Browse

Search for: rheumatoid arthritis    methotrexate    autoimmune disease    biomarker    gene expression    GWAS    HLA genes    non-HLA genes   

ID PMID Title PublicationDate abstract
27166176 PTPN22 polymorphisms, but not R620W, were associated with the genetic susceptibility of sy 2016 Aug OBJECTIVES: The present study aimed to detect a possible association between PTPN22 gene polymorphisms and rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) in a Chinese Han population. METHODS: 7 PTPN22 SNPs were genotyped in 358 patients with RA and 713 patients with SLE, as well as 564 RA controls and 672 SLE controls by Restriction Fragment Length Polymorphism (RFLP). Association analyses were conducted on the whole data set. Significant relationships were also examined between clinical features and SNPs for both RA and SLE. RESULTS: Rs2476601 was lack of polymorphism with a ⩽0.1% frequency in both SLE and RA patients and healthy controls in our study. The two SNPs rs1217414 and rs3811021 of PTPN22 shown strong association with both SLE (rs1217414T: padj = 6.07e-004, OR=0.57; rs3811021C: padj = 4.68e-005, OR=0.65) and RA (rs1217414T: padj = 2.01e-008, OR=0.26; rs3811021C: padj = 0.028, OR=0.70). And the rs3765598 revealed a strong risk factor for SLE (p=9.38e-009, padj = 6.57e-008, OR=1.93), but not for RA (p=0.48, OR=1.12). Moreover, protective haplotype ACTTC in RA (p=7.73e-016, padj = 5.51-015, OR[95%CI]=0.02[0.002-0.10]) and SLE (p=8.29e-018, padj = 5.80e-017, OR[95%CI]=0.11[0.06-0.21]) were observed. In addition, the distribution of risk haplotypes ACGTC and GCTTT in RA (ACGTC: p=0.0006, padj = 0.004, OR[95%CI]=1.85[1.29-2.63]; GCTTT: p=2.62e-005, padj = 1.85e-004, OR[95%CI]=2.40[1.57-3.65]) and SLE (ACGTC: p=0.0006, padj = 0.004, OR[95%CI]=1.85[1.29-2.63]; ACGTC: p=7.74e-011, padj = 6.81e-010, OR[95%CI]=2.21[1.12-3.34]; GCTTT: p=2.40[1.57-3.65], padj = 2.26e-006, OR[95%CI]=2.64[1.79-3.87]) were significant different from that in controls. Furthermore, significant association was observed between the PTPN22 rs3765598 and antinuclear antibodies 1 (ANA1) in SLE. CONCLUSIONS: Our data provide strong evidence that the rs1217414 and rs3811021 in PTPN22 gene might be common protective factors contributed to SLE and RA susceptibility in the Chinese Han population. While, the rs3765598 might increase the genetic susceptibility of SLE, but not RA.
25904188 Reappraisal of the diagnostic and prognostic value of morning stiffness in arthralgia and 2015 Apr 23 INTRODUCTION: Morning stiffness is assessed daily in the diagnostic process of arthralgia and arthritis, but large-scale studies on the discriminative ability are absent. This study explored the diagnostic value of morning stiffness in 5,202 arthralgia and arthritis patients and the prognostic value in early rheumatoid arthritis (RA). METHODS: In arthralgia patients referred to the Early Arthritis Recognition Clinics (EARC) of Leiden (n = 807) and Groningen (n = 481) or included in the Rotterdam Early Arthritis Cohort (REACH) study (n = 353), the associations (cross-sectional analyses) between morning stiffness and presence of arthritis at physical examination were studied. In early arthritis patients, included in the Leiden Early Arthritis Clinic (EAC) (n = 2,748) and Evaluation et Suivi de POlyarthrites Indifférenciées Récentes (ESPOIR) (n = 813), associations with fulfilling the 2010-RA criteria after one year were assessed. In 2010-RA patients included in the EAC (n = 1,140) and ESPOIR (n = 677), association with the long-term outcomes of disease-modifying antirheumatic drug (DMARD)-free sustained remission and radiological progression were determined. Morning stiffness was defined as a duration ≥60 minutes; sensitivity analyses were performed for other definitions. RESULTS: In arthralgia, morning stiffness (≥60 minutes) associated with the presence of arthritis; Leiden EARC odds ratio (OR) 1.49 (95% CI 1.001 to 2.20), Groningen EARC OR 2.21 (1.33 to 3.69) and REACH OR 1.55 (0.97 to 2.47) but the areas under the receiver operating characteristic curve (AUCs) were low (0.52, 0.57, 0.54). In early arthritis, morning stiffness was associated with 2010-RA independent of other predictors (Leiden EAC OR 1.72 (95% CI 1.31 to 2.25, AUC 0.68), ESPOIR OR 1.68 (1.03 to 2.74, AUC 0.64)). Duration of ≥30 minutes provided optimal discrimination for RA in early arthritis. Morning stiffness was not associated with radiological progression or DMARD-free sustained remission. CONCLUSIONS: Morning stiffness in arthralgia and early arthritis is associated with arthritis and RA respectively. This supports the incorporation of morning stiffness in the diagnostic process.
