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ID PMID Title PublicationDate abstract
24252024 Clinical value of ¹⁸F-fluoro-dexoxyglucose positron emission tomography/computed tomogr 2014 Jul OBJECTIVES: While there are a few reports describing 18F-fluoro-dexoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) findings in patients with adult-onset Still's disease (AOSD), no summary report has yet been published. In this study, we evaluated the usefulness of FDG-PET/CT for diagnosis and activity evaluation in patients with AOSD by summarizing the findings of our patients and those reported in the literature. METHODS: Seven consecutive AOSD patients who had undergone PET/CT at our department between 2007 and 2012 were included. We evaluated FDG uptake for characteristic findings in patients with AOSD. In addition, we reviewed the literature on seven previously reported AOSD patients who had undergone PET/CT. RESULTS: FDG accumulation was positive mainly in the bone marrow (100%), spleen (90.9%), lymph nodes (80.0%) and joints (75.0%). In addition, FDG uptake was positive in the pericardium, pleura, salivary glands, eyelids, muscle and major blood vessels. Six patients underwent follow-up FDG PET/CT for evaluation of treatment efficacy. Follow-up PET/CT showed diminished FDG accumulation in the bone marrow, spleen and lymph nodes, with maximum standardized uptake value (SUVmax) being substantially reduced from 4.03 ± 0.95 to 2.20 ± 0.75 (p = 0.04), 4.04 ± 1.10 to 2.55 ± 1.13 (p = 0.04) and 5.63 ± 4.99 to 2.10 ± 1.91 (p = 0.11), respectively. No significant correlation was found between SUVmax in each lesion and the laboratory data, except for a significant correlation between lactate dehydrogenase (LDH) and spleen SUV. CONCLUSIONS: FDG-PET/CT is useful for long-term assessments of AOSD activity in individual patients. However, PET/CT findings alone are not sufficient to make a differential diagnosis of AOSD versus malignant lymphoma.
25707089 Gene therapy in dentistry: present and future. 2014 Dec Gene therapy is one of several novel biological treatments under active study for a wide variety of clinical applications, including many relevant to dentistry. This review will provide some background on this therapeutic approach, assess the current state of its applications generally, and in the oral cavity, and suggest the implications for its use in the next 25 years.
24090683 Meta-analysis of differentially expressed genes in primary Sjogren's syndrome by using mic 2014 Jan INTRODUCTION: The purpose of this study was to identify differentially expressed (DE) genes and biological processes associated with changes in gene expression in primary Sjogren's syndrome (pSS). METHODS: We performed a meta-analysis using the INMEX program (integrative meta-analysis of expression data) of publicly available microarray GEO datasets of pSS. We performed Gene Ontology (GO) enrichment analyses and pathway analysis using Kyoto Encyclopedia of Genes and Genomes (KEGG). RESULTS: Three GEO datasets including 37 cases and 33 controls were available for the meta-analysis. We identified 179 genes across the studies which were consistently DE in pSS (146 up-regulated and 33 down-regulated). The up-regulated gene with the largest effect size (ES) (ES = -2.4228) was SELL (selectin L), whose product is required for the binding and subsequent rolling of leucocytes on endothelial cells to facilitate their migration into secondary lymphoid organs and inflammation sites. The most significant enrichment was in the immune response GO category (P = 2.52 × 10(-25)). The most significant pathway in our KEGG analysis was Epstein-Barr virus infection (P = 9.91 × 10(-06)). CONCLUSIONS: Our meta-analysis demonstrated genes that were consistently DE and biological pathways associated with gene expression changes with pSS.
