Role In Pathogenesis Of Rheumatoid Arthritis Research Articles

Comprehensive TCR repertoire analysis of CD4+ T-cell subsets in rheumatoid arthritis

The pathogenesis of rheumatoid arthritis (RA), a systemic autoimmune disease characterized by autoreactive T-cell accumulation and pro-inflammatory cytokine overproduction, is unclear. Systematically addressing T-cell receptor (TCR) repertoires of different CD4+ T-cell subsets could help understand RA pathogenesis. Here, peripheral CD4+ T cells from treatment-naïve RA patients and healthy controls were sorted into seven subsets including naïve, effector, central memory, effector memory (EMT), Th1, Th17, and regulatory T cells. T-cell receptor β chain repertoires were then analyzed by next-generation sequencing. We identified T-cell clonal expansion in EMT and Th17 cells of RA patients, with highly similar TCR repertoires. Ex vivo experiments demonstrated the preferred differentiation from EMT to Th17 cells in RA. Notably, we showed that TCR diversity and abundance of differentiated T cells of Th17 were significantly correlated with RA disease activity. Based on these observations, we propose that abnormal differentiation from EMT to Th17 and expansion of Th17 play pivotal role in RA pathogenesis.

Association of Seropositivity and Mortality in Rheumatoid Arthritis and the Impact of Treatment With Disease‐Modifying Antirheumatic Drugs: Results From a Real‐World Study

ObjectiveSeropositivity for anti–citrullinated protein antibody (ACPA)/rheumatoid factor (RF) in rheumatoid arthritis (RA) is associated with increased overall mortality; however, the association between antibody titers and mortality is not well established. Investigating relationships between antibody titers and mortality may clarify their role in RA pathogenesis. This study was undertaken to evaluate the association of antibody titers with mortality and its modification by disease‐modifying antirheumatic drugs (DMARDs).MethodsEligible patients with established RA were identified through administrative claims data linked to laboratory results (2005–2016). Patients were categorized by positivity status for ACPA, RF, or both. Patients were further divided into groups by autoantibody titers. DMARD‐exposed patients were categorized into biologic DMARD (bDMARD) and conventional DMARD (cDMARD) subcohorts. Crude mortality rates/1,000 patient‐years and Kaplan‐Meier curves were compared between antibody categories. Adjusted Cox proportional hazards regression and sensitivity (propensity‐matched patients) analyses were conducted.ResultsOverall, 53,849 and 79,926 patients had evaluable ACPA and RF status, respectively. For both autoantibodies, mortality rates were significantly higher in seropositive versus seronegative patients (risk increase of 48.0% and 44.0% in ACPA‐ and RF‐positive patients, respectively; P < 0.001 each). Mortality rates were greatest in patients with higher versus lower autoantibody titers (ACPA hazard ratio [HR] 1.60 [95% confidence interval (95% CI]) 1.45–1.76]; RF HR 1.78 [95% CI 1.66–1.91]). In cDMARD‐exposed patients, HRs were higher in seropositive versus seronegative cohorts; in bDMARD‐exposed patients, there was no difference in mortality by serostatus.ConclusionElevated ACPA/RF titers were independently associated with increased mortality among patients with RA and persisted in patients treated with cDMARDs but not with bDMARDs.

Expression and activity of AIM2-inflammasome in rheumatoid arthritis patients.

AIM2 inflammasome activation leads to the release of IL-β, which plays an important role in rheumatoid arthritis pathogenesis. In this work, we evaluated AIM2 expression and activity in RA patients and healthy controls. AIM2 and RANKL expression were evaluated by flow cytometry. Inflammasome activity was determined in monocyte cultures stimulated with synthetic DNA by measuring IL-1β levels in supernatants using an ELISA assay. The caspase-1 expression in monocytes was measured by western blot, the POP3 expression was analysed by qPCR, and serum levels of IFN-γ were evaluated using ELISA assay. We observed a diminution of CD14+AIM2+ cells in RA patients, associated with disease activity and evolution. Likewise, the levels of IL-1β were increased in monocyte cultures un-stimulated and stimulated with LPS from RA patients with DAS28 ≥ 4. The Caspase-1 activity and RANKL + monocytes in RA patients were slightly increased. Finally, augmented POP3 expression and diminished IFN-γ serum levels were detected in RA patients. Our results showed that the monocytes from RA patients were prone to release IL-1β in the absence of the AIM2 inflammasome signal. The down-regulation of AIM2 to a systemic level in RA patients might be a consequence of augmented POP3 expression and might imply the survival of pro-inflammatory cells contributing to the inflammation process.

