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      Interferon and Biologic Signatures in Dermatomyositis Skin: Specificity and Heterogeneity across Diseases

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          Abstract

          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 g, 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.

          Conclusions and Significance

          As in the blood and muscle, DM skin is characterized by an overwhelming presence of an IFN signature, although it is difficult to conclusively define this response as type I or type II. Understanding the significance of the IFN signature in this wide array of inflammatory diseases will be furthered by identification of the nature of the cells that both produce and respond to IFN, as well as which IFN subtype is biologically active in each diseased tissue.

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          Most cited references25

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          Identification of genes differentially regulated by interferon alpha, beta, or gamma using oligonucleotide arrays.

          The pleiotropic activities of interferons (IFNs) are mediated primarily through the transcriptional regulation of many downstream effector genes. The mRNA profiles from IFN-alpha, -beta, or -gamma treatments of the human fibrosarcoma cell line, HT1080, were determined by using oligonucleotide arrays with probe sets corresponding to more than 6,800 human genes. Among these were transcripts for known IFN-stimulated genes (ISGs), the expression of which were consistent with previous studies in which the particular ISG was characterized as responsive to either Type I (alpha, beta) or Type II (gamma) IFNs, or both. Importantly, many novel IFN-stimulated genes were identified that were diverse in their known biological functions. For instance, several novel ISGs were identified that are implicated in apoptosis (including RAP46/Bag-1, phospholipid scramblase, and hypoxia inducible factor-1alpha). Furthermore, several IFN-repressed genes also were identified. These results demonstrate the usefulness of oligonucleotide arrays in monitoring mammalian gene expression on a broad and unprecedented scale. In particular, these findings provide insights into the basic mechanisms of IFN actions and ultimately may contribute to better therapeutic uses for IFNs.
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            Type I interferon-inducible gene expression in blood is present and reflects disease activity in dermatomyositis and polymyositis.

            To apply gene expression profiling to the study of peripheral blood mononuclear cells from patients with inflammatory myopathies, in order to provide insight into disease pathogenesis and identify potential biomarkers associated with disease activity. We used Affymetrix whole-genome microarrays to measure the expression of approximately 38,500 genes in 65 blood and 15 muscle samples from 44 patients with dermatomyositis (DM), polymyositis (PM), inclusion body myositis (IBM), myasthenia gravis, or genetically determined myopathies and from 12 healthy volunteers. In 9 patients, 2 samples were obtained at different time points, when disease was either active or improving, and these paired blood samples were also compared. Bioinformatics techniques were used to identify genes with significant differential expression among diagnostic categories and in relation to disease activity. We corroborated the microarray data with quantitative real-time reverse transcriptase-polymerase chain reaction. Most patients with active DM or PM, but not patients with IBM, had significant and high up-regulation of the type I interferon-alpha/beta (IFNalpha/beta)-inducible genes in blood. Furthermore, the up-regulation of these genes correlated with disease activity in DM and PM, with down-regulation occurring when disease was controlled with treatment. DM and PM are diseases characterized by the systemic overexpression of IFNalpha/beta-inducible genes. The magnitude of the overexpression of these genes is higher in DM and correlates with disease activity in both disorders. Although PM and IBM have been modeled as having similar immunologic processes occurring within muscle, there are substantial differences in the expression of IFNalpha/beta-inducible genes in blood in these diseases.
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              Assessment of the psoriatic transcriptome in a large sample: additional regulated genes and comparisons with in vitro models.

              To further elucidate molecular alterations in psoriasis, we performed a gene expression study of 58 paired lesional and uninvolved psoriatic and 64 control skin samples. Comparison of involved psoriatic (PP) and normal (NN) skin identified 1,326 differentially regulated transcripts encoding 918 unique genes (549 up- and 369 downregulated), of which over 600 are to our knowledge previously unreported, including S100A7A, THRSP, and ELOVL3. Strongly upregulated genes included SERPINB4, PI3, DEFB4, and several S100-family members. Strongly downregulated genes included Wnt-inhibitory factor-1 (WIF1), beta-cellulin (BTC), and CCL27. Enriched gene ontology categories included immune response, defense response, and keratinocyte differentiation. Biological processes regulating fatty acid and lipid metabolism were enriched in the down-regulated gene set. Comparison of the psoriatic transcriptome to the transcriptomes of cytokine-stimulated cultured keratinocytes (IL-17, IL-22, IL-1alpha, IFN-gamma, TNF-alpha, and OSM) showed surprisingly little overlap, with the cytokine-stimulated keratinocyte expression representing only 2.5, 0.7, 1.5, 5.6, 5.0, and 1.9% of the lesional psoriatic dysregulated transcriptome, respectively. This comprehensive analysis of differentially regulated transcripts in psoriasis provides additional insight into the pathogenic mechanisms involved and emphasizes the need for more complex yet tractable experimental models of psoriasis.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2012
                3 January 2012
                : 7
                : 1
                : e29161
                Affiliations
                [1 ]Department of Dermatology, Stanford University School of Medicine, Stanford, California, United States of America
                [2 ]Department of Biochemistry, Stanford University School of Medicine, Stanford, California, United States of America
                [3 ]MedImmune, Translational Sciences, One MedImmune Way, Gaithersburg, Maryland, United States of America
                University of Lyon, France
                Author notes

                Conceived and designed the experiments: DW BK DF. Performed the experiments: DW BK RP BH WZ DF. Analyzed the data: DW BK BH YY PB DF. Contributed reagents/materials/analysis tools: DW BK WZ YY PB DF. Wrote the paper: DW BK DF.

                Article
                PONE-D-11-10904
                10.1371/journal.pone.0029161
                3250414
                22235269
                a045d0dc-10bb-4698-9d4b-cf18e460b519
                Wong et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
                History
                : 15 June 2011
                : 22 November 2011
                Page count
                Pages: 14
                Categories
                Research Article
                Biology
                Anatomy and Physiology
                Immune Physiology
                Computational Biology
                Developmental Biology
                Molecular Development
                Genomics
                Immunology
                Immune System
                Immunity
                Medicine
                Anatomy and Physiology
                Immune Physiology
                Clinical Immunology
                Autoimmune Diseases
                Immune System
                Dermatology

                Uncategorized
                Uncategorized

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