26090596 Production of a High-affinity Monoclonal Antibody Reactive with Folate Receptors Alpha and 2015 Jun Folate receptors α (FRα) and β (FRβ) are two isoforms of the cell surface glycoprotein that binds folate. The expression of FRα is rare in normal cells and elevated in cancer cells. Thus, FRα-based tumor-targeted therapy has been a focus area of laboratory research and clinical trials. Recently, it was shown that a significant fraction of tumor-associated macrophages expresses FRβ and that these cells can enhance tumor growth. Although FRα and FRβ share 70% identity in their deduced amino acid sequence, a monoclonal antibody (MAb) reactive with both receptors has not been developed. A MAb that can target both FRα-expressing cancer cells and FRβ-expressing tumor-associated macrophages may provide a more potent therapeutic tool for cancer than individual anti-FRα or anti-FRβ MAbs. In this study, we developed a MAb that recognizes both FRα and FRβ (anti-FRαβ). The anti-FRαβ specifically stained trophoblasts and macrophages from human placenta, synovial macrophages from rheumatoid arthritis patient, liver macrophages from cynomolgus monkey and common marmoset, and cancer cells and tumor-associated macrophages from ovary and lung carcinomas. Surface plasmon resonance showed that the anti-FRαβ bound to soluble forms of the FRα and FRβ proteins with high affinity (KD=6.26×10(-9) M and 4.33×10(-9) M, respectively). In vitro functional analysis of the anti-FRαβ showed that this MAb mediates complement-dependent cytotoxicity, antibody-dependent cellular cytotoxicity, and antibody-dependent cellular phagocytosis of FRα-expressing and FRβ-expressing cell lines. The anti-FRαβ MAb is a promising therapeutic candidate for cancers in which macrophages promote tumor progression.
27086257 [Psoas abscess caused by Staphylococcus lugdunensis]. 2016 Apr Staphylococcus lugdunensis is a coagulase-negative staphylococcus of growing importance and atypical behavior. The infections caused by this microorganism are becoming more frequent, having a broader spectrum. Psoas abscesses caused by this germ are rare, with few cases reported in the literature. In this work, we present a case of a psoas abscess caused by S. lugdunensis in a patient suffering from diabetes mellitus and rheumatoid arthritis, which was treated with intravenous cloxacillin with a good outcome.
27107507 HLA and anti-citrullinated protein antibodies: Building blocks in RA. 2015 Dec Antibodies against citrullinated proteins (ACPAs) are specific for rheumatoid arthritis (RA). ACPA-positive RA is a chronic inflammatory disease resulting from the complex interaction between genetic (mainly HLA class II genes) and environmental factors (mainly smoking). Recent findings have offered new insights into where, when and how anti-citrulline immunity develops. Some studies have found that a mucosal site, such as the lungs, may function as the initiating site for the immune response against citrullinated proteins, in line with the known association between smoking and ACPA. Other studies, focusing rather on the HLA associations, have suggested that cross-reactivity between microbial sequences and citrullinated self-proteins may lead to ACPA formation. Once ACPAs have developed, they can circulate throughout the body and upon reaching the joints exert direct pathogenic effects themselves. ACPAs can target first the bone compartment of the joints to activate osteoclasts and release interleukin (IL)-8 that in turn will promote bone loss and pain-like behaviour. In the current review, we will present the current understanding of the genetic associations in RA contributing to ACPA occurrence and offer insight in the latest findings explaining how and why autoimmunity generated in the lungs of genetically susceptible hosts might lead to chronic inflammation in the joints.