Dissecting the Role of NF-κb Protein Family and Its Regulators in Rheumatoid Arthritis Using Weighted Gene Co-Expression Network.

Rheumatoid arthritis (RA) is a chronic synovial autoinflammatory disease that destructs the cartilage and bone, leading to disability. The functional regulation of major immunity-related pathways like nuclear factor kappa B (NF-κB), which is involved in the chronic inflammatory reactions underlying the development of RA, remains to be explored. Therefore, this study has adopted statistical and knowledge-based systemic investigations (like gene correlation, semantic similarity, and topological parameters based on graph theory) to study the gene expression status of NF-κB protein family (NKPF) and its regulators in synovial tissues to trace the molecular pathways through which these regulators contribute to RA. A complex protein–protein interaction map (PPIM) of 2,742 genes and 37,032 interactions was constructed from differentially expressed genes (p ≤ 0.05). PPIM was further decomposed into a Regulator Allied Protein Interaction Network (RAPIN) based on the interaction between genes (5 NKPF, 31 seeds, 131 hubs, and 652 bottlenecks). Pathway network analysis has shown the RA-specific disturbances in the functional connectivity between seed genes (RIPK1, ATG7, TLR4, TNFRSF1A, KPNA1, CFLAR, SNW1, FOSB, PARVA, CX3CL1, and TRPC6) and NKPF members (RELA, RELB, NFKB2, and REL). Interestingly, these genes are known for their involvement in inflammation and immune system (signaling by interleukins, cytokine signaling in immune system, NOD-like receptor signaling, MAPK signaling, Toll-like receptor signaling, and TNF signaling) pathways connected to RA. This study, for the first time, reports that SNW1, along with other NK regulatory genes, plays an important role in RA pathogenesis and might act as potential biomarker for RA. Additionally, these genes might play important roles in RA pathogenesis, as well as facilitate the development of effective targeted therapies. Our integrative data analysis and network-based methods could accelerate the identification of novel drug targets for RA from high-throughput genomic data.

Anti-TNFα Biologics in the Pharmacotherapy of Rheumatoid Arthritis: Effectiveness and Safety of Infliximab, Adalimumab and Etanercept

Rheumatoid arthritis (RA) is a chronic inflammatory disease of unknown etiology. Traditionally, pharmacotherapy of RA involved non-steroidal anti-inflammatory drugs (NSAIDs) and disease-modifying antirheumatic drugs (DMARDs). However, focus now has been diverted to biologic DMARDs. Tumor necrosis factor alpha (TNFα) plays pleiotropic roles in RA pathogenesis. Hence, anti-TNF biologics offer attractive therapeutic utility. Literature contains numerous studies comparing either the effectiveness or the safety of the three drugs of interest; infliximab, adalimumab and etanercept, in terms of; patient response to treatment in a cohort and in vitro properties of the drugs. Concern at the absence of a review that comprehensively exploits both the effectiveness and safety, this review aims towards not only presenting the observed discrepancies, but also discussing the causes for them and providing experimental results from studies obtained via an extensive literature survey. Critical analysis of the effectiveness and safety profiles of licensed anti-TNF agents; infliximab, adalimumab and etanercept revealed that, a single drug cannot be named as the most efficacious. Nevertheless, anti-TNF therapy associates challenges of systemic toxicity, heterogenous patient response and partial remission. Advancement in research aiming at alleviating the existing drawbacks of anti-TNF therapy is essential.

