Genomic signatures characterize leukocyte infiltration in myositis muscles

BMC Medical Genomics

Yihong Yao⁵  Steven A Greenberg⁴  Bahija Jallal⁵  David Fiorentino³  Laura Richman⁵  Koustubh Ranade⁵  Anthony A Amato¹  Lydia Greenlees⁵  Chris Morehouse⁵  Brandon W Higgs⁵  Nan Shen²  Katie Streicher⁵  Wei Zhu⁵ 

[1] Department of Neurology, Brigham and Women’s Hospital Harvard Medical School, Boston, MA, USA;Shanghai Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China;Department of Dermatology, Stanford University School of Medicine, Palo Alto, CA, USA;Children’s Hospital Informatics Program, Harvard Medical School, Boston, MA, USA;Translational Sciences, MedImmune, LLC, One MedImmune Way, Gaithersburg, MD, 20878, USA

关键词: miR-146a;    Type 1 interferon;    Leukocyte infiltration;    Genomics;    Myositis;   

Others  :  1121288
DOI  :  10.1186/1755-8794-5-53

 received in 2012-04-10, accepted in 2012-10-23,  发布年份 2012

【 摘 要 】

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.

【 授权许可】

   
2012 Zhu et al.; licensee BioMed Central Ltd.

【 图 表 】

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