25832955 Central nervous system manifestations of tuberculosis-associated immune reconstitution inf 2015 A 64-year-old neurologically asymptomatic woman with rheumatoid arthritis who was treated with the tumor necrosis factor (TNF)-α antagonist adalimumab developed disseminated tuberculosis (TB). After receiving anti-TB therapy and discontinuing adalimumab, she exhibited paradoxical worsening due to immune reconstitution inflammatory syndrome (IRIS) with the appearance of meningitis and brain tuberculomas. This case indicates that continuing anti-TNF therapy may be necessary to prevent IRIS in patients who develop TB, particularly disseminated TB, during the course of anti-TNF therapy. In addition, careful screening for central nervous system (CNS) TB should be performed prior to the initiation of therapy, as even neurologically asymptomatic patients can develop CNS manifestations of IRIS.
25729243 Eupatilin ameliorates collagen induced arthritis. 2015 Mar Eupatilin is the main active component of DA-9601, an extract from Artemisia. Recently, eupatilin was reported to have anti-inflammatory properties. We investigated the anti-arthritic effect of eupatilin in a murine arthritis model and human rheumatoid synoviocytes. DA-9601 was injected into collagen-induced arthritis (CIA) mice. Arthritis score was regularly evaluated. Mouse monocytes were differentiated into osteoclasts when eupatilin was added simultaneously. Osteoclasts were stained with tartrate-resistant acid phosphatase and then manually counted. Rheumatoid synoviocytes were stimulated with TNF-α and then treated with eupatilin, and the levels of IL-6 and IL-1β mRNA expression in synoviocytes were measured by RT-PCR. Intraperitoneal injection of DA-9601 reduced arthritis scores in CIA mice. TNF-α treatment of synoviocytes increased the expression of IL-6 and IL-1β mRNAs, which was inhibited by eupatilin. Eupatilin decreased the number of osteoclasts in a concentration dependent manner. These findings, showing that eupatilin and DA-9601 inhibited the expression of inflammatory cytokines and the differentiation of osteoclasts, suggest that eupatilin and DA-9601 is a candidate anti-inflammatory agent.
27924645 Cardiovascular outcomes and tumour necrosis factor antagonists in chronic inflammatory rhe 2016 Dec Many chronic rheumatic diseases have an inflammatory etiology, leading to accelerated atherosclerosis and increased occurrence of vascular diseases. In rheumatoid arthritis (RA), a reduction in cardiovascular (CV) events has been reported under treatments reducing systemic inflammation. Areas covered: Given the central role of tumour necrosis factor alpha (TNFα) in chronic inflammatory conditions and in atherosclerosis, it has been suggested that TNFα-antagonists may reduce CV risk and mortality. Although there are no randomized controlled or head-to-head trials investigating the effect of specific anti-TNF-agents on CV outcomes, observational cohort studies, national registry data, and meta-analyses in RA have reported improved CV outcomes with anti-TNF therapy. Expert opinion: It is unclear whether this is due to reduced systemic inflammation or a specific anti-TNF effect at the atherosclerotic plaque level. Observed CV benefits appear to correlate with anti-TNF response. Conversely, although inconsistently, anti-TNF agents have also been linked with increased incidence/worsening of heart failure. Additional CV adverse events with anti-TNFs include vasculitis and venous thromboembolic events. We provide an overview of the likely effects of anti-TNF therapy on CV risk and adverse events, and evaluated differences in CV outcomes among different anti-TNF-agents.
26582809 Non-articular Felty's syndrome: An uncommon diagnosis. 2015 Nov Felty's syndrome is a triad of rheumatoid arthritis, neutropenia, and splenomegaly. We hereby report an unusual case of non-articular Felty's syndrome and its management along with discussing the importance of appropriately ruling out alternate causes of neutropenia with splenomegaly.