Long Non-Coding RNAs Target Pathogenetically Relevant Genes and Pathways in Rheumatoid Arthritis.

Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease driven by genetic, environmental and epigenetic factors. Long non-coding RNAs (LncRNAs) are a key component of the epigenetic mechanisms and are known to be involved in the development of autoimmune diseases. In this work we aimed to identify significantly differentially expressed LncRNAs (DE-LncRNAs) that are functionally connected to modulated genes strictly associated with RA. In total, 542,500 transcripts have been profiled in peripheral blood mononuclear cells (PBMCs) from four patients with early onset RA prior any treatment and four healthy donors using Clariom D arrays. Results were confirmed by real-time PCR in 20 patients and 20 controls. Six DE-LncRNAs target experimentally validated miRNAs able to regulate differentially expressed genes (DEGs) in RA; among them, only FTX, HNRNPU-AS1 and RP11-498C9.15 targeted a large number of DEGs. Most importantly, RP11-498C9.15 targeted the largest number of signalling pathways that were found to be enriched by the global amount of RA-DEGs and that have already been associated with RA and RA–synoviocytes. Moreover, RP11-498C9.15 targeted the most highly connected genes in the RA interactome, thus suggesting its involvement in crucial gene regulation. These results indicate that, by modulating both microRNAs and gene expression, RP11-498C9.15 may play a pivotal role in RA pathogenesis.

Evaluation of Toll-like Receptor 2 Gene Expression in Rheumatoid Arthritis and Correlation with the Disease Activity

Background: Rheumatoid Arthritis (RA) is an autoimmune, chronic, and systematic disease. It affects joints and bones. The exact etiology of RA is still unclear. Varied genetic and environmental factors have been associated with the increased risk for RA. Overactivation of Toll-Like Receptors (TLRs) could initiate the development of autoimmune diseases including RA. Objective: The aim of the study was to evaluate TLR2 gene expression in rheumatoid arthritis patients and investigate its correlation with the disease activity. Materials and Methods: This study included 60 patients and 20 healthy individuals. The patients were diagnosed with RA according to the 2010 American College of Rheumatology/ European League Against Rheumatism criteria (ACR/EULAR). All included subjects did not have any joint disorders and /or autoimmune diseases. RA disease activity was determined by the disease activity score of 28 joints. Whole blood was collected from all participants. Total RNA extraction was done. TLR2 mRNA expression was assessed by reverse transcription-PCR (RT-PCR). Results: TLR2 mRNA expression was found to be significantly higher in RA patients compared to healthy controls. Also, a strong positive correlation was found between TLR2 expression level and the disease activity score. A non significant positive correlation was found between TLR2 expression and serum Rheumatoid Factor (RF) level. Conclusion: TLR2 pathway may have an important role in RA pathogenesis and could be a new biomarker for diagnosis and monitoring disease activity.

Role of interleukin-35 in rheumatoid arthritis pathogenesis and its relation to disease activity and joint damage

AimThis study aimed to discuss the role of interleukin-35 (IL-35) in the pathogenesis of rheumatoid arthritis (RA) and its relation to disease activity and radiological severity.Patients and methodsThirty patients diagnosed with RA were selected from the outpatient clinic and inpatient unit of Physical Medicine, Rheumatology and Rehabilitation Department, Tanta University Hospitals fulfilling the American College of Rheumatology/ European League Against Rheumatism 2010 criteria for the diagnosis of RA, and 20 apparently healthy individuals who were matched in age and sex participated as controls. Patients with other autoimmune diseases, malignancy, or any current infections were excluded. Disease activity score in 28 joints was assessed for all patients. Rheumatoid factor, anticyclic citrullinated peptide, complete blood count, erythrocyte sedimentation rate and C-reactive protein and serum level of IL-35 measured by enzyme-linked immunosorbent assay were evaluated. The degree of joint destruction was assessed by Larsen score.ResultsOf the RA patients, 73.3%showed low serum levels of IL-35 with significant difference compared with controls, and its levels showed negative association with disease activity. IL-35 serum levels were significantly correlated with hemoglobin level, erythrocyte sedimentation rate, C-reactive protein, and rheumatoid factor and not correlated with anticyclic citrullinated peptide antibodies. Also IL-35 serum levels significantly correlated with radiological disease severity were assessed by Larsen score.ConclusionIL-35 had an immunoregulatory role in RA pathogenesis as its serum level is significantly low in RA patients and correlated with different parameters of disease activity and radiological severity.