24194774 Altered sympathetic-to-immune cell signaling via β₂-adrenergic receptors in adjuvant ar 2013 Adjuvant-induced arthritic (AA) differentially affects norepinephrine concentrations in immune organs, and in vivo β-adrenergic receptor (β-AR) agonist treatment distinctly regulates ex vivo cytokine profiles in different immune organs. We examined the contribution of altered β-AR functioning in AA to understand these disparate findings. Twenty-one or 28 days after disease induction, we examined β₂-AR expression in spleen and draining lymph nodes (DLNs) for the arthritic limbs using radioligand binding and western blots and splenocyte β-AR-stimulated cAMP production using enzyme-linked immunoassay (EIA). During severe disease, β-AR agonists failed to induce splenocyte cAMP production, and β-AR affinity and density declined, indicating receptor desensitization and downregulation. Splenocyte β₂-AR phosphorylation (pβ₂-AR) by protein kinase A (pβ₂-AR(PKA)) decreased in severe disease, and pβ₂-AR by G protein-coupled receptor kinases (pβ₂-AR(GRK)) increased in chronic disease. Conversely, in DLN cells, pβ₂-AR(PKA) rose during severe disease, but fell during chronic disease, and pβ₂-AR(GRK) increased during both disease stages. A similar pβ₂-AR pattern in DLN cells with the mycobacterial cell wall component of complete Freund's adjuvant suggests that pattern recognition receptors (i.e., toll-like receptors) are important for DLN pβ₂-AR patterns. Collectively, our findings indicate lymphoid organ- and disease stage-specific sympathetic dysregulation, possibly explaining immune compartment-specific differences in β₂-AR-mediated regulation of cytokine production in AA and rheumatoid arthritis.
25140767 [Risk factors for pleural lung disease in children with juvenile idiopathic arthritis]. 2014 Aug OBJECTIVE: To investigate the risk factors for pleural lung disease (PLD) in children with juvenile idiopathic arthritis (JIA) and to provide a basis for the early diagnosis and timely treatment of this disease. METHODS: A total of 360 children with a confirmed diagnosis of JIA were enrolled, and their clinical data were retrospectively analyzed. All patients underwent a chest X-ray. The patients with PLD were assigned to PLD group, while those without PLD were assigned to non-PLD group. The clinical, imaging, and laboratory results of JIA patients with PLD were analyzed. RESULTS: Among the 360 JIA patients, 43 (11.9%) had PLD, and 9 (21%) of them had respiratory symptoms. Chest X-ray findings mainly included interstitial pneumonitis (53.5%) and pleurisy and/or pleural effusion (38.1%). In the 43 cases of JIA-PLD, 4 (9.3%) had normal chest X-ray findings but abnormal chest CT findings. The incidence of PLD was relatively high in patients aged under 3 years and those aged 12 years or above. Children with systemic JIA had a relatively high incidence of PLD. Compared with the non-PLD group, the PLD group had a significantly higher incidence of anemia, elevated white blood cell (WBC) count and IgG levels in peripheral blood, and positive rheumatoid factors or antinuclear antibodies (P<0.05). CONCLUSIONS: Among children with JIA, PLD is mostly seen in patients with systemic JIA or aged <3 years or ≥ 12 years, especially those with anemia, elevated WBC count and IgG levels, and positive rheumatoid factors or antinuclear antibodies. For JIA patients with PLD, interstitial pneumonitis is usually seen on chest X-ray or CT, but respiratory symptoms are rarely observed. Routine use of high-resolution chest CT is recommended for early diagnosis and timely treatment of PLD in children with JIA.
23886979 Microscopic polyangiitis secondary to silica exposure. 2014 May There is sufficient evidence of the capacity of silica to induce autoimmunity in patients with some type of genetic susceptibility. There are several autoimmune diseases related to this exposure (rheumatoid arthritis, Sjögren's syndrome, sarcoidosis, systemic sclerosis). Nodular silicosis (clinical expression of this exposure in lungs) generates apoptosis, inflammation, loss of tolerance and a respiratory burst. There is evidence that relates silica with induction of antineutrophil cytoplasmic antibodies, but, until it is better explained, the reports of systemic vasculitis secondary to silica exposure are inconclusive. We describe a case of a patient with a history of occupational exposure to silica who developed microscopic polyangiitis.
