Expanding the Psoriasis Disease Profile: Interrogation of the Skin and Serum of Patients with Moderate-to-Severe Psoriasis

Abstract

Psoriasis is a complex disease with an expanding definition of its pathological features. We sought to expand/refine the psoriasis transcriptome using 85 paired lesional and non-lesional samples from a cohort of patients with moderate-to-severe psoriasis vulgaris who were not receiving active psoriasis therapy. This new analysis identified 4,175 probe sets (representing 2,725 unique known genes) as being differentially expressed in psoriasis lesions compared with matched biopsies of non-lesional skin when the following criteria were applied: >2-fold change and false discovery rate <0.05. These probe sets represent the largest and most comprehensive set of genes defining psoriasis at the molecular level and within the previously unidentified genes, a link to functional pathways associated with metabolic diseases/diabetes and to cardiovascular risk pathways is identified. In addition, we profiled the serum of moderate-to-severe psoriatics compared with healthy controls to assess the overlap of overexpressed lesional genes with overexpressed systemic proteins. We identified linkage of functional pathways in lesional skin associated with metabolic diseases/diabetes and cardiovascular risk with those pathways overexpressed in the serum, suggesting a potential linkage between altered gene transcription in the skin and comorbidities commonly seen in patients with moderate-to-severe psoriasis.

Reduction of CD18 Promotes Expansion of Inflammatory γδ T Cells Collaborating with CD4+ T Cells in Chronic Murine Psoriasiform Dermatitis

“…This cytokine expression pattern is similar to the inflammatory response in human psoriatic plaques and therefore validates the CD18 hypo PL/J psoriasis model (44,45). Although skin gd T cells have previously been reported to primarily produce IL-17, our IF analyses of CD18 hypo PL/J skin sections convincingly demonstrated that dermal gd T cells significantly contributed to IL-17, IL-22, and TNF-a production.…”

A GRHL3-regulated repair pathway suppresses immune-mediated epidermal hyperplasia

“…While GRHL3 was similarly expressed between normal and uninvolved psoriasis skin, it was found to be consistently and significantly upregulated 2.62-fold in psoriasis lesions in 3 independent datasets ( Figure 3, A and B, and refs. [31][32][33]. Intriguingly, patients with stronger upregulation of GRHL3 expression (lesional versus uninvolved) also showed stronger upregulation of genes induced by IL-17 and IL-22 (P ≤ 1 × 10 -10 and P ≤ 3.03 × 10 -5 , respectively; Figure 3C, Supplemental Table 1, and ref.…”

“…To begin investigating the above hypothesis, we compared our prior GRHL3 siRNA knockdown gene expression and GRHL3 ChIP-Seq datasets from normal differentiating human keratinocytes (NHEK) (35) with the human psoriasis gene expression data (31)(32)(33). Of the 1,206 GRHL3-regulated genes in differentiating NHEKs, 312 were also differentially expressed in human psoriasis lesions compared with nonlesional skin (overlap significant, P ≤ 3.65 × 10 -5 ; Figure 3D and Supplemental Figure 5A).…”

Early intervention in psoriasis and immune-mediated inflammatory diseases: A hypothesis paper

“…The recent finding that patients with psoriasis show an overexpression in lesional skin of mRNA from genes linked to cardiovascular risk (e.g. inflammatory mediators and renin), corresponding to increased levels of the relevant proteins in the serum, is highly suggestive in this regard (88).…”