26233239 Apoptotic Effect of Geniposide on Fibroblast-Like Synoviocytes in Rats with Adjuvant-Induc 2016 Feb Stimulating fibroblast-like synoviocyte (FLS) apoptosis in rheumatoid arthritis (RA) is a promising strategy for clinical treatment. Previous studies have confirmed that geniposide shows a certain anti-arthritic effect in vivo. However, whether geniposide can induce RA FLS apoptosis and the underlying mechanisms has not been elucidated. Herein, adjuvant-induced arthritis (AIA) in rat was induced and FLS was isolated from synovial tissues by tissue explant cultivation method. MTT assay, Hoechst staining, and flow cytometric apoptosis assay were applied to evaluate apoptotic effect of geniposide on AIA FLS. Bcl-2, Bax, and caspase 3 messenger RNA (mRNA) levels, and extracellular-signal-regulated kinases (ERKs) and phosphorylated ERK protein levels were examined by real-time PCR and western blot, respectively. We found that geniposide dose-dependently inhibited AIA FLS proliferation in vitro. AIA FLS treated with geniposide displayed typical apoptotic morphological characteristics including nuclear shrinkage and chromatin condensation. Flow cytometric apoptosis assay indicated that geniposide significantly increased the apoptosis rate of AIA FLS. Additionally, geniposide treatment on AIA FLS decreased Bcl-2 mRNA level and increased Bax and caspase 3 mRNA levels, accompanied by reduced protein levels of phosphorylated-ERK1/2, without affecting total ERK1/2. In conclusion, geniposide effectively induces AIA FLS apoptosis through regulating the apoptosis-related gene expressions and inhibiting ERK signal pathway.
28057980 Periploca forrestii Saponin Ameliorates Murine CFA-Induced Arthritis by Suppressing Cytoki 2016 Periploca forrestii Schltr. has been used as a Chinese folk medicine due to its versatile pharmacological effects such as promoting wounds and rheumatoid arthritis. However, the antiarthritic activity of Periploca forrestii saponin (PFS) and its active compound Periplocin has still not been demonstrated. Here, we evaluated the antiarthritic effects of PFS in adjuvant-induced arthritis (AIA) rats by intragastric administration at a dose of 50 mg/kg. The anti-inflammatory activities of Periplocin were also examined in LPS-induced AIA splenocytes and synoviocytes. PFS significantly ameliorated joint swelling; inhibited bone erosion in joints; lowered levels of IL-6 and TGF-β1 in AIA rat splenocyte; and reduced joint protein expression levels of phospho-STAT3 and IKKα. Using LPS-induced AIA splenocytes, we demonstrate that Periplocin suppressed the key proinflammatory cytokines levels of IL-6, IFN-γ, TGF-β1, and IL-13 and IL-22 and transcription factor levels of T-bet, GATA3, and C-Jun genes. Periplocin also suppressed LPS-induced cytokine secretion from synoviocytes. Our study highlights the antiarthritic activity of PFS and its derived Periplocin and the underlying mechanisms. These results provide a strong rationale for further testing and validation of the use of Periploca forrestii Schltr. as an alternative modality for the treatment of RA.
26749043 Association Between Ischemic Stroke and Tumor Necrosis Factor Inhibitor Therapy in Patient 2016 Jun OBJECTIVE: Patients with rheumatoid arthritis (RA) are at an increased risk of ischemic stroke. Tumor necrosis factor inhibitors (TNFi) may influence risk and mortality after ischemic stroke by reducing inflammation. This study was undertaken to examine the association of TNFi with the risk of incident ischemic stroke and with 30-day and 1-year mortality after ischemic stroke. METHODS: Patients with RA starting therapy with TNFi and a biologics-naive comparator group treated with synthetic disease-modifying antirheumatic drugs (DMARDs) only were recruited to the British Society for Rheumatology Biologics Register for Rheumatoid Arthritis from 2001 to 2009. Patients were followed up via clinical and patient questionnaires as well as the national death register. Incident strokes were classified as ischemic if brain imaging reports suggested ischemia or if ischemic stroke was reported as the underlying cause of death on a death certificate. Patients with a previous stroke were excluded. Risk of ischemic stroke was compared between patients receiving synthetic DMARDs only and those ever-exposed to TNFi using a Cox proportional hazards regression model adjusted for potential confounders. Mortality after ischemic stroke was compared between synthetic DMARD-treated patients and TNFi-treated patients using logistic regression, adjusted for age and sex. RESULTS: To April 2010, 127 verified incident ischemic strokes (21 in 3,271 synthetic DMARD-treated patients and 106 in 11,642 TNFi-treated patients) occurred during 11,973 and 61,226 person-years of observation, respectively (incidence rate 175 versus 173 per 100,000 person-years). After adjustment for confounders, there was no association between ever-exposure to TNFi and ischemic stroke (hazard ratio 0.99 [95% confidence interval (95% CI) 0.54-1.81]). Mortality 30 days or 1 year after ischemic stroke was not associated with concurrent TNFi exposure (odds ratio 0.18 [95% CI 0.03-1.21] and 0.60 [95% CI 0.16-2.28], respectively). CONCLUSION: Exposure to TNFi does not appear to influence the occurrence of ischemic stroke in the medium term in patients with RA. The impact on mortality after ischemic stroke remains inconclusive.
