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      Serum microRNA Profiles Serve as Novel Biomarkers for Autoimmune Diseases

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          Abstract

          Autoimmune diseases involve a complex dysregulation of immunity. Autoimmune diseases include many members [e.g., rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE)], and most of them are classified according to what organs and tissues are targeted by the damaging immune response. Many studies have focused on finding specific biomarkers for single autoimmune diseases, but so far, there are no universal biomarkers for detecting almost all autoimmune diseases. Serum miRNAs have served as potential biomarkers for detecting various diseases. The purpose of this study was to find a universal biomarker for diagnosing autoimmune diseases. Regulatory T cells (Tregs) play a crucial role in protecting an individual from autoimmunity, and depletion of Tregs in mice is considered a representative animal model of autoimmune disease. Two mouse models for Treg depletion, in which Treg was depleted by CD25mAb (in C57 mice) or by diphtheria toxin (DT) (in Foxp3 DTR mice), were investigated, and 381 miRNAs were identified in the serum of mice with Treg depletion. A distinctive circulating miRNA profile was identified in Treg-depleted mice and in patients with autoimmune disease. QRT-PCR confirmation and ROC curve analysis determined that six miRNAs (miR-551b, miR-448, miR-9, miR-124, miR-148, and miR-34c) in the Treg-depleted mouse models and three miRNAs [miR-551b (specificity 73.5%, sensitivity 88.4%), miR-448 (specificity 82.4%, sensitivity 91.3%), and miR-124 (specificity 76.5%, sensitivity 91.3%)] in patients with RA, SLE, Sjogren's syndrome (SS), and ulcerative colitis (UC) could serve as valuable specific biomarkers. These circulating miRNAs may represent potential universal biomarkers for autoimmune diseases diagnosis and prognosis.

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          Most cited references39

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          Circulating microRNA in body fluid: a new potential biomarker for cancer diagnosis and prognosis.

          In the past several years, the importance of microRNA (miRNA) in cancer cells has been recognized. Proper control of miRNA expression is essential for maintaining a steady state of the cellular machinery. Recently, it was discovered that extracellular miRNAs circulate in the blood of both healthy and diseased patients, although ribonuclease is present in both plasma and serum. Most of the circulating miRNAs are included in lipid or lipoprotein complexes, such as apoptotic bodies, microvesicles, or exosomes, and are, therefore, highly stable. The existence of circulating miRNAs in the blood of cancer patients has raised the possibility that miRNAs may serve as a novel diagnostic marker. However, the secretory mechanism and biological function, as well as the meaning of the existence of extracellular miRNAs, remain largely unclear. In this review, we summarize the usefulness of circulating miRNA for cancer diagnosis, prognosis, and therapeutics. Furthermore, we propose a mechanism for the secretion and incorporation of miRNA into the cells. © 2010 Japanese Cancer Association.
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            MicroRNA-124 promotes microglia quiescence and suppresses EAE by deactivating macrophages via the C/EBP-α-PU.1 pathway.

            MicroRNAs are a family of regulatory molecules involved in many physiological processes, including differentiation and activation of cells of the immune system. We found that brain-specific miR-124 is expressed in microglia but not in peripheral monocytes or macrophages. When overexpressed in macrophages, miR-124 directly inhibited the transcription factor CCAAT/enhancer-binding protein-α (C/EBP-α) and its downstream target PU.1, resulting in transformation of these cells from an activated phenotype into a quiescent CD45(low), major histocompatibility complex (MHC) class II(low) phenotype resembling resting microglia. During experimental autoimmune encephalomyelitis (EAE), miR-124 was downregulated in activated microglia. Peripheral administration of miR-124 in EAE caused systemic deactivation of macrophages, reduced activation of myelin-specific T cells and marked suppression of disease. Conversely, knockdown of miR-124 in microglia and macrophages resulted in activation of these cells in vitro and in vivo. These findings identify miR-124 both as a key regulator of microglia quiescence in the central nervous system and as a previously unknown modulator of monocyte and macrophage activation.
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              Selective depletion of Foxp3+ regulatory T cells induces a scurfy-like disease

              The scurfy mutant mouse strain suffers from a fatal lymphoproliferative disease leading to early death within 3–4 wk of age. A frame-shift mutation of the forkhead box transcription factor Foxp3 has been identified as the molecular cause of this multiorgan autoimmune disease. Foxp3 is a central control element in the development and function of regulatory T cells (T reg cells), which are necessary for the maintenance of self-tolerance. However, it is unclear whether dysfunction or a lack of T reg cells is etiologically involved in scurfy pathogenesis and its human correlate, the IPEX syndrome. We describe the generation of bacterial artificial chromosome–transgenic mice termed “depletion of regulatory T cell” (DEREG) mice expressing a diphtheria toxin (DT) receptor–enhanced green fluorescent protein fusion protein under the control of the foxp3 gene locus, allowing selective and efficient depletion of Foxp3+ T reg cells by DT injection. Ablation of Foxp3+ T reg cells in newborn DEREG mice led to the development of scurfy-like symptoms with splenomegaly, lymphadenopathy, insulitis, and severe skin inflammation. Thus, these data provide experimental evidence that the absence of Foxp3+ T reg cells is indeed sufficient to induce a scurfy-like phenotype. Furthermore, DEREG mice will allow a more precise definition of the function of Foxp3+ T reg cells in immune reactions in vivo.
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                Author and article information

                Contributors
                Journal
                Front Immunol
                Front Immunol
                Front. Immunol.
                Frontiers in Immunology
                Frontiers Media S.A.
                1664-3224
                16 October 2018
                2018
                : 9
                : 2381
                Affiliations
                [1] 1State Key Laboratory of Pharmaceutical Biotechnology, Jiangsu Engineering Research Center for MicroRNA Biology and Biotechnology, School of Life Sciences, NJU Advanced Institute for Life Sciences, Nanjing University , Nanjing, China
                [2] 2Department of Rheumatology and Immunology, The Affiliated Drum Tower Hospital of Nanjing University Medical School , Nanjing, China
                Author notes

                Edited by: Laurence Morel, University of Florida, United States

                Reviewed by: Claudio Pignata, Università degli Studi di Napoli Federico II, Italy; Peter Igaz, Semmelweis University, Hungary

                *Correspondence: Yanbo Wang ybwang@ 123456nju.edu.cn

                This article was submitted to Autoimmune and Autoinflammatory Disorders, a section of the journal Frontiers in Immunology

                †These authors have contributed equally to this work

                Article
                10.3389/fimmu.2018.02381
                6232775
                30459760
                71976061-18b9-4274-8baa-6f655697a4a8
                Copyright © 2018 Jin, Hu, Xu, Zhan, Wang, Zhang and Chen.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 17 July 2018
                : 25 September 2018
                Page count
                Figures: 5, Tables: 0, Equations: 0, References: 49, Pages: 9, Words: 5523
                Categories
                Immunology
                Original Research

                Immunology
                autoimmune disease,treg,serum,mirna,biomarker
                Immunology
                autoimmune disease, treg, serum, mirna, biomarker

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