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. 2021 Jul;148(1):148-163.
doi: 10.1016/j.jaci.2021.01.001. Epub 2021 Jan 13.

The molecular features of normal and atopic dermatitis skin in infants, children, adolescents, and adults

Yael Renert-Yuval  1 , Ester Del Duca  2 , Ana B Pavel  3 , Milie Fang  4 , Rachel Lefferdink  4 , Jianni Wu  5 , Aisleen Diaz  5 , Yeriel D Estrada  5 , Talia Canter  4 , Ning Zhang  5 , Annette Wagner  4 , Sarah Chamlin  4 , James G Krueger  6 , Emma Guttman-Yassky  7 , Amy S Paller  8
Affiliations

The molecular features of normal and atopic dermatitis skin in infants, children, adolescents, and adults

Yael Renert-Yuval et al. J Allergy Clin Immunol. 2021 Jul.

Abstract

Background: Although atopic dermatitis (AD) often presents in infancy and persists into adulthood, comparative characterization of AD skin among different pediatric age groups is lacking.

Objective: We sought to define skin biopsy profiles of lesional and nonlesional AD across different age groups (0-5-year-old infants with disease duration <6 months, 6-11-year-old children, 12-17-year-old adolescents, ≥18-year-old adults) versus age-appropriate controls.

Methods: We performed gene expression analyses by RNA-sequencing and real-time PCR (RT-PCR) and protein expression analysis using immunohistochemistry.

Results: TH2/TH22 skewing, including IL-13, CCL17/thymus and activation-regulated chemokine, IL-22, and S100As, characterized the common AD signature, with a global pathway-level enrichment across all ages. Nevertheless, specific cytokines varied widely. For example, IL-33, IL-1RL1/IL-33R, and IL-9, often associated with early atopic sensitization, showed greatest upregulations in infants. TH17 inflammation presented a 2-peak curve, with highest increases in infants (including IL-17A and IL-17F), followed by adults. TH1 polarization was uniquely detected in adults, even when compared with adolescents, with significant upregulation in adults of IFN-γ and CXCL9/CXCL10/CXCL11. Although all AD age groups had barrier abnormalities, only adults had significant decreases in filaggrin expression. Despite the short duration of the disease, infant AD presented robust downregulations of multiple barrier-related genes in both lesional and nonlesional skin. Clinical severity scores significantly correlated with TH2/TH22-related markers in all pediatric age groups.

Conclusions: The shared signature of AD across ages is TH2/TH22-skewed, yet differential expression of specific TH2/TH22-related genes, other TH pathways, and barrier-related genes portray heterogenetic, age-specific molecular fingerprints.

Keywords: Atopic dermatitis; T(H)2; T(H)22; biomarkers; epidermal barrier; maturation; normal skin; pediatric.

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Conflict of interest statement

Disclosure of potential conflict of interest:

E. Guttman-Yassky is an employee of Mount Sinai and has received research funds (grants paid to the institution) from AbbVie, Celgene, Eli Lilly, Janssen, Medimmune/Astra Zeneca, Novartis, Pfizer, Regeneron, Vitae, Glenmark, Galderma, Asana, Innovaderm, Dermira, and UCB; is also a consultant for Sanofi Aventis, Regeneron, Stiefel/GlaxoSmithKline, MedImmune, Celgene, Anacor, AnaptysBio, Dermira, Galderma, Glenmark, Novartis, Pfizer, Vitae, Leo Pharma, AbbVie, Eli Lilly, Kyowa, Mitsubishi Tanabe, Asana Biosciences, and Promius. J. G. Krueger has received research support (grants paid to his institution) and/or personal fees from Pfizer, Amgen, Janssen, Lilly, Merck, Novartis, Kadmon, Dermira, Boehringer, Innovaderm, Kyowa, BMS, Serono, BiogenIdec, Delenex, AbbVie, Sanofi, Baxter, Paraxel, Xenoport, and Kineta. A. S. Paller has received research support (grants paid to her institution) from AbbVie, Anaptysbio, Celgene, Eli Lilly, Galderma, Incyte, Leo, Janssen, Novartis, and Regeneron and has been a consultant for Almirall, Amgen, Asana, Boehringer-Ingelheim, Castle Creek, Celgene, Dermavant, Dermira, Eli Lilly, Exicure, Forte, Galderma, Lenus, Leo, Novan, Novartis, Pfizer, Regeneron, Sanofi-Genzyme, and Sol Gel. The rest of the authors declare that they have no relevant conflicts of interest.

Figures

Fig 1.
Fig 1.
Immune genes. Summary heatmap of immune genes from multiple pathways in lesional and nonlesional AD vs normal skin across age groups using RNA-seq, by criteria of FCH more than 2 and FDR less than 0.05. Samples are sorted by hierarchical clustering. Tables show DEGs presenting comparable (top) and differential (bottom) expression across AD age groups. LS, Lesional; N, normal; NL, nonlesional. ***FDR < 0.001, **FDR < 0.01, *FDR < 0.05, +FDR < 0.1.
Fig 2.
Fig 2.
A-E, Gene set variation analyses for major TH immune pathways. Red bars represent means. Black symbols: significance of comparison to normal; red symbols: significance of comparison between lesional and nonlesional skin; symbols in other colors: significance of comparison between respective groups. LS, Lesional; NL, nonlesional. ***P < .001, **P < .01, *P < .05, +P < .1.
Fig 3.
Fig 3.
Epidermal barrier-related genes. Summary heatmap of barrier-associated genes in lesional and nonlesional AD vs normal skin across age groups using RNA-seq, by criteria of FCH more than 2 and FDR less than 0.05. Samples are sorted by hierarchical clustering. LS, Lesional; N, normal; NL, nonlesional. ***FDR < .001, **FDR < .01, *FDR < .05, +FDR < .1.
Fig 4.
Fig 4.
qRT-PCR analysis of selected inflammatory genes in skin of different AD age groups and age-appropriate controls. Values show log2 expression and are presented as means ± SEMs. Red bars represent means. Black symbols: significance of comparison to normal; red symbols: significance of comparison between lesional and nonlesional skin; symbols in other colors: significance of comparison between respective groups. CCL17, C-C motif chemokine ligand 17; CON, controls; LS, lesional; MMP12, matrix metallopeptidase 12; NL, nonlesional. ***P < .001, **P < .01, *P < .05, +P < .1.
Fig 5.
Fig 5.
qRT-PCR analysis of selected inflammatory and barrier genes of different AD and normal skin age groups presented as line charts, representing developmental trajectories. Values show log2 normalized expression and are presented as means ± SEMs. ***P < .001, **P < .01, *P < .05, +P < .1.
Fig 6.
Fig 6.
IHC studies assessing AD across pediatric and adult age groups. A and B, Representative IHC images of keratin 16 (K16) and FLG staining at 10× magnification in AD age groups and age-appropriate controls. C and D, Corresponding mRNA expression levels by qRT-PCR. Values show log2 expression presented as means ± SEMs. Red bars represent means. E-L, Boxplots depicting cell counts of skin infiltrates in nonlesional/lesional AD and healthy skin across age groups. Values are presented as means ± SEMs. Black symbols: significance of comparison to normal; red symbols: significance of comparison between lesional and nonlesional skin; symbols in other colors: significance of comparison between respective groups. DC-LAMP, Dendritic cell - lysosomal associated membrane protein; LS, lesional; NL, nonlesional. ***P < .001, **P < .01, *P < .05, +P < .1.
See this image and copyright information in PMC

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