Molecular Phenotyping Small (Asian) versus Large (Western) Plaque Psoriasis Shows Common Activation of IL-17 Pathway Genes but Different Regulatory Gene Sets

Abstract

Psoriasis is present in all racial groups, but in varying frequencies and severity. Considering that small plaque psoriasis is specific to the Asian population and severe psoriasis is more predominant in the Western population, we defined Asian small and intermediate plaque psoriasis as psoriasis subtypes and compared their molecular signatures with the classic subtype of Western large plaque psoriasis. Two different characteristics of psoriatic spreading-vertical growth and radial expansion-were contrasted between subtypes, and genomic data were correlated to histologic and clinical measurements. Compared with Western large plaque psoriasis, Asian small plaque psoriasis revealed limited psoriasis spreading, but IL-17A and IL-17-regulated proinflammatory cytokines were highly expressed. Paradoxically, IL-17A and IL-17-regulated proinflammatory cytokines were lower in Western large plaque psoriasis, whereas T cells and dendritic cells in total psoriatic skin area were exponentially increased. Negative immune regulators, such as CD69 and FAS, were decreased in both Western large plaque psoriasis and psoriasis with accompanying arthritis or obesity, and their expression was correlated with psoriasis severity index. Based on the disease subtype comparisons, we propose that dysregulation of T-cell expansion enabled by downregulation of immune negative regulators is the main mechanism for development of large plaque psoriasis subtypes.

Conflict of interest statement

Conflict of Interest: The authors are not aware of any affiliations, memberships, funding, or financial holdings that might be perceived as affecting the objectivity of this article. J.G.K. has been a consultant to and receives research support from companies developing therapeutics for psoriasis, including Amgen, Boehringer, Centocor/Janssen, Merck, Pfizer, Idera, and Astellas.

Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

Figures

Figure 1. Comparison of epidermal thickness, PASI, differentially expressed genes (DEGs), and meta-analysis-derived psoriasis transcriptome between Asian small, Asian intermediate, and Western large psoriasis

(a) Asian small psoriasis with limited epidermal thickness in comparison to Asian intermediate or Western large psoriasis. (b) Western large psoriasis with higher PASI in comparison to Asian small or intermediate psoriasis. (c) Area-proportional Venn diagram comparing DEGs. 27.7% of all DEGs were shared by the three comparison subtypes. (d) DEGs among meta-analysis-derived psoriasis transcriptome for Affymetrix Human Genome U133 Plus 2.0 Array (MAD3)(Suarez-Farinas et al., 2012). 66.9% of the meta-analysis-derived psoriasis transcriptome was differentially expressed in all subtypes (> 2 FCH and < 0.05 FDR, PASI: Psoriasis Area and Severity Index, FCH: fold change, FDR: false discovery rate)

Figure 2. Exploratory models of disease progression

(a) Vertical growth and radial expansion models emerged from contrasting epidermal thickness and PASI between Asian small, Asian intermediate, and Western large psoriasis. (b) In the model of vertical growth phase, epidermal thickness was correlated with the numbers of CD3+ T cells and CD11c+ dendritic cells within the epidermis and dermal papillae (method of counting cells in epidermis and dermal papillae: Supplementary Figure S6 online). (c) In the model of radial expansion phase, PASI was correlated with CD3+ T cells and CD11c+ dendritic cells in total psoriasis body surface area (d) Summary of exploratory models (r = Pearson correlation, p < 0.0001, PASI: Psoriasis Area and Severity Index, Number of inflammatory cells in total psoriasis body surface area = cell count in the slide section × body surface area × proportion of psoriasis involvement).

Figure 3. Quantitative comparison of gene expression in psoriatic lesional and non-lesional skin between Asian small (N=16), Asian intermediate (N=21), and Western large (N=20) psoriasis

Expression levels of genes involved in psoriasis disease progression were quantified by RT-PCR (Gene expression: Log2 conversion of mRNA expression normalized to human acidic ribosomal protein (HARP), *p < 0.05).

Figure 4. Psoriasis pathway enrichment scores

(a) The enrichment of pivotal immune pathways of IL-17 and IFN-γ signaling was not different between Asian small, Asian intermediate, and Western large psoriasis. Negative regulator signaling in Western large psoriasis was downregulated compared to Asian intermediate psoriasis. (*p < 0.01 and FDR < 0.01) (b) Pathways involved in psoriasis comorbidities (psoriatic arthritis, cardiovascular disease, and atherosclerosis) were significantly enriched only in Western large psoriasis (p < 0.001 and FDR < 0.001). The scores were generated by GSVA with the combined z-score method. Gene sets for pathway analysis were curated from published papers (Belasco et al., 2014; Chiricozzi et al., 2014), Molecular signatures database (http://www.broadinstitute.org/gsea/msigdb), and Gene ontology consortium (http://geneontology.org).

Figure 5. Correlation between PASI and expression levels of negative regulators in lesional and non-lesional skin

Overlay scatter plot to display the correlation between PASI and expression levels of negative regulators (CD69, FAS, CTLA4, PD-L1, and FoxP3) in lesional (red) and non-lesional (blue) skin. The expression of TNF-α in lesional and non-lesional skin is presented as a control (Gene expression: Log2 conversion of mRNA expression normalized to human acidic ribosomal protein (HARP), PASI: Psoriasis Area and Severity Index).

Figure 6. Downregulation of negative regulators and upregulation of driver cytokines in the skin of psoriasis patients with psoriatic arthritis/obesity

Overlay scatter plot to display different expression levels of negative regulators (CD69, FAS, and FoxP3) and driver cytokines (TNF-α, IL-1B, and IL-17A) in lesional (red) and non-lesional (blue) skin between psoriasis without (No) and with (Yes) comorbidities (Psoriatic arthritis (a), Obesity (b)). The data include total study population of Asian small, Asian intermediate, and Western large psoriasis. Gene expression: Log2 conversion of mRNA expression normalized to human acidic ribosomal protein.

Figure 7. Molecular determinants of disease progression in psoriasis

Potential molecular determinants of disease progression at different stages were explored by correlating cellular and molecular signatures to histologic and clinical measurements of disease progression.