scholarly journals A DNA-Methylated Sight on Autoimmune Inflammation Network across RA, pSS, and SLE

2018 ◽  
Vol 2018 ◽  
pp. 1-13 ◽  
Author(s):  
Xingqiang Wang ◽  
Dongyun Lei ◽  
Jie Ding ◽  
Shuang Liu ◽  
Li Tao ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Lupus Erythematosus ◽  
Inflammatory Process ◽  
Methylation Status ◽  
Differential Methylation ◽  
Promoter Regions ◽  
Bioinformatics Analyses ◽  
Epigenetic Biomarkers ◽  
The Difference ◽  
Autoimmune Tautology

Methylation variabilities of inflammatory cytokines play important roles in the development of systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and primary Sjögren’s syndrome (pSS). With heightened focus on personalized and precise medicine, it is necessary to compare and contrast the difference and similarity of cytokine methylation status between the 3 most classic autoimmune diseases (AIDs). In this study, we integrated 5 Cytokine-Chips from genome-wide DNA methylation datasets of the 3 kind of AIDs, delta-beta value was calculated for intergroup difference, and comprehensive bioinformatics analyses of cytokine genes with aberrant methylations were performed. 125 shared differential methylation variabilities (DMVs) were identified. There were 102 shared DMVs with similar methylation status; 3 hypomethylated differential methylation regions (DMRs) across the AIDs were found, and all 3 DMRs were hypomethylated. DMRs (AZU1, LTBR, and RTEL1) were likely to serve as activator in the inflammatory process. Particularly, AZU1 and LTBR with hypomethylated TSS and first exon located in the promoter regions were able to trigger inflammation signaling cascades and play critical roles in autoimmune tautology. Moreover, functional epigenetic module (FEM) algorithm showed that different inflammatory networks are involved in different AIDs; 5 hotspots were identified as biologically plausible pathways in inducing or perpetuating of inflammation which are epigenetically deregulated in AIDs. We concluded methylation variabilities among the same cytokines can greatly impact the perpetuation of inflammatory process or signal pathway of AIDs. Differentiating the cytokine methylation status will serve as valuable resource for researchers alike to gain better understanding of the epigenetic mechanisms of the three AIDs. Even more importantly, better understanding of cytokine methylation variability existing between the three classic AIDs will aid in identification of potential epigenetic biomarkers and therapeutic targets. This trial is registered with ChiCTR-INR-16010290, a clinical trial for the treatment of rheumatoid arthritis with Warming yang and Smoothening Meridians.

Palindromic Rheumatism with Positive Anticitrullinated Peptide/Protein Antibodies Is Not Synonymous with Rheumatoid Arthritis. A Longterm Followup Study

2012 ◽  
Vol 39 (10) ◽  
pp. 1929-1933 ◽  
Author(s):  
RAIMON SANMARTÍ ◽  
SONIA CABRERA-VILLALBA ◽  
JOSÉ A. GÓMEZ-PUERTA ◽  
VIRGINIA RUIZ-ESQUIDE ◽  
M. VICTORIA HERNÁNDEZ ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Lupus Erythematosus ◽  
Characteristic Curve ◽  
Significant Proportion ◽  
Positive Likelihood Ratio ◽  
Outcome Variable ◽  
Palindromic Rheumatism ◽  
The Difference ◽  
Acpa Status

Objective.To analyze longterm progression to rheumatoid arthritis (RA) and the predictive value of anticitrullinated peptide/protein antibodies (ACPA) in palindromic rheumatism (PR).Methods.We selected all patients in our clinic with PR who had at least 1 ACPA measurement. We included only patients with pure PR, defined as no evidence of associated rheumatic disease at the first serum ACPA measurement. Clinical characteristics, serum ACPA levels, duration of PR until serum ACPA measurement, and total followup time were recorded. The outcome variable was the definitive diagnosis of RA. The prognostic value of ACPA status in pure PR for a definite diagnosis of RA was analyzed by different statistical methods.Results.Seventy-one patients (54 women/17 men) with a PR diagnosis were included. Serum ACPA were positive in 52.1%. After a mean followup of 7.6 ± 4.7 years since the first ACPA measurement, 24 patients (33.8%) progressed to chronic disease: 22% RA, 5.6% systemic lupus erythematosus, and 5.6% other diseases. The positive likelihood ratio of ACPA status for RA was 1.45, and the area under the receiver-operating characteristic curve of ACPA titers was 0.60 (95% CI 0.45−0.75). Progression to RA was more frequently seen in ACPA-positive than in ACPA-negative patients (29.7% vs 14.7%), but the difference was not significant (hazard ratio 2.46, 95% CI 0.77−7.86). Mean ACPA levels of patients with pure PR did not differ significantly from those of patients who progressed to RA.Conclusion.ACPA are frequently found in the sera of patients with PR, and a significant proportion of these patients do not progress to RA in the long term.

