scholarly journals Epigenetic Regulation Mediated by microRNAs in the Susceptibility and Pathogenesis of Rheumatoid Arthritis

2020 ◽  
Author(s):  
Shicheng Guo ◽  
Cen Chang ◽  
Lingxia Xu ◽  
Runrun Zhang ◽  
Yehua Jin ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Immune System ◽  
Target Genes ◽  
Cell Types ◽  
Therapeutic Interventions ◽  
Current Evidence ◽  
The Novel ◽  
Diagnosis And Prognosis ◽  
Therapy Targets ◽  
System Differentiation

MicroRNAs (miRNAs) play crucial roles in the regulation of the transcriptome and development of diseases including cancer and autoimmune diseases, such as rheumatoid arthritis (RA). Currently, a comprehensive map, illustrating how miRNAs regulate transcripts, pathways, immune system differentiation, and their interaction with terminal cells, such as T cells, fibroblast-like synoviocytes (FLS), osteoblasts, and osteoclasts, is still missing. In this review, we provide a thorough summary of the roles of miRNAs in the susceptibility to pathogenesis, diagnosis, therapeutic intervention, and prognosis of RA. Numerous miRNAs are abnormally expressed in cells involved in RA, and regulate target genes and pathways including the NF-κB, Fas-FasL, JAK-STAT, IRE1-RIDD, and mTOR pathways. By regulating gene expression, miRNAs affect T cell differentiation to diverse cell types, including Th17 and T-reg cells, and thus constitute promising gene therapy targets to modulate the immune system in RA. We summarize the diagnostic and prognostic potential of blood-circulating and cell-free miRNAs, highlighting the novel opportunities to combine these with rheumatoid factor (RF) and anti-cyclic citrullinated peptide (anti-CCP) to provide accurate diagnosis and prognosis, especially for seronegative patients. Furthermore, we outline how functional genetic variants of miR-499 and miR-146a partly explain the unmet susceptibility to RA. Additionally, we review the evidence implicating miRNAs as promising biomarkers of efficiency, response, and resistance to disease-modifying anti-rheumatic drugs (DMRDs) and immunotherapy. Finally, we discuss the autotherapeutic effect of miRNA intervention as a step toward the development of miRNA-based anti-RA drugs. Collectively, the current evidence supports miRNAs as interesting targets to better understand the pathogenetic mechanisms of RA and design more efficient therapeutic interventions.

scholarly journals Epigenetic Regulation Mediated by miRNA in the Susceptibility and Pathogenesis of Rheumatoid Arthritis

2020 ◽  
Author(s):  
Shicheng Guo ◽  
Cen Chang ◽  
Lingxia Xu ◽  
Runrun Zhang ◽  
Yehua Jin ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Therapeutic Intervention ◽  
Target Genes ◽  
Cell Types ◽  
Micro Rna ◽  
Current Evidence ◽  
Diagnosis And Prognosis ◽  
Transcriptome Regulation ◽  
Therapy Target ◽  
Different Cell Types

micro-RNA (miRNA) has been demonstrated to play important roles in the transcriptome regulation and disease development including cancer and autoimmune disease such as rheumatoid arthritis. However, a comprehensive map on how the mRNAs regulate transcripts, pathways, immune system differentiation and interaction with terminal cells like T-cells, fibroblast-like synoviocytes (FLS), osteoblast and osteoclast still unknown. In this review, we have provided a thorough summary on the roles of miRNAs in the susceptibility, pathogenesis, diagnosis, therapeutic intervention and prognosis. Numerous miRNAs were found abnormally expressed in rheumatoid arthritis relevant cells and regulated the target genes and pathways like NF-κB, Fas-FasL, JAK-STAT, IRE1-RIDD, mTOR pathway. In addition, miRNA act as gene expression regulators affect the T-cell differentiate to different cell types including Th17 and T-reg cells which provide promising gene therapy target to regulate immune systems in rheumatoid arthritis. We also summarized interesting diagnosis and prognosis roles of blood and cell-free based miRNAs which provided novel opportunity to work together with rheumatoid factors (RF), anti-CCP to provide accurate diagnosis and prognosis especially for seronegative patients. Furthermore, functional genetic variants in miRNA-499 and miRNA-146a explained part of missing susceptibility of rheumatoid arthritis. Finally, miRNAs were showed as promising biomarker to indicate the DMRDS and immunotherapy efficiency, drug response and resistance. What’s more, autotherapeutic effect of miRNA intervention provided promising to develop miRNA based rheumatoid arthritis drugs. Overall, current evidence supports miRNAs as the interesting targets to better understand the pathogenetic mechanism and therapeutic intervention of rheumatoid arthritis.

