Abstract
Psoriasis is a chronic cutaneous inflammatory disease. The immunopathogenesis is a complex interplay between T cells, dendritic cells and the epidermis in which T cells and dendritic cells maintain skin inflammation. Anti-tumour necrosis factor (anti-TNF)-α agents have been approved for therapeutic use across a range of inflammatory disorders including psoriasis, but the anti-inflammatory mechanisms of anti-TNF-α in lesional psoriatic skin are not fully understood. We investigated early events in skin from psoriasis patients after treatment with anti-TNF-α antibodies by use of bioinformatics tools. We used the Human Gene 1.0 ST Array to analyse gene expression in punch biopsies taken from psoriatic patients before and also 4 and 14 days after initiation of treatment with the anti-TNF-α agent adalimumab. The gene expression was analysed by gene set enrichment analysis using the Functional Annotation Tool from DAVID Bioinformatics Resources. The most enriched pathway was visualised by the Pathview Package on Kyoto Encyclopedia of Genes and Genomes (KEGG) graphs. The analysis revealed new very early events in psoriasis after adalimumab treatment. Some of these events have been described after longer periods of anti-TNF-α treatment when clinical and histological changes appear, suggesting that effects of anti-TNF-α treatment on gene expression appear very early before clinical and histological changes. Combining microarray data on biopsies from psoriasis patients with pathway analysis allowed us to integrate in vitro findings into the identification of mechanisms that may be important in vivo. Furthermore, these results may reflect primary effect of anti-TNF-α treatment in contrast to studies of gene expression changes following clinical and histological changes, which may reflect secondary changes correlated to the healing of the skin.
Highlights
The skin harbors multiple systems that eg. encompasses the skin immunesytem in order to protect the body and maintain local homeostasis [1,2,3]
Studies of skin samples from patients treated with anti-tumour necrosis factor-α agents have confirmed that dendritic cells (DCs) and T cells play a role in the pathogenesis of psoriasis, and anti-TNF-α has been shown to regulate both Th17 responses and IL-23 and Th17 cytokine expression in lesional psoriatic skin [8, 9]
RNA from samples collected from psoriasis patients on days 0 and 4 (n = 10) and on day 14 (n = 7) after adalimumab treatment initiation was analysed using the Affymetrix microarray
Summary
The skin harbors multiple systems that eg. encompasses the skin immunesytem in order to protect the body and maintain local homeostasis [1,2,3]. Many gene expression studies of the in vivo effect of anti-TNF-α has been conducted two weeks or later after treatment start where the histological and clinical changes start appearing Findings at these time points reveal genes that may be important in the pathogenesis of psoriasis as well as direct or indirect targets of anti-TNF-α agents [10, 11]. Inhibition of TNF-α is known to modulate a wide panel of genes involved in immune and inflammatory responses Some of these genes, including IL-8, IL-1β, CXCL10, and CXCL11 represent direct targets of TNF-α [19,20,21], whereas others are the result of an indirect effect that reflects changes in the cell and cytokine network occurring within the target tissues [8,9,10, 22, 23]. The most enriched pathway was visualised using the Pathview Package on KEGG graphs [26]
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