scholarly journals Methylation Pattern of the SOCS3 and IL6R Promoters in Rheumatoid Arthritis

2020 ◽  
Vol 2020 ◽  
pp. 1-7
Author(s):  
Marek Cieśla ◽  
Bogdan Kolarz ◽  
Maria Majdan ◽  
Dorota Darmochwał-Kolarz
Keyword(s):  
Rheumatoid Arthritis ◽  
Signaling Pathway ◽  
Methylation Status ◽  
Joint Destruction ◽  
Methylation Pattern ◽  
Cytokine Signaling ◽  
Healthy Controls ◽  
Promoter Regions ◽  
Specific Pcr ◽  
Genes Encoding

Interleukin-6 (IL-6) plays an essential function in the development of rheumatoid arthritis (RA), mainly through its proinflammatory effect, which may lead to joint destruction. The genes encoding IL-6 receptor (IL6R) and suppressor of cytokine signaling 3 (SOCS3) play a key role in the IL-6 signaling pathway, but their epigenetic regulation remains unclear. The aim of the study was to investigate how the presence of methylation in the SOCS3 and IL6R promoters is associated with the morbidity and severity of RA. A total of 146 unrelated individuals, 122 with RA and 24 healthy controls, were enrolled in the study. All subjects were genotyped with regard to the rs4969168 and rs4969170 polymorphisms in the SOCS3 gene and the rs2228145 and rs4129267 polymorphisms in IL6R. The methylation study included 52 patients with RA and 24 healthy controls. Qualitative real-time methylation-specific PCR was used to evaluate methylation status. We found no differences between patients and healthy controls in the methylation pattern in the IL6R and SOCS3 promoter regions and in variants frequency. The methylation profiles of the SOCS3 and IL6R promoters do not support the hypothesis that the genes SOCS3 and IL6R involved in the JAK-STAT signaling pathway are epigenetically deregulated in whole blood.

Optimization of the Expression of 1,3-1,4-β-glucanase Gene from Rhizomucor miehei in the Komagataella kurtzmanii yeast

2019 ◽  
Vol 35 (5) ◽  
pp. 3-11 ◽  
Author(s):  
I.I. Gubaidullin ◽  
A.S. Fedorov ◽  
D.G. Kozlov
Keyword(s):  
Target Gene ◽  
Rhizomucor Miehei ◽  
Leader Peptide ◽  
Promoter Regions ◽  
Functional Elements ◽  
Resource Center ◽  
The Status ◽  
Pichia Pastoris Yeast ◽  
The Difference ◽  
Genetic Constructs

Key functional elements of the vector (promoter, leader and terminator regions) that provide the expression of a target l,3-l,4-(3-glucanase gene from Rhizomucor miehei in the Komagataella kurtzmanii yeast have been optimized. It was shown that the promoter regions of the gene AOX1 from the Pichia pastoris yeast currently reclassified as Komagataella phaffti and from К. kurtzmanii yeast as parts of a vector provided equal levels of expression of the target gene in the cells of the recipient strain К. kurtzmanii Y727his4, i.e. they were completely interchangeable. This means that genetic constructs that were previously developed for the biosynthesis of recombinant proteins in К. phajfii are able to provide an effective expression in the К kurtzmanii yeast. The leader peptide MF4I (used as a variant of mif4I containing one amino acid substitution) and the leader peptide maxHH (containing the double proregion of the Hspl50 protein from Saccharomyces cerevisiae) confirmed the status of the most powerful elements among the five leader sequences analyzed. Their efficiency was 1.7 times higher than that of the standard leader from the yeast alpha-factor, and by 20% higher than the characteristics of the second group of artificial leaders. At the same time, it was found that, the choice of the terminator region had the strongest influence on the expression of the target gene among all of the vector functional elements. The best terminator elements were variants derived from the transcription termination region of the AOX1 gene, and the difference in the expression level of the target gene using different terminators was approximately 4.5 times. Based on the analysis of the obtained data, the optimal composition of the key functional elements of the expression vector was determined ; it included the promoter and terminator regions of the AOX1 yeast gene and one of the artificial leaders, mif4I or maxHH. β-glucanase, Komagataella kurtzmanii, yeast, secretion, strain producer The work was financially supported by the Ministry of Science and Higher education of the Russian Federation (Unique Project Identifier RFMEFI60717X0179) using the Unique Scientific Facility of the National Bio-Resource Center «All-Russian Collection of Industrial Microorganisms», NRC «Kurchatov Institute» - GOSNIIGENETIKA

scholarly journals Plasma expression of microRNA-425-5p and microRNA-451a as biomarkers of cardiovascular disease in rheumatoid arthritis patients

