scholarly journals Gαq Regulates the Development of Rheumatoid Arthritis by Modulating Th1 Differentiation

2017 ◽  
Vol 2017 ◽  
pp. 1-9 ◽  
Author(s):  
Dashan Wang ◽  
Yuan Liu ◽  
Yan Li ◽  
Yan He ◽  
Jiyun Zhang ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Bone Marrow ◽  
Immune Regulation ◽  
Inflammatory Arthritis ◽  
Mammalian Cells ◽  
Th1 Cells ◽  
Th1 Cell ◽  
Th1 Cytokine ◽  
Negative Role

The Gαq-containing G protein, an important member ofGq/11class, is ubiquitously expressed in mammalian cells. Gαq has been found to play an important role in immune regulation and development of autoimmune disease such as rheumatoid arthritis (RA). However, how Gαq participates in the pathogenesis of RA is still not fully understood. In the present study, we aimed to find out whether Gαq controls RA via regulation of Th1 differentiation. We observed that the expression of Gαq was negatively correlated with the expression of signature Th1 cytokine (IFN-γ) in RA patients, which suggests a negative role of Gαq in differentiation of Th1 cells. By using Gαq knockout (Gnaq−/−) mice, we demonstrated that loss of Gαq led to enhanced Th1 cell differentiation. Gαq negative regulated the differentiation of Th1 cell by modulating the expression of T-bet and the activity of STAT4. Furthermore, we detected the increased ratio of Th1 cells inGnaq−/−bone marrow (BM) chimeras spontaneously developing inflammatory arthritis. In conclusion, results presented in the study demonstrate that loss of Gαq promotes the differentiation of Th1 cells and contributes to the pathogenesis of RA.

scholarly journals THU0517 THE ROLE OF ULTRASOUND-DEFINED SYNOVITIS GRADE I IN PATIENTS PRESENTING WITH INFLAMMATORY ARTHRALGIA, A RETROSPECTIVE STUDY

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 497.2-497
Author(s):  
J. Arroyo Palomo ◽  
M. Arce Benavente ◽  
C. Pijoan Moratalla ◽  
B. A. Blanco Cáceres ◽  
A. Rodriguez
Keyword(s):  
Rheumatoid Arthritis ◽  
Inflammatory Arthritis ◽  
Statistical Tests ◽  
Median Number ◽  
Painful Joint ◽  
Significant Difference ◽  
The Mean ◽  
Specialized Unit

