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“Mastering the Generals”: Targeting deregulated microRNAs of dendritic cells to reverse B and T cell activation in Sjögren’s syndrome

Thursday 26 March 2015

“Mastering the Generals”: Targeting deregulated microRNAs of dendritic cells to reverse B and T cell activation in Sjögren’s syndrome

Background/Research objectives
Dendritic cells: orchestrators of inflammation in primary Sjogren’s syndrome (pSS).

Recently we demonstrated a clear association between enhanced lymphoid foci, B cell activation and increased morbidity and mortality in patients with pSS. Myeloid and plasmacytoid dendritic cells (mDCs and pDCs) are among the most potent T cell- and B cell-activating cells in our body and have been considered as the generals of the immune system, orchestrating inflammation. Several observations indicate that these cells play a key role in the immunopathology of pSS, however, detailed analysis of these cells in pSS has not been performed. Novel technological platforms allow detailed analysis of such rare cells. Recently, we demonstrated novel phenotypic, molecular and functional properties of mDCs and pDCs from patients with (systemic) autoimmune diseases, including pSS.
MicroRNAs: master switches of dendritic cells. MicroRNAs are small non-coding RNAs that are epigenetic master switches regulating the expression of multiple functionally related genes. As a proof of concept we recently demonstrated that one of the newly identified microRNAs is a key regulator of IFN related genes of pDCs. Also our preparatory work, specifically relevant to the current study, identified a number of differentially expressed microRNAs in pDCs and mDCs in pSS patients vs healthy controls. Interestingly, target prediction models of these newly identified microRNAs revealed several target molecular pathways that are associated to interferon-, JAK/STAT-, mTOR- and virus-induced pathways and have previously been implicated in pSS. Intriguingly, 3 microRNAs were identified that were shared by mDCs and pDCs, pointing towards shared and potentially commonly targetable pathways.

Considering the strong potential of mDCs, pDCs and microRNAs to orchestrate inflammation we hypothesize that targeting newly identified deregulated microRNAs of DCs will functionally switch these cells and inhibit DC and successively B and T cell activation in Sjögren’s syndrome.
The following objectives will be addressed:
1) Identify genes modified by pSS-deregulated microRNAs
2) Assess to what extent microRNAs of DCs are associated with immune activation, disease activity, lymphoid neogenesis and immunopathology.
3) Identify upstream pathways underlying microRNA expression pattern in DCs.
4) Restoring DC aberrances by targeting the microRNA imbalance

Culture of human tissue and/or cells; MACS cell sorting to isolate CD4 T cells (and subsets) and mDCs and pDCs; cell phenotyping by FACS analysis; intra-cellular cytokine staining; cytokine assessment by ELISA/Luminex; proliferation assays; quantitative PCR, knock-in and knock-down by transfection using lamellar bodies.

Duration: 6/9 months

J.vanRoon@umcutrecht.nl, 088-755 4009
Prof. Tim Radstake
T.R.D.J.Radstake@umcutrecht.nl, 088-755 7357

Laboratory of Translational Immunology and Dept of Rheumatology & Clinical Immunology