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Delia Taverner ◽  
Dídac Llop ◽  
Roser Rosales ◽  
Raimon Ferré ◽  
Luis Masana ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Cardiovascular Disease ◽  
Pulse Wave Velocity ◽  
Wave Velocity ◽  
Pulse Wave ◽  
Disease Risk ◽  
Intima Media Thickness ◽  
Carotid Intima Media Thickness ◽  
Media Thickness ◽  
Epigenetic Biomarkers

AbstractTo validate in a cohort of 214 rheumatoid arthritis patients a panel of 10 plasmatic microRNAs, which we previously identified and that can facilitate earlier diagnosis of cardiovascular disease in rheumatoid arthritis patients. We identified 10 plasma miRs that were downregulated in male rheumatoid arthritis patients and in patients with acute myocardial infarction compared to controls suggesting that these microRNAs could be epigenetic biomarkers for cardiovascular disease in rheumatoid arthritis patients. Six of those microRNAs were validated in independent plasma samples from 214 rheumatoid arthritis patients and levels of expression were associated with surrogate markers of cardiovascular disease (carotid intima-media thickness, plaque formation, pulse wave velocity and distensibility) and with prior cardiovascular disease. Multivariate analyses adjusted for traditional confounders and treatments showed that decreased expression of microRNA-425-5p in men and decreased expression of microRNA-451 in women were significantly associated with increased (β = 0.072; p = 0.017) and decreased carotid intima-media thickness (β = −0.05; p = 0.013), respectively. MicroRNA-425-5p and microRNA-451 also increased the accuracy to discriminate patients with pathological carotid intima-media thickness by 1.8% (p = 0.036) in men and 3.5% (p = 0.027) in women, respectively. In addition, microRNA-425-5p increased the accuracy to discriminate male patients with prior cardiovascular disease by 3% (p = 0.008). Additionally, decreased expression of microRNA-451 was significantly associated with decreased pulse wave velocity (β = −0.72; p = 0.035) in overall rheumatoid arthritis population. Distensibility showed no significant association with expression levels of the microRNAs studied. We provide evidence of a possible role of microRNA-425-5p and microRNA-451 as useful epigenetic biomarkers to assess cardiovascular disease risk in patients with rheumatoid arthritis.

scholarly journals DNA methylome signatures of prenatal exposure to synthetic glucocorticoids in hippocampus and peripheral whole blood of female guinea pigs in early life

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Aya Sasaki ◽  
Margaret E. Eng ◽  
Abigail H. Lee ◽  
Alisa Kostaki ◽  
Stephen G. Matthews
Keyword(s):  
Dna Methylation ◽  
Whole Blood ◽  
Guinea Pigs ◽  
Critical Role ◽  
Methylation Status ◽  
Peripheral Tissues ◽  
Epigenetic Biomarkers ◽  
Differentially Methylated Genes ◽  
Increased Risk ◽  
Synthetic Glucocorticoids

AbstractSynthetic glucocorticoids (sGC) are administered to women at risk of preterm delivery, approximately 10% of all pregnancies. In animal models, offspring exposed to elevated glucocorticoids, either by administration of sGC or endogenous glucocorticoids as a result of maternal stress, show increased risk of developing behavioral, endocrine, and metabolic dysregulation. DNA methylation may play a critical role in long-lasting programming of gene regulation underlying these phenotypes. However, peripheral tissues such as blood are often the only accessible source of DNA for epigenetic analyses in humans. Here, we examined the hypothesis that prenatal sGC administration alters DNA methylation signatures in guinea pig offspring hippocampus and whole blood. We compared these signatures across the two tissue types to assess epigenetic biomarkers of common molecular pathways affected by sGC exposure. Guinea pigs were treated with sGC or saline in late gestation. Genome-wide modifications of DNA methylation were analyzed at single nucleotide resolution using reduced representation bisulfite sequencing in juvenile female offspring. Results indicate that there are tissue-specific as well as common methylation signatures of prenatal sGC exposure. Over 90% of the common methylation signatures associated with sGC exposure showed the same directionality of change in methylation. Among differentially methylated genes, 134 were modified in both hippocampus and blood, of which 61 showed methylation changes at identical CpG sites. Gene pathway analyses indicated that prenatal sGC exposure alters the methylation status of gene clusters involved in brain development. These data indicate concordance across tissues of epigenetic programming in response to alterations in glucocorticoid signaling.

