new treatments, the need for efficient in vitro assays has become crucial.…”

“…Although extensive progress has been made in our understanding of the pathogenesis of AD, the barrier dysfunction linked to a complex inflammatory environment remains poorly understood. Most importantly, current therapies usually aim to decrease cutaneous inflammation and alleviate pruritus, but fail to correct the underlying barrier defects driving the process . To meet this need, intense research is being performed to develop specific strategies to restore epidermal integrity.…”

The IL‐13–OVOL1–FLG axis in atopic dermatitis

“…Skin barrier function is disrupted in AD compared with that in normal controls . The epidermal barrier is formed by the coordinated and sequential cross‐linking of epidermal differentiation molecules such as FLG and intercellular lipids and corneocyte adhesion .…”

“…Skin barrier function is disrupted in AD compared with that in normal controls. [47][48][49] The epidermal barrier is formed by the coordinated and sequential cross-linking of epidermal differentiation molecules such as FLG and intercellular lipids and corneocyte adhesion. [47][48][49] The expression of FLG and the other differentiation molecules loricrin and involucrin is down-regulated or expressed prematurely in the lesional and non-lesional skin of AD compared with their expression in the normal skin of healthy individuals.…”

The skin barrier: Epidermis vs environment

“…Topics important for the basic understanding of the skin barrier include the ultrastructure and molecular composition of the skin barrier, the processes of epidermal protein phosphorylation and citrullination, the maintenance of tight junctions during keratinocyte differentiation, the synthesis of sphingomyelin in the epidermis and the evolutionary history of the genes that control the human skin barrier . The importance of the skin barrier at the crossroads of health and disease is shown by articles dealing with atopic dermatitis, occupational contact dermatitis, autoinflammation of the skin, dermatophyte infections, transglutaminase‐associated skin diseases, diabetes, acne, skin barrier modulation by tannic acid and a mouse model with atopic dermatitis‐like symptoms . Of particular interest for experimental dermatologists, advances in the proteomics of the skin barrier, corneocyte morphometry, non‐invasive techniques of skin barrier assessment and measurement of biomechanical features of skin are reported in this issue.…”