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

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Science Translational Medicine  20 Feb 2019:
Vol. 11, Issue 480, eaav2685
DOI: 10.1126/scitranslmed.aav2685
  • Fig. 1 TEWL AUC and TEWL after sequential STS by group.

    The primary end point comparisons between groups were TEWL AUC assessed on nonlesional skin of 62 participants. (A) Boxplots: Solid horizontal line and filled circle within a box represent the median and mean, respectively, the box margins are the interquartile range (50% of the observations), whisker lines extend for 1.5 times the interquartile range, and observations outside the whisker are marked by an open circle. The annotations are the P values from pairwise comparisons between groups obtained from a one-way analysis of variance (ANOVA). (B) TEWL measurements after 5, 10, 15, and 20 STS. The line figure represents means and SEs from a linear mixed model (green line represents NA, purple line represents AD FA−, and orange line represents AD FA+). Colored asterisks represent statistically significant differences: green represents a statistically significant difference between AD FA+ and NA, whereas purple compares AD FA+ and AD FA−.

  • Fig. 2 Correlation of TEWL AUC with SCORAD in nonlesional skin for AD FA+ and AD FA− group.

    Correlation between SCORAD and TEWL AUC in nonlesional skin stratified by AD FA+ (A) and AD FA− (B). The annotations in each panel are the Pearson correlations [95% confidence interval (CI)] and P values.

  • Fig. 3 FLG breakdown products and the proportion of EOS CER content in nonlesional skin.

    Comparisons between groups for FLG breakdown products total UCA (A), PCA (B), and EOS CER/NS CER ratio (C) were all assessed at skin tapes 15 and 16 on nonlesional skin. In the boxplot, the solid horizontal line represents the median, and the filled circle represents the mean. The box margins are the interquartile range, and the whiskers extend 1.5 times the interquartile range. Observations outside the whisker are marked by an open circle. The annotations are the P values from pairwise comparisons between groups obtained from a one-way ANOVA.

  • Fig. 4 Staphylococcus, S. aureus, and S. hominis correlations with TEWL AUC for AD FA+, AD FA−, and NA.

    Correlations between overall Staphylococcal species including S. aureus and S. hominis relative abundance (%, square root transformed) and TEWL AUC assessed on nonlesional skin from AD FA+, AD FA−, and NA. Relative abundance of Staphylococcus species were obtained by mapping the trimmed reads to reference genomes. Correlation between relative abundance and TEWL was obtained using Pearson correlation (95% CI) and P values. Linear regression models were used to estimate the best-fitting line and SE.

  • Fig. 5 Keratin expression in nonlesional skin.

    Comparisons between groups for markers of keratin expression measured as cumulative reporter ion signal to noise: KRT5 (A), KRT14 (B), and KRT16 (C) all assessed at skin tapes 15 and 16 on nonlesional skin. In the boxplot, the solid horizontal line represents the median, and the filled circle represents the mean. The box margins are the interquartile range, and the whiskers extend 1.5 times the interquartile range. Observations outside the whisker are marked by an open circle. The annotations are the P values from pairwise comparisons between groups obtained from a one-way ANOVA.

  • Fig. 6 Dendritic cell and immune activation signatures in nonlesional skin of AD FA+ are similar to lesional AD FA+ and AD FA− skin.

    Heat map and dendrogram for the transcriptome dataset (A). In this map, each row represents a transcriptome, and each column represents a participant. The cell color represents normalized levels from high (red) to middle (yellow) to low (blue), and the top column color represents the diagnostic group with appropriate annotations at the bottom (+ for AD FA+ and − for AD FA−). Boxplot for nonlesional skin (B) and lesional skin (C) of the first principal component. In the boxplots, the solid horizontal line represents the median, and the filled circle represents the mean. The box margins are the interquartile range, and the whiskers extend 1.5 times the interquartile range. Observations outside the whisker are marked by an open circle. The annotations are the P values from pairwise comparisons between groups obtained from a one-way ANOVA.

  • Fig. 7 Network and relative importance analyses.

    Network (A) of the intercorrelations between the measurements of TEWL (TEWL), total UCA (UCA), PCA (PCA), EOS CER/NS CER ratio (EOSNS), AD severity indices (EASI, NESS, and SCORAD), keratin expression (KRT5, KRT14, and KRT16), transcriptome PC1 (TPC1), the relative abundance of S. aureus (SAUR) and S. hominis (SHOM), and an indicator variable for AD FA+ (yes/no) based on peanut wheal size of ≥8 mm. TEWL measurements were done at STS 15; UCA, PCA and EOS CER/NS CER ratio were evaluated at STS layers 15 and 16. The color saturation and the width of the connecting lines correspond to the strength of the Pearson correlation coefficient, and the color of each connecting line indicates a positive (red) or negative (blue) correlation. Connecting lines are only shown for significant Pearson correlations (P < 0.01). Relative importance for prediction of AD FA+ (B) and TEWL STS 15 (C).