ACPAs promote IL-1β production in rheumatoid arthritis by activating the NLRP3 inflammasome.

Anti-citrullinated protein antibodies (ACPAs) are a group of autoantibodies targeted against citrullinated proteins/peptides and are informative rheumatoid arthritis (RA) biomarkers. ACPAs also play a crucial role in RA pathogenesis, and their underlying mechanism merits investigation. Immunohistochemical (IHC) assays were carried out to determine IL-1β levels in ACPA+ and ACPA- RA patients. PBMC-derived monocytes were differentiated into macrophages before stimulation with ACPAs purified from RA patients. The localization and interaction of molecules were analyzed by confocal microscopy, co-IP, and surface plasmon resonance. In our study, we found that IL-1β levels were elevated in ACPA+ RA patients and that ACPAs promoted IL-1β production by PBMC-derived macrophages. ACPAs interacted with CD147 to enhance the interaction between CD147 and integrin β1 and, in turn, activate the Akt/NF-κB signaling pathway. The nuclear localization of p65 promoted the expression of NLRP3 and pro-IL-1β, resulting in priming. Moreover, ACPA stimulation activated pannexin channels, leading to ATP release. The accumulated ATP bound to the P2X7 receptor, leading to NLRP3 inflammasome activation. Our study suggests a new hypothesis regarding IL-1β production in RA involving ACPAs, which may be a potential therapeutic target in RA treatment.

Regulatory effects of paeoniflorin-6'-O-benzene sulfonate (CP-25) on dendritic cells maturation and activation via PGE2-EP4 signaling in adjuvant-induced arthritic rats.

Rheumatoid arthritis (RA) is a chronic, systemic autoimmune disease. Dendritic cells (DCs) are one of the most powerful antigen-presenting cells, and they play an important role in RA pathogenesis. Prostaglandin E2 (PGE2) is a potent lipid mediator that can regulate the maturation and activation of DCs, but the molecular mechanisms have not been elucidated. In this study, both in vitro and in an RA rat model, we investigated the mechanisms involved by focusing on PGE2-mediated signaling and using a novel anti-inflammatory compound, paeoniflorin-6'-O-benzene sulfonate (CP-25). PGE2 combined with tumor necrosis factor-α promoted DC maturation and activation through EP4-cAMP signaling. Treatment with CP-25 increased the endocytic capacity of DCs induced by PGE2. CP-25 inhibited the potency of DCs induced by the EP4 receptor agonist, CAY10598, to stimulate allogeneic T cells. Consistent with these findings, the CAY10598-induced upregulation of DC surface activation markers and production of IL-23 was significantly inhibited by CP-25 in a concentration-dependent manner. In vivo administration of CP-25 alleviated adjuvant arthritis (AA) in rats through inhibition of DC maturation and activation. Our results indicate that PGE2-EP4-cAMP signal hyperfunction can lead to abnormal activation of DC functions, which correlates with the course of disease in AA rats and provides a possible treatment target. The inhibition of DC maturation and activation by CP-25 interference of the PGE2-EP4 pathway may significantly contribute to the immunoregulatory profile of CP-25 when used to treat RA and other immune cell-mediated disorders.