Background:Musculoeskeletal ultrasound (MSUS) is frequently used in several rheumatology units to detect subclinical inflammation in patients with joint symptoms suspected for progression to inflammatory arthritis (IA). Synovitis grade I (EULAR-OMERACT combined score) is known to be a casual finding in healthy individuals, but studies headed to unravel its possible role on rheumatic diseases are sparse.Objectives:To investigate the correlation between synovitis grade I, and the diagnosis of IA made after a year follow-up period since MSUS findings, in patients of an MSUS-specialized unit of a Rheumatology Department.Methods:We conducted a descriptive, retrospective and unicentric study. 30 patients were selected from the MSUS-specialized unit of our Rheumatology Department from July-18 to January-19. Patients presenting synovitis grade 0 (exclusively), 2 and/or 3 on combined score were excluded. Data collection at baseline included age, sex, immunological profile and previous physical examination to the MSUS findings, as well as the diagnosis made by the rheumatologist in 1-year visit follow-up: dividing the patient sample into two groups: those who were diagnosed with IA and those not. Non-parametric statistical tests for comparing means were used.Results:The mean age was 51,6 years and 70% were females. 6 (20%) patients were diagnosed with inflammatory arthritis after a year follow-up: 2 (4,8%) psoriatic arthritis, 1 (3,3%) undifferentiated arthritis, 1 (3,3%) rheumatoid arthritis, 1 (3,3%) Sjögren’s syndrome. Non-inflammatory arthropathies were also found 24 (80%), of which, 12 (40%) were non-specific arthralgias and 8 (19%) osteoarthritis.In the group of patients who did not developed an IA the mean C-reactive protein (CPR) value was 3,12 mg/L and erythrocyte sedimentation rate (ESR) was 8,2 mm; all of them were rheumatoid factor (RF) positive and ACPA-negative except one patient. 5 (31,3%) patients presented low antinuclear antibodies (ANAs) levels. In those who HLA B-27 and Cw6 were tested (4,25%); both were negative except for one that was HLA B-27 positive. The median number of swollen and painful joint count was 0, and the mean of joints with MSUS involvement was 3,5; the mean involved metacarpophalangeal (MCP) joints was 1,83; proximal interphalangeal (PIP) joints was 1,48 and distal interphalangeal (DIP) joints 0,21.Among the group of patients that developed an IA the mean of CPR and ESR was 9,27 mg/L and 14,17 mm respectively; 2 (33%) patients were RF- positive, and 1 ACPA-positive. ANAs were positive in 3 cases (50%). The median of swollen joint count was 2 and for painful joint count was 0, the median of joints with MSUS involvement was 4,5. The mean of MSUS involvement was for MCP, PIP and DIP joints: 1,67, 2 and 0. Comparing the means of CPR values in the two groups with Student’s t-test we obtained a statistically significant difference (p=0,023). No other significant differences were found.Conclusion:Despite the limitations and possible statistical bias, the presence of MSUS-defined synovitis grade I and elevated CRP levels could be related to further diagnoses of inflammatory arthropathy. Besides, the absence of synovitis in DIP joints might have a diagnostic role. Normal physical exploration and normal levels of CRP might suggest low MSUS value. However, further research is needed to clarify the role of MSUS-defined synovitis grade I.References:[1]D’Agostino MA et al. Scoring ultrasound synovitis in rheumatoid arthritis: a EULAR-OMERACT ultrasound taskforce-Part 1: definition and development of a standardized, consensus-based scoring system. RMD Open. 2017;3(1):e000428.[2]Van den Berg R et al. What is the value of musculoskeletal ultrasound in patients presenting with arthralgia to predict inflammatory arthritis development? A systematic literature review. Arthritis Research & Therapy (2018) 20:228.Disclosure of Interests:None declared

scholarly journals P05 Involving patients in the discussion about results from the National Early Inflammatory Arthritis Audit

Rheumatology ◽  
2020 ◽  
Vol 59 (Supplement_2) ◽  
Author(s):  
Oliver Wade ◽  
Jack Loh ◽  
Joshua Withers ◽  
Sarah Fish ◽  
Elizabeth MacPhie
Keyword(s):  
Rheumatoid Arthritis ◽  
Inflammatory Arthritis ◽  
First Year ◽  
Quality Improvements ◽  
North West ◽  
Patient Support Group ◽  
Patient Pathway ◽  
The North ◽  
Early Inflammatory Arthritis

Abstract Background The National Early Inflammatory Arthritis Audit (NEIAA) has provided the opportunity for rheumatology services to benchmark the care they provide. It provides a mechanism to identify where services can make improvements and to raise awareness about inflammatory arthritis. We felt it important to share our results with patients and involve patients in the discussion about how we improve the service we deliver. This project outlines how we went about doing this. Methods Data submitted to the NEIAA online tool were downloaded for analysis. This included all patients recruited during the first year of the audit. Results were presented initially to the Rheumatology Multi-Disciplinary Team. Driver diagrams were developed by the team and areas for improvement identified. A patient poster for the waiting area was also developed. This provided information about our performance in the audit and what changes we were looking to make. Results, driver diagrams and the patient poster were then presented to our National Rheumatoid Arthritis Society (NRAS) patient support group at one of their lunchtime meetings. We met again two weeks later with members from the patient group to get feedback on the driver diagrams and patient poster. Results Results from the first year of the audit demonstrated that there was significant room for improvement across all seven quality standards. Driver diagrams identified areas for improvement across the whole patient pathway. Forty-five patients and carers attended the lunchtime meeting presentation. Patients identified various areas where they could get involved with improving the patient pathway. These included putting up posters in the community to raise awareness about rheumatoid arthritis and running another Rheumatoid Arthritis Awareness Day. Other proposals were to provide more lunchtime meetings to improve understanding about the condition and management and promote aspects of self-management and developing the role of the Expert Patient locally to support newly diagnosed patients. The patient poster received lots of positive comments, it was suggested that we remove any statistics which might cause alarm and be difficult to interpret and to focus on what quality improvements had already happened locally. Conclusion Involving patients in the discussion has been a fascinating and rewarding experience. Patients have been empowered and their input has been valued. Patients have provided additional suggestions as to how they can get involved to support the service and improve the patient pathway. The patient poster now tells a positive story and acknowledges our unsatisfactory performance in the first year of the audit and more importantly focuses on what we are doing to improve the service we deliver. Disclosures O. Wade None. J. Loh None. J. Withers None. S. Fish None. E. MacPhie Other; EM is the secretary of the North West Rheumatology Club; meetings are supported by an unrestricted educational grant from UCB.

