title: Genomic signatures characterize leukocyte infiltration in myositis muscles.
abstract: BACKGROUND
  Leukocyte infiltration plays an important role in the pathogenesis and progression of myositis, and is highly associated with disease severity. Currently, there is a lack of: efficacious therapies for myositis; understanding of the molecular features important for disease pathogenesis; and potential molecular biomarkers for characterizing inflammatory myopathies to aid in clinical development.
  
  
  METHODS
  In this study, we developed a simple model and predicted that 1) leukocyte-specific transcripts (including both protein-coding transcripts and microRNAs) should be coherently overexpressed in myositis muscle and 2) the level of over-expression of these transcripts should be correlated with leukocyte infiltration. We applied this model to assess immune cell infiltration in myositis by examining mRNA and microRNA (miRNA) expression profiles in muscle biopsies from 31 myositis patients and 5 normal controls.
  
  
  RESULTS
  Several gene signatures, including a leukocyte index, type 1 interferon (IFN), MHC class I, and immunoglobulin signature, were developed to characterize myositis patients at the molecular level. The leukocyte index, consisting of genes predominantly associated with immune function, displayed strong concordance with pathological assessment of immune cell infiltration. This leukocyte index was subsequently utilized to differentiate transcriptional changes due to leukocyte infiltration from other alterations in myositis muscle. Results from this differentiation revealed biologically relevant differences in the relationship between the type 1 IFN pathway, miR-146a, and leukocyte infiltration within various myositis subtypes.
  
  
  CONCLUSIONS
  Results indicate that a likely interaction between miR-146a expression and the type 1 IFN pathway is confounded by the level of leukocyte infiltration into muscle tissue. Although the role of miR-146a in myositis remains uncertain, our results highlight the potential benefit of deconvoluting the source of transcriptional changes in myositis muscle or other heterogeneous tissue samples. Taken together, the leukocyte index and other gene signatures developed in this study may be potential molecular biomarkers to help to further characterize inflammatory myopathies and aid in clinical development. These hypotheses need to be confirmed in separate and sufficiently powered clinical trials.
authors.affiliation: Translational Sciences, MedImmune, LLC, Gaithersburg, MD 20878, USA. ZhuW@medimmune.com
authors.forename: Wei
authors.initials: W
authors.lastname: Zhu
authors.forename: Katie
authors.initials: K
authors.lastname: Streicher
authors.forename: Nan
authors.initials: N
authors.lastname: Shen
authors.forename: Brandon W
authors.initials: BW
authors.lastname: Higgs
authors.forename: Chris
authors.initials: C
authors.lastname: Morehouse
authors.forename: Lydia
authors.initials: L
authors.lastname: Greenlees
authors.forename: Anthony A
authors.initials: AA
authors.lastname: Amato
authors.forename: Koustubh
authors.initials: K
authors.lastname: Ranade
authors.forename: Laura
authors.initials: L
authors.lastname: Richman
authors.forename: David
authors.initials: D
authors.lastname: Fiorentino
authors.forename: Bahija
authors.initials: B
authors.lastname: Jallal
authors.forename: Steven A
authors.initials: SA
authors.lastname: Greenberg
authors.forename: Yihong
authors.initials: Y
authors.lastname: Yao
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D016022:Case-Control Studies; D002465:Cell Movement / Q000235:genetics*; D016000:Cluster Analysis; D015536:Down-Regulation / Q000235:genetics; D020869:Gene Expression Profiling; D015894:Genome, Human / Q000235:genetics; D023281:Genomics; D006801:Humans; D007370:Interferon Type I / Q000378:metabolism; D007962:Leukocytes / Q000473:pathology*; D051379:Mice; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D008875:Middle Aged; D032342:Muscle Cells / Q000378:metabolism / Q000473:pathology; D009119:Muscle Contraction / Q000235:genetics; D018482:Muscle, Skeletal / Q000276:immunology / Q000473:pathology*; D009220:Myositis / Q000235:genetics* / Q000276:immunology* / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation / Q000235:genetics
chemical_list: D007370:Interferon Type I; D035683:MicroRNAs; D012333:RNA, Messenger