scholarly journals From Rheumatoid Factor to Anti-Citrullinated Protein Antibodies and Anti-Carbamylated Protein Antibodies for Diagnosis and Prognosis Prediction in Patients with Rheumatoid Arthritis

2021 ◽  
Vol 22 (2) ◽  
pp. 686
Author(s):  
Chao-Yi Wu ◽  
Huang-Yu Yang ◽  
Shue-Fen Luo ◽  
Jenn-Haung Lai
Keyword(s):  
Rheumatoid Arthritis ◽  
Treatment Options ◽  
Clinical Manifestations ◽  
Bone Destruction ◽  
Response To Therapy ◽  
Current Evidence ◽  
Prognosis Prediction ◽  
Diagnosis And Prognosis ◽  
Systemic Inflammatory Disease ◽  
Citrullinated Protein

Rheumatoid arthritis (RA) is a chronic systemic inflammatory disease mainly involving synovial inflammation and articular bone destruction. RA is a heterogeneous disease with diverse clinical presentations, prognoses and therapeutic responses. Following the first discovery of rheumatoid factors (RFs) 80 years ago, the identification of both anti-citrullinated protein antibodies (ACPAs) and anti-carbamylated protein antibodies (anti-CarP Abs) has greatly facilitated approaches toward RA, especially in the fields of early diagnosis and prognosis prediction of the disease. Although these antibodies share many common features and can function synergistically to promote disease progression, they differ mechanistically and have unique clinical relevance. Specifically, these three RA associating auto-antibodies (autoAbs) all precede the development of RA by years. However, while the current evidence suggests a synergic effect of RF and ACPA in predicting the development of RA and an erosive phenotype, controversies exist regarding the additive value of anti-CarP Abs. In the present review, we critically summarize the characteristics of these autoantibodies and focus on their distinct clinical applications in the early identification, clinical manifestations and prognosis prediction of RA. With the advancement of treatment options in the era of biologics, we also discuss the relevance of these autoantibodies in association with RA patient response to therapy.

Peptide secretory pathways in GI tract: cytochemical contributions to regulatory physiology of the gut

1980 ◽  
Vol 239 (4) ◽  
pp. G237-G246 ◽  
Author(s):  
L. I. Larsson
Keyword(s):  
Regulatory Peptides ◽  
Cell Types ◽  
Biologically Active ◽  
Current Evidence ◽  
The Novel ◽  
Active Peptides ◽  
Biologically Active Peptides ◽  
Cell Processes ◽  
Gastrointestinal Peptides ◽  
Physiological And Biochemical

Numerous biologically active peptides are produced by specialized cells of the gastrointestinal tract. Most of these peptides are also produced outside the gut, and current evidence suggests that they not only regulate digestive events per se but also participate in many other regulatory mechanisms working as hormonal, paracrine, and neuronal messengers. The physiological functions of the gastrointestinal peptides are yet very incompletely known. Immunocytochemical tracing of the destinations of neuronal and paracrine cell processes may, together with available physiological and biochemical data, provide valuable clues to the sites of actions of many of the novel regulatory peptides. Moreover, immunocytochemistry has given evidence for the occurrence of multiple secretory peptides in certain endocrine cell types and suggested that certain peptides simultaneously may be secreted by multiple endocrine, paracrine, and neural cell types. This review emphasizes the continued need for concerted cytochemical, physiological, and biochemical studies of the sites of synthesis, secretion, and action of gastrointestinal regulatory peptides.

scholarly journals GWAS for systemic sclerosis identifies multiple risk loci and highlights fibrotic and vasculopathy pathways

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Elena López-Isac ◽  
◽  
Marialbert Acosta-Herrera ◽  
Martin Kerick ◽  
Shervin Assassi ◽  
...  
Keyword(s):  
Systemic Sclerosis ◽  
Target Genes ◽  
Genome Wide Association Study ◽  
Meta Analysis ◽  
Cell Types ◽  
The Novel ◽  
Genome Wide ◽  
Credible Sets ◽  
Causal Variants ◽  
Work Supports

Abstract Systemic sclerosis (SSc) is an autoimmune disease that shows one of the highest mortality rates among rheumatic diseases. We perform a large genome-wide association study (GWAS), and meta-analysis with previous GWASs, in 26,679 individuals and identify 27 independent genome-wide associated signals, including 13 new risk loci. The novel associations nearly double the number of genome-wide hits reported for SSc thus far. We define 95% credible sets of less than 5 likely causal variants in 12 loci. Additionally, we identify specific SSc subtype-associated signals. Functional analysis of high-priority variants shows the potential function of SSc signals, with the identification of 43 robust target genes through HiChIP. Our results point towards molecular pathways potentially involved in vasculopathy and fibrosis, two main hallmarks in SSc, and highlight the spectrum of critical cell types for the disease. This work supports a better understanding of the genetic basis of SSc and provides directions for future functional experiments.