scholarly journals The Role of Intracellular Organisms in the Pathogenesis of Inflammatory Arthritis

2014 ◽  
Vol 2014 ◽  
pp. 1-8 ◽  
Author(s):  
Animesh Singh ◽  
Sarah Karrar
Keyword(s):  
Rheumatoid Arthritis ◽  
Reactive Arthritis ◽  
Inflammatory Arthritis ◽  
Molecular Mimicry ◽  
Joint Inflammation ◽  
Joint Space ◽  
Low Grade ◽  
Infectious Episode ◽  
Persistent Symptoms

Inflammatory arthritis is a condition which is characterised by recurrent episodes of joint pain and swelling. It encompasses a spectrum of disorders ranging from rheumatoid arthritis to ankylosing spondylitis. In these conditions, for reasons that are poorly understood, the immune system raises an inflammatory response within the joint space. In some cases, autoantigens have been identified (e.g., anticitrullinated peptides in rheumatoid arthritis), but the absence of these, in the seronegative arthritides, for example, raises question as to the underlying pathogenesis. Interest has, therefore, turned to host-pathogen interactions and whether aberrant immune responses to these could explain the development of arthritis. This has been most widely studied in reactive arthritis (ReA), where an infectious episode precedes the development of the joint symptoms. In this review, we present the evidence for the role of host-bacterial interactions in the pathogenesis of joint inflammation with particular emphasis on ReA. We discuss a range of possible mechanisms including molecular mimicry, persistent low grade infections, and abnormal host responses to common bacterial causes of reactive arthritis as well as discussing some of the clinical challenges that we face in making the diagnosis and in treatment of persistent symptoms.

scholarly journals P222 Vitamin D in early rheumatoid arthritis

Rheumatology ◽  
2020 ◽  
Vol 59 (Supplement_2) ◽  
Author(s):  
Stephanie R Harrison ◽  
Gurpreet Jutley ◽  
Danyang Li ◽  
Ilfita Sahbudin ◽  
Andrew Filer ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Vitamin D ◽  
Disease Activity ◽  
Inflammatory Arthritis ◽  
Demographic Data ◽  
Vitamin D Metabolites ◽  
Serum 25Ohd ◽  
Early Ra ◽  
Baseline Demographic

