Distinct activation of positive and negative regulatory immune genes during an evolving T cell response to diphencyprone (DPCP) in human skin
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ABSTRACT:
ORGANISM(S): Homo sapiens
SUBMITTER: Mayte Suarez-Farinas
PROVIDER: E-GEOD-52360 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
Similar Datasets
Project description:We sought to characterize delayed-type hypersensitivity (DTH) responses elicited by topical hapten DPCP in normal human skin
2014-03-29 | GSE52360 | GEO
Project description:Atopic dermatitis (AD) is the most common inflammatory skin disease, with high unmet need for new therapies that are safe for chronic use. Emerging data suggest that TH2-cytokines play important roles in a variety of allergic and atopic conditions, including asthma and AD. In early phase clinical trials, dupilumab (a fully human monoclonal antibody against IL-4R? that potently blocks IL-4 and IL-13 signaling) rapidly and markedly improved clinical measures in adults with either asthma (with elevated eosinophil counts) or moderate-to-severe AD. The pathomechanisms that may be impacted by IL-4/13 blockade in these disease settings have not yet been characterized in detail. Transcriptome analyses in pre- and post-treatment skin biopsies from patients with moderate-to-severe AD treated with dupilumab or placebo in two completed clinical trials 18 Patients with AD treated with dupilumab or placebo. 28 biopsies in lesional (LS) Skin (16 pre-treatment and 12 post-treatment). 12 biopsies in non-lesional (NL) Skin (7 pre-treatment and 5 post treatment)
2014-12-04 | E-GEOD-59294 | biostudies-arrayexpress
Project description:Diphencyprone (DPCP) is a hapten that induces delayed-type hypersensitivity (DTH) reactions. MicroRNAs (miRNAs) are short non-coding RNAs that negatively regulate gene expression, and have been implicated in various inflammatory skin diseases, but their role in DTH reactions is not well understood. We generated global miRNA expression profiles (using next-generation sequencing) of DPCP reactions in skin of 7 healthy volunteers at 3, 14, and 120 days after challenge. Compared to placebo-treated sites, DPCP-challenged skin at 3 days (peak inflammation) had 127 miRNAs significantly deregulated. At 14 days (during resolution of inflammation), 43 miRNAs were deregulated and, at 120 days (when inflammation had completely resolved), 6 miRNAs were upregulated. While some miRNAs have been observed in psoriasis or atopic dermatitis, most of the deregulated miRNAs have not yet been studied in the context of skin biology or immunology. Across the three time points studied, many but not all miRNAs were uniquely expressed. As various miRNAs may influence T cell activation, this may indicate that the miRNAs exclusively expressed at different time points function to promote or resolve skin inflammation, and therefore may inform on the paradoxical ability of DPCP to treat both autoimmune conditions (alopecia areata) and conditions of ineffective immunity (melanoma).
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Project description:Epigallocatechin-3-gallate (EGCG), a polyphenol, influences cutaneous wound healing due to its anti-angiogenic, anti-inflammatory and anti-oxidant properties. We previously showed EGCG is effective in improving skin scarring when applied immediately post-injury. Here, this double-blinded randomized placebo-controlled trial compared the effects of pre-emptive priming versus immediate and delayed topical EGCG compared with placebo. This was evaluated in 40 healthy human volunteers, over 8 weeks, in scars created in their upper inner arms using skin punch biopsies. Participants were split into 4 groups; each undergoing different modes of application versus placebo: Group 1=priming (7D) pre-injury, Group 2=priming (3D) pre-injury, Group 3=immediate (0D) day-of-injury, Group 4=delayed application (14D) post-injury. RNA sequencing was used here based on 72 samples: Group 1: day 0 (n=3 placebo, n=3 EGCG), week 4 (n=3 placebo, n=3 EGCG), week 8 (n=3 placebo, n=3 EGCG); Group 2: day 0 (n=3 placebo, n=3 EGCG), week 4 (n=3 placebo, n=3 EGCG), week 8 (n=3 placebo, n=3 EGCG), Group 3: day 0 (n=6), week 4 (n=3 placebo, n=3 EGCG), week 8 (n=3 placebo, n=3 EGCG), Group 4: day 0 (n=6), week 4 (n=3 placebo, n=3 EGCG), week 8 (n=3 placebo, n=3 EGCG). The common differentially expressed genes identified between treated (EGCG) and placebo samples were grouped according to time point and group. Further exploration of these genes using Gene Ontology and Ingenuity Pathway Analysis revealed gene signatures of relevant biological processes and pathways. Here, RNA sequencing revealed a number of angiogenic, inflammatory genes that were significantly downregulated with EGCG particularly in pre-emptive priming Group 1 at week 4 including; hemoglobin subunit beta (HBB), hemoglobin subunit alpha-1 (HBA1) and hemoglobin subunit alpha-2 (HBA2) at week-4.
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Project description:To understand the mechanism of disease progression in psoriasis, we defined Asian small plaque psoriasis (small psoriasis) and Asian intermediate plaque psoriasis (intermediate psoriasis) as psoriasis subtypes with limited disease progression, and compared their cellular and molecular signatures with the classic subtype of Western large plaque psoriasis (large psoriasis; GSE30999). Transcriptome analyses in pre-treatment skin biopsies from patients with Asian small and intermediate plaque psoriasis. 12 Asian small plaque psoriasis skin biopsy tissues (7 lesional and 5 non-lesional skin) and 15 Asian intermediate plaque psoriasis skin biopsy tissues (7 lesional and 8 non-lesional skin). GCRMA (using gcrma package from R/Bioconductor) and adjusted for batch effect. The expression data was combined with Western large psoriasis (GSE30999). Using a normalization based upon quantiles, the expression data was normalized based upon a specified normalization distribution of GSE30999 (see publication for GSE67853). The complete dataset representing: (1) 12 Asian small plaque psoriasis Samples, (2) 15 Asian intermediate plaque psoriasis Samples, and (3) 130 Western large plaque psoriasis Samples from GSE30999 (re-processed), is linked below as a supplementary file.