25108433 [The circulating fibrocytes are associated with the lung inflammation and fibrosis of mice 2014 Aug OBJECTIVE: To study the pathological process and characteristics of bleomycin (BLM)-induced interstitial lung disease (ILD) model and collagen-induced arthritis (CIA) complicated by BLM-induced ILD (CIA-ILD) model in mice and explore the correlations with circulating fibrocytes. METHODS: Ninety mice were randomly divided into normal saline group (S group), BLM group (B group), CIA-BLM group (CB group), with 30 mice in each group. On the 2, 7, 14, 21 and 28 days after BLM challenge, mice of each group were sacrificed. HE staining was used to detect the degrees of acute inflammation and sirius red staining to detect lung fibrosis. Immunohistochemicstry was adopted to detect alpha-smooth muscle actin expression. The peripheral blood was obtained to count the proportion of circulating fibrocytes (CD45⁺COL1⁺) by flow cytometry. The correlations between circulating fibrocytes and pathological changes of ILD were analyzed statistically. RESULTS: Both of the ILD model groups showed the dynamic process from pulmonary alveolitis to fibrosis gradually. Inflammatory lesion in the lungs of B group was the most obvious on the 7-14th day, and then there was a slow rehabilitation process on the 21th and 28th day. CB group began to present alveoli destruction and collagen deposition on the 14th day, and the inflammation was the most severe on the 28th day. Pulmonary hydroxyproline content was obviously ascended in CB group as compared with B group (P<0.05) after 14 days. An increase in the total number of circulating fibrocytes was observed in both B and CB groups. It tended to increase at first, and subsequently declined. The level of circulating fibrocytes was higher in CB group than in B group on day 14, 21 and 28 (P<0.05). The immunohistochemical results showed that there were many myofibroblasts infiltrating in CB group from the 14th day to 28th day. The number of circulating fibrocytes in peripheral blood was positively correlated with pulmonary inflammation, fibrosis degree and hydroxyproline content (r=0.847, 0.826, 0.735, P<0.01). CONCLUSION: The pathological process of CIA-ILD animal model is more close to rheumatoid arthritis-induced ILD development. Circulating fibrocytes may be involved in the inflammation and fibrosis progression of lung.
25278501 Increased rheumatoid factor and deep venous thrombosis: 2 cohort studies of 54628 individu 2015 Feb BACKGROUND: The risk of deep venous thrombosis is increased in patients with rheumatoid arthritis. We tested the hypothesis that increased concentrations of rheumatoid factor are associated with increased risk of deep venous thrombosis in individuals without autoimmune rheumatic disease in the general population. METHODS: We included 54628 participants from the Copenhagen City Heart Study (1981-83) and the Copenhagen General Population Study (2004-12), all with a measured concentration of IgM rheumatoid factor and without autoimmune rheumatic disease or venous thromboembolism. The main outcome was incident deep venous thrombosis. There were no losses to follow-up. RESULTS: During 368381 person-years, 670 individuals developed deep venous thrombosis. A rheumatoid factor concentration ≥ vs <110 IU/mL showed the strongest association with deep venous thrombosis, with multivariable adjusted hazard ratios of 9.0 (95% CI 3.1-26) for 1-year follow-up, 4.3 (2.2-8.5) for 5-year follow-up, and 3.1 (1.7-5.6) for up to 32 years of follow-up. Compared with rheumatoid factor concentrations <15 IU/mL, the multivariable adjusted hazard ratios for deep venous thrombosis during maximum follow-up were 1.3 (1.0-1.5) for 15-29 IU/mL, 1.7 (1.0-2.8) for 30-59 IU/mL, 2.4 (1.3-4.3) for 60-119 IU/mL, and 3.0 (1.6-5.6) for ≥120 IU/mL (trend P = 6 × 10(-7)). Results were similar in the 2 studies separately. Obese men and women age >60 years with rheumatoid factor concentrations ≥120 IU/mL had 10% and 8% 5-year risk of deep venous thrombosis. CONCLUSIONS: Increased rheumatoid factor in the general population was associated with up to 3-fold increased long-term risk and up to 9-fold increased 1-year risk of deep venous thrombosis.
