The nonlesional skin surface distinguishes atopic dermatitis with food allergy as a unique endotype

Abstract

Skin barrier dysfunction has been reported in both atopic dermatitis (AD) and food allergy (FA). However, only one-third of patients with AD have FA. The purpose of this study was to use a minimally invasive skin tape strip sampling method and a multiomics approach to determine whether children with AD and FA (AD FA+) have stratum corneum (SC) abnormalities that distinguish them from AD without FA (AD FA−) and nonatopic (NA) controls. Transepidermal water loss was found to be increased in AD FA+. Filaggrin and the proportion of ω-hydroxy fatty acid sphingosine ceramide content in nonlesional skin of children with AD FA+ were substantially lower than in AD FA− and NA skin. These abnormalities correlated with morphologic changes in epidermal lamellar bilayer architecture responsible for barrier homeostasis. Shotgun metagenomic studies revealed that the nonlesional skin of AD FA+ had increased abundance of Staphylococcus aureus compared to NA. Increased expression of keratins 5, 14, and 16 indicative of hyperproliferative keratinocytes was observed in the SC of AD FA+. The skin transcriptome of AD FA+ had increased gene expression for dendritic cells and type 2 immune pathways. A network analysis revealed keratins 5, 14, and 16 were positively correlated with AD FA+, whereas filaggrin breakdown products were negatively correlated with AD FA+. These data suggest that the most superficial compartment of nonlesional skin in AD FA+ has unique properties associated with an immature skin barrier and type 2 immune activation.

Review—Current Concepts in Inflammatory Skin Diseases Evolved by Transcriptome Analysis: In-Depth Analysis of Atopic Dermatitis and Psoriasis

“…In addition to localized skin manifestations, cutaneous inflammatory diseases are commonly accompanied by systemic pathological features [26,108,109]. The complex interplay was also revealed by studies investigating the connection between food allergy or oral tolerance and atopic dermatitis [110,111], as discussed beneath in this review. In order to acquire the full picture of the association between localized skin and systemic features, a side-by-side study of different body compartments would be necessary.…”

“…Future approaches should increasingly focus on the integration of additional dimensions of information as transcriptomics by itself only transmits a limited view on the cellular status. Not all biological functions are reliably reflected by the transcriptome, and may rather be detected in the proteome [110,245,246]. With the integration of genomic information of patients (i.e., GWAS) the functional relevance might be directly evaluated through transcriptomic analyses [247].…”

“…It is therefore crucial to improve the barrier function in a primary and secondary disease setting through topical agents. This treatment approach might be especially beneficial in FA+ patients [110].…”

The role of filaggrin in atopic dermatitis and allergic disease

“…73 Filaggrin and ceramide content in the nonlesional skin of AD FAþ was substantially lower when compared with AD FAe and NA skin. 74 The relationship between FA and AD may primarily involve an inferior epidermal barrier. Ziyab et al 75 showed that the combined effects of 'preceding allergic sensitisation and FLG variants' and 'preceding atopic dermatitis and FLG variants 'increased the risk of subsequent asthma by 4.93 and 3.33-fold respectively.…”

Recent developments and highlights in food allergy

“…Consequently, epithelial dysregulation and mutations or polymorphisms of genes important for skin barrier, such as filaggrin, SPINK5, 1 and SERPINB7, have been linked to eczema development and also food allergy. [2][3][4][5][6] Recently, electrical impedance spectroscopy has shown promising results in rodents to measure skin barrier function. This is of relevance since it can be easily adapted for usage on humans.…”