26474633 [Renal damage caused by Rhupus syndrome associated with anti-neutrophil cytoplasmic antibo 2015 Oct 18 We analyzed the clinicopathological characteristics of one patient with Rhupus syndrome associated nephropathy in Peking University People's Hospital, and reviewed the related literature. The patient was a middle aged female. She developed rheumatoid arthritis first, and then manifested mild systemic lupus erythematosus together with positive anti-neutrophil cytoplasmic antibodies (ANCA) and cryoglobulinemia several years later. The renal biopsy was performed and manifested as lupus nephritis. The transmission electron microscopy revealed cryoglobulinemia associated renal damage. This report shows that the clinicopathological characteristics in patients with Rhupus syndrome associated nephropathy are complicated. The renal pathology can be used as a diagnostic tool.
26531309 Investigation of the cytokine response to NF-κB decoy oligonucleotide coated polysacchari 2015 Nov 4 INTRODUCTION: The transcription factor nuclear factor-kappa B (NF-κB) is highly involved in regulation of a number of cellular processes, including production of inflammatory mediators. Thus, this transcription factor plays a role in pathology of many diseases, including rheumatoid arthritis, an autoimmune disease hallmarked by an imbalance of pro and anti-inflammatory cytokines. Small nucleic acids with sequences that mimic the native binding site of NF-κB have been proposed as treatment options for RA; however due to low cellular penetration and a high degree of instability, clinical applications of these therapeutics have been limited. METHODS: Here, we describe the use of N-trimethyl chitosan-polysialic acid (PSA-TMC) nanoparticles coated with decoy oligodeoxynucleotides (ODNs) specific to transcription factor NF-κB (PSA-TMC-ODN) as a method to enhance the stability of the nucleic acids and facilitate increased cellular penetration. In addition to decoy ODN, PSA-TMC nanoparticles were loaded with RA therapeutic methotrexate (MTX), to assess the anti-inflammatory efficacy of a combination therapy approach. Two different in vitro models, a cell line based model as well as a primary RA cell model were used to investigate anti-inflammatory activity. One way ANOVA followed by Holm-Sidak stepdown comparisons was used to determine statistical significance. RESULTS: In general, free ODN did not significantly affect secretion of pro-inflammatory cytokines interleukin-6 (IL-6) and interleukin-8, (IL-8) while free MTX had variable efficacy. However, PSA-TMC-ODN and PSA-TMC-ODN-MTX resulted in significant decreases in the inflammatory mediators IL-6 and IL-8 in both cell models. In addition, PSA-TMC exhibited sufficient cellular uptake, as observed through fluorescence microscopy. CONCLUSIONS: These results support our previous findings that PSA-TMC nanoparticles are an effective delivery vehicle for small nucleic acids, and effectively alter the pro-inflammatory state characteristic of RA.
25887296 (5R)-5-Hydroxytriptolide (LLDT-8) inhibits osteoclastogenesis via RANKL/RANK/OPG signaling 2015 Mar 24 BACKGROUND: The aim of this study was to investigate the regulative activity of (5R)-5-hydroxytriptolide (LLDT-8) on receptor activator of nuclear factor κ-B ligand (RANKL)/receptor activator of nuclear factor κ-B (RANK)/Osteoprotegerin (OPG) system in rheumatoid arthritis (RA) and its anti-osteoclastogenesis mechanism. METHODS: The expression of OPG, RANK and RANKL in CD3(+) T leukomonocytes in both peripheral blood and synovial fluid of RA patients was evaluated by flow cytometry. The levels of interleukin (IL) 1β, IL-6, IL-10, IL-21 and IL-23 in the supernatants of peripheral blood mononuclear cells (PBMCs) and synovial fluid mononuclear cells (SFMCs) were assayed by ELISA. Tartaric acid phosphatase (TRAP) staining was used to identify the osteoclast-like cells derived from RAW264.7. Western blotting analysis was used to check the downstream molecules of RANKL. RESULTS: LLDT-8 increased the rate of OPG expression in CD3(+) T leukomonocytes in peripheral blood as well as the ratio of OPG/RANKL in both peripheral blood and synovial fluid. LLDT-8 inhibited IL-1β, IL-6, IL-21 and IL-23 secretion, but promoted the secretion of IL-10 in the supernatants of PBMCs and SFMCs. In addition, LLDT-8 decreased the number of TRAP-positive cells derived from RAW264.7 in the presence of RANKL and M-CSF. Furthermore, LLDT-8 also inhibited the expression of p-IκB, a key regulator of RANKL signaling pathway. CONCLUSIONS: LLDT-8 exerts its anti-osteoclastogenesis effect in RA probably through regulating RANKL/RANK/OPG system and its downstream signaling pathway as well as cytokine productions.