23203851 Therapeutic efficacy of Tyro3, Axl, and Mer tyrosine kinase agonists in collagen-induced a 2013 Mar OBJECTIVE: Hyperactivation of innate immunity by Toll-like receptors (TLRs) can contribute to the development of autoinflammatory or autoimmune diseases. This study evaluated the activation of Tyro3, Axl, Mer (TAM) receptors, physiologic negative regulators of TLRs, by their agonists, growth arrest-specific protein 6 (GAS-6) and protein S, in the prevention of collagen-induced arthritis (CIA). METHODS: Adenoviruses overexpressing GAS-6 and protein S were injected intravenously or intraarticularly into mice during CIA. Splenic T helper cell subsets from intravenously injected mice were studied by flow cytometry, and the knee joints of mice injected intravenously and intraarticularly were assessed histologically. Synovium from mice injected intraarticularly was evaluated for cytokine and suppressor of cytokine signaling (SOCS) expression. RESULTS: Protein S significantly reduced ankle joint swelling when overexpressed systemically. Further analysis of knee joints revealed a moderate reduction in pathologic changes in the joint and a significant reduction in the number of splenic Th1 cells when protein S was overexpressed systemically. Local overexpression of GAS-6 decreased joint inflammation and joint pathology. Protein S treatment showed a similar trend of protection. Consistently, GAS-6 and protein S reduced cytokine production in the synovium. Moreover, levels of messenger RNA for interleukin-12 (IL-12) and IL-23 were reduced by GAS-6 and protein S treatment, with a corresponding decrease in the production of interferon-γ and IL-17. TAM ligand overexpression was associated with an increase in SOCS-3 levels, which likely contributed to the amelioration of arthritis. CONCLUSION: This study provides the first evidence that TAM receptor stimulation by GAS-6 and protein S can be used to ameliorate arthritis when applied systemically or locally. TAM receptor stimulation limits proinflammatory signaling and adaptive immunity. This pathway provides a novel strategy by which to combat rheumatoid arthritis.
23001748 The Japanese version of the modified ACR preliminary diagnostic criteria for fibromyalgia 2013 Sep PURPOSE: The aim of this study is to investigate the reliability and validity of the Japanese version of the modified American College of Rheumatology (ACR) Preliminary Diagnostic Criteria for Fibromyalgia (mACR 2010-J) and the Fibromyalgia Symptom Scale (mFS-J). METHODS: According to the ACR 1990 classification criteria, patients with chronic pain were divided into the fibromyalgia group and nonfibromyalgia group (rheumatoid arthritis and osteoarthritis). Patients in both groups were assessed using mACR 2010-J and mFS-J. RESULTS: 294 of 462 (64 %) patients in the fibromyalgia group met mACR 2010-J, whereas 4 % (9/231) of the nonfibromyalgia group did, with sensitivity of 64 %, specificity of 96 %, positive predictive value of 97 %, negative predictive value of 56 %, and positive likelihood ratio of 16.3. Mean total scores on mFS-J significantly differentiated the fibromyalgia from the nonfibromyalgia group. According to the value of the Youden index, the best cutoff score for the mFS-J was 9/10. CONCLUSION: Our findings indicate that mACR 2010-J as a positive test and mFS-J as a quantification scale might be suitable for assessing fibromyalgia among Japanese chronic pain populations.