Differential expression and regulation of the non-integrin 37/67-kDa laminin receptor on peripheral blood leukocytes of healthy individuals and patients with rheumatoid arthritis

The non-integrin 37/67-kDa laminin receptor (LAMR1) is a complex protein with diverse functions. LAMR1 is widely expressed in epithelial cells and recently it was reported on neutrophils and a subset of activated T cells. Ligation of LAMR1 on peripheral blood mononuclear cells (PBMC) downregulated LPS-induced TNFα production, suggesting immune functions. However, its expression on primary monocytes remain unknown. Interestingly, LAMR1 mRNA is downregulated in PBMC of patients with early rheumatoid arthritis (RA), and low gene expression is an independent predictor of poor response to anti-TNFα treatment, suggesting a role in RA pathogenesis. We found LAMR1 was constitutively expressed on all peripheral blood monocytes and a subset of B cells from healthy individuals and patients with RA and it was abundantly present in synovial tissue of patients with RA. On monocytes and synovial tissue lower levels of LAMR1 expression tended to correlate with increased disease activity scores. In vitro treatment of monocytes with IFNγ or IL-10 up-regulated surface LAMR1 in healthy individuals and patients with RA with greater effects observed in healthy individuals. Importantly, treatment with IFNγ significantly increased specific binding of monocytes to laminin-1. TNFα and IL-1β caused marginal downregulation of LAMR1 in patients but effects in controls were variable. Taken together, constitutively expressed LAMR1 on monocytes is differentially regulated by pro-inflammatory and immune-regulatory cytokines suggesting LAMR1 may regulate the threshold and amplitude of their activation and migration. Decreased levels in patients with RA may indicate loss of this potentially critical homeostatic regulation thereby contributing to the excessive inflammation.

Diet, Microbiota, and Gut Permeability-The Unknown Triad in Rheumatoid Arthritis.

Growing experimental and clinical evidence suggests that a chronic inflammatory response induced by gut dysbiosis can critically contribute to the development of rheumatic diseases, including rheumatoid arthritis (RA). Of interest, an adherence to a Mediterranean diet has been linked to a reduction in mortality and morbidity in patients with inflammatory diseases. Diet and intestinal microbiota are modifying factors that may influence intestinal barrier strength, functional integrity, and permeability regulation. Intestinal microbiota may play a crucial role in RA pathogenesis, but up to now no solid data has clarified a mechanistic relationship between gut microbiota and the development of RA. Nonetheless, microbiota composition in subjects with RA differs from that of controls and this altered microbiome can be partially restored after prescribing disease modifying antirheumatic drugs. High levels of Prevotella copri and similar species are correlated with low levels of microbiota previously associated with immune regulating properties. In addition, some nutrients can alter intestinal permeability and thereby influence the immune response without a known impact on the microbiota. However, critical questions remain to be elucidated, such as the way microbiome fluctuates in relation to diet, and how disease activity may be influenced by changes in diet, microbiota or diet-intestinal microbiota equilibrium.

Effect of genetically modified gene tolerant dendritic cell therapy on some blood parameters in experimental mouse arthritis model

Rheumatoid arthritis (RA) is an inflammatory autoimmune disease that causes chronic pain and joint destruction. T cells activation has an important role in RA pathogenesis. Activation of T lymphocytes requires the co-stimulatory signals provided by antigen-presenting cells. T-cell activation without co-stimulation results in anergy. In this study, to inhibit the activation of T lymphocytes formed in the experimental arthritis, tolerogenic dendritic cells were aimed to be obtained by the genetical modification of dendritic cells with CTLA4-KDEL overexpression in endoplasmic reticulum. Then, RA created animals treated with tolDCs and the effect of treatment on blood parameters were investigated.For this purpose, mouse collagen induced arthritis model was used. The mice with arthritis were intraarticularly treated with modified tolDCs. It was observed that the treatment group significantly reversed the increase in the joint thickness and the increase in the number of white blood cells, especially with the increase in neutrophils when compared with control groups.As a result, genetically modified tolDCs reduced the clinical symptoms of experimental arthritis and also reversed the changes in blood parameters due to experimental arthritis in mice.

Small RNAs detected in exosomes derived from the MH7A synovial fibroblast cell line with TNF-α stimulation.