Supplementary Materials

  • www.sciencetranslationalmedicine.org/cgi/content/full/11/480/eaav2685/DC1

    Materials and Methods

    Fig. S1. Lesional skin has similar baseline TEWL in AD FA+ and AD FA− groups.

    Fig. S2. Pruritus correlates with TEWL AUC in AD FA+ but not AD FA−.

    Fig. S3. Lamellar bilayer structural integrity is abnormal in the skin of AD FA+.

    Fig. S4. Shannon diversity index.

    Fig. S5. Staphylococcus and Micrococcus species are more abundant on nonlesional skin of AD FA+ versus NA.

    Fig. S6. Relative abundance of various bacterial genera are similar in AD lesional skin, regardless of FA.

    Fig. S7. S. aureus is more abundant in nonlesional skin of AD FA+ than NA skin but similar to AD FA−.

    Fig. S8. Skin lesions of AD FA+ and AD FA− have similar abundance of the Staphylococcus species.

    Fig. S9. SPLOM showing all bivariate relationships between the variables in the network diagram (Fig. 7A).

    Fig. S10. Type 2 immune response gene expression in the nonlesional skin of AD FA+, AD FA−, and NA groups.

    Table S1. Characteristics of study participants by diagnostic group.

    Table S2. Comparisons between groups for TEWL.

    Table S3. Correlations between food-specific IgE and skin test results with TEWL.

    Table S4. Comparisons between groups for FLG breakdown products.

    Table S5. Comparisons between groups for FLG breakdown products with the corresponding TEWL.

    Table S6. Comparisons between groups total EOS CER, total C18 NS CER, and NS CER.

    Table S7. Correlations between groups for total EOS CER, total C18 NS CER, and NS CER with the corresponding TEWL.

    Table S8. Comparisons between groups for keratin expression in nonlesional skin.

    Table S9. Correlations between keratin expression in nonlesional skin and TEWL.

    Table S10. Genes (n = 288) associated with the AD FA+, AD FA−, and NA groups.

    Table S11. Top 10 ingenuity canonical pathways.

    Data file S1. Primary data.

    Data file S2. Data for the skin microbiome.

    Data file S3. Data for the skin transcriptome.

    References (6773)

  • The PDF file includes:

    • Materials and Methods
    • Fig. S1. Lesional skin has similar baseline TEWL in AD FA+ and AD FA− groups.
    • Fig. S2. Pruritus correlates with TEWL AUC in AD FA+ but not AD FA−.
    • Fig. S3. Lamellar bilayer structural integrity is abnormal in the skin of AD FA+.
    • Fig. S4. Shannon diversity index.
    • Fig. S5. Staphylococcus and Micrococcus species are more abundant on nonlesional skin of AD FA+ versus NA.
    • Fig. S6. Relative abundance of various bacterial genera are similar in AD lesional skin, regardless of FA.
    • Fig. S7. S. aureus is more abundant in nonlesional skin of AD FA+ than NA skin but similar to AD FA−.
    • Fig. S8. Skin lesions of AD FA+ and AD FA− have similar abundance of the Staphylococcus species.
    • Fig. S9. SPLOM showing all bivariate relationships between the variables in the network diagram (Fig. 7A).
    • Fig. S10. Type 2 immune response gene expression in the nonlesional skin of AD FA+, AD FA−, and NA groups.
    • Table S1. Characteristics of study participants by diagnostic group.
    • Table S2. Comparisons between groups for TEWL.
    • Table S3. Correlations between food-specific IgE and skin test results with TEWL.
    • Table S4. Comparisons between groups for FLG breakdown products.
    • Table S5. Comparisons between groups for FLG breakdown products with the corresponding TEWL.
    • Table S6. Comparisons between groups total EOS CER, total C18 NS CER, and NS CER.
    • Table S7. Correlations between groups for total EOS CER, total C18 NS CER, and NS CER with the corresponding TEWL.
    • Table S8. Comparisons between groups for keratin expression in nonlesional skin.
    • Table S9. Correlations between keratin expression in nonlesional skin and TEWL.
    • Table S10. Genes (n = 288) associated with the AD FA+, AD FA−, and NA groups.
    • Table S11. Top 10 ingenuity canonical pathways.
    • References (6773)

    [Download PDF]

    Other Supplementary Material for this manuscript includes the following:

    • Data file S1 (Microsoft Excel format). Primary data.
    • Data file S2 (Microsoft Excel format). Data for the skin microbiome.
    • Data file S3 (Microsoft Excel format). Data for the skin transcriptome.

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