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Minimally invasive skin tape strip RNA sequencing identifies novel characteristics of the type 2–high atopic dermatitis disease endotype  Nathan Dyjack,

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Presentation on theme: "Minimally invasive skin tape strip RNA sequencing identifies novel characteristics of the type 2–high atopic dermatitis disease endotype  Nathan Dyjack,"— Presentation transcript:

1 Minimally invasive skin tape strip RNA sequencing identifies novel characteristics of the type 2–high atopic dermatitis disease endotype  Nathan Dyjack, BA, Elena Goleva, PhD, Cydney Rios, MS, Byung Eui Kim, MD, PhD, Lianghua Bin, MD, PhD, Patricia Taylor, NP, Caroline Bronchick, RN, Clifton F. Hall, MS, Brittany N. Richers, BS, Max A. Seibold, PhD, Donald Y.M. Leung, MD, PhD  Journal of Allergy and Clinical Immunology  Volume 141, Issue 4, Pages (April 2018) DOI: /j.jaci Copyright © 2018 American Academy of Allergy, Asthma & Immunology Terms and Conditions

2 Fig 1 Nonlesional AD skin tape strip transcriptomes differ from skin biopsy transcriptomes and better assay the stratum corneum. A, The top 10 expressed genes by tissue type are listed in rank order. B, Multidimensional scaling (MDS) of the top 500 variant genes in nonlesional tape strip, epidermal, and dermal samples separates the samples by tissue. C, The top 10 GO cellular component enrichments in nonlesional tape strip, skin biopsy–separated epidermal, and skin biopsy dermal samples. GO categories highlighted in red were only observed in epidermal and skin tape strip samples. D, Expression of canonical epidermal genes is consistently greatest in skin tape strip samples, next highest in epidermal samples, and lowest in dermal samples. Journal of Allergy and Clinical Immunology  , DOI: ( /j.jaci ) Copyright © 2018 American Academy of Allergy, Asthma & Immunology Terms and Conditions

3 Fig 2 Hierarchical clustering of nonlesional skin tape gene expression separates samples from patients with AD from those from healthy control subjects and identifies immune-activated patients with AD. A, Expression heat map and hierarchical clustering of patients with AD and healthy control subjects using nonlesional skin tape expression of genes differentially expressed in patients with AD. B, Expression heat map and hierarchical clustering of the 75 most recurrent leading-edge genes from all immune-related GO categories significantly enriched in patients with AD. A cluster of AD samples (immune activated) is identified that demonstrates distinct upregulation of immune-related genes compared with other patients with AD and healthy control subjects. Journal of Allergy and Clinical Immunology  , DOI: ( /j.jaci ) Copyright © 2018 American Academy of Allergy, Asthma & Immunology Terms and Conditions

4 Fig 3 Immune activation signature in patients with AD reflects significant upregulation of type 2 inflammatory genes and the presence of activated TH2 and DCs. A, Ingenuity Pathway Analysis canonical pathway analysis was performed with nonlesional skin tape differentially expressed genes between immune-activated patients with AD and nonactivated patients with AD. The 15 most significantly enriched canonical pathways indicate upregulation of TH2 and DC activity in immune-activated patients with AD. iCOS, Inducible costimulator; iCOSL, inducible costimulator ligand; NFAT, nuclear factor of activated T cells; PKC, protein kinase C. B, Expression of canonical type 2 inflammatory genes is upregulated in skin tape samples of immune-activated patients with AD. C, Graphic display of the canonical Ingenuity Pathway Analysis TH2 pathway showing genes overlaid on an APC and a T cell. Differentially expressed genes are colored by log2 FC. TCR, T-cell receptor. Journal of Allergy and Clinical Immunology  , DOI: ( /j.jaci ) Copyright © 2018 American Academy of Allergy, Asthma & Immunology Terms and Conditions

5 Fig 4 IL-4R protein expression is increased in nonlesional skin of patients with type 2-high AD. Skin biopsy specimens were stained for IL-4R with fluorescent immunohistochemistry. A and B, IL-4R staining in patients with type 2–high (Fig 4, A) and type 2–low (Fig 4, B) AD. IL-4R (Cy3) is shown in red, wheat germ agglutinin (fluorescein isothiocyanate) is shown in green, magnification is ×400, and the bar equals 20 μm. Arrows point to IL-4R–expressing keratinocytes in the epidermis. C, Quantification of IL-4R staining revealed significantly greater IL-4R levels in nonlesional skin of patients with type 2–high than patients with type 2–low AD. Journal of Allergy and Clinical Immunology  , DOI: ( /j.jaci ) Copyright © 2018 American Academy of Allergy, Asthma & Immunology Terms and Conditions

6 Fig 5 Nonlesional skin of patients with type 2–high AD is characterized by inflammatory DC signatures. A, Gene expression log2 FCs for DC markers between nonlesional skin of patients with type 2–high versus patients with type 2–low AD is plotted. Gene expression log2 FCs for these DC genes in published IDECs or monocyte-derived DCs versus Langerhans DCs28 and pDCs versus Langerhans DCs.29 B, Immunohistochemistry of skin biopsy specimens reveals numbers of CD207+ (langerin) DCs are greatest in patients with type 2–high AD, followed by patients with type 2–low AD and healthy control subjects. C, CD207 (langerin) staining of skin biopsy specimens from patients with type 2–high AD reveals extension of DC dendrites into the superficial layers of the epidermis. Langerin (Cy3) is shown in red, wheat germ agglutinin (fluorescein isothiocyanate) is shown in green, magnification if ×400, and bar equals 20 μm. Arrows point to langerin-positive cells and dendrites in the upper granular layer of the epidermis. Fluorescein isothiocyanate/Cy3 channels or the Cy3 channel only are shown. D, Genes upregulated in nonlesional skin of patients with type 2–high versus patients with type 2–low AD are plotted by using log2 FCs of differential expressions from IDECs versus Langerhans DCs28 and pDCs versus Langerhans DCs29 generated from published gene expression data. Log2 FCs of type 2–high upregulated genes indicate a skew toward IDECs. Plotted genes were filtered by using a significance threshold of an FDR of less than 0.05. Journal of Allergy and Clinical Immunology  , DOI: ( /j.jaci ) Copyright © 2018 American Academy of Allergy, Asthma & Immunology Terms and Conditions

7 Fig 6 Nonlesional skin type 2 inflammatory gene expression patterns are reflective of disease severity and lesional skin expression profiles in patients with AD. A-C, Principal component analysis was performed on nonlesional skin tape strip expression from 656 differentially expressed genes between samples from patients with type 2–high and patients with type 2–low AD. PC2 was strongly correlated (Pearson) with clinical measurements of AD. PC2 positively correlated with EASI score (ρ = 0.616, P = 1.11 × 10−2; Fig 6, A), percentage BSA covered with lesions (ρ = 0.438, P = 1.89 × 10−2; Fig 6, B), and log2 serum IgE level (ρ = 0.705, P = 1.56 × 10−3; Fig 6, C). Type two–low samples are denoted with blue circles, and type 2–high samples are plotted in red circles. D, PC2 values displayed a positive significant trend (by using the Cochran-Armitage trend test) across AD severity levels (P = 5.12 × 10−2). E, The top 250 differentially expressed genes between AD lesional and healthy control tape strips agnostically group nonlesional type 2–high samples with lesional tape strips and type 2–low with healthy control tape strips. Journal of Allergy and Clinical Immunology  , DOI: ( /j.jaci ) Copyright © 2018 American Academy of Allergy, Asthma & Immunology Terms and Conditions

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