Rheumatoid arthritis (RA) is an autoimmune disease that causes the chronic inflammation of the joints. Intercellular communication containing synovial fibroblasts seems to play a major role in RA pathogenesis. In this study, to better understand intercellular communication related to RA pathogenesis, we identified exosomal microRNAs (miRNAs) derived from synovial fibroblasts. Exosomes were collected from an RA synovial fibroblast (RASF) cell line, namely, MH7A, with or without stimulation by tumor necrosis factor alpha (TNF-α). We used small RNA sequencing to analyze the profile of small RNAs, including miRNAs, in MH7A exosomes and cells. By using differential expression analysis, we identified four miRNAs (miR-155-5p, miR-146a-5p, miR-323a-5p, and miR-1307-3p) that are upregulated in exosomes with TNF-α stimulation. The identification of miR-155-5p and miR-146a-5p which have been reported in RA patients demonstrated the validity of our experimental model. Other two miRNAs were newly identified. miR-323a-5p was predicted to target the protein encoding gene CD6, which attenuates T-cell activation signals, and miR-1307-3p was predicted to target the protein encoding gene N-myc downstream-regulated gene 2 (NDRG2), which inhibits osteoclast-related gene expression. The results suggested that these miRNAs might be involved in RA pathogenesis. We hope our results will help us understand the role of RASF exosomes in RA pathogenesis.

Role of CXCL13 and CCL20 in the recruitment of B cells to inflammatory foci in chronic arthritis

BackgroundB cells exert their pathogenic action in rheumatoid arthritis (RA) locally in the synovium. This study was undertaken to elucidate the chemokines responsible for the recruitment of B cells in the inflamed synovium, taking into account that the rich chemokine milieu present in the synovial tissue can fine-tune modulate discrete chemokine receptors.MethodsExpression levels of chemokine receptors from the CC and CXC family, as well as CD27, were assessed by flow cytometry in CD20+ mononuclear cells isolated from the peripheral blood (PB) and synovial fluid (SF) of RA and psoriatic arthritis patients. Transwell experiments were used to study migration of B cells in response to a chemokine or in the presence of multiple chemokines.ResultsB cells from the SF of arthritis patients showed a significant increase in the surface expression of CCR1, CCR2, CCR4, CCR5 and CXCR4 with respect to PB. Conversely, SF B cells expressed consistently lower amounts of CXCR5, CXCR7 and CCR6, independent of CD27 expression. Analysis of permeabilized B cells suggested internalization of CXCR5 and CCR6 in SF B cells. In Transwell experiments, CCL20 and CXCL13, ligands of CCR6 and CXCR5, respectively, caused a significantly higher migration of B cells from PB than of those from SF of RA patients. Together, these two chemokines synergistically increased B-cell migration from PB, but not from SF.ConclusionsThese results suggest that CXCL13 and CCL20 might play major roles in RA pathogenesis by acting singly on their selective receptors and synergistically in the accumulation of B cells within the inflamed synovium.

The correlation between rheumatoid factor and anti cyclic citrullinated peptides with gene expression of FoxP3 in rheumatoid artheritis patients

Introduction: Rheumatoid arthritis (RA) is a chronic autoimmune disorder that affect 1-2% of people worldwide. Inflammation is an important factor in the pathogenesis of RA. Anti- Cyclic Citrullinated Peptid (Anti-CCP) antibody and Rheumatoid Factor (RF) are autoantibodies that promotes inflammatory reactions and have a crucial role in RA pathogenesis. Treg cells are necessary for the maintenance of immune homeostasis and prevention of autoimmunity. FoxP3 is essential transcription factor for development of these regulatory cells. In this study, we surveyed the effects of FoxP3 gene expression in peripheral blood on plasma levels of Anti-CCP and RF. Methods: Peripheral blood samples were collected from 47 patients and 44 healthy subjects. Then plasma levels of Anti-CCP have been evaluated using ELISA method. Also RF was detected with latex agglutination test, and gene expression of FoxP3 analyzed by real time PCR . Results: The amount of Anti-CCP and RF were significantly higher in our patients in comparison with healthy subjects (P<0.001) and (P< 0.001) respectively. Also significant reverse correlation between RF and Anti-CCP with gene expression of FoxP3 have been shown in our study (r: -0.630, r: -0.584) respectivly. The sensitivity and specificity of Anti-CCP and RF was (89.1%, 86.95%) and (91.3%, 91.1%) respectively for the diagnosis of RA. Conclusion: Our data illustrated that FoxP3 gene expression have reverse significant correlation with plasma concentration of anti-CCP and RF.

