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      Involvement of miR-126 in autoimmune disorders

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          Abstract

          Background

          Micro-RNA represent a great family of small non-condign ribonucleic acid molecules; in particular microRNA-126 is an important member of this family and is expressed in many human cells such as cardiomyocytes, endothelial and lung cells. Some studies have shown the implication of miR-126 in cancer, but recently significant progresses have also been made in determining the role of miR-126 regulating immune-related diseases; probably, in a near future, they could potentially serve as diagnostic biomarkers or therapeutic targets.

          Objective

          The purpose of this review is to investigate the role of miR-126 in autoimmune diseases, so as to offer innovative therapies.

          Results

          According literature, it was concluded that miRNAs, especially miR-126, are involved in many pathologies and that their expression levels increase in autoimmune diseases because they interfere with the transcription of the proteins involved. Since microRNAs can be detected from several biological sources, they may be attractive as potential biomarkers for the diagnosis, prognosis, disease activity and severity of various diseases. In fact, once confirmed the involvement of miR-126 in autoimmune diseases, it was speculated that it could be used as a promising biomarker. These discovers implicate that miR-126 have a central role in many pathways leading to the development and sustain of autoimmune diseases. Its key role make this microRNA a potential therapeutic target in autoimmunity.

          Conclusion

          Although miR-126 relevant role in several immune-related diseases, further studies are needed to clear its molecular mechanisms; the final step of these novel researches could be the blockage or the prevention of the diseases onset by creating of new targeted therapy.

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          Most cited references 52

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          MicroRNA-21 and microRNA-148a contribute to DNA hypomethylation in lupus CD4+ T cells by directly and indirectly targeting DNA methyltransferase 1.

          Systemic lupus erythematosus is a complex autoimmune disease caused by genetic and epigenetic alterations. DNA methylation abnormalities play an important role in systemic lupus erythematosus disease processes. MicroRNAs (miRNAs) have been implicated as fine-tuning regulators controlling diverse biological processes at the level of posttranscriptional repression. Dysregulation of miRNAs has been described in various disease states, including human lupus. Whereas previous studies have shown miRNAs can regulate DNA methylation by targeting the DNA methylation machinery, the role of miRNAs in aberrant CD4+ T cell DNA hypomethylation of lupus is unclear. In this study, by using high-throughput microRNA profiling, we identified that two miRNAs (miR-21 and miR-148a) overexpressed in CD4+ T cells from both patients with lupus and lupus-prone MRL/lpr mice, which promote cell hypomethylation by repressing DNA methyltransferase 1 (DNMT1) expression. This in turn leads to the overexpression of autoimmune-associated methylation-sensitive genes, such as CD70 and LFA-1, via promoter demethylation. Further experiments revealed that miR-21 indirectly downregulated DNMT1 expression by targeting an important autoimmune gene, RASGRP1, which mediated the Ras-MAPK pathway upstream of DNMT1; miR-148a directly downregulated DNMT1 expression by targeting the protein coding region of its transcript. Additionally, inhibition of miR-21 and miR-148a expression in CD4+ T cells from patients with lupus could increase DNMT1 expression and attenuate DNA hypomethylation. Together, our data demonstrated a critical functional link between miRNAs and the aberrant DNA hypomethylation in lupus CD4+ T cells and could help to develop new therapeutic approaches.
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            MicroRNA-126 regulates DNA methylation in CD4+ T cells and contributes to systemic lupus erythematosus by targeting DNA methyltransferase 1.

            To identify microRNA genes with abnormal expression in the CD4+ T cells of patients with systemic lupus erythematosus (SLE) and to determine the role of microRNA-126 (miR-126) in the etiology of SLE. MicroRNA expression patterns in CD4+ T cells from patients with SLE and healthy control subjects were analyzed by microRNA microarray and stem loop quantitative polymerase chain reaction (qPCR). Luciferase reporter gene assays were performed to identify miR-126 targets. Dnmt1, CD11a, and CD70 messenger RNA and protein levels were determined by real-time qPCR, Western blotting, and flow cytometry. CD11a, CD70, and EGFL7 promoter methylation levels were detected by bisulfite sequencing. IgG levels in T cell-B cell cocultures were determined by enzyme-linked immunosorbent assay. The expression of 11 microRNA was significantly increased or decreased in CD4+ T cells from patients with SLE relative to that in CD4+ T cells from control subjects. Among these, miR-126 was up-regulated, and its degree of overexpression was inversely correlated with Dnmt1 protein levels. We demonstrated that miR-126 directly inhibits Dnmt1 translation via interaction with its 3'-untranslated region, and that overexpression of miR-126 in CD4+ T cells can significantly reduce Dnmt1 protein levels. The overexpression of miR-126 in CD4+ T cells from healthy donors caused the demethylation and up-regulation of genes encoding CD11a and CD70, thereby causing T cell and B cell hyperactivity. The inhibition of miR-126 in CD4+ T cells from patients with SLE had the opposite effects. Expression of the miR-126 host gene EGFL7 was also up-regulated in CD4+ T cells from patients with SLE, possibly in a hypomethylation-dependent manner. Our data suggest that miR-126 regulates DNA methylation in CD4+ T cells and contributes to T cell autoreactivity in SLE by directly targeting Dnmt1. Copyright © 2011 by the American College of Rheumatology.
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              Sifalimumab, a Human Anti–Interferon-α Monoclonal Antibody, in Systemic Lupus Erythematosus: A Phase I Randomized, Controlled, Dose-Escalation Study

