title: Gene expression profiling in DQA1*0501+ children with untreated dermatomyositis: a novel model of pathogenesis.
abstract: Juvenile dermatomyositis (JDM), the most common pediatric inflammatory myopathy, is a systemic vasculopathy affecting young children. Epidemiology studies documenting an antecedent illness in the 3 mo before the first definite symptom (rash and/or weakness) of JDM are supported by immunologic data that suggest that the disease pathophysiology is Ag driven. The purpose of this study was to compare the gene expression profiles in muscle biopsies of four untreated DQA1*0501(+) JDM children with profiles from children with a known necrotizing myopathy (Duchenne muscular dystrophy), as well as an in vitro antiviral model (NF90), and healthy pediatric controls. Nearly half (47%) of the dysregulated genes in JDM were associated with the immune response. In particular, increased expression of IFN-alphabeta-inducible genes 6-16, myxovirus resistance protein p78, latent cytosolic transcription factor, LMP2, and TAP1 was observed. This profile is consistent with an IFN-alphabeta transcription cascade seen in the in vitro viral resistance model. The IFN-alphabeta-inducible profile was superimposed on transcription profiles reflective of myofiber necrosis and regeneration shared with Duchenne muscular dystrophy. Expressed genes were confirmed by quantitative real-time PCR (6-16), immunofluorescence (thrombospondin 4), and immunolocalization (IFN-gamma, p21). We hypothesize that these data support a model of Ag (?viral) induction of an apparent autoimmune disease based on dynamic interaction between the muscle, vascular, and immune systems in the genetically susceptible (DQA1*0501(+)) child.
authors.affiliation: Research Center for Genetic Medicine, Children's National Medical Center, Washington, DC, USA.
authors.forename: Zivana
authors.initials: Z
authors.lastname: Tezak
authors.forename: Eric P
authors.initials: EP
authors.lastname: Hoffman
authors.forename: Jennica L
authors.initials: JL
authors.lastname: Lutz
authors.forename: Tamara O
authors.initials: TO
authors.lastname: Fedczyna
authors.forename: Dietrich
authors.initials: D
authors.lastname: Stephan
authors.forename: Eric G
authors.initials: EG
authors.lastname: Bremer
authors.forename: Irina
authors.initials: I
authors.lastname: Krasnoselska-Riz
authors.forename: Ajit
authors.initials: A
authors.lastname: Kumar
authors.forename: Lauren M
authors.initials: LM
authors.lastname: Pachman
mesh_terms: D000293:Adolescent; D002460:Cell Line; D002648:Child; D002675:Child, Preschool; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000096:biosynthesis / Q000235:genetics; D003882:Dermatomyositis / Q000235:genetics* / Q000276:immunology* / Q000628:therapy / Q000821:virology; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods*; D005786:Gene Expression Regulation / Q000276:immunology; D015967:Gene Expression Regulation, Viral / Q000276:immunology; D020022:Genetic Predisposition to Disease; D006683:HLA-DQ Antigens / Q000096:biosynthesis / Q000235:genetics*; D059848:HLA-DQ alpha-Chains; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis / Q000235:genetics; D008565:Membrane Proteins; D018482:Muscle, Skeletal / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D020388:Muscular Dystrophy, Duchenne / Q000235:genetics / Q000276:immunology; D014176:Protein Biosynthesis; D011506:Proteins / Q000235:genetics; D019699:Thrombospondins / Q000096:biosynthesis / Q000235:genetics
chemical_list: C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D006683:HLA-DQ Antigens; D059848:HLA-DQ alpha-Chains; C069050:HLA-DQA1 antigen; C406887:IFI27 protein, human; D008565:Membrane Proteins; D011506:Proteins; D019699:Thrombospondins; C101864:thrombospondin 4; D007371:Interferon-gamma