Background/Purpose: The integrity of the microRNA machinery is required for the normal reactivity of the immune system both during differentiation and upon antigen engagement. Dicer1 is a pivotal molecule of the microRNA biogenesis. Suppression of Dicer1 in lymphoid progenitors from mice render cells auto-reactive. In this study we have looked into Dicer1 gene expression in relationship with the activation of mononuclear cell subsets in patients with lupus.

Methods: The study was conducted in 36 patients with lupus (34 women) fulfilling ACR classification criteria, of which 21 were considered to have active disease. Circulating monocytes, T cells and B cells were sorted with magnetic beads, and gene expression analysis was carried out using Sybr green based qPCR techniques after RNA isolation and retro-transcription. Statistics were run with SPSS using non-parametric methods.

Results: Levels of Dicer1 in monocytes and in T cells were found to drop in association to c’4 decrease (p 0.09, p 0.03). Lower expression levels of Dicer1 were found in monocytes from patients with anti phospholipid antibodies (p 0.09), while in T cells the fall of Dicer1 levels was associated to lower platelet counts (p 0.002). Patients with positive antiDNA antibodies at the time of the study showed lower levels of Dicer1 in B lymphocytes (p 0.02). There was an inverse association between levels of Dicer1 in B cells and SLEDAI scores (p 0.04), C-reactive protein (p 0.03), and proteinuria (p 0.09). In addition to these activity features, we analysed the relationship between suppression of Dicer1 and mechanisms of cell growth. Globally, the down-regulation of Dicer1 gene expression was associated to an enhancement of miR181a, a master miRNA involved in positive selection of immune cells, in each of the mononuclear cell subpopulations. On the other hand, there was an inverse relationship between Dicer1 levels in monocytes and circulating NK cells (p 0.02).

Conclusion: Overall, the relative suppression of Dicer1 gene expression in patients with lupus identified a subgroup of patients with activation of the complement classical pathway and enhanced lymphocyte survival. Particularly in B cells, the drop of Dicer1 appeared to be a marker of activity and nephritis. Together, our data suggest that a deregulation of the microRNA system contributes to the abnormal activation of immune cells in lupus. In addition, measuring Dicer1 expression could be of interest as a biomarker of distinct subgroups of patients.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/fall-in-dicer1-gene-expression-flags-abnormal-lymphocyte-activation-in-lupus/