Abstract Background Rheumatoid arthritis (RA) is the commonest chronic inflammatory arthritis, predominantly affecting small/medium joints and associated with extra-articular features. Previous studies have linked RA risk and disease activity with vitamin D-deficiency, but a causal role for vitamin D in RA is still unclear, partly due to heterogeneous study methods and sample populations. Moreover, no studies have focused specifically on vitamin D status (serum levels of 25-hydroxyvitamin D, 25OHD) in early RA, or whether low 25OHD is linked to progression from undifferentiated inflammatory arthritis to RA. Our objectives were therefore (1) to analyse serum 25OHD in early inflammatory arthritis, (2) to compare 25OHD levels with disease activity and fatigue in early RA and (3) to determine whether low serum 25OHD is associated with progression to RA. Methods We analysed 791 patients enrolled in the Birmingham Early Arthritis Cohort from 2013-19 at Sandwell and West Birmingham Hospitals NHS Trust and University Hospitals Birmingham NHS Trust. We collect baseline demographic data, serum 25OHD (ng/ml), and clinical variables including: duration of symptoms, duration of early morning stiffness (EMS), CRP, ESR, anti-CCP antibody status, Rheumatoid factor status, tender and swollen joint counts, DAS28-ESR, DAS28-CRP, Visual Analogue Scale (VAS) pain/fatigue and FACIT scores. Diagnosis was recorded at 0 and 12 months onwards as either RA, psoriatic arthritis (PsA), Undifferentiated Inflammatory Arthritis (UIA; synovitis not meeting other classification/diagnostic criteria), Clinical Suspect Arthralgia (CSA; arthralgia of an inflammatory type without synovitis), or Other. Data were analysed using SPSSv25. Full ethical approval was given for the study (REC12/WM/0258). Results Baseline demographic data were similar between all groups, with a median symptom duration of 16.8-34.0 days. Baseline 25OHD was not significantly different between groups [median, interquartile range (IQR): RA 46.7, 30.0-73.3; PsA 41.2, 30.0-65.0; UIA 51.4, 30.0-72.3; CSA 47.7, 30.3-73.0; Other 37.0, 24.9-55.3]. In the RA group (n = 335), there were no significant differences between 25OHD and any measures of disease activity/fatigue. Finally, we found no association between 25OHD and progression from UIA (n = 121) or CSA (n = 150) to RA (p = 0.554 and p = 0.741 respectively). Conclusion Overall we found no clear association between serum 25OHD and baseline diagnosis, RA disease activity, or progression from UIA/CSA to RA in this large cohort of early RA patients. Limitations of the study include that we were unable to report on levels of vitamin D metabolites which may be more important than total vitamin D. In addition, we were unable to adjust for supplement use/ time of year the sample was taken due to missing data. Future studies into the role of different metabolites of vitamin D in aetiopathogenesis of inflammatory arthritis would provide invaluable insight into the role of vitamin D in inflammatory arthritis better defining the complex role of vitamin D in RA. Disclosures S.R. Harrison: None. G. Jutley: None. D. Li: None. I. Sahbudin: None. A. Filer: None. M. Hewison: None. K. Raza: None.

Anemia of chronic disease in rheumatoid arthritis is associated with increased apoptosis of bone marrow erythroid cells: improvement following anti–tumor necrosis factor-α antibody therapy

Blood ◽  
2002 ◽  
Vol 100 (2) ◽  
pp. 474-482 ◽  
Author(s):  
Helen A. Papadaki ◽  
Heraklis D. Kritikos ◽  
Vasilis Valatas ◽  
Dimitrios T. Boumpas ◽  
George D. Eliopoulos
Keyword(s):  
Rheumatoid Arthritis ◽  
Bone Marrow ◽  
Chronic Disease ◽  
Tumor Necrosis ◽  
Tumor Necrosis Factor Α ◽  
Anemia Of Chronic Disease ◽  
Tnf Α ◽  
Factor Α ◽  
Necrosis Factor

Abstract Circumstantial evidence has implicated tumor necrosis factor α (TNF-α) in the pathogenesis of anemia of chronic disease (ACD) in rheumatoid arthritis (RA). We investigated the role of TNF-α in erythropoiesis of patients with active RA (n = 40) and the effect of anti–TNF-α antibody administration (cA2). Patients with RA had lower numbers of CD34+/CD71+ and CD36−/glycophorin A+ (glycoA+) bone marrow (BM) cells and increased proportions of apoptotic cells within the CD34+/CD71+ and CD36+/glycoA+ cell compartments, compared to healthy controls (n = 24). Erythroid burst-forming units (BFU-Es) obtained by BM mononuclear or purified CD34+ cells were significantly lower in RA patients compared to controls. These abnormalities were more pronounced among patients with ACD. Increased TNF-α levels in patient long-term BM culture supernatants inversely correlated with BFU-Es and hemoglobin levels and positively with the percentage of apoptotic CD34+/CD71+ and CD36+/glycoA+ cells. Following cA2 therapy, a normalization was documented in the number of CD34+/CD71+ and CD36−/glycoA+ cells, the number of BFU-Es, and the proportion of apoptotic CD34+/CD71+ and CD36+/glycoA+ cells, which was associated with a significant increase in hemoglobin levels compared to baseline. Recovery from anemia was more prominent in patients with ACD. The exogenous addition of an anti–TNF-α antibody in the cultures increased BFU-E number in patients prior to cA2 treatment but not after treatment, further substantiating the inhibitory role of TNF-α on patients' erythropoiesis. We conclude that TNF-α–mediated apoptotic depletion of BM erythroid cells may account for ACD in RA and that cA2 administration may ameliorate ACD in these patients by down-regulating the apoptotic mechanisms involved in erythropoiesis.

