The Spectrum of Mild to Severe Psoriasis Vulgaris Is Defined by a Common Activation of IL-17 Pathway Genes, but with Key Differences in Immune Regulatory.

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The Spectrum of Mild to Severe Psoriasis Vulgaris Is Defined by a Common Activation of IL-17 Pathway Genes, but with Key Differences in Immune Regulatory Genes Jaehwan Kim, Robert Bissonnette, Jongmi Lee, Joel Correa da Rosa, Mayte Suárez-Fariñas, Michelle A. Lowes, James G. Krueger Journal of Investigative Dermatology Volume 136, Issue 11, Pages 2173-2182 (November 2016) DOI: 10.1016/j.jid.2016.04.032 Copyright © 2016 The Authors Terms and Conditions

Figure 1 Comparison of epidermal thickness, keratinocyte hyperproliferation, and activated T-cell, dendritic cell, and regulatory T-cell infiltration between mild and severe psoriasis skin. (a, b) Hematoxylin and eosin (H&E) stain. (c) Epidermal thickness. (d, e) Keratin 16 (K16) stain. (f) K16 stain density. (g, h) CD3 stain. (i) CD3+ T cell count. (j, k) CD11c stain. (l) CD11c+ dendritic cell count. (m, n) FoxP3 stain. (o) FoxP3+ T cell count. (p, q) CTLA4 stain. (r) CTLA4+ T-cell count (scale bar = 200 μm). Journal of Investigative Dermatology 2016 136, 2173-2182DOI: (10.1016/j.jid.2016.04.032) Copyright © 2016 The Authors Terms and Conditions

Figure 2 Comparison of disease-associated cytokine expression in the skin between mild and severe psoriasis. (a) TH17 axis, (b) TH1 axis, and (c) immunoregulatory molecules. Differentially expressed cytokines involved in psoriasis pathogenesis are quantified by reverse transcription PCR. Gene expression: log2 conversion of messenger RNA expression normalized to human acidic ribosomal protein. ∗False discovery rate < 0.05. HARP, human acidic ribosomal protein; mRNA, messenger RNA; TH, T helper. Journal of Investigative Dermatology 2016 136, 2173-2182DOI: (10.1016/j.jid.2016.04.032) Copyright © 2016 The Authors Terms and Conditions

Figure 3 The association of disease severity (PASI) and disease-associated cytokine expression in the skin. (a) Heatmap displaying Spearman correlation between PASI score and disease-associated cytokine expression in the skin. (b) Pearson correlation between PASI score and CD3+ T-cell accumulation (red), pathogenic driver molecule expression (IL-17A and Mx1, red), and negative immune regulator expression (CTLA4 and CD69, blue) in the skin. As a control, no correlation between PASI score and keratinocyte hyperproliferation (K16) is observed (black). Gene expression: log2 conversion of messenger RNA expression normalized to human acidic ribosomal protein (HARP). PASI: Psoriasis Area and Severity Index. Journal of Investigative Dermatology 2016 136, 2173-2182DOI: (10.1016/j.jid.2016.04.032) Copyright © 2016 The Authors Terms and Conditions

Figure 4 Global messenger RNA expression patterns of mild and severe psoriasis. (a) Principal component analysis and (b) unsupervised hierarchical clustering for global messenger RNA expression patterns of mild psoriasis, severe psoriasis, and normal skin (Affymetrix Human Genome U133 Plus 2.0 Array, Affymetrix, Santa Clara, CA). (c) Scatterplot and (d) correlation plot of differentially expressed genes, defined by contrasting lesional psoriasis skin and normal skin. (e) Area-proportional Venn diagram of differentially expressed genes (>2-fold change and <0.05 false discovery rate). PASI, Psoriasis Area and Severity Index; PC, principal component; PCA, principal component analysis. Journal of Investigative Dermatology 2016 136, 2173-2182DOI: (10.1016/j.jid.2016.04.032) Copyright © 2016 The Authors Terms and Conditions

Figure 5 Gene set variation analysis (GSVA) scores of psoriasis transcriptome and immune pathways. The scores for (a) psoriasis transcriptome and (b) immune pathways are generated by GSVA with the combined z-score method. Gene sets for pathway analysis are curated from published papers (Bowcock et al., 2001; Chiricozzi et al., 2011; Chiricozzi et al., 2014; Gudjonsson et al., 2009; Jabbari et al., 2011; Layland et al., 2010; Prots et al., 2011; Suárez-Fariñas et al., 2012; Suárez-Fariñas et al., 2010; Tian et al., 2012; Yao et al., 2008) and the Molecular Signatures Database (http://www.broadinstitute.org/gsea/msigdb). ∗False discovery rate < 0.05. FDR, false discovery rate; MAD, meta-analysis derived transcriptome; TH, T helper. Journal of Investigative Dermatology 2016 136, 2173-2182DOI: (10.1016/j.jid.2016.04.032) Copyright © 2016 The Authors Terms and Conditions