27209224 [Effect of tumour necrosis factor α blockade on bone metabolism in chronic inflammatory j 2016 Jul 15 BACKGROUND AND OBJECTIVE: To evaluate the effect of anti-TNF treatments on bone mineral density (BMD), bone remodelling markers (BRM) and receptor activator of nuclear factor κB ligand (RANKL) and osteoprotegerin (OPG) in patients with chronic inflammatory joint diseases. METHODS: A longitudinal prospective study was performed under clinical practice conditions on 31 patients diagnosed of rheumatoid arthritis, psoriatic arthropathy and ankylosing spondylitis who had received treatment with anti-TNF alpha drugs for one year. BMD, OPG and RANKL soluble form (sRANKL) were studied at the onset and end of the study. During the study (0, 3, 6, 9 and 12 month), disease activity (SDAI, BASDAI and CRP), functional capacity (HAQ, BASFI), BRM and vitamin D were studied. RESULTS: BMD was not modified after one year of treatment. The patients who took corticosteroids had a mean bone mass loss of 3% in the lumbar spine (±1.6, P=.02). In regards to the BRM, did not experience significant changes over the course of the study. Disease activity, both SDAI (P=.002) and BASDAI (P=.002), decreased. OPG was maintained without changes during the year of treatment while both the sRANKL (0.28±0.22, P=.013) and sRANKL/OPG ratio significantly decreased (0.04±0.03, P=.031). CONCLUSION: The patients being treated with anti-TNF did not present with a significant loss of DMO during the study (one year), at the same time experiencing an improvement in disease activity. This protection has been clearer in the responding patients.
26316022 C5orf30 is a negative regulator of tissue damage in rheumatoid arthritis. 2015 Sep 15 The variant rs26232, in the first intron of the chromosome 5 open reading frame 30 (C5orf30) locus, has recently been associated with both risk of developing rheumatoid arthritis (RA) and severity of tissue damage. The biological activities of human C5orf30 are unknown, and neither the gene nor protein show significant homology to any other characterized human sequences. The C5orf30 gene is present only in vertebrate genomes with a high degree of conservation, implying a central function in these organisms. Here, we report that C5orf30 is highly expressed in the synovium of RA patients compared with control synovial tissue, and that it is predominately expressed by synovial fibroblast (RASF) and macrophages in the lining and sublining layer of the tissue. These cells play a central role in the initiation and perpetuation of RA and are implicated in cartilage destruction. RASFs lacking C5orf30 exhibit increased cell migration and invasion in vitro, and gene profiling following C5orf30 inhibition confirmed up-regulation of genes involved in cell migration, adhesion, angiogenesis, and immune and inflammatory pathways. Importantly, loss of C5orf30 contributes to the pathology of inflammatory arthritis in vivo, because inhibition of C5orf30 in the collagen-induced arthritis model markedly accentuated joint inflammation and tissue damage. Our study reveal C5orf30 to be a previously unidentified negative regulator of tissue damage in RA, and this protein may act by modulating the autoaggressive phenotype that is characteristic of RASFs.