scholarly journals The Golgi-associated Protein GRASP65 Regulates Spindle Dynamics and Is Essential for Cell Division

2005 ◽  
Vol 16 (7) ◽  
pp. 3211-3222 ◽  
Author(s):  
Christine Sütterlin ◽  
Roman Polishchuk ◽  
Matt Pecot ◽  
Vivek Malhotra
Keyword(s):  
Mammalian Cells ◽  
Protein Transport ◽  
Direct Role ◽  
Golgi Stack ◽  
Spindle Poles ◽  
C Terminus ◽  
Spindle Dynamics ◽  
Negative Role ◽  
Golgi Fragmentation

At the onset of mitosis, the pericentriolar Golgi apparatus of mammalian cells is converted into small fragments, which are dispersed throughout the cytosol. The Golgi-associated protein GRASP65 is involved in this process. To address the role of GRASP65 in mitotic Golgi fragmentation, we depleted the protein from HeLa cells by RNAi. In the absence of GRASP65, the number of cisternae per Golgi stack is reduced without affecting the overall organization of Golgi membranes and protein transport. GRASP65-depleted cells entered mitosis, but accumulated in metaphase with condensed chromatin and multiple aberrant spindles and eventually died. Although Centrin2 and g-tubulin were detected in two of the spindle poles, the other spindle poles contained g-tubulin, but not Centrin2. Furthermore, we provide evidence that the expression of the C-terminus of GRASP65 interferes with entry of cells into mitosis. Our results suggest the requirement for GRASP65 in the regulation of spindle dynamics rather than a direct role in the stacking of Golgi cisternae. This novel function is in addition to the previously established negative role of GRASP65 at the G2/M transition, which is mediated by its C-terminus.

scholarly journals Tim3 binding to galectin-9 stimulates antimicrobial immunity

2010 ◽  
Vol 207 (11) ◽  
pp. 2343-2354 ◽  
Author(s):  
Pushpa Jayaraman ◽  
Isabel Sada-Ovalle ◽  
Sarah Beladi ◽  
Ana C. Anderson ◽  
Valerie Dardalhon ◽  
...  
Keyword(s):  
T Cell ◽  
Macrophage Activation ◽  
Th1 Cells ◽  
Th1 Cell ◽  
Cell Surface Molecule ◽  
Tissue Inflammation ◽  
Regulatory Molecule ◽  
Domain 3 ◽  
Antimicrobial Immunity

T cell immunoglobulin and mucin domain 3 (Tim3) is a negative regulatory molecule that inhibits effector TH1-type responses. Such inhibitory signals prevent unintended tissue inflammation, but can be detrimental if they lead to premature T cell exhaustion. Although the role of Tim3 in autoimmunity has been extensively studied, whether Tim3 regulates antimicrobial immunity has not been explored. Here, we show that Tim3 expressed on TH1 cells interacts with its ligand, galectin-9 (Gal9), which is expressed by Mycobacterium tuberculosis–infected macrophages to restrict intracellular bacterial growth. Tim3–Gal9 interaction leads to macrophage activation and stimulates bactericidal activity by inducing caspase-1–dependent IL-1β secretion. We propose that the TH1 cell surface molecule Tim3 has evolved to inhibit growth of intracellular pathogens via its ligand Gal9, which in turn inhibits expansion of effector TH1 cells to prevent further tissue inflammation.

scholarly journals Bone Marrow Mesenchymal Stem Cells Regulate IL-4 and INF-γ Expression in AR Mouse Model

2020 ◽  
Author(s):  
Chuanliang Zhao ◽  
Jingwen Sun ◽  
Xiaojing Cai ◽  
Wentao Zou ◽  
Jiaxiong Zhang
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Flow Cytometry ◽  
Mesenchymal Stem Cells ◽  
Mouse Model ◽  
Th1 Cell ◽  
Differentiation Potential ◽  
Th2 Cell ◽  
Marrow Mesenchymal Stem Cells