              Objective To evaluate the safety and tolerability of multiple intravenous (IV) doses of sifalimumab in adults with moderate-to-severe systemic lupus erythematosus (SLE). Methods In this multicenter, double-blind, placebo-controlled, sequential dose-escalation study, patients were randomized 3:1 to receive IV sifalimumab (0.3, 1.0, 3.0, or 10.0 mg/kg) or placebo every 2 weeks to week 26, then followed up for 24 weeks. Safety assessment included recording of treatment-emergent adverse events (AEs) and serious AEs. Pharmacokinetics, immunogenicity, and pharmacodynamics were evaluated, and disease activity was assessed. Results Of 161 patients, 121 received sifalimumab (26 received 0.3 mg/kg; 25, 1.0 mg/kg; 27, 3.0 mg/kg; and 43, 10 mg/kg) and 40 received placebo. Patients were predominantly female (95.7%). At baseline, patients had moderate-to-severe disease activity (mean SLE Disease Activity Index score 11.0), and most (75.2%) had a high type I interferon (IFN) gene signature. In the sifalimumab group versus the placebo group, the incidence of ≥1 treatment-emergent AE was 92.6% versus 95.0%, ≥1 serious AE was 22.3% versus 27.5%, and ≥1 infection was 67.8% versus 62.5%; discontinuations due to AEs occurred in 9.1% versus 7.5%, and death occurred in 3.3% (n = 4) versus 2.5% (n = 1). Serum sifalimumab concentrations increased in a linear and dose-proportional manner. Inhibition of the type I IFN gene signature was sustained during treatment in patients with a high baseline signature. No statistically significant differences in clinical activity (SLEDAI and British Isles Lupus Assessment Group score) between sifalimumab and placebo were observed. However, when adjusted for excess burst steroids, SLEDAI change from baseline showed a positive trend over time. A trend toward normal complement C3 or C4 level at week 26 was seen in the sifalimumab groups compared with baseline. Conclusion The observed safety/tolerability and clinical activity profile of sifalimumab support its continued clinical development for SLE.
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                Author and article information

                Contributors
                mcasciaro@unime.it
                eleonora.disalvo6@gmail.com
                terebrizzi@gmail.com
                crodolico@unime.it
                +39 090 2212049 , mcasciaro@unime.it , gangemis@unime.it
                Journal
                Clin Mol Allergy
                Clin Mol Allergy
                Clinical and Molecular Allergy : CMA
                BioMed Central (London )
                1476-7961
                2 May 2018
                2 May 2018
                2018
                : 16
                Affiliations
                [1 ]ISNI 0000 0001 2178 8421, GRID grid.10438.3e, School and Division of Allergy and Clinical Immunology, Department of Clinical and Experimental Medicine, , Messina University Hospital, ; 98125 Messina, Italy
                [2 ]ISNI 0000 0001 2178 8421, GRID grid.10438.3e, Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, , University of Messina, ; Messina, Italy
                [3 ]ISNI 0000 0001 2178 8421, GRID grid.10438.3e, Department of Clinical and Experimental Medicine, , University of Messina, ; 98125 Messina, Italy
                [4 ]ISNI 0000 0001 2178 8421, GRID grid.10438.3e, Operative Unit of Allergy and Clinical Immunology, Department of Clinical and Experimental Medicine, , University of Messina, ; Messina, Italy
                Article
                89
                10.1186/s12948-018-0089-4
                5930861
                ee2e953d-2be4-4d87-bae2-e59d4a9b6f96
                © The Author(s) 2018

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

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                © The Author(s) 2018

                Immunology

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