Heterogeneity of Inflammatory and Cytokine Networks in Chronic Plaque Psoriasis

Abstract

The clinical features of psoriasis, characterized by sharply demarcated scaly erythematous plaques, are typically so distinctive that a diagnosis can easily be made on these grounds alone. However, there is great variability in treatment response between individual patients, and this may reflect heterogeneity of inflammatory networks driving the disease. In this study, whole-genome transcriptional profiling was used to characterize inflammatory and cytokine networks in 62 lesional skin samples obtained from patients with stable chronic plaque psoriasis. We were able to stratify lesions according to their inflammatory gene expression signatures, identifying those associated with strong (37% of patients), moderate (39%) and weak inflammatory infiltrates (24%). Additionally, we identified differences in cytokine signatures with heightened cytokine-response patterns in one sub-group of lesions (IL-13-strong; 50%) and attenuation of these patterns in a second sub-group (IL-13-weak; 50%). These sub-groups correlated with the composition of the inflammatory infiltrate, but were only weakly associated with increased risk allele frequency at some psoriasis susceptibility loci (e.g., REL, TRAF3IP2 and NOS2). Our findings highlight variable points in the inflammatory and cytokine networks known to drive chronic plaque psoriasis. Such heterogeneous aspects may shape clinical course and treatment responses, and can provide avenues for development of personalized treatments.

Characterization and profiling of immunomodulatory genes in resident mesenchymal stem cells reflect the Th1-Th17/Th2 imbalance of psoriasis

“…As postulated, the most part of the genes encoding for Th2 cytokines in PSO-MSCs (CCL1, CCL22, CXCL12, IL2, IL3, IL4, IL13B, IL 22, IL 27, TGF-b1) are not downor up-regulated, confirming previous results on differentiated skin cells: psoriasis is characterized by a cytokine production profile polarized toward Th1-Th17, rather than Th2 [28,37] pathway.…”

Cell-type deconvolution with immune pathways identifies gene networks of host defense and immunopathology in leprosy

“…In order to be able to connect specific genes that comprise the leprosy subtype signatures with immune cell types, a deconvolution analysis was performed. Cell-type-specific signatures were previously developed by Swindell et al (20,21) by comparing relative gene expression fold changes for a set of publicly available microarray data, which was selected as being representative of specific cell types. Briefly, the 50 genes most enriched for each cell type were identified using moderated t tests and fold changes (20,21).…”

“…Cell-type-specific signatures were previously developed by Swindell et al (20,21) by comparing relative gene expression fold changes for a set of publicly available microarray data, which was selected as being representative of specific cell types. Briefly, the 50 genes most enriched for each cell type were identified using moderated t tests and fold changes (20,21). Scores for each cell-type signature were assessed in disease subtype gene expression profiles by computing log intensities of the genes in that subtype relative to all others and then calculating an arithmetic mean of the log expression gene specificity to a certain cell type.…”

Immunology of Psoriasis

“…To visualize how psoriasis-related cytokine-response pathways are reflected in different mouse models, a graphic representation of cytokine pathway expression is shown in Figure 7. In this figure, normalized enrichment scores (NES) from Gene Set Enrichment Analysis (126) have been created for gene sets that are induced in cultured human cells or reconstructed human epidermis by the cytokines IL-17, IL-22, IFN-γ, IFN-α, TNF, IL-1, IL-4, and IL-13, either alone or in combinations that produced additive or synergistic effects in psoriasis lesions (12, 90, 127–129). High expression of that pathway in a target tissue produces a NES of greater than 2, whereas low expression of that pathway would be a NES of 1 or less.…”