scholarly journals The Emerging Role of TLR and Innate Immunity in Cardiovascular Disease

2012 ◽  
Vol 2012 ◽  
pp. 1-12 ◽  
Author(s):  
Rolf Spirig ◽  
Janice Tsui ◽  
Sidney Shaw
Keyword(s):  
Cardiovascular Disease ◽  
Innate Immunity ◽  
Immune System ◽  
Inflammatory Responses ◽  
Therapeutic Potential ◽  
Ischemia Reperfusion ◽  
Microvascular Complications ◽  
Cell Types ◽  
Current Evidence

Cardiovascular disease is a complex disorder involving multiple pathophysiological processes, several of which involve activation of toll-like receptors (TLRs) of the innate immune system. As sentinels of innate immunity TLRs are nonclonally germline-encoded molecular pattern recognition receptors that recognize exogenous as well as tissue-derived molecular dangers signals promoting inflammation. In addition to their expression in immune cells, TLRs are found in other tissues and cell types including cardiomyocytes, endothelial and vascular smooth muscle cells. TLRs are differentially regulated in various cell types by several cardiovascular risk factors such as hypercholesterolemia, hyperlipidemia, and hyperglycemia and may represent a key mechanism linking chronic inflammation, cardiovascular disease progression, and activation of the immune system. Modulation of TLR signaling by specific TLR agonists or antagonists, alone or in combination, may be a useful therapeutic approach to treat various cardiovascular inflammatory conditions such as atherosclerosis, peripheral arterial disease, secondary microvascular complications of diabetes, autoimmune disease, and ischemia reperfusion injury. In this paper we discuss recent developments and current evidence for the role of TLR in cardiovascular disease as well as the therapeutic potential of various compounds on inhibition of TLR-mediated inflammatory responses.

scholarly journals ZEB2, the Mowat-Wilson Syndrome Transcription Factor: Confirmations, Novel Functions, and Continuing Surprises

Genes ◽  
2021 ◽  
Vol 12 (7) ◽  
pp. 1037
Author(s):  
Judith C. Birkhoff ◽  
Danny Huylebroeck ◽  
Andrea Conidi
Keyword(s):  
Transcription Factor ◽  
Immune System ◽  
Cell Fate ◽  
Developmental Disorders ◽  
Target Genes ◽  
Epithelial Mesenchymal Transition ◽  
Cell Communication ◽  
Cell Types ◽  
Fibrotic Liver ◽  
Mesenchymal Transition

After its publication in 1999 as a DNA-binding and SMAD-binding transcription factor (TF) that co-determines cell fate in amphibian embryos, ZEB2 was from 2003 studied by embryologists mainly by documenting the consequences of conditional, cell-type specific Zeb2 knockout (cKO) in mice. In between, it was further identified as causal gene causing Mowat-Wilson Syndrome (MOWS) and novel regulator of epithelial–mesenchymal transition (EMT). ZEB2’s functions and action mechanisms in mouse embryos were first addressed in its main sites of expression, with focus on those that helped to explain neurodevelopmental and neural crest defects seen in MOWS patients. By doing so, ZEB2 was identified in the forebrain as the first TF that determined timing of neuro-/gliogenesis, and thereby also the extent of different layers of the cortex, in a cell non-autonomous fashion, i.e., by its cell-intrinsic control within neurons of neuron-to-progenitor paracrine signaling. Transcriptomics-based phenotyping of Zeb2 mutant mouse cells have identified large sets of intact-ZEB2 dependent genes, and the cKO approaches also moved to post-natal brain development and diverse other systems in adult mice, including hematopoiesis and various cell types of the immune system. These new studies start to highlight the important adult roles of ZEB2 in cell–cell communication, including after challenge, e.g., in the infarcted heart and fibrotic liver. Such studies may further evolve towards those documenting the roles of ZEB2 in cell-based repair of injured tissue and organs, downstream of actions of diverse growth factors, which recapitulate developmental signaling principles in the injured sites. Evident questions are about ZEB2’s direct target genes, its various partners, and ZEB2 as a candidate modifier gene, e.g., in other (neuro)developmental disorders, but also the accurate transcriptional and epigenetic regulation of its mRNA expression sites and levels. Other questions start to address ZEB2’s function as a niche-controlling regulatory TF of also other cell types, in part by its modulation of growth factor responses (e.g., TGFβ/BMP, Wnt, Notch). Furthermore, growing numbers of mapped missense as well as protein non-coding mutations in MOWS patients are becoming available and inspire the design of new animal model and pluripotent stem cell-based systems. This review attempts to summarize in detail, albeit without discussing ZEB2’s role in cancer, hematopoiesis, and its emerging roles in the immune system, how intense ZEB2 research has arrived at this exciting intersection.