24223854 Grape seed proanthocyanidin extract-mediated regulation of STAT3 proteins contributes to T 2013 Grape seed proanthocyanidin extract (GSPE) is a natural flavonoid that exerts anti-inflammatory properties. Obesity is an inflammatory condition and inflammatory cells and their secretion of pro-inflammatory molecules contribute to the pathogenesis of obesity. Rheumatoid arthritis (RA) is a chronic autoimmune disease that is characterized by inflammation of joints lined by synovium. Previously, we demonstrated that obesity augmented arthritis severity in collagen induced arthritis (CIA), a murine model of human RA. Here, we investigated whether oral administration of GSPE showed antiobesity and anti-arthritic effects in high-fat diet-induced obese (DIO) mice and in obese CIA mice, respectively. The pathophysiologic mechanisms by which GSPE attenuates weight gain and arthritis severity in vivo were also investigated. In DIO mice, GSPE administration significantly inhibited weight gain, reduced fat infiltration in liver and improved serum lipid profiles. The antiobesity effect of GSPE was associated with increased populations of regulatory T (Treg) cells and those of decreased Th17 cells. Decrease of Th17 cells was associated with significant inhibition of their key transcriptional factors, pSTAT3(Tyr705) and pSTAT3(Ser727). On the contrary, GSPE-induced Treg induction was associated with enhanced pSTAT5 expression. To identify the anti-arthritis effects of GSPE, GSPE was given orally for 7 weeks after type II collagen immunization. GSPE treatment significantly attenuated the development of autoimmune arthritis in obese CIA model. In line with DIO mice, GSPE administration decreased Th17 cells and reciprocally increased Treg cells by regulating STAT proteins in autoimmune arthritis model. The expressions of pro-inflammatory cytokines and nitrotyrosine in synovium were significantly inhibited by GSPE treatment. Taken together, GSPE functions as a reciprocal regulator of T cell differentiation - suppression of Th17 cells and induction of Tregs in both DIO and obese CIA mice. GSPE may act as a therapeutic agent to treat immunologic diseases related with enhanced STAT3 activity such as metabolic disorders and autoimmune diseases.
23947692 Imatinib mesylate: an innovation in treatment of autoimmune diseases. 2013 Sep Imatinib mesylate is a selective protein tyrosine kinase inhibitor, which can inhibit BCR/Abl, PDGF-R, c-KIT, c-fms, TCR/Abl, Lck, FLT-3 and MAPKs activities on various cell types. On immune system, imatinib has antiproliferative activity and immunomodulatory effects in lymphocytes, macrophages, mast cells and dendritic cells with abrogating multiple signal transduction pathways involved in pathogenesis of autoimmune diseases e.g. inhibiting IFN-γ, TNF-α, IL-1β and IL-17 pro-inflammatory cytokines and MMPs secretion. To date, the efficacy of imatinib in numerous animal model of autoimmune diseases (rheumatoid arthritis, multiple sclerosis, autoimmune diabetes and glomerulonephritis) has been demonstrated, but application of this drug in human autoimmune diseases should be tested in future clinical trials. This review provides an update on the use of tyrosine kinase inhibitor imatinib mesylate in treatment of autoimmune diseases and its related recent patents that could be developed as a novel and available therapy for the management of the autoimmunity improvement.
23280397 G-protein signaling modulator-3, a gene linked to autoimmune diseases, regulates monocyte 2013 Jun Polymorphism at the GPSM3 gene locus is inversely associated with four systemic autoimmune diseases, including rheumatoid arthritis and ankylosing spondylitis. G-protein signaling modulator-3 (GPSM3) expression is most pronounced in myeloid cells, in which it targets heterotrimeric G-protein Gαi subunits of chemokine receptors, critical to immune function. To begin to explore the regulatory role of GPSM3 in monocytes, human THP-1 and primary mouse myeloid cells were cultured under stimulus conditions; GPSM3 was found by immunoblotting to be expressed at highest levels in the mature monocyte. To evaluate the effects of GPSM3 deficiency on a myeloid-dependent autoimmune disease, collagen antibody-induced arthritis (CAIA) was induced in Gpsm3-/- and control mice, which were then analyzed for clinical score, paw swelling, intra-articular proinflammatory markers, and histopathology. Mice lacking GPSM3 were protected from CAIA, and expression of monocyte-representative pro-inflammatory chemokine receptors and cytokines in paws of Gpsm3-/- mice were decreased. Flow cytometry, apoptosis, and transwell chemotaxis experiments were conducted to further characterize the effect of GPSM3 deficiency on survival and chemokine responsiveness of monocytes. GPSM3-deficient myeloid cells had reduced migration ex vivo to CCL2, CX3CL1, and chemerin and enhanced apoptosis in vitro. Our results suggest that GPSM3 is an important regulator of monocyte function involving mechanisms of differentiation, survival, and chemotaxis, and deficiency in GPSM3 expression is protective in acute inflammatory arthritis.