26751012 IL-9, a local growth factor for synovial T cells in inflammatory arthritis. 2016 Mar OBJECTIVE: The regulatory role of the Th9 cells along with its signature cytokine IL-9 in human immune system and its aberrant activation in autoimmune diseases is currently under investigation. We are reporting the functional significance of IL-9 in the pathogenesis of autoimmune inflammatory arthritis. METHODS: CD3(+) T cells were obtained from peripheral blood (PB) and synovial fluid (SF) of psoriatic arthritis (PsA), rheumatoid arthritis (RA), and osteoarthritis (OA) patients. MTT, FACS based CFSE dilution assay and apoptosis assay (Annexin-V) were performed to determine the pro-growth/survival effect of human recombinant IL-9 on activated CD3(+) T cells. Immunoblots were performed to determine the signaling proteins responsible for the progrowth/survival effect of IL-9. RESULTS: SF of PsA and RA was enriched with IL-9 producing CD3(+) T cells compared to the SF in OA. IL-9 level measured by ELISA was significantly elevated in PsA and RA patients compared to SF in OA (<.001). Activated T cells of PsA and RA had higher levels of IL-9 receptors. IL-9 promoted proliferation and survival of the CD3(+) T cells of PB and SF of PsA and RA and compared to untreated (media) controls (p<.005, t-test). IL-9 induced proliferation of T cells was dependent on PI3K/Akt/mTOR signaling pathway. CONCLUSION: IL-9 is functionally active, and is a pro-growth/survival factor for the localized pathologic T cells in the synovium of inflammatory arthritis. The pro-growth/survival effect is mediated by the activation of mTOR kinase cascade. To our knowledge, this is the first report of a functional role of IL-9 in human autoimmune arthritis.
26228975 Suberoylanilide Hydroxamic Acid, an Inhibitor of Histone Deacetylase, Induces Apoptosis in 2016 Feb Here, we explored the effects of suberoylanilide hydroxamic acid (SAHA) on the viability and apoptosis of rheumatoid arthritis of fibroblast-like synoviocytes (rheumatoid arthritis (RA) fibroblast-like synoviocytes (FLS)). FLS obtained from RA patients were treated with SAHA. SAHA significantly inhibited the viability of RA FLS in a concentration-dependent manner up to 5 μM. SAHA-treated FLS showed a significant increase in the percentage of apoptosis and the expression and activity of caspase-3 and higher intracellular ROS levels. N-acetyl-l-cysteine (NAC) pretreatment significantly attenuated SAHA-induced apoptosis, decreasing the percentage of apoptosis by about 60 %. A significant decline in phosphorylated IκBα and nuclear factor kappa B (NF-κB) p65 and concomitant increase in total IκBα were shown in SAHA-treated FLS. Additionally, the levels of anti-apoptotic Bcl-2 proteins (Bcl-xL and Mcl-1) were significantly reduced by SAHA. Collectively, SAHA induces apoptosis of RA FLS, at least partially, through generation of ROS and suppression of NF-κB activation and Bcl-xL and Mcl-1 expression.
26253344 Atopic dermatitis is associated with an increased risk for rheumatoid arthritis and inflam 2016 Jan BACKGROUND: Atopic dermatitis (AD) is characterized by epidermal barrier failure and immune-mediated inflammation. Evidence on AD as a potential risk factor for inflammatory comorbidities is scarce. OBJECTIVES: We sought to test the hypothesis that prevalent AD is a risk factor for incident rheumatoid arthritis (RA) and inflammatory bowel disease (IBD; Crohn disease [CD], ulcerative colitis [UC]) and is inversely related to type 1 diabetes (T1D) and to investigate established RA, IBD, and T1D susceptibility loci in AD. METHODS: This cohort study used data from German National Health Insurance beneficiaries aged 40 years or younger (n = 655,815) from 2005 through 2011. Prevalent AD in the period 2005 to 2006 was defined as primary exposure, and incident RA, IBD, and T1D in the period 2007 to 2011 were defined as primary outcomes. Risk ratios were calculated with generalized linear models. Established RA, IBD, and T1D loci were explored in high-density genotyping data from 2,425 cases with AD and 5,449 controls. RESULTS: Patients with AD (n = 49,847) were at increased risk for incident RA (risk ratio [RR], 1.72; 95% CI, 1.25-2.37) and/or IBD (CD: RR, 1.34; 95% CI, 1.11-1.61; UC: RR, 1.25; 95% CI, 1.03-1.53). After adjusting for health care utilization, there was a nominally significant inverse effect on T1D risk (RR, 0.72; 95% CI, 0.53-0.998). There was no disproportionate occurrence of known RA, CD, UC, or T1D risk alleles in AD. CONCLUSIONS: AD is a risk factor for the development of RA and IBD. This excess comorbidity cannot be attributed to major known IBD and RA genetic risk factors.