Copyright ©The Author(s) 2015. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Dermatol. Feb 2, 2015; 4(1): 16-32
Published online Feb 2, 2015. doi: 10.5314/wjd.v4.i1.16
From the outside-in: Epidermal targeting as a paradigm for atopic disease therapy
Rachel MC Gillespie, Sara J Brown
Rachel MC Gillespie, Department of Life Sciences, Imperial College London, SW7 2AZ London, United Kingdom
Sara J Brown, Dermatology and Genetic Medicine, College of Medicine, Dentistry and Nursing, University of Dundee, James Arrott Drive, Ninewells Hospital and Medical School, DD1 9SY Dundee, United Kingdom
Author contributions: Gillespie RMC performed the literature review, drafted the article and created the figures; Brown SJ supervised the work, reviewed and revised the manuscript and figures, and provided the clinical images with patient/parental consent.
Supported by Wellcome Trust Intermediate Clinical Fellowship, No. 086398/Z/08/Z.
Conflict-of-interest: The authors declare that they have no competing interests.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:
Correspondence to: Sara J Brown, MD, Dermatology and Genetic Medicine, College of Medicine, Dentistry and Nursing, University of Dundee, James Arrott Drive, Ninewells Hospital and Medical School, DD1 9SYD undee, United Kingdom.
Telephone: +44-13-82381056 Fax: +44-13-82740359
Received: September 21, 2014
Peer-review started: September 22, 2014
First decision: November 1, 2014
Revised: November 29, 2014
Accepted: December 16, 2014
Article in press: December 17, 2014
Published online: February 2, 2015

Atopic dermatitis (AD) is a chronic inflammatory skin disorder which can precede asthma and allergic rhinitis in a disease trajectory known as the atopic march. The pathophysiology of AD includes cutaneous inflammation, disrupted epidermal barrier function, xerosis and propensity to secondary infections. AD had previously been thought to arise from the systemic atopic immune response and therapies are therefore directed towards ameliorating Th2-mediated inflammation. However in recent years the focus has shifted towards primary defects in the skin barrier as an initiating event in AD. Links between loss-of-function variants in the gene encoding filaggrin and disrupted activity of epidermal serine proteases and AD have been reported. Based on these observations, a mechanism has been described by which epidermal barrier dysfunction may lead to inflammation and allergic sensitization. Exogenous and endogenous stressors can further exacerbate inherited barrier abnormalities to promote disease activity. Pathways underlying progression of the atopic march remain unclear, but recent findings implicate thymic stromal lymphopoietin as a factor linking AD to subsequent airway inflammation in asthma. This new appreciation of the epidermis in the development of AD should lead to deployment of more specific strategies to restore barrier function in atopic patients and potentially halt the atopic march.

Keywords: Atopic dermatitis, Eczema, Filaggrin, Skin barrier, Kallikrein, Thymic stromal lymphopoietin, Allergic sensitization, Atopic march

Core tip: Atopic diseases [including atopic dermatitis (AD), allergic rhinitis and asthma] are characterised by Th2-type inflammation. Research over the past decade has highlighted a crucial role for primary skin barrier impairment in the pathogenesis of AD and associated atopic phenotypes. Notably, the epidermal protein, filaggrin, epidermal serine proteases, and the pro-Th2 cytokine thymic stromal lymphopoietin, have been implicated in disease development. We review the evidence upholding a role for epidermal defects in the initiation of skin inflammation in AD, allergic sensitization and pathogenesis of the “atopic march”, and discuss the clinical implications of these findings.