scholarly journals AB1043 AWARENESS OF THYROID EYE DISEASE, AN AUTOIMMUNE CONDITION, AMONG RHEUMATOLOGISTS

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 1813.1-1813
Author(s):  
B. Lamoreaux ◽  
M. Francis-Sedlak ◽  
R. Holt ◽  
J. Rosenbaum
Keyword(s):  
Rheumatoid Arthritis ◽  
Lupus Erythematosus ◽  
Granulomatosis With Polyangiitis ◽  
The United States ◽  
Thyroid Eye Disease ◽  
Eye Disease ◽  
Infusion Therapy ◽  
Graves Disease ◽  
Ocular Motility ◽  
Referral Patterns

Background:Autoimmune inflammatory conditions of the eye may be associated with rheumatic diseases such as rheumatoid arthritis, systemic lupus erythematosus, and granulomatosis with polyangiitis. This is also observed with thyroid eye disease (TED). Loss of immune tolerance to the thyroid stimulating hormone receptor has thyroidal consequences and nearly 40% of patients with Graves’ disease also have clinically evident Graves’ orbitopathy or TED.1TED results from tissue inflammation that causes retro orbital fat expansion2and extraocular muscle enlargement2and stiffening.3Because the orbital cavity is bony and of limited volume, proptosis and, in severe cases, optic nerve compression, can result. In many patients, muscle changes also cause ocular motility issues and double-vision. Because TED can have a similar presentation to other inflammatory orbital diseases (e.g., granulomatosis with polyangiitis) and Graves’ disease patients frequently have other autoimmune conditions (10% of Graves’s patients also have rheumatoid arthritis),4rheumatologists are likely to care for, or even diagnose, patients with TED.Objectives:This analysis sought to understand rheumatologists’ knowledge, and degree of participation in the treatment, of TED including referral patterns from ophthalmologists and endocrinologists for infusion therapies.Methods:Rheumatologists practicing in the United States attended an educational session and agreed to complete a 12-item survey regarding TED awareness, referral patterns, and management.Results:Of the 47 rheumatologists surveyed, 45 (96%) were familiar with TED. Ten (21%) physicians reported managing patients with TED, but the majority of physicians (62%) reported that they co-managed other autoimmune diseases in patients who also had TED. Additionally, 98% and 64% of polled rheumatologists had received referrals from ophthalmologists and endocrinologists, respectively, for autoimmune disease management or infusion therapy. Ophthalmology referrals for intravenous (IV) medication administration were most frequently for biologics (82%), but some referrals were also made for corticosteroids (2%) or other medication (13%) infusions. Only 23% of rheumatologists had administered a biologic specifically for TED (rituximab: 17%, tocilizumab: 2%, other: 4%), but 89% expressed an interest in administering a TED-specific monoclonal antibody therapy, awaiting FDA approval.Conclusion:Nearly all surveyed rheumatologists were aware of the signs and symptoms of TED, although most did not actively manage or administer medication for TED. Given the high level of interest in infusing novel, TED-specific biologics, rheumatologists may become an integral part of TED patient management with the approval of a new biologic, teprotumumab, for thyroid eye disease.References:[1]Bartley GB, et al.Am J Ophthalmol1996;121:284-90.[2]Forbes G, et al.AJNR Am J Neuroradiol1986;7:651-656.[3]Simonsz HJ, et al.Strabismus1994;2:197-218.[4]Cardenas Roldan J, et al.Arthritis2012 2012;864907.Disclosure of Interests:Brian LaMoreaux Shareholder of: Horizon Therapeutics, Employee of: Horizon Therapeutics, Megan Francis-Sedlak Shareholder of: Horizon Therapeutics, Employee of: Horizon Therapeutics, Robert Holt Shareholder of: Horizon Therapeutics, Employee of: Horizon Therapeutics, James Rosenbaum Consultant of: AbbVie, Corvus, Eyevensys, Gilead, Novartis, Janssen, Roche, UCB Pharma; royalties from UpToDate

Sign in / Sign up

Export Citation Format

Share Document