Association of interleukin-6 and its -174G/C promoter polymorphism with clinical and laboratory characteristics of non hepatitis C virus rheumatoid arthritis patients

BackgroundInterleukin-6 is a cytokine protein, which causes inflammation, maintains immune homeostasis and shows a role in rheumatoid arthritis pathogenesis. IL-6-174G/C promoter polymorphism may have a role in susceptibility to RA. Aim of the workTo evaluate the clinical significance of serum levels of IL-6 and its -174G/C promoter polymorphism in RA patients in comparison with the controls. Patients and methodsThis study enrolled 25 non hepatitis C virus RA patients versus 25 age and gender matched controls. Demographic, clinical and laboratory data were prospectively evaluated. Serum IL-6 level and promoter (-174G/C) genotype were determined. ResultsSerum IL-6 levels was significantly higher in RA patients compared to control subjects (p = .001), especially those with CC promoter polymorphism. There was a significant correlation between IL and 6 level and duration of morning stiffness, disease activity, hemoglobin concentration and ESR level. 15/25 patients had (-174G/G) gene promoter polymorphism, 8/25 were GC and 2/25 were CC. All controls were GG. There was significant association between gene polymorphism and age at disease onset (p = .0172), which was older in those with GG genotype (38.5 ± 10.25 years) than those with CC (33.5 ± 0.71 years) and younger in GC genotypes (27.9 ± 7.9 years). None of the other clinical, laboratory or radiological parameters would predict the IL-6 promoter polymorphism. ConclusionSerum IL-6 levels and -174G/C promoter polymorphism were higher in RA patients than in healthy controls. The positive correlation of IL-6 level with the DAS28 and duration of morning stiffness may confirm its’ increased involvement in the pathogenesis of RA and may point to the need for considering of anti-IL-6 agents in their management plan. The negative correlation of IL-6 level with the hemoglobin level may confirm IL-6 play a significant role in anemia of RA.

