| Abstract |
Systemic lupus erythematosus (SLE) is the prototypic autoimmune disease that involves multiple genetic and environmental contributions. Although its etiology is not established, it is considered that the immune system of SLE patients is predisposed to aberrant responsiveness. The hallmark of the disease is the production of anti-nuclear autoantibodies and the formation of immunocomplexes that promote injury to various target organs. Defects in T cell antigen receptor–mediated signaling have been shown to lead to breakdown of immunological tolerance. Aberrant co-stimulation and skewed cytokine production by CD4+ T lymphocytes are important mechanisms that lead to B cell hyper-responsiveness in SLE. Considering the complexity of the disease, high
disease mechanisms and identify novel molecules involved in the deregulation of the immune response in human SLE. cDNA microarrays have been used in SLE and have found unique gene signatures in the disease. Although these studies have provided important insights into genetic pathways involved in lupus pathogenesis, they offer only limited information with regard to regulatory mechanisms that control gene expression.
Micro-RNAs (miRNAs) are potent negative modulators of genes involved in a variety of cellular processes. In animal cells, miRNAs regulate their targets by translational inhibition and mRNA destabilization. Deregulation of miRNA expression has been implicated in the pathogenesis of several human diseases and they are considered as potential biomarkers and therapeutic targets. Compared with other gene regulatory mechanisms such as epigenetic and transcription factors, miRNA-mediated effects occur prior to protein synthesis, thus allowing for the fine tuning of gene expression. This is particularly important for the immune system that has to adjust rapidly in response to environmental changes. MiRNAs have the potential to regulate the development of function of both the innate and the adaptive immune system and several miRNAs have been shown to be activated after stimulation of various immune pathways. Deregulation of miRNAs leads to uncontrolled immune response and development of autoimmunity in mice. Altered miRNA expression has also been reported in human autoimmune diseases, such as SLE, rheumatoid arthritis and multiple sclerosis but the mechanisms by which these changes promote autoimmunity hane not been thorougjly investigated.
In this study, we investigated the role of this new class of gene modulators in human SLE. To this end, we analyzed the miRNA profile in peripheral blood mononuclear cells (PBMCs) of SLE patients with microarray technology aiming to identify novel genes involved in disease pathogenesis. We found a set of differentially expressed miRNAS in SLE patients compared to healthy individuals and in patients with active versus inactive disease. Several miRNAs displayed a strong correlation with disease activity. Longitudinal studies in large patients cohorts are needed to define the use of miRNAs as disease biomakers. Importantly, the identified miRNAs are predicted to regulate genesa and processes pertinent to the pathogenesis of SLE.
Among these genes, mir-21 was one of the highest up-regulated in SLE patients and displayed the strongest correlation with disease activity (r2=0,92).
development of autoimmunity in mice. Altered miRNA expression has also been reported in human autoimmune diseases, such as SLE, rheumatoid arthritis and multiple sclerosis but the mechanisms by which these changes promote autoimmunity have not been thoroughly investigated.
end, we analyzed the miRNA profile in peripheral blood mononuclear cells (PBMCs) of SLE patients by microarray technology aiming to identify novel genes involved in disease pathogenesis. We found a set of differentially expressed miRNAs in SLE patients compared to healthy individuals and in patients with active versus inactive disease. Several miRNAs displayed a strong correlation with disease activity. Longitudinal studies in large patient cohorts are needed to define the use of miRNAs as disease biomarkers. Importantly, the identified miRNAs are predicted to regulate genes and processes pertinent to the pathogenesis of SLE.
Among these genes, mir-21 was one of the highest up-regulated in SLE patients and displayed the strongest correlation with 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, IL10 production, CD40L expression and their capacity to drive B cell maturation into Ig-secreting CD19+CD38 hi IgD−plasma cells. Overexpression of miR-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. Together these data suggest that miRNAs may regulate major pathogenic pathways in SLE.
|
Διερεύνηση του ρόλου των microRNAs στην ρύθμιση της έκφρασης γονιδίων που υπεισέρχονται στην παθογένεια του Συστηματικού Ερυθηματώδους Λύκου (ΣΕΛ) σε πειραματικά πρότυπα και ασθενείς με ΣΕΛ
