Project description:Background: Atopic eczema (AE) is a common chronic inflammatory skin disorder. In order to dissect the genetic background several linkage and genetic association studies have been performed. Yet very little is known about specific genes involved in this complex skin disease, and the underlying molecular mechanisms are not fully understood. Results: We used human DNA microarrays to identify a molecular picture of the programmed responses of the human genome to AE. The transcriptional program was analyzed in skin biopsy samples from lesional and patch-tested skin from AE patients sensitized to Malassezia sympodialis (M. sympodialis), and corresponding biopsies from healthy individuals. The most notable feature of the global gene-expression pattern observed in AE skin was a reciprocal expression of induced inflammatory genes and repressed lipid metabolism genes. The overall transcriptional response in M. sympodialis patch-tested AE skin was similar to the gene-expression signature identified in lesional AE skin. In the constellation of genes differentially expressed in AE skin compared to healthy control skin, we have identified several potential susceptibility genes that may play a critical role in the pathological condition of AE. Many of these genes, including genes with a role in immune responses, lipid homeostasis, and epidermal differentiation, are localized on chromosomal regions previously linked to AE. Conclusion: Through genome-wide expression profiling, we were able to discover a distinct reciprocal expression pattern of induced inflammatory genes and repressed lipid metabolism genes in skin from AE patients. We found a significant enrichment of differentially expressed genes in AE with cytobands associated to the disease, and furthermore new chromosomal regions were found that could potentially guide future region-specific linkage mapping in AE. A disease state experiment design type is where the state of some disease such as infection, pathology, syndrome, etc is studied. Disease State: Skin biopsies from normal ('normal') and lesional and patch-tested ('leisonal') skin from Atopic eczema patients sensitized to Malassezia sympodialis Organism Part: location of skin biopsy Keywords: disease state analysis

Project description:Background: Atopic eczema (AE) is a common chronic inflammatory skin disorder. In order to dissect the genetic background several linkage and genetic association studies have been performed. Yet very little is known about specific genes involved in this complex skin disease, and the underlying molecular mechanisms are not fully understood. Results: We used human DNA microarrays to identify a molecular picture of the programmed responses of the human genome to AE. The transcriptional program was analyzed in skin biopsy samples from lesional and patch-tested skin from AE patients sensitized to Malassezia sympodialis (M. sympodialis), and corresponding biopsies from healthy individuals. The most notable feature of the global gene-expression pattern observed in AE skin was a reciprocal expression of induced inflammatory genes and repressed lipid metabolism genes. The overall transcriptional response in M. sympodialis patch-tested AE skin was similar to the gene-expression signature identified in lesional AE skin. In the constellation of genes differentially expressed in AE skin compared to healthy control skin, we have identified several potential susceptibility genes that may play a critical role in the pathological condition of AE. Many of these genes, including genes with a role in immune responses, lipid homeostasis, and epidermal differentiation, are localized on chromosomal regions previously linked to AE. Conclusion: Through genome-wide expression profiling, we were able to discover a distinct reciprocal expression pattern of induced inflammatory genes and repressed lipid metabolism genes in skin from AE patients. We found a significant enrichment of differentially expressed genes in AE with cytobands associated to the disease, and furthermore new chromosomal regions were found that could potentially guide future region-specific linkage mapping in AE. A disease state experiment design type is where the state of some disease such as infection, pathology, syndrome, etc is studied. Disease State: Skin biopsies from normal ('normal') and lesional and patch-tested ('leisonal') skin from Atopic eczema patients sensitized to Malassezia sympodialis Organism Part: location of skin biopsy Keywords: disease state analysis Computed

