Fiorentino 2006-7 dermatomyositis, lupus, control skin
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE32245 | GEO | 2012/01/12
SECONDARY ACCESSION(S): PRJNA147367
REPOSITORIES: GEO
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Project description:Background: Dermatomyositis (DM) is an autoimmune disease that mainly affects the skin, muscle, and lung. The pathogenesis of skin inflammation in DM is not well understood. Methodology and Findings: We analyzed genome-wide expression data in DM skin and compared them to those from healthy controls. We observed a robust upregulation of interferon (IFN)-inducible genes in DM skin, as well as several other gene modules pertaining to inflammation, complement activation, and epidermal activation and differentiation. The interferon (IFN)-inducible genes within the DM signature were present not only in DM and lupus, but also cutaneous herpes simplex-2 infection and to a lesser degree, psoriasis. This IFN signature was absent or weakly present in atopic dermatitis, allergic contact dermatitis, acne vulgaris, systemic sclerosis, and localized scleroderma/morphea. We observed that the IFN signature in DM skin appears to be more closely related to type I than type II IFN based on in vitro IFN stimulation expression signatures. However, quantitation of IFN mRNAs in DM skin shows that the majority of known type I IFNs, as well as IFN gamma, are overexpressed in DM skin. In addition, both IFN-beta and IFN-gamma (but not other type I IFN) transcript levels were highly correlated with the degree of the in vivo IFN transcriptional response in DM skin. disease_state_design
2012-01-12 | E-GEOD-32245 | biostudies-arrayexpress
Project description:Dermatomyositis is a cutaneous and muscular auto-immune condition associated with specific autoantibodies. MDA5 antibody-associated DM has higher mortality. We demonstrate here for the first time using skin microarray analysis that MDA5+ DM is associated with a greater type I interferon skin signature than MDA5- DM, mainly involving the IFN- κ member produced by skin keratinocytes
2019-10-27 | GSE128314 | GEO
Project description:Ultraviolet (UV) radiation is a major melanoma risk factor, yet underlying mechanisms remain poorly understood. Here we introduce a mouse model permitting fluorescence-aided melanocyte imaging and isolation following in vivo UV irradiation. We use expression profiling to show that activated neonatal skin melanocytes isolated following a melanomagenic UVB dose bear a distinct, persistent interferon-response signature, including genes associated with immunoevasion. UVB-induced melanocyte activation, characterized by aberrant growth and migration, was abolished by antibody-mediated systemic blockade of interferon-gamma (IFN-gamma), but not type-I interferons. IFN-gamma was produced by macrophages recruited to neonatal skin by UVB-induced chemokine receptor Ccr2 ligands. Admixed recruited skin macrophages enhanced transplanted melanoma growth by inhibiting apoptosis; notably, IFN-gamma blockade abolished macrophage-associated melanoma growth and survival. IFN-gamma-producing macrophages were identified in 70% of human melanomas examined. Our data reveal an unanticipated role for IFN-gamma in promoting melanocytic cell survival/immunoevasion, and suggest IFN-gamma-R signaling represents a novel therapeutic melanoma target. Biologic replicates of UVA- and UVB-treated mouse melanocytes, as well as untreated mouse melanocytes and mouse keratinocytes, were used to define melanocyte expression signatures associated with UV treatment.
2011-01-01 | E-GEOD-25164 | biostudies-arrayexpress
Project description:Ultraviolet (UV) radiation is a major melanoma risk factor, yet underlying mechanisms remain poorly understood. Here we introduce a mouse model permitting fluorescence-aided melanocyte imaging and isolation following in vivo UV irradiation. We use expression profiling to show that activated neonatal skin melanocytes isolated following a melanomagenic UVB dose bear a distinct, persistent interferon-response signature, including genes associated with immunoevasion. UVB-induced melanocyte activation, characterized by aberrant growth and migration, was abolished by antibody-mediated systemic blockade of interferon-gamma (IFN-gamma), but not type-I interferons. IFN-gamma was produced by macrophages recruited to neonatal skin by UVB-induced chemokine receptor Ccr2 ligands. Admixed recruited skin macrophages enhanced transplanted melanoma growth by inhibiting apoptosis; notably, IFN-gamma blockade abolished macrophage-associated melanoma growth and survival. IFN-gamma-producing macrophages were identified in 70% of human melanomas examined. Our data reveal an unanticipated role for IFN-gamma in promoting melanocytic cell survival/immunoevasion, and suggest IFN-gamma-R signaling represents a novel therapeutic melanoma target.
