Deciphering the complexities of atopic dermatitis: shifting paradigms in treatment approaches

Abstract

Atopic dermatitis (AD) is the most common chronic inflammatory skin disease. It often precedes the development of food allergy and asthma. Recent insights into AD reveal abnormalities in terminal differentiation of the epidermal epithelium leading to a defective stratum corneum, which allows enhanced allergen penetration and systemic IgE sensitization. Atopic skin is also predisposed to colonization or infection by pathogenic microbes, most notably Staphylococcus aureus and herpes simplex virus. Causes of this abnormal skin barrier are complex and driven by a combination of genetic, environmental, and immunologic factors. These factors likely account for the heterogeneity of AD onset and the severity and natural history of this skin disease. Recent studies suggest prevention of AD can be achieved through early interventions to protect the skin barrier. Onset of lesional AD requires effective control of local and systemic immune activation for optimal management. Early intervention might improve long-term outcomes for AD and reduce the systemic allergen sensitization that leads to associated allergic diseases in the gastrointestinal and respiratory tract.

Keywords: Atopic dermatitis; eczema; filaggrin; immune; infection; skin epithelium.

Figure 1

Is it clinically relevant whether skin barrier dysfunction or an immune response occurred first? Once AD is established, the physician needs to address both aspects of AD pathophysiology! However, prevention of AD may require identification of patients with primary defects in barrier vs immune dysfunction. Figure courtesy of Boyd Jacobson, National Jewish Health, Denver, CO.

Figure 2

The skin as a multi-tiered barrier. The stratum corneum (SC) is the first physical barrier protecting the skin from the environment. Gene mutations, e.g. filaggrin null mutations) or cytokines (e.g. IL-4, Il-13, IL-25, IL-33, etc) downregulating epidermal proteins including filaggrin, leads to allergen or microbial penetration through this barrier. Tight junctions (TJs) found at the level of the stratum granulosum (SG) provide an additional barrier. Disruption of both physical barriers enables the uptake of allergens, irritants, and microbes by Langerhans cells (LC)/DCs. Keratinocytes produce AMPs as a chemical barrier in response to pathogen colonization/infection. The skin surface is colonized with a diverse array of microorganisms (microbiome barrier), which iregulates local immune responses and inhibits pathologic microbes. Infiltration of a number of cells into the AD skin lesion, including T cells, eosinophils (Eos), DCs, NK cells, and mast cells/basophils. Collectively, these cells constitute the cutaneous immunologic barrier. Pattern recognition receptors (PRRs) regulate the function of all of these barriers (physical, chemical, microbiome, and immunologic). SB, Stratum basale; SG, stratum granulosum; SS, stratum spinosum. This figure is modified from Kuo I, et al. J Allergy Clin Immunol 2013;131:266-78.

Figure 3

Immunologic Pathways involved in different phases of Atopic Dermatitis. Nonlesional AD skin lesions contain immune infiltrates that produce cytokines, e.g. IL-4 and IL-13, which contribute to a defective epidermal barrier. Barrier defects lead to penetration by epicutaneous allergens that encounter Langerhans cells in the epidermis and dermal DCs in the dermis to activate TH2 and TH22 cells involved in acute disease onset. Smaller increases in TH1 and TH17 immune axes are also found in acute lesions. A progressive activation of TH2 and TH22, as well as TH1, pathways is characteristic of chronic AD. IL-22 induces epidermal hyperplasia and, synergistically with the TH17 cytokine IL-17, drives an abrupt increase in a subset of terminal differentiation genes, specifically S100A7, S100A8, and S100A9 proteins. The increases in these barrier proteins contrast with the uniformly disrupted epidermal differentiation gene products (eg, filaggrin, loricrin, and corneodesmosin) throughout nonlesional, acute, and chronic AD skin. The TH2 and TH22 cytokines contribute to inhibition of the terminal differentiation proteins. IL-31 is thought to contribute to the itch in acute AD. Updated with permission from Gittler JK, et al. J Allergy Clin Immunol 2012;130:1344-54.

Figure 4

Clinical Phenotypes in Atopic Dermatitis: Eczema herpeticum (panel A), S. aureus colonized AD (panel B), Mild AD (panel C), Severe AD (panel D). Panels A and B are from: Boguniewicz M and Leung DYM. J Allergy Clin Immunol. 2010; 125: 4-13; Panels C and D are contributed by Dr Emma Guttman- Yassky at The Icahn School of Medicine at Mt Sinai, NYC.

Figure 5

Measures of mRNA levels (normalized to hARP mRNA) for specific Th17/IL-23 and Th22 cytokines and inflammatory products in non-lesional (ANL) and lesional AD (AL) skin from patients with intrinsic versus extrinsic disease. From: Suarez-Farinas M, et al. J Allergy Clin Immunol 2013;132:361-70.