Project description:BackgroundAtopic eczema (AE) is characterized by skin barrier and immune dysfunction. Null mutations in filaggrin (FLG), a key epidermal barrier protein, strongly predispose to AE; however, the precise role of FLG deficiency in AE pathogenesis remains incompletely understood.ObjectivesWe sought to identify global proteomic changes downstream of FLG deficiency in human epidermal living skin-equivalent (LSE) models and validate findings in skin of patients with AE.MethodsDifferentially expressed proteins from paired control (nontargeting control short hairpin RNA [shNT]) and FLG knockdown (FLG knockdown short hairpin RNA [shFLG]) LSEs were identified by means of proteomic analysis (liquid chromatography-mass spectrometry) and Ingenuity Pathway Analysis. Expression of key targets was validated in independent LSE samples (quantitative RT-PCR and Western blotting) and in normal and AE skin biopsy specimens (immunofluorescence).ResultsProteomic analysis identified 17 (P ≤ .05) differentially expressed proteins after FLG knockdown, including kallikrein-7 (KLK7; 2.2-fold), cyclophilin A (PPIA; 0.9-fold), and cofilin-1 (CFL1, 1.3-fold). Differential protein expression was confirmed in shNT/shFLG LSEs; however, only KLK7 was transcriptionally dysregulated. Molecular pathways overrepresented after FLG knockdown included inflammation, protease activity, cell structure, and stress. Furthermore, KLK7 (1.8-fold) and PPIA (0.65-fold) proteins were differentially expressed in lesional biopsy specimens from patients with AE relative to normal skin.ConclusionsFor the first time, we show that loss of FLG in the absence of inflammation is sufficient to alter the expression level of proteins relevant to the pathogenesis of AE. These include proteins regulating inflammatory, proteolytic, and cytoskeletal functions. We identify PPIA as a novel protein with levels that are decreased in clinically active AE skin and show that the characteristic upregulation of KLK7 expression in patients with AE occurs downstream of FLG loss. Importantly, we highlight disconnect between the epidermal proteome and transcriptome, emphasizing the utility of global proteomic studies.

Project description:ImportancePrevious studies report both coexistence and mutual exclusivity of atopic eczema (AE) and psoriasis, but these have not been appraised systematically. Knowledge of such disease association throws light on disease mechanisms and may influence therapeutic choices.ObjectiveTo summarise evidence for AE and psoriasis occurring in the same person at the same point in time. Planned primary outcome was the incidence, prevalence or risk of psoriasis or eczema.MethodsOvid MEDLINE and Ovid Embase were searched from inception to 1st February 2020. The search strategy was built around the key terms 'atopic eczema', 'psoriasis' and 'co-existence'. Observational studies (cohort, case-control, cross-sectional and case-series) with a minimum of 10 consecutive patients were included. There were no restrictions on participants, geography or language. Studies were selected, data extracted and critically appraised by two independent reviewers. Data were extracted on the method of diagnosis: health professional (dermatologist, criteria, other), self-reported, not specified. Study quality was assessed using validated Joanna Brigg's Institute critical appraisal tools. A random-effects model was used to combine studies. The effect of study quality on the pooled estimate was investigated using stratification. Heterogeneity was explored by subgroup analysis.ResultsThis review included 31 studies and 20 523 individuals with psoriasis and 1 405 911 with AE. Eight studies reported the prevalence of AE in those with psoriasis and values ranged from 0.17% to 20%: the pooled prevalence was 2% (95% confidence interval [CI]: 1, 3). Seven studies reported the prevalence of psoriasis in those with AE and values ranged from 0.3% to 12.6%; the pooled prevalence was 2% (95% CI: 1, 3). Ten studies were assessed as low risk of bias. Geographical area, method of diagnosis, setting and whether the assessment of diagnosis was blinded, partly contributed to the heterogeneity.ConclusionsThis review provides some evidence for the coexistence of AE and psoriasis. Clinicians should be aware of coexistence at diagnosis, when selecting therapies and when reviewing poor response to treatment.

Dataset Information

Atopic Eczema: Genetic Analysis of COL6A5, COL8A1, and COL10A1 in Mediterranean Populations.

Publications

Atopic Eczema: Genetic Analysis of <i>COL6A5</i>, <i>COL8A1</i>, and <i>COL10A1</i> in Mediterranean Populations.

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