scholarly journals CRUP: a comprehensive framework to predict condition-specific regulatory units

2019 ◽  
Vol 20 (1) ◽  
Author(s):  
Anna Ramisch ◽  
Verena Heinrich ◽  
Laura V. Glaser ◽  
Alisa Fuchs ◽  
Xinyi Yang ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Gene Expression ◽  
Histone Modification ◽  
Candidate Genes ◽  
Target Genes ◽  
Cell Types ◽  
Disease Genes ◽  
Epigenetic Marks ◽  
Arthritis Model ◽  
Comprehensive Framework

Abstract We present the software Condition-specific Regulatory Units Prediction (CRUP) to infer from epigenetic marks a list of regulatory units consisting of dynamically changing enhancers with their target genes. The workflow consists of a novel pre-trained enhancer predictor that can be reliably applied across cell types and species, solely based on histone modification ChIP-seq data. Enhancers are subsequently assigned to different conditions and correlated with gene expression to derive regulatory units. We thoroughly test and then apply CRUP to a rheumatoid arthritis model, identifying enhancer-gene pairs comprising known disease genes as well as new candidate genes.

scholarly journals Regulation of Transcription Factor NF-κB in Its Natural Habitat: The Nucleus

Cells ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 753
Author(s):  
Susanne Bacher ◽  
Johanna Meier-Soelch ◽  
Michael Kracht ◽  
M. Lienhard Schmitz
Keyword(s):  
Transcription Factor ◽  
Target Genes ◽  
Natural Habitat ◽  
Transcriptional Response ◽  
Gene Clusters ◽  
Cell Types ◽  
Therapeutic Interventions ◽  
Specific Cell ◽  
Regulation Of Transcription ◽  
Specific Regulation

Activation of the transcription factor NF-κB elicits an individually tailored transcriptional response in order to meet the particular requirements of specific cell types, tissues, or organs. Control of the induction kinetics, amplitude, and termination of gene expression involves multiple layers of NF-κB regulation in the nucleus. Here we discuss some recent advances in our understanding of the mutual relations between NF-κB and chromatin regulators also in the context of different levels of genome organization. Changes in the 3D folding of the genome, as they occur during senescence or in cancer cells, can causally contribute to sustained increases in NF-κB activity. We also highlight the participation of NF-κB in the formation of hierarchically organized super enhancers, which enable the coordinated expression of co-regulated sets of NF-κB target genes. The identification of mechanisms allowing the specific regulation of NF-κB target gene clusters could potentially enable targeted therapeutic interventions, allowing selective interference with subsets of the NF-κB response without a complete inactivation of this key signaling system.

Immune system and bone cells in early rheumatoid arthritis

2016 ◽  
Author(s):  
Ilaria Buondonno ◽  
Francesca Sassi ◽  
Micol Rigoni ◽  
Guido Rovera ◽  
Giovanni Carlo Isaia ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Immune System ◽  
Early Rheumatoid Arthritis ◽  
Bone Cells

MicroRNAs and their role in hematological malignant diseases

2012 ◽  
Vol 153 (52) ◽  
pp. 2051-2059 ◽  
Author(s):  
Zsuzsanna Gaál ◽  
Éva Oláh
Keyword(s):  
Target Genes ◽  
Lymphoblastic Leukemia ◽  
Cancer Tissue ◽  
Altered Expression ◽  
Diagnosis And Prognosis ◽  
Oncologic Patients ◽  
Different Types ◽  
Non Coding Rnas ◽  
Success Of Treatment ◽  
Posttranscriptional Level

MicroRNAs are a class of small non-coding RNAs regulating gene expression at posttranscriptional level. Their target genes include numerous regulators of cell cycle, cell proliferation as well as apoptosis. Therefore, they are implicated in the initiation and progression of cancer, tissue invasion and metastasis formation as well. MicroRNA profiles supply much information about both the origin and the differentiation state of tumours. MicroRNAs also have a key role during haemopoiesis. An altered expression level of those have often been observed in different types of leukemia. There are successful attempts to apply microRNAs in the diagnosis and prognosis of acute lymphoblastic leukemia and acute myeloid leukemia. Measurement of the expression levels may help to predict the success of treatment with different kinds of chemotherapeutic drugs. MicroRNAs are also regarded as promising therapeutic targets, and can contribute to a more personalized therapeutic approach in haemato-oncologic patients. Orv. Hetil., 2012, 153, 2051–2059.

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