Project description:Morphea is an inflammatory disorder of the skin and soft tissue characterized by fibrosis that has been likened to systemic sclerosis (SSc). We sought to capture the molecular heterogeneity of morphea by examining lesional skin gene expression and blood biomarkers, and compare the gene expression profiles with those from SSc lesional and site matched non lesional skin, as well as sera obtained from adult patients with untreated morphea. We found the morphea transcriptome is dominated by IFNg-mediated Th1 immune dysregulation, with relative paucity of pathways associated with fibrosis. These results were mirrored when morphea gene expression profiles were compared with SSc. Interestingly, expression profiles of morphea skin samples clustered with the SSc inflammatory subset and distinct from the SSc fibro-proliferative subset. Unaffected morphea skin also differed from unaffected SSc skin in that it did not exhibit pathological gene expression signatures. Examination of downstream IFNg-mediated chemokines, CXCL9 and CXCL10, revealed increased transcription in the skin but not in sera. While elevated serum CXCL9 proteins quantified by ELISA were associated with active disease and widespread cutaneous disease. Taken together, these results indicate that inflammatory and sclerotic morphea is a skin directed process characterized by Th1 immune mediated dysregulation, which contrasts with fibrotic signatures and systemic transcriptional changes associated with SSc. The association of circulating CXCL9 concentration with clinical activity and burden of skin disease supports its potential as a readily accessible biomarker.
Project description:To explore the psoriasis phenotype and pathways involved in psoriasis, we characterized gene expression in lesional and non-lesional skin from psoriasis patients. Furthermore, we explored the effects of various doses of brodalumab on lesional skin over time. From each of the 25 psoriasis patients, we obtained two pre-dose biopsies, one from a lesion and the other from non-lesional skin in the same general body geography, and two post-dose biopsies. Total RNA was extracted from 6mm punch biopsies that were split in half. A total of 99 samples were run on Affymetrix HU133 Plus 2.0 microarrays. There was no paired non-lesional sample for 'T_lesional_pre-dose' (skn55789).
Project description:Background: Plaque psoriasis is a chronic autoimmune disorder characterized by the development of red scaly plaques. To date psoriasis lesional skin transcriptome has been extensively studied, whereas only few proteomic studies of psoriatic skin are available. Aim: The aim of this study was to compare protein expression patterns of lesional and normally looking skin of psoriasis patients with skin of the healthy volunteers, reveal differentially expressed proteins and identify changes in cell metabolism caused by the disease. Methods: Skin samples of normally looking and lesional skin donated by psoriasis patients (n = 5) and samples of healthy skin donated by volunteers (n = 5) were analyzed by liquid chromatography-tandem mass spectrometry (LC-MS/MS). After protein identification and data processing, the set of differentially expressed proteins was subjected to protein ontology analysis to characterize changes in biological processes, cell components and molecular functions in the patients' skin compared to skin of the healthy volunteers. Results: The performed analysis identified 405 and 59 differentially expressed proteins in lesional and normally looking psoriatic skin compared to healthy control. We discovered decreased expression of KNG1, APOE, HRG, THBS1 and PLG in normally looking skin of the patients. Presumably, these changes were needed to protect the epidermis from spontaneous activation of kallikrein-kinin system and delay the following development of inflammatory response. In lesional skin, we identified several large groups of proteins with coordinated expression. Mainly, these proteins were involved in different aspects of protein and RNA metabolism, namely ATP synthesis and consumption; intracellular trafficking of membrane-bound vesicles, pre-RNA processing, translation, chaperoning and degradation in proteasomes/immunoproteasomes. Conclusion: Our findings explain the molecular basis of metabolic changes caused by disease in skin lesions, such as faster cell turnover and higher metabolic rate. They also indicate on downregulation of kallikrein-kinin system in normally looking skin of the patients that would be needed to delay exacerbation of the disease.
Project description:To explore the psoriasis phenotype and pathways involved in psoriasis, we characterized gene expression in lesional and non-lesional skin from psoriasis patients. Furthermore, we explored the effects of various doses of brodalumab on lesional skin over time.
Project description:To explore the psoriasis phenotype, we characterize gene expression in lesional and non-lesional skin from psoriasis patients. We extracted total RNA from 5mm punch biopsies taken from 14 psoriatic patients. From each patient, we obtained two biopsies, one from a lesion and the other from non-lesional skin in the same general body geography. A total of 28 samples were run on Affymetrix HU133 Plus 2.0 microarrays.