2011-01-01 | GSE25164 | GEO
Project description:Psoriasis is a chronic, debilitating, immune-mediated inflammatory skin disease. As IFN-gamma is involved in many cellular processes, including activation of T cells and dendritic cells (DCs), antigen processing and presentation, cell adhesion and trafficking, and cytokine and chemokine production, IFN-gamma-producing Th1 cells were proposed to be integral to the pathogenesis of psoriasis. Recently, IFN-gamma was shown to enhance IL-23 and IL-1 production by DCs and subsequently induce Th17 cells, important contributors to the inflammatory cascade in psoriasis lesions. To determine if IFN-gamma indeed induces the pathways leading to the development of psoriasis lesions, a single intradermal injection of IFN-gamma was administered to an area of clinically normal, non-lesional skin of psoriasis patients and biopsies were collected 24 hours later. Although there were no visible changes in the skin, IFN-gamma induced molecular and histological features characteristic of psoriasis lesions. IFN-gamma increased a number of differentially expressed genes in the skin, including many chemokines concomitant with an influx of T cells and inflammatory DCs. Furthermore, inflammatory DC products TNF, iNOS, IL-23, and TRAIL were present in IFN-gamma-treated skin. Thus, IFN-gamma, which is significantly elevated in non-lesional skin compared to healthy skin, appears to be a key pathogenic cytokine that can induce the inflammatory cascade in psoriasis. RNA was isolated from whole skin punch biopsies of either healthy or non-lesional psoraisis patients at baseline or 24 hours after placebo or IFN-g injection.
2011-11-30 | E-GEOD-32407 | biostudies-arrayexpress
Project description:The immune mechanisms that control resistance vs. susceptibility to mycobacterial infection in humans were investigated by studying leprosy skin lesions, the site where the battle between the host and the pathogen is joined. Using an integrative genomics approach, we found an inverse correlation between of IFN-beta and IFN-gamma gene expression programs at the site of disease. The Type II IFN, IFN-gamma and its downstream vitamin D-dependent antimicrobial genes were preferentially expressed in the lesions from patients with the self-healing tuberculoid form of the disease and mediated antimicrobial activity against the pathogen, Mycobacterium leprae in vitro. In contrast, the Type I IFN, IFN-beta and its downstream genes, including IL-27 and IL-10, were induced in monocytes by M. leprae in vitro, and were preferentially expressed in the lesions of disseminated and progressive lepromatous form. The IFN-gamma induced macrophage antimicrobial response was inhibited by IFN-beta/IL-10, by a mechanism involving blocking the generation of bioactive 1,25-dihyroxy vitamin D as well as inhibiting induction of antimicrobial peptides cathelicidin and DEFB4. The ability of IFN-B to inhibit the IFN-gamma induced vitamin D pathway including antimicrobial activity was reversed by neutralization of IL-10, suggesting a possible target for therapeutic intervention. Finally, a common IFN-beta and IL-10 gene signature was identified in both the skin lesions of leprosy patients and in the peripheral blood of active tuberculosis patients. Together these data suggest that the ability of IFN-beta to downregulate protective IFN-gamma responses provides one general mechanism by which some bacterial pathogens of humans evade protective host responses and contribute to pathogenesis.
2013-03-05 | GSE43700 | GEO
Project description:Psoriasis is a chronic, debilitating, immune-mediated inflammatory skin disease. As IFN-γ is involved in many cellular processes, including activation of T cells and dendritic cells (DCs), antigen processing and presentation, cell adhesion and trafficking, and cytokine and chemokine production, IFN-γ-producing Th1 cells were proposed to be integral to the pathogenesis of psoriasis. Recently, IFN-γ was shown to enhance IL-23 and IL-1 production by DCs and subsequently induce Th17 cells, important contributors to the inflammatory cascade in psoriasis lesions. To determine if IFN-γ indeed induces the pathways leading to the development of psoriasis lesions, a single intradermal injection of IFN-γ was administered to an area of clinically normal, non-lesional skin of psoriasis patients and biopsies were collected 24 hours later. Although there were no visible changes in the skin, IFN-γ induced molecular and histological features characteristic of psoriasis lesions. IFN-γ increased a number of differentially expressed genes in the skin, including many chemokines concomitant with an influx of T cells and inflammatory DCs. Furthermore, inflammatory DC products TNF, iNOS, IL-23, and TRAIL were present in IFN-γ-treated skin. Thus, IFN-γ, which is significantly elevated in non-lesional skin compared to healthy skin, appears to be a key pathogenic cytokine that can induce the inflammatory cascade in psoriasis.
