Identification of novel immune and barrier genes in atopic dermatitis by means of laser capture microdissection
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE120721 | GEO | 2018/10/02
REPOSITORIES: GEO
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Project description:Insight into the pathophysiology of inflammatory skin diseases, especially at the proteomic level, is severely hampered by the lack of adequate in situ data. Skin microdialysis samples from patients with atopic dermatitis (AD, n=6), psoriasis vulgaris (PSO, n=7) or prurigo nodularis (PN, n=6), as well as healthy controls (n=7) were subjected to proteomics and multiplex cytokine analysis. Single-cell RNA sequencing of skin biopsy specimens was used to identify the cellular origin of cytokines. Among the top 20 enriched GO annotations, NAD metabolic process, regulation of secretion by cell, and pyruvate metabolic process were elevated in microdialysates from lesional AD skin compared with both nonlesional skin and controls. The top 20 enriched KEGG pathways in these three groups overlapped almost completely. In contrast, nonlesional skin from patients with PSO or PN and control skin showed no overlap with lesional skin in this KEGG pathway analysis. Lesional skin from patients with PSO, but not AD or PN, showed significantly elevated protein levels of IL-22 and MCP-1 compared to nonlesional skin. IL-8 was elevated in lesional vs nonlesional AD and PSO skin, whereas IL-12p40 was higher only in lesional PSO skin. Integrated single-cell RNA-seq data revealed identical cellular sources of these cytokines in AD, PSO and PN. Based on microdialysate, proteomic data of lesional PSO and PN skin, but not lesional AD skin, differed significantly from those of nonlesional skin. IL-8, IL-22, MCP-1 and IL-12p40 might be suitable markers for minimally invasive molecular profiling.
2024-08-22 | PXD050245 | Pride
Project description:Canine atopic dermatitis (AD) is clinically similar to human AD, implicating it as a useful model of human eosinophilic allergic disease. To identify cutaneous gene transcription changes in relatively early inflammation of canine AD, microarrays were used to monitor transcription in normal skin (n=13) and in acute lesional AD (ALAD) and nearby visibly nonlesional AD (NLAD) skin (n=13) from dogs. Scanning the putative abnormally-transcribed genes, several potentially relevant genes, some abnormally transcribed in both NLAD and ALAD (e.g. IL6, NFAM1, MSRA, and SYK), were observed. Comparison for abnormally-transcribed genes common to two related human diseases, human AD and asthmatic chronic rhinosinusitis with nasal polyps (aCRSwNP), further identified genes or gene sets likely relevant to eosinophilic allergic inflammation. These included 1) genes associated with alternatively-activated monocyte-derived cells, including members of the monocyte chemotactic protein (MCP) gene cluster, 2) members of the IL1 family gene cluster, 3) eosinophil-associated seven transmembrane receptor EMR1 and EMR3 genes, 4) interferon-inducible genes, and 5) keratin genes associated with hair and nail formation. Overall, numerous abnormally-transcribed genes were observed only in canine AD; however, many others are common to related human eosinophilic allergic diseases and represent therapeutic targets testable in dogs with AD. Total RNA from skin biopsy specimens from 13 Healthy (i.e. Normal) dogs were compared to total RNA from acute lesional skin biopsy specimens (i.e. ALAD) and nearby visibly nonlesional skin biopsy specimens (i.e. NLAD) from 13 dogs with atopic dermatitis.
2012-07-11 | E-GEOD-39278 | biostudies-arrayexpress
Project description:Atopic dermatitis (AD) is a common pruritic dermatitis with macroscopically nonlesional skin that is often abnormal. Therefore, we used high-density oligonucleotide arrays to identify cutaneous gene transcription changes associated with early AD inflammation as potential disease control targets. Skin biopsy specimens analyzed included normal skin from five healthy nonatopic adults and both minimally lesional skin and nearby or contralateral nonlesional skin from six adult AD patients. Keywords: disease state analysis
2006-10-01 | GSE5667 | GEO
Project description:After 2 and 12 weeks of treatment, we observed significant reductions of 51% and 72%, respectively, in SCORAD scores. Clinical improvements were associated with significant gene expression changes in lesional but also nonlesional skin, particularly reductions in levels of TH2-, TH22-, and some TH17-related molecules (ie, IL-13, IL-22, CCL17, S100As, and elafin/peptidase inhibitor 3), and modulation of epidermal hyperplasia and differentiation measures. Cyclosporine A (CsA)'s effects on AD skin pathology were evaluated by using gene expression and immunohistochemistry studies in baseline, week 2, and week 12 lesional and nonlesional biopsy specimens from 19 patients treated with 5 mg/kg/day CsA for 12 weeks.