Abstract Background: Bone marrow mesenchymal stem cells can promote the recovery of immune balance and regulate the balance of Th1/2 cells. Allergic rhinitis is a disease with Th1/2 imbalance mediated by IgE. It’s unclear whether BMSCs could regulate AR disease. In this study, the possible role of BMSCs was explored. Methods : AR mouse model was established by ovalbumin (OVA). 18 models were randomly divided into three groups: AR-sensitized, Stem-cell-returned, Medium-returned; six unsensitized mouses named normal-control. IgE, IL-4 and INF-γ levels were measured by Elisa. Observing migration of BMSCs by immunofluorescence. Flow cytometry used to detect changes of Th1/2. STAT 4/6 protein level was detected by Western-blot. Results : After OVA-sensitization, IgE, IL-4 and STAT6 levels were higher, INF-γ and STAT4 level was lower. Flow cytometry revealed a decrease in Th1 cell and an increase in Th2 cell in AR group. After BMSCs treatment, t IgE, IL-4 and STAT6 levels in SCRg and MRg were lower than that in AR group, and tINF-γ and STAT4 level were higher than hat inAR group. Flow cytometry showed that the content of Th1 cell increased while Th2 cell decreased. Conclusions: BMSCs return treatment could decrease the expression of IL-4, promote the expression of INF-γ and regulate the balance of Th cell, and the mechanism was closely related to STAT4/6 signaling pathway. However there was no statistical difference between SCRg and MRg, so the role of BMSCs maybe achieved through paracrine function rather than multi-directional differentiation potential.

scholarly journals Anti-IFN-γ Antibody Promotes Osteoclastogenesis in Human Bone Marrow Monocyte-Derived Macrophages Co-Cultured with Tuberculosis-Activated Th1 Cells

2018 ◽  
Vol 49 (4) ◽  
pp. 1512-1522
Author(s):  
Jiezhong Deng ◽  
Dong Sun ◽  
Fei Luo ◽  
Qiang Zhang ◽  
Feifan Chen ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Bone Resorption ◽  
Osteoclast Differentiation ◽  
Osteoclast Formation ◽  
Th1 Cells ◽  
Actin Ring ◽  
Tnf Α ◽  
Ifn Γ ◽  
Trap Staining

Background/Aims: Tuberculosis induces bone loss and activates Th1 cells that play an important role in the host defense of Bacille Calmette-Guérin tuberculosis vaccine. However, the role of tuberculosis-activated Th1 cells in differentiation of osteoclast precursors to osteoclasts is unclear. As secretion of IFN-γ in Th1 cells is induced by tuberculosis, we aimed to investigate the role of anti-IFN-γ antibody on the differentiation and activation of osteoclasts in bone marrow monocyte-derived macrophages (BMMs). Methods: BMMs were isolated and co-cultured with CD4+T helper 1 cells (Th1 cells), pretreated with anti-IFN-γ antibody. Then, cell proliferation, expression and release of cytokines, formation of actin ring, differentiation of osteoclasts and bone resorption function were measured by CCK8 assay, qRT-PCR/Western blot/flow cytometry, ELISA, immunofluorescence, tartrate-resistant acidic phosphatase (TRAP) staining and bone absorbance assay, respectively. Results: Anti-IFN-γ antibody inhibited the cell viability of BMMs, and induced the expressions of RANKL, TNF-α, NF-κB and TRAF6 in BMMs. In addition, it led to increased expression levels of RANK on cell surfaces, and increased production of RANKL, TNF-α, MCP-1 and SDF-1. Anti-IFN-γ antibody also induced the expression of osteoclast differentiation factor and actin ring formation, but inhibited the expression of osteoprotegerin. TRAP staining and bone resorption assays showed that anti-IFN-γ antibody induced an increase in osteoclast formation and bone resorption. Conclusion: The anti-IFN-γ antibody induced osteoclast formation, and is probably mediated by RANKL-induced activation of NF-κB, that induces TRAF6 in the RANKL-RANK signaling pathway. Our data suggest an inhibitory role for IFN-γ in osteoclast formation induced by tuberculosis.

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