2011-11-30 | GSE32407 | GEO
Project description:Immune checkpoint blockade (ICB) is therapeutically successful in multiple cancer types. However, immune-related adverse events (irAE) frequently occur and can sometimes be life-threatening. It is critical to understand the immunologic mechanisms of irAEs with the goal of finding novel treatment targets. Therefore, we studied tissues from irAE dermatitis cases using multiparameter immunofluorescence (IF), spatial transcriptomics, and RNA in situ hybridization. Skin psoriasis cases were studied as a comparison, as a known Th17-driven disease, and colitis was investigated as a comparison. IF analysis revealed that CD4+ and CD8+ tissue resident memory T (TRM) cells were preferentially expanded in the inflamed portion of skin in cutaneous irAEs compared to healthy skin controls. Spatial transcriptomics allowed focusing attention on areas containing TRM cells to discern their functional phenotype, and revealed expression of Th1-associated genes in irAE, compared to Th17-asociated genes in psoriasis. Expression of a range of inhibitory checkpoint molecules was observed, including PD-1, CTLA-4, LAG-3, and TIGIT. RNA in situ hybridization (RISH) technology combined with IF confirmed expression of IFN-γ, CXCL9, CXCL10, and TNF-α in additional irAE dermatitis cases and allowed us to identify production of IFN-γ within TRM cells specifically. The Th1-skewed phenotype was confirmed in irAE colitis cases compared to healthy colon.
2022-08-08 | GSE210037 | GEO
Project description:The immune mechanisms that control resistance vs. susceptibility to mycobacterial infection in humans were investigated by studying leprosy skin lesions, the site where the battle between the host and the pathogen is joined. Using an integrative genomics approach, we found an inverse correlation between of IFN-beta and IFN-gamma gene expression programs at the site of disease. The Type II IFN, IFN-gamma and its downstream vitamin D-dependent antimicrobial genes were preferentially expressed in the lesions from patients with the self-healing tuberculoid form of the disease and mediated antimicrobial activity against the pathogen, Mycobacterium leprae in vitro. In contrast, the Type I IFN, IFN-beta and its downstream genes, including IL-27 and IL-10, were induced in monocytes by M. leprae in vitro, and were preferentially expressed in the lesions of disseminated and progressive lepromatous form. The IFN-gamma induced macrophage antimicrobial response was inhibited by IFN-beta/IL-10, by a mechanism involving blocking the generation of bioactive 1,25-dihyroxy vitamin D as well as inhibiting induction of antimicrobial peptides cathelicidin and DEFB4. The ability of IFN-M-oM-^AM-" to inhibit the IFN-gamma induced vitamin D pathway including antimicrobial activity was reversed by neutralization of IL-10, suggesting a possible target for therapeutic intervention. Finally, a common IFN-beta and IL-10 gene signature was identified in both the skin lesions of leprosy patients and in the peripheral blood of active tuberculosis patients. Together these data suggest that the ability of IFN-beta to downregulate protective IFN-gamma responses provides one general mechanism by which some bacterial pathogens of humans evade protective host responses and contribute to pathogenesis. Peripheral blood monuclear cells derived through Ficoll-Hypaque from the blood of healthy human donors (n=4). Cells adhered to tissue culture treated 6-well plates for 2 hours in 1% Fetal Bovine Serum (FBS) RPMI and then stimulated by IL-10 (R&D Systems) 10ng/ml or media alone in 10% FBS RPMI for 24 hours at 37M-BM-0C, 5% CO2. After stimulation, cells harvested and monocytes isolated through CD14 positive selection (Miltenyi Biotec). RNA from purified monocytes extracted by Trizol and purified by Qiagen RNeasy Kit. RNA probe and microarray performed by UCLA Clinical Microarray Core using Ambion labeling kit and Affymetrix Human U133 Plus 2.0 array.
2013-03-05 | E-GEOD-43700 | biostudies-arrayexpress
Project description:An early and sustained clinical response was seen, with 83.3% of patients responsive at week 16. Our molecular data identified a unique, oligoclonal IFN-γ, CD8+, CXCL13+ cytotoxic T-cell population in LP skin and demonstrated a rapid decrease in IFN signature within 2 weeks of treatment, most prominently in the basal layer of the epidermis.
2024-12-14 | GSE280584 | GEO