THE ASSOCIATION OF EPSTEIN-BARR VIRUS ANTIBODIES WITH RHEUMATOID ARTHRITIS AMONG YEMENI PATIENTS IN SANA’A CITY

Objectives: Rheumatoid arthritis (RA) is a chronic autoimmune disease that is associated with progressive disability, systemic complications and early death. Etiology of RA is unknown. It is assumed that environmental factors initiate RA development in genetically susceptible individuals. Epstein- Barr Virus (EBV) stimulates polyclonal B cell activation and has been suggested to play a role in RA pathogenesis. Current study aimed to study the association between EBV and RA. Methods: One hundred and sixty subjects were enrolled in the study. Eighty individuals were clinically diagnosed to have RA and confirmed by anti-CCP3 test. The remaining 80 individuals were healthy controls matched for age and sex. Serum IgG and IgM antibodies against EBV viral capsid antigen (VCA) were tested by an enzyme-linked immunosorbent assay (ELISA). Results: The crude prevalence rate of EBV-VCA IgM antibodies among patients was (21.2%) while in healthy individuals was (8.7%) with significant OR equals to 2.8 times for RA patient's. The female prevalence rate of EBV-VCA IgM antibodies was (21.8%) higher than of male (18.7%). The female prevalence rate of EBV-VCA IgG antibodies was (95.3%) higher than of male (75%). EBV-VCA IgG and IgM antibodies titers were elevated in RA patients than in healthy controls. However, the causative relationship between EBV and RA is complex and involves different mechanisms. Conclusion: In conclusion, high titers of EBV antibodies are associated with RA. However, the causative relationship between EBV and autoimmune diseases is complex and involves different mechanisms. Peer Review History: Received 16 August; Revised 28 August; Accepted 5 September, Available online 15 September 2017 Academic Editor: Dr. Amany Mohamed Alboghdadly, Princess Nourah bint abdulrahman university, Riyadh, amalbgadley@pnu.edu.sa UJPR follows the most transparent and toughest ‘Advanced OPEN peer review’ system. The identity of the authors and, reviewers will be known to each other. This transparent process will help to eradicate any possible malicious/purposeful interference by any person (publishing staff, reviewer, editor, author, etc) during peer review. As a result of this unique system, all reviewers will get their due recognition and respect, once their names are published in the papers. We expect that, by publishing peer review reports with published papers, will be helpful to many authors for drafting their article according to the specifications. Auhors will remove any error of their article and they will improve their article(s) according to the previous reports displayed with published article(s). The main of it is ‘to improve the quality of a candidate manuscript’. Our reviewers check the ‘strength and weakness of a manuscript honestly’. There will increase in the perfection, and transparency. Received file: Reviewer's Comments: Average Peer review marks at initial stage: 5.5/10 Average Peer review marks at publication stage: 8.0/10 Reviewer(s) detail: Dr. Mujde Eryilmaz, Ankara University,Turkey, meryilmaz@ankara.edu.tr Dr. Tamer Elhabibi, Suez Canal University, Egypt, tamer_hassan@pharm.suez.edu.eg Similar Articles: SEROPREVALENCE OF ANTI-MANNOSE BINDING LECTIN AUTOANTIBODIES IN PATIENTS WITH RHEUMATOID ARTHRITIS IN SANA'A CITY- YEMEN

NLRC5 promotes cell proliferation via regulating the NF-κB signaling pathway in Rheumatoid arthritis

Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disease and the pathogenesis remains unclear. Previous studies suggested that fibroblast-like synoviocytes (FLSs) play an important role in RA pathogenesis, including the injury of cartilage, the hyperplasia of the synovium and the release of inflammatory cytokines. We used complete Freund’s adjuvant (CFA) induced rats as animal models for studying the RA pathogenesis. NLRC5 as the largest member of the NLR family has been reported to play a critical role in regulating immune responses. Increasing evidence suggests that NLRC5 is an pivotal negative modulator of inflammatory pathways. We investigated the mechanisms and signaling pathways of NLRC5 in RA progression. Significantly increased expression of NLRC5 was found in AA rats synovial tissues and cells. And high expression of inflammatory cytokine and cell proliferation of FLSs accompanied with NLRC5 overexpression, but inhibited in cells with NLRC5 silencing treatment. Interestingly, we found that overexpression of NLRC5 also coordinated the activation of NF-κB signaling pathway. These results suggested that NLRC5 promotes RA progression via the NF-κB signaling pathway potentially.

Thymosin β4 in rheumatoid arthritis: Friend or foe.

Rheumatoid arthritis (RA) has characteristic pannus tissues, which show tumor-like growth of the synovium through chronic joint inflammation. The synovium is highly penetrated by various immune cells, and the synovial lining becomes hyperplastic due to increased numbers of macrophage-like and fibroblast-like synoviocytes. Thus, a resultant hypoxic condition stimulates the expression of inflammation-related genes in various cells, in particular, vascular endothelial growth factor. Thymosin β4 (Tβ4), a 5-kDa protein, is known to play a significant role in various biological activities, such as actin sequestering, cell motility, migration, inflammation, and damage repair. Recent studies have provided evidence that Tβ4 may have a role in RA pathogenesis. The Tβ4 level has been shown to increase significantly in the joint fluid and serum of RA patients. However, whether Tβ4 stimulates or inhibits activation of RA immune responses remains to be determined. In the present study, we discuss the logical and clinical justifications for Tβ4 as a potential target for RA therapeutics.