Altered RIG-I/DDX58-mediated innate immunity in dermatomyositis
We investigated the molecular mechanisms involved in the pathogenesis of three inflammatory myopathies, dermatomyositis (DM), polymyositis (PM) and inclusion body myositis (IBM). We performed microarray experiments† using microdissected pathological muscle fibres from 15 patients with these disorder...
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| Veröffentlicht in: | The Journal of pathology 2014-07, Vol.233 (3), p.258-268 |
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| creator | Suárez-Calvet, Xavier Gallardo, Eduard Nogales-Gadea, Gisela Querol, Luis Navas, Miquel Díaz-Manera, Jordi Rojas-Garcia, Ricard Illa, Isabel |
| description | We investigated the molecular mechanisms involved in the pathogenesis of three inflammatory myopathies, dermatomyositis (DM), polymyositis (PM) and inclusion body myositis (IBM). We performed microarray experiments† using microdissected pathological muscle fibres from 15 patients with these disorders and five controls. Differentially expressed candidate genes were validated by immunohistochemistry on muscle biopsies, and the altered pathways were analysed in human myotube cultures. Up‐regulation of genes involved in viral and nucleic acid recognition were found in the three myopathies but not in controls. In DM, retinoic acid‐inducible gene 1 (RIG‐I, DDX58) and the novel antiviral factor DDX60, which promotes RIG‐I‐mediated signalling, were significantly up‐regulated, followed by IFIH1 (MDA5) and TLR3. Immunohistochemistry confirmed over‐expression of RIG‐I in pathological muscle fibres in 5/5 DM, 0/5 PM and 0/5 IBM patients, and in 0/5 controls. Stimulation of human myotubes with a ligand of RIG‐I produced a significant secretion of interferon‐β (IFNβ; p < 0.05) and up‐regulation of class I MHC, RIG‐I and TLR3 (p < 0.05) by IFNβ‐dependent and TLR3‐independent mechanisms. RIG‐I‐mediated innate immunity, triggered by a viral or damage signal, plays a significant role in the pathogenesis of DM, but not in that of PM or IBM. Copyright © 2014 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd |
| doi_str_mv | 10.1002/path.4346 |
| format | Article |
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We performed microarray experiments† using microdissected pathological muscle fibres from 15 patients with these disorders and five controls. Differentially expressed candidate genes were validated by immunohistochemistry on muscle biopsies, and the altered pathways were analysed in human myotube cultures. Up‐regulation of genes involved in viral and nucleic acid recognition were found in the three myopathies but not in controls. In DM, retinoic acid‐inducible gene 1 (RIG‐I, DDX58) and the novel antiviral factor DDX60, which promotes RIG‐I‐mediated signalling, were significantly up‐regulated, followed by IFIH1 (MDA5) and TLR3. Immunohistochemistry confirmed over‐expression of RIG‐I in pathological muscle fibres in 5/5 DM, 0/5 PM and 0/5 IBM patients, and in 0/5 controls. Stimulation of human myotubes with a ligand of RIG‐I produced a significant secretion of interferon‐β (IFNβ; p < 0.05) and up‐regulation of class I MHC, RIG‐I and TLR3 (p < 0.05) by IFNβ‐dependent and TLR3‐independent mechanisms. RIG‐I‐mediated innate immunity, triggered by a viral or damage signal, plays a significant role in the pathogenesis of DM, but not in that of PM or IBM. Copyright © 2014 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd</description><identifier>ISSN: 0022-3417</identifier><identifier>EISSN: 1096-9896</identifier><identifier>DOI: 10.1002/path.4346</identifier><identifier>PMID: 24604766</identifier><language>eng</language><publisher>Chichester, UK: John Wiley & Sons, Ltd</publisher><subject>Adult ; Aged ; Case-Control Studies ; Cells, Cultured ; DDX58 ; DEAD Box Protein 58 ; DEAD-box RNA Helicases - genetics ; DEAD-box RNA Helicases - metabolism ; dermatomyositis ; Dermatomyositis - genetics ; Dermatomyositis - immunology ; Dermatomyositis - metabolism ; Female ; Gene Expression Profiling - methods ; Gene Expression Regulation ; Genetic Association Studies ; Histocompatibility Antigens Class I - metabolism ; Humans ; Immunity, Innate ; Immunohistochemistry ; Inclusion Bodies - immunology ; Inclusion Bodies - metabolism ; inflammatory myopathy ; innate immunity ; Interferon-beta - metabolism ; Interferon-Induced Helicase, IFIH1 ; Male ; Microdissection ; Middle Aged ; Muscle Fibers, Skeletal - immunology ; Muscle Fibers, Skeletal - metabolism ; Oligonucleotide Array Sequence Analysis ; Polymyositis - genetics ; Polymyositis - immunology ; Polymyositis - metabolism ; Receptors, Immunologic ; RIG-I ; Signal Transduction ; Toll-Like Receptor 3 - genetics ; Toll-Like Receptor 3 - metabolism</subject><ispartof>The Journal of pathology, 2014-07, Vol.233 (3), p.258-268</ispartof><rights>Copyright © 2014 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd</rights><rights>Copyright © 2014 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4246-12487c9e88e64d93f1e3e7ccfd5492a971d6c638202da8a79c4be5baeff411073</citedby><cites>FETCH-LOGICAL-c4246-12487c9e88e64d93f1e3e7ccfd5492a971d6c638202da8a79c4be5baeff411073</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1002%2Fpath.4346$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1002%2Fpath.4346$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>315,781,785,1418,27928,27929,45578,45579</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24604766$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Suárez-Calvet, Xavier</creatorcontrib><creatorcontrib>Gallardo, Eduard</creatorcontrib><creatorcontrib>Nogales-Gadea, Gisela</creatorcontrib><creatorcontrib>Querol, Luis</creatorcontrib><creatorcontrib>Navas, Miquel</creatorcontrib><creatorcontrib>Díaz-Manera, Jordi</creatorcontrib><creatorcontrib>Rojas-Garcia, Ricard</creatorcontrib><creatorcontrib>Illa, Isabel</creatorcontrib><title>Altered RIG-I/DDX58-mediated innate immunity in dermatomyositis</title><title>The Journal of pathology</title><addtitle>J. Pathol</addtitle><description>We investigated the molecular mechanisms involved in the pathogenesis of three inflammatory myopathies, dermatomyositis (DM), polymyositis (PM) and inclusion body myositis (IBM). We performed microarray experiments† using microdissected pathological muscle fibres from 15 patients with these disorders and five controls. Differentially expressed candidate genes were validated by immunohistochemistry on muscle biopsies, and the altered pathways were analysed in human myotube cultures. Up‐regulation of genes involved in viral and nucleic acid recognition were found in the three myopathies but not in controls. In DM, retinoic acid‐inducible gene 1 (RIG‐I, DDX58) and the novel antiviral factor DDX60, which promotes RIG‐I‐mediated signalling, were significantly up‐regulated, followed by IFIH1 (MDA5) and TLR3. Immunohistochemistry confirmed over‐expression of RIG‐I in pathological muscle fibres in 5/5 DM, 0/5 PM and 0/5 IBM patients, and in 0/5 controls. Stimulation of human myotubes with a ligand of RIG‐I produced a significant secretion of interferon‐β (IFNβ; p < 0.05) and up‐regulation of class I MHC, RIG‐I and TLR3 (p < 0.05) by IFNβ‐dependent and TLR3‐independent mechanisms. RIG‐I‐mediated innate immunity, triggered by a viral or damage signal, plays a significant role in the pathogenesis of DM, but not in that of PM or IBM. Copyright © 2014 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd</description><subject>Adult</subject><subject>Aged</subject><subject>Case-Control Studies</subject><subject>Cells, Cultured</subject><subject>DDX58</subject><subject>DEAD Box Protein 58</subject><subject>DEAD-box RNA Helicases - genetics</subject><subject>DEAD-box RNA Helicases - metabolism</subject><subject>dermatomyositis</subject><subject>Dermatomyositis - genetics</subject><subject>Dermatomyositis - immunology</subject><subject>Dermatomyositis - metabolism</subject><subject>Female</subject><subject>Gene Expression Profiling - methods</subject><subject>Gene Expression Regulation</subject><subject>Genetic Association Studies</subject><subject>Histocompatibility Antigens Class I - metabolism</subject><subject>Humans</subject><subject>Immunity, Innate</subject><subject>Immunohistochemistry</subject><subject>Inclusion Bodies - immunology</subject><subject>Inclusion Bodies - metabolism</subject><subject>inflammatory myopathy</subject><subject>innate immunity</subject><subject>Interferon-beta - metabolism</subject><subject>Interferon-Induced Helicase, IFIH1</subject><subject>Male</subject><subject>Microdissection</subject><subject>Middle Aged</subject><subject>Muscle Fibers, Skeletal - immunology</subject><subject>Muscle Fibers, Skeletal - metabolism</subject><subject>Oligonucleotide Array Sequence Analysis</subject><subject>Polymyositis - genetics</subject><subject>Polymyositis - immunology</subject><subject>Polymyositis - metabolism</subject><subject>Receptors, Immunologic</subject><subject>RIG-I</subject><subject>Signal Transduction</subject><subject>Toll-Like Receptor 3 - genetics</subject><subject>Toll-Like Receptor 3 - metabolism</subject><issn>0022-3417</issn><issn>1096-9896</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqNkU1PGzEQhq2qqAmBA3-gitRLOSzxt9cnFKBNUkUBIVq4Wc7urOqwH6m9qzb_HkcJOSBV4jSamWfe0cyL0BnBFwRjOlrb9vcFZ1x-QH2CtUx0quVH1I89mjBOVA8dh7DCGGstxCfUo1xirqTso8tx2YKHfHg_mySz0c3Nk0iTCnJn21h0dR3j0FVVV7t2E_NhDr6ybVNtmuBaF07QUWHLAKf7OEA_v397uJ4m89vJ7Ho8TzIelyWE8lRlGtIUJM81KwgwUFlW5IJrarUiucwkSymmuU2t0hlfglhaKApOCFZsgL7udNe--dNBaE3lQgZlaWtoumCI4PHYVGj-DpQJSSXDOKJf3qCrpvN1PGRLcUGwYDRS5zsq800IHgqz9q6yfmMINlsDzNYAszUgsp_3it0yvvFAvn48AqMd8NeVsPm_krkbP0z3ksluwoUW_h0mrH82UjElzONiYn79WFxN5RUzj-wFfPGcQw</recordid><startdate>201407</startdate><enddate>201407</enddate><creator>Suárez-Calvet, Xavier</creator><creator>Gallardo, Eduard</creator><creator>Nogales-Gadea, Gisela</creator><creator>Querol, Luis</creator><creator>Navas, Miquel</creator><creator>Díaz-Manera, Jordi</creator><creator>Rojas-Garcia, Ricard</creator><creator>Illa, Isabel</creator><general>John Wiley & Sons, Ltd</general><general>Wiley Subscription Services, Inc</general><scope>BSCLL</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QP</scope><scope>7QR</scope><scope>7T5</scope><scope>7TK</scope><scope>7TM</scope><scope>7TO</scope><scope>8FD</scope><scope>FR3</scope><scope>H94</scope><scope>K9.</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope></search><sort><creationdate>201407</creationdate><title>Altered RIG-I/DDX58-mediated innate immunity in dermatomyositis</title><author>Suárez-Calvet, Xavier ; Gallardo, Eduard ; Nogales-Gadea, Gisela ; Querol, Luis ; Navas, Miquel ; Díaz-Manera, Jordi ; Rojas-Garcia, Ricard ; Illa, Isabel</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4246-12487c9e88e64d93f1e3e7ccfd5492a971d6c638202da8a79c4be5baeff411073</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2014</creationdate><topic>Adult</topic><topic>Aged</topic><topic>Case-Control Studies</topic><topic>Cells, Cultured</topic><topic>DDX58</topic><topic>DEAD Box Protein 58</topic><topic>DEAD-box RNA Helicases - genetics</topic><topic>DEAD-box RNA Helicases - metabolism</topic><topic>dermatomyositis</topic><topic>Dermatomyositis - genetics</topic><topic>Dermatomyositis - immunology</topic><topic>Dermatomyositis - metabolism</topic><topic>Female</topic><topic>Gene Expression Profiling - methods</topic><topic>Gene Expression Regulation</topic><topic>Genetic Association Studies</topic><topic>Histocompatibility Antigens Class I - metabolism</topic><topic>Humans</topic><topic>Immunity, Innate</topic><topic>Immunohistochemistry</topic><topic>Inclusion Bodies - immunology</topic><topic>Inclusion Bodies - metabolism</topic><topic>inflammatory myopathy</topic><topic>innate immunity</topic><topic>Interferon-beta - metabolism</topic><topic>Interferon-Induced Helicase, IFIH1</topic><topic>Male</topic><topic>Microdissection</topic><topic>Middle Aged</topic><topic>Muscle Fibers, Skeletal - immunology</topic><topic>Muscle Fibers, Skeletal - metabolism</topic><topic>Oligonucleotide Array Sequence Analysis</topic><topic>Polymyositis - genetics</topic><topic>Polymyositis - immunology</topic><topic>Polymyositis - metabolism</topic><topic>Receptors, Immunologic</topic><topic>RIG-I</topic><topic>Signal