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Project description:Discoid lupus erythematosus (DLE) is the most common skin manifestation of lupus. Despite its high frequency in systemic lupus in addition to cases without extracutaneous manifestations, targeted treatments for DLE are lacking, likely because of a dearth of knowledge of the molecular landscape of DLE skin. Here, we profiled the transcriptome of DLE skin in order to identify signaling pathways and cellular signatures that may be targeted for treatment purposes. Further comparison of the DLE transcriptome with that of psoriasis, a useful reference given our extensive knowledge of molecular pathways in this disease, provided a framework to identify potential therapeutic targets. Although a growing body of data support a role for IL-17 and T helper type 17 (Th17) cells in systemic lupus, we show a relative enrichment of IFN-γ-associated genes without that for IL-17-associated genes in DLE. Extraction of T cells from the skin of DLE patients identified a predominance of IFN-γ-producing Th1 cells and an absence of IL-17-producing Th17 cells, complementing the results from whole-skin transcriptomic analyses. These data therefore support investigations into treatments for DLE that target Th1 cells or the IFN-γ signaling pathway. Comparison of transcriptomes between skin conditions
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Project description:We sought to understand the differences between the basal and suprabasal layers of normal human skin epidermis. Comparison of transcriptomes among basal epidermis, suprabasal epidermis, whole epidermis, and reticular dermis
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Project description:Background: IL-17 is the defining cytokine of the Th17, Tc17, and γδ T cell populations that plays a critical role in mediating inflammation and autoimmunity. Psoriasis vulgaris is an inflammatory skin disease mediated by Th1 and Th17 cytokines with relevant contributions of IFN-γ, TNF-α, and IL-17. Despite the pivotal role IL-17 plays in psoriasis, and in contrast to the other key mediators involved in the psoriasis cytokine cascade that are capable of inducing broad effects on keratinocytes, IL-17 was demonstrated to regulate the expression of a limited number of genes in monolayer keratinocytes cultured in vitro. Methodology/Principal Findings: Given the clinical efficacy of anti-IL-17 agents is associated with an impressive reduction in a large set of inflammatory genes, we sought a full-thickness skin model that more closely resemble in vivo epidermal architecture. Using a reconstructed human epidermis (RHE), IL-17 was able to upregulate 419 gene probes and downregulate 216 gene probes. As possible explanation for the increased gene induction in the RHE model is that CEBPβ, the transcription factor regulating IL-17-responsive genes, is expressed in differentiated KCs. Conclusions/Significance: The genes identified in IL-17-treated RHE are likely relevant to the IL-17 effects in psoriasis, since ixekizumab (anti-IL-17A agent) strongly suppressed the “RHE” genes in psoriasis patients treated in vivo with this IL-17 antagonist. RHE samples were treated with IFNg, IL-22 and IL-17 and compared with control
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Project description:Dimethyl fumarate (DMF) is an effective oral treatment for psoriasis administered in Europe for nearly 60 years. Its potential, however, has been limited by contact dermatitis that prohibits topical application. This paper characterizes a DMF derivative, isosorbide di-(methyl fumarate) (IDMF), which was designed to have anti-psoriatic effects without skin-sensitizing properties. We show that IDMF exhibits neither genotoxicity nor radiation sensitivity in skin fibroblasts and is non-irritating and non-sensitizing in animal models (rat, rabbit, guinea pig). Microarray analysis of cytokine-stimulated keratinocytes showed that IDMF represses the expression of genes specifically up-regulated in psoriatic skin lesions but not those of other skin diseases. IDMF also down-regulated genes induced by IL-17A and TNF in keratinocytes, as well as predicted targets of NF-κB and the anti-differentiation ncRNA (ANCR). IDMF further stimulated transcription of oxidative stress response genes (NQO1, GPX2, GSR) with stronger Nrf2/ARE activation compared to DMF. Finally, IDMF reduced erythema and scaling while repressing expression of immune response genes in psoriasiform lesions elicited by topical application of imiquimod in mice. These data demonstrate that IDMF exbibits anti-psoriatic activity that is similar or improved compared to DMF, without the harsh skin-sensitizing effects that have prevented topical delivery of the parent molecule.
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Project description:Dimethyl fumarate (DMF) is an effective oral treatment for psoriasis administered in Europe for nearly 60 years. Its potential, however, has been limited by contact dermatitis that prohibits topical application. This paper characterizes a DMF derivative, isosorbide di-(methyl fumarate) (IDMF), which was designed to have anti-psoriatic effects without skin-sensitizing properties. We show that IDMF exhibits neither genotoxicity nor radiation sensitivity in skin fibroblasts and is non-irritating and non-sensitizing in animal models (rat, rabbit, guinea pig). Microarray analysis of cytokine-stimulated keratinocytes showed that IDMF represses the expression of genes specifically up-regulated in psoriatic skin lesions but not those of other skin diseases. IDMF also down-regulated genes induced by IL-17A and TNF in keratinocytes, as well as predicted targets of NF-κB and the anti-differentiation ncRNA (ANCR). IDMF further stimulated transcription of oxidative stress response genes (NQO1, GPX2, GSR) with stronger Nrf2/ARE activation compared to DMF. Finally, IDMF reduced erythema and scaling while repressing expression of immune response genes in psoriasiform lesions elicited by topical application of imiquimod in mice. These data demonstrate that IDMF exbibits anti-psoriatic activity that is similar or improved compared to DMF, without the harsh skin-sensitizing effects that have prevented topical delivery of the parent molecule.
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