Reviews and feature article
Basis for the barrier abnormality in atopic dermatitis: Outside-inside-outside pathogenic mechanisms

https://doi.org/10.1016/j.jaci.2008.01.022Get rights and content

Until quite recently, the pathogenesis of atopic dermatitis (AD) has been attributed to primary abnormalities of the immune system. Intensive study revealed the key roles played by TH1/TH2 cell dysregulation, IgE production, mast cell hyperactivity, and dendritic cell signaling in the evolution of the chronic, pruritic, inflammatory dermatosis that characterizes AD. Accordingly, current therapy has been largely directed toward ameliorating TH2-mediated inflammation and pruritus. In this review we will assess emerging evidence that inflammation in AD results from inherited and acquired insults to the barrier and the therapeutic implications of this paradigm.

Section snippets

Broad barrier failure in AD

Like permeability barrier dysfunction, the antimicrobial barrier is also compromised in patients with AD. Colonization by Staphylococcus aureus is a common feature of AD,21 and although colonization is highest on lesional skin, colony counts often are high on the clinically normal skin of patients with AD.14, 15 Moreover, overt secondary infections, manifesting commonly as impetiginization, widespread folliculitis, or, less frequently, cutaneous abscesses or cellulitis, are well-recognized

Basis for the permeability barrier in normal skin

The permeability barrier resides in the SC, a multilayered tissue composed of flattened anucleate corneocytes surrounded by multiple planer lamellae sheets enriched in ceramides, cholesterol, and free fatty acids (FFAs).26 It is the localization of these highly hydrophobic lipids within the extracellular domains of the SC that inhibits the outward movement of water. These lipids are delivered to the SC as their precursors through secretion of a unique organelle, the epidermal lamellar body (LB).

Inherited barrier abnormalities in atopic dermatitis

Based on inherited abnormalities either in serine protease (SP)/antiprotease expression or filaggrin (FLG) production, the development of AD is now increasingly linked to primary defects in the structure and function of the SC. The most compelling case for the role of excess SP activity in the pathogenesis of AD comes from Netherton syndrome (NS), an autosomal recessive disorder caused by loss-of-function mutations in SPINK5, the gene encoding the SP inhibitor lymphoepithelial Kazal-type

Exogenous and endogenous stressors further aggravate barrier function in AD

Acquired pH-dependent increases in SP activity could also contribute to AD pathogenesis. That FLG mutations alone do not suffice is shown in ichthyosis vulgaris, where the same single- or double-allele FLG mutations reduce FLG content, but inflammation (ie, AD) does not always occur.61, 62 Certain stressors could elicit disease by aggravating the barrier abnormality by provoking an incremental increase in the pH of the SC, leading to a further amplification of SP activity. Such a

Outside-inside and then back to outside pathogenic mechanism in AD

Despite accumulating evidence in support of a barrier-initiated pathogenesis of AD, recent studies suggest specific mechanisms whereby TH2-generated cytokines could also further aggravate AD. Exogenous applications of the TH2 cytokine IL-4 impede permeability barrier recovery after acute perturbations.69 The basis for the negative effects of IL-4 could include (1) the observation that exogenous IL-4 also inhibits ceramide synthesis,70 providing yet another mechanism accounting for decreased

Impaired antimicrobial defense further compromises barrier function in AD

In the prior sections, we discussed first how genetic and acquired factors can converge to provoke or amplify AD and second how inflammation can be attributed both to an epidermis-derived cytokine cascade, as well as to stimulation of a TH2-dominant inflammatory infiltrate because of sustained antigen ingress. Increased colonization with S aureus2, 14, 73 occurs as a result of the barrier abnormality (a structurally competent, lipid-replete, acidic SC itself comprises a formidable barrier to

Therapeutic implications

Together, the converging pathogenic features described above create a strong rationale for the deployment of specific strategies to restore barrier function in patients with AD. Based on the mechanisms described above, these approaches could range from a simple reduction in the pH of SC alone (hyperacidification), applications of SP inhibitors, topical plasminogen activator type 2 receptor antagonists, general moisturization measures, or specific lipid replacement therapy. Moisturizers are

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      Citation Excerpt :

      More than 40 different FLG mutations have been reported in ichthyosis vulgaris and/or AD worldwide (Akiyama, 2010), and at present, 11 mutations in FLG have been reported in Japanese patients with AD (Teye et al., 2017). Moreover, ceramides in SC are major components of intercellular lipids and are crucial for cutaneous barrier function and water-holding capacity (Elias et al., 2008; Elias and Wakefield, 2014). There are many ceramide species in human SC, and these molecules are divided into 11 classes on the basis of their fatty acid and sphingoid structures, including ceramides containing nonhydroxy fatty acids and dihydrosphingosines (NDS); ceramides containing nonhydroxy fatty acids and sphingosines (NS); ceramides containing nonhydroxy fatty acids and 6-hydroxysphingosines (NH); ceramides containing nonhydroxy fatty acids and phytosphingosines (NP); ceramides containing a-hydroxy fatty acids and dihydrosphingosines; ceramides containing a-hydroxy fatty acids and sphingosines; ceramides containing a-hydroxy fatty acids and 6-hydroxysphingosines (AH); ceramides containing a-hydroxy fatty acids and phytosphingosines; ceramides containing ester-linked fatty acids, o-hydroxy fatty acids, and sphingosines; ceramides containing ester-linked fatty acids, o-hydroxy fatty acids, and 6-hydroxysphingosines; and ceramides containing ester-linked fatty acids, o-hydroxy fatty acids, and phytosphingosines (Masukawa et al., 2008) (defined in Supplementary Figure S1).

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    Supported by National Institutes of Health grant AR19098 and Department of Defense grant W81XWH-05-2-0094 and by the Medical Research Service, Department of Veterans Affairs.

    Disclosure of potential conflict of interest: P. M. Elias has served as a member for Ceragenix and has served as an expert witness in immunomodification and systemic retinoid litigation. M. L. Williams' husband has served as a member of Ceragenix. Y. Hatano has declared that he has no conflict of interest.

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