Transduction</topic><topic>Toll-Like Receptor 3 - genetics</topic><topic>Toll-Like Receptor 3 - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Suárez-Calvet, Xavier</creatorcontrib><creatorcontrib>Gallardo, Eduard</creatorcontrib><creatorcontrib>Nogales-Gadea, Gisela</creatorcontrib><creatorcontrib>Querol, Luis</creatorcontrib><creatorcontrib>Navas, Miquel</creatorcontrib><creatorcontrib>Díaz-Manera, Jordi</creatorcontrib><creatorcontrib>Rojas-Garcia, Ricard</creatorcontrib><creatorcontrib>Illa, Isabel</creatorcontrib><collection>Istex</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Chemoreception Abstracts</collection><collection>Immunology Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>The Journal of pathology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Suárez-Calvet, Xavier</au><au>Gallardo, Eduard</au><au>Nogales-Gadea, Gisela</au><au>Querol, Luis</au><au>Navas, Miquel</au><au>Díaz-Manera, Jordi</au><au>Rojas-Garcia, Ricard</au><au>Illa, Isabel</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Altered RIG-I/DDX58-mediated innate immunity in dermatomyositis</atitle><jtitle>The Journal of pathology</jtitle><addtitle>J. Pathol</addtitle><date>2014-07</date><risdate>2014</risdate><volume>233</volume><issue>3</issue><spage>258</spage><epage>268</epage><pages>258-268</pages><issn>0022-3417</issn><eissn>1096-9896</eissn><abstract>We investigated the molecular mechanisms involved in the pathogenesis of three inflammatory myopathies, dermatomyositis (DM), polymyositis (PM) and inclusion body myositis (IBM). We performed microarray experiments† using microdissected pathological muscle fibres from 15 patients with these disorders and five controls. Differentially expressed candidate genes were validated by immunohistochemistry on muscle biopsies, and the altered pathways were analysed in human myotube cultures. Up‐regulation of genes involved in viral and nucleic acid recognition were found in the three myopathies but not in controls. In DM, retinoic acid‐inducible gene 1 (RIG‐I, DDX58) and the novel antiviral factor DDX60, which promotes RIG‐I‐mediated signalling, were significantly up‐regulated, followed by IFIH1 (MDA5) and TLR3. Immunohistochemistry confirmed over‐expression of RIG‐I in pathological muscle fibres in 5/5 DM, 0/5 PM and 0/5 IBM patients, and in 0/5 controls. Stimulation of human myotubes with a ligand of RIG‐I produced a significant secretion of interferon‐β (IFNβ; p < 0.05) and up‐regulation of class I MHC, RIG‐I and TLR3 (p < 0.05) by IFNβ‐dependent and TLR3‐independent mechanisms. RIG‐I‐mediated innate immunity, triggered by a viral or damage signal, plays a significant role in the pathogenesis of DM, but not in that of PM or IBM. Copyright © 2014 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd</abstract><cop>Chichester, UK</cop><pub>John Wiley & Sons, Ltd</pub><pmid>24604766</pmid><doi>10.1002/path.4346</doi><tpages>11</tpages></addata></record> |
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| subjects | Adult Aged Case-Control Studies Cells, Cultured DDX58 DEAD Box Protein 58 DEAD-box RNA Helicases - genetics DEAD-box RNA Helicases - metabolism dermatomyositis Dermatomyositis - genetics Dermatomyositis - immunology Dermatomyositis - metabolism Female Gene Expression Profiling - methods Gene Expression Regulation Genetic Association Studies Histocompatibility Antigens Class I - metabolism Humans Immunity, Innate Immunohistochemistry Inclusion Bodies - immunology Inclusion Bodies - metabolism inflammatory myopathy innate immunity Interferon-beta - metabolism Interferon-Induced Helicase, IFIH1 Male Microdissection Middle Aged Muscle Fibers, Skeletal - immunology Muscle Fibers, Skeletal - metabolism Oligonucleotide Array Sequence Analysis Polymyositis - genetics Polymyositis - immunology Polymyositis - metabolism Receptors, Immunologic RIG-I Signal Transduction Toll-Like Receptor 3 - genetics Toll-Like Receptor 3 - metabolism |
| title | Altered RIG-I/DDX58-mediated innate immunity in dermatomyositis |
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