2014-06-17 | E-GEOD-58558 | biostudies-arrayexpress
Project description:Atopic Dermatitis (AD) is the most common inflammatory skin disease and characterized by a deficient epidermal barrier and cutaneous inflammation. Genetic studies suggest a key role of keratinocytes in AD pathogenesis, but the alterations in the proteome that occur in the entire epidermis have not been defined. Employing a pressure-cycling technology-data-independent acquisition (PCT-DIA) approach, we performed quantitative proteomics of epidermis from healthy volunteers and lesional and non-lesional skin of AD patients. Results were validated by targeted proteomics using parallel reaction monitoring mass spectrometry or by immunofluorescence staining. The identified proteins reflect the strong inflammation in lesional skin and the defect in keratinocyte differentiation and epidermal stratification. Most importantly, they reveal impaired activation of the NRF2-antioxidant pathway and reduced abundance of mitochondrial proteins involved in key metabolic pathways in the epidermis. These results provide insight into the molecular alterations in the epidermis of AD patients and identify novel targets for pharmaceutical intervention.
2022-10-04 | PXD025431 | Pride
Project description:Atopic dermatitis (AD) is a common inflammatory skin disease with underlying defects in epidermal function and immune responses. The goal of this study was to investigate differences in gene expression in lesional skin from patients with mild extrinsic or intrinsic AD compared to skin from healthy controls and from lesional psoriasis skin. The aim was to identify differentially expressed genes involved in skin barrier formation and inflammation, and to compare our results with those reported for patients with moderate and severe AD. A total of 31 samples were analyzed: 8 healthy skin, 9 psoriatic plaques, 4 extrinsic AD lesional skin, 10 intrinsic AD lesional skin.
2016-03-08 | E-GEOD-75890 | biostudies-arrayexpress
Project description:Background: Dupilumab is an IL-4 receptor a mAb inhibiting signaling of IL-4 and IL-13, key drivers of type 2-driven inflammation, as demonstrated by its efficacy in patients with atopic/allergic diseases. Objective: This placebo-controlled, double-blind trial (NCT01979016) evaluated the efficacy, safety, and effects of dupilumab on molecular/cellular lesional and nonlesional skin phenotypes and systemic type 2 biomarkers of patients with moderate-to-severe atopic dermatitis (AD). Methods: Skin biopsy specimens and blood were evaluated from 54 patients randomized 1:1 to weekly subcutaneous doses of 200 mg of dupilumab or placebo for 16 weeks. Results: Dupilumab (vs placebo) significantly improved clinical signs and symptoms of AD, was well tolerated, and progressively shifted the lesional transcriptome toward a nonlesional phenotype (weeks 4-16). Mean improvements in a meta-analysis-derived AD transcriptome (genes differentially expressed between lesional and nonlesional skin) were 68.8% and 110.8% with dupilumab and 210.5% and 55.0% with placebo (weeks 4 and 16, respectively; P < .001). Dupilumab significantly reduced expression of genes involved in type 2 inflammation (IL13, IL31, CCL17, CCL18, and CCL26), epidermal hyperplasia (keratin 16 [K16] and MKi67), T cells, dendritic cells (ICOS, CD11c, and CTLA4), and Th17/Th22 activity (IL17A, IL-22, and S100As) and concurrently increased expression of epidermal differentiation, barrier, and lipid metabolism genes (filaggrin [FLG], loricrin [LOR], claudins, and ELOVL3). Dupilumab reduced lesional epidermal thickness versus placebo (week 4, P 5 .001; week 16, P 5 .0002). Improvements in clinical and histologic measures correlated significantly with modulation of gene expression. Dupilumab also significantly suppressed type 2 serum biomarkers, including CCL17, CCL18, periostin, and total and allergen- specific IgEs. Conclusion: Dupilumab-mediated inhibition of IL-4/IL-13 signaling through IL-4 receptor a blockade significantly and progressively improved disease activity, suppressed cellular/ molecular cutaneous markers of inflammation and systemic measures of type 2 inflammation, and reversed AD-associated epidermal abnormalities. (J Allergy Clin Immunol 2019;143:155-72.)