23512174 Prevalence of juvenile idiopathic arthritis in Sharkia Governorate, Egypt: epidemiological 2013 Sep Our objective was to determine the prevalence juvenile idiopathic arthritis (JIA) in Sharkia Governorate, Egypt. Population-based study was performed to identify the prevalence of JIA in Sharkia Governorate, Egypt, between November 2009 and November 2010. Prevalence of JIA was 3.43 per 100,000 (95 % CI 3.1-4.3). Prevalence in boys was 2.58 per 100,000 (95 % CI 2.4-3.6) and in girls 4.33 per 100,000 (95 % CI 3.3-5.1). Uveitis presented in 19.7 % of cases, antinuclear antibody in 48.5 %, and rheumatoid factor in 27.2 %. Oligoarthritis representing 52.2 % of the total population, and enthesitis-related arthritis presented only in 6 patients. No cases of undifferentiated arthritis or psoriatic arthritis were found. This is the first epidemiological study of JIA in Sharkia, Egypt. Oligoarthritis was the most common subtype.
24028747 Anti-interleukin-6 receptor antibody prevents systemic bone mass loss via reducing the num 2014 Feb Systemic bone loss is a hallmark of rheumatoid arthritis (RA). Inflammatory cytokines such as interleukin (IL)-6 promote bone resorption by osteoclasts. Sphingosine-1-phosphate (S1P) controls the migration of osteoclast precursor cells (OCPs) between the blood and bone marrow, in part via S1P receptors (S1PR1 and S1PR2) expressed on the surface of OCPs. OCPs (CD11b(+) Gr-1(low+med) ) isolated from bone marrow of DBA/1J mice were stimulated with IL-6. S1P-directed chemotaxis of OCPs was evaluated using a transwell plate. mRNA expression of S1PR1 and S1PR2 was measured. DBA/1J mice were immunized with bovine type II collagen (days 0 and 21) and anti-mouse IL-6 receptor antibody (MR16-1) was administered on days 0 and/or 21. Trabecular bone volume was analysed using micro-computed tomography. The percentage of OCPs in tibial bone marrow and S1PR1 and S1PR2 mRNA expression in OCPs were measured. IL-6 stimulation significantly decreased S1P-directed chemotaxis of OCPs. IL-6 induced S1PR2 mRNA expression, but not S1PR1 mRNA expression, in OCPs. Bone volume was significantly lower in arthritic mice than in non-arthritic control mice on day 35. Treatment of immunized mice with MR16-1 significantly inhibited bone loss. In MR16-1-treated mice, the percentage of OCPs and expression of S1PR2 mRNA was each decreased compared with arthritic mice on day 14, but not on day 35. IL-6 increased the number of OCPs in tibial bone marrow via up-regulating S1PR2, thus playing a crucial role in systemic bone loss induced by inflammation.
23178558 Etanercept attenuates collagen-induced arthritis by modulating the association between BAF 2013 Feb Anti-tumour necrosis factor-α (TNF-α) drugs are approved for the treatment of rheumatoid arthritis (RA). Many studies have investigated the effect of these drugs on the T cell response; however, some clues have indicated that it may also target B cells. This study was carried out to explore the potential effects and mechanisms of etanercept, a soluble TNF-α receptor, on the function of B cells and their development into memory B cells in type II collagen (CII)-induced arthritis (CIA). Beginning on day 24 after CII immunisation, the mice were evaluated every 2-3 days to determine two clinical parameters: their arthritis global assessment and swollen joint count (SJC). The serum concentrations of IgG1, IgG2a and anti-CII antibodies and the splenic pathology and proliferation of B cells were measured. The percentage of total memory B cells in the spleen was analysed with flow cytometry. BAFFR was detected by immunohistochemistry. In CIA mice, etanercept markedly suppressed the arthritis global assessment and the SJC, reduced the production of anti-CII, IgG1 and IgG2a antibodies, and prevented spleen histopathology to varying degrees; however, it had no obvious effect on splenic B cell proliferation. Etanercept also decreased the percentage of total CD27(+) memory B cells in the spleen. Treatment with etanercept was associated with a further increase in BAFFR expression, a significant reduction in CD27 expression, and a negative correlation between the levels of BAFFR and the percentage of memory B cells