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Identification of novel microRNA signatures linked to human lupus disease activity and pathogenesis: miR-21 regulates aberrant T cell responses through regulation of PDCD4 expression
  1. Elias Stagakis1,2,
  2. George Bertsias1,2,
  3. Panayotis Verginis1,3,
  4. Magdalene Nakou1,2,
  5. Maria Hatziapostolou4,5,
  6. Heraklis Kritikos1,,
  7. Dimitrios Iliopoulos4,5,
  8. Dimitrios T Boumpas1,3
  1. 1Laboratory of Autoimmunity and Inflammation, University of Crete Medical School, Heraklion, Greece
  2. 2Graduate Program on Molecular Basis of Human Disease, School of Medicine, University of Crete, Heraklion, Greece
  3. 3Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology, Heraklion, Greece
  4. 4Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Boston, Massachusetts, USA
  5. 5Department of Pathology, Harvard Medical School, Boston, Massachusetts, USA
  6. Deceased
  1. Correspondence to Dimitrios T Boumpas, Laboratory of Autoimmunity and Inflammation, Department of Rheumatology, Clinical Immunology and Allergy, University of Crete, School of Medicine, PO Box 2208, Heraklion, Greece; boumpasd{at}med.uoc.gr

Abstract

Objective MicroRNAs (miRNAs) regulate the expression of genes involved in immune activation. A study was undertaken to characterise the miRNA signature and identify novel genes involved in the regulation of immune responses in systemic lupus erythematosus (SLE).

Methods The expression of 365 miRNAs in peripheral blood mononuclear cells of patients with SLE and healthy controls was analysed using TaqMan Low Density Arrays. The results were validated by quantitative real-time PCR and potential target genes were identified using prediction analysis software. The effect of miR-21 on T cell function was assessed by transfection with antago-miR-21 or pre-miR-21.

Results A 27-miRNA signature was identified in patients with SLE; 19 miRNAs correlated with disease activity. Eight miRNAs were deregulated specifically in T cells and four miRNAs in B cells. miR-21 was upregulated and strongly correlated with SLE disease activity (r2=0.92). Compared with controls, CD4 T lymphocytes from patients with SLE had higher basal and activation-induced miR-21 expression. Silencing of miR-21 reversed the activated phenotype of T cells from patients with SLE—namely, enhanced proliferation, interleukin 10 production, CD40L expression and their capacity to drive B cell maturation into Ig-secreting CD19+CD38hiIgD−(plasma cells. Overexpression of mMiR-21 in normal T cells led to acquisition of an activated phenotype. Investigation of putative gene- targets showed that PDCD4 (a selective protein translation inhibitor) was suppressed by miR-21 and its expression was decreased in active SLE.

Conclusions miRNAs represent potential biomarkers in SLE as their expression reflects underlying pathogenic processes and correlates with disease activity. Upregulated miR-21 affects PDCD4 expression and regulates aberrant T cell responses in human SLE.

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Footnotes

  • ES, GB, AI and DTB contributed equally

  • Funding This work is supported by the Hellenic Society of Rheumatology, the Pancretan Health Association, the Hellenic Ministry of Education, Hellenic Republic and the European Union (EPEAEK Fund and Sixth Framework Programme AutoCure program).

  • Competing interests None.

  • Patient consent Obtained.

  • Ethics approval This study was conducted with the approval of the University Hospital of Heraklion, Crete, Greece.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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