2019-05-02 | GSE130588 | GEO
Project description:The molecular signature of atopic dermatitis (AD) lesions is associated with TH2 and TH22 activation and epidermal alterations. However, the epidermal and dermal AD transcriptomes and their respective contributions to abnormalities in respective immune and barrier phenotypes are unknown.We sought to establish the genomic profile of the epidermal and dermal compartments of lesional and nonlesional AD skin compared with normal skin.Laser capture microdissection was performed to separate the epidermis and dermis of lesional and nonlesional skin from patients with AD and normal skin from healthy volunteers, followed by gene expression (microarrays and real-time PCR) and immunostaining studies.Our study identified novel immune and barrier genes, including the IL-34 cytokine and claudins 4 and 8, and showed increased detection of key AD genes usually undetectable on arrays (ie, IL22, thymic stromal lymphopoietin [TSLP], CCL22, and CCL26). Overall, the combined epidermal and dermal transcriptomes enlarged the AD transcriptome, adding 674 upregulated and 405 downregulated differentially expressed genes between lesional and nonlesional skin to the AD transcriptome. We were also able to localize individual transcripts as primarily epidermal (defensin, beta 4A [DEFB4A]) or dermal (IL22, cytotoxic T-lymphocyte antigen 4 [CTLA4], and CCR7) and link their expressions to possible cellular sources.This is the first report that establishes robust epidermal and dermal genomic signatures of lesional and nonlesional AD skin and normal skin compared with whole tissues. These data establish the utility of laser capture microdissection to separate different compartments and cellular subsets in patients with AD, allowing localization of key barrier or immune molecules and enabling detection of gene products usually not detected on arrays.
| S-EPMC4452382 | biostudies-literature
Project description:Canine atopic dermatitis (AD) is clinically similar to human AD, implicating it as a useful model of human eosinophilic allergic disease. To identify cutaneous gene transcription changes in relatively early inflammation of canine AD, microarrays were used to monitor transcription in normal skin (n=13) and in acute lesional AD (ALAD) and nearby visibly nonlesional AD (NLAD) skin (n=13) from dogs. Scanning the putative abnormally-transcribed genes, several potentially relevant genes, some abnormally transcribed in both NLAD and ALAD (e.g. IL6, NFAM1, MSRA, and SYK), were observed. Comparison for abnormally-transcribed genes common to two related human diseases, human AD and asthmatic chronic rhinosinusitis with nasal polyps (aCRSwNP), further identified genes or gene sets likely relevant to eosinophilic allergic inflammation. These included 1) genes associated with alternatively-activated monocyte-derived cells, including members of the monocyte chemotactic protein (MCP) gene cluster, 2) members of the IL1 family gene cluster, 3) eosinophil-associated seven transmembrane receptor EMR1 and EMR3 genes, 4) interferon-inducible genes, and 5) keratin genes associated with hair and nail formation. Overall, numerous abnormally-transcribed genes were observed only in canine AD; however, many others are common to related human eosinophilic allergic diseases and represent therapeutic targets testable in dogs with AD.
2012-07-12 | GSE39278 | GEO
Project description:Purpose: To determine the transcriptional differences between lesional skin and nonlesional skin from patients with atopic dermatitis Methods: Skin biopsies of lesional and non-lesional sites on atopic dermatitis patients were obtained and stored in RNA Later. Ribosomal RNA was removed and cDNA was generated with the SMARTer kit (CloneTech) with 10 ng of total RNA per sample. Samples were sequenced to an average depth of 34 million 1x50 reads on a HiSeq3000 (Illumina). Reads were aligned to Ensembl release 76 using STAR, gene counts were determined with Subread:featureCount, and sequence performance was assessed with RSeQC.
2019-11-13 | GSE140227 | GEO