The atopic march: current insights into skin barrier dysfunction and epithelial cell‐derived cytokines

Abstract

Summary Atopic dermatitis often precedes the development of other atopic diseases. The atopic march describes this temporal relationship in the natural history of atopic diseases. Although the pathophysiological mechanisms that underlie this relationship are poorly understood, epidemiological and genetic data have suggested that the skin might be an important route of sensitization to allergens. Animal models have begun to elucidate how skin barrier defects can lead to systemic allergen sensitization. Emerging data now suggest that epithelial cell-derived cytokines such as thymic stromal lymphopoietin (TSLP), IL-33, and IL-25 may drive the progression from atopic dermatitis to asthma and food allergy. This review focuses on current concepts of the role of skin barrier defects and epithelial cell-derived cytokines in the initiation and maintenance of allergic inflammation and the atopic march.

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

“…Interleukin‐13 also inhibits the involucrin expression but in an OVOL1‐independent manner and exacerbates barrier dysfunction. Epidermal keratinocytes in barrier‐disrupted skin produce large amounts of TSLP, IL‐25 and IL‐33, which promote the differentiation of Th2 cells and ILC2s and stimulate the production of IL‐13 . Hence, a vicious cycle is formed to develop atopic dry skin.…”

“…Epidermal keratinocytes in barrier-disrupted skin produce large amounts of TSLP, IL-25 and IL-33, which promote the differentiation of Th2 cells and ILC2s and stimulate the production of IL-13. 29,62 Hence, a vicious cycle is formed to develop atopic dry skin. These results suggest the crucial involvement of the IL-13-OVOL1-FLG axis in the pathogenesis of AD.…”

Worms: Pernicious parasites or allies against allergies?

“…Although the critical involvement of DCs in Th2 development is clear, the precise signals that lead to priming of a Th2‐inducing DC are incompletely characterized. In recent years, the importance of epithelial‐derived cytokines such as interleukin‐25 (IL‐25), IL‐33 and thymic stromal lymphopoietin (TSLP) in allergy and parasitic infection has become appreciated . These cytokines can act directly on DCs, skewing resultant responses to Th2, and also directly activate type 2 innate lymphoid cells (ILC2s), inducing a rapid innate type 2 response.…”

Oral immunotherapy for food allergy

“…3. It is possible that exposure to food allergens through a compromised epithelial barrier in the skin may lead to allergic sensitization [32]; atopic dermatitis is the first step of the atopic march to food allergy [33,34]. In the gastrointestinal tract, epithelial damage allows food Ag to bypass the selective mechanisms of transport into the lamina propria, prompting the release of the alarmins IL-25, IL-33 and thymic stromal lymphopoietin (TSLP), epithelium-derived cytokines implicated in initiating inflammatory immune responses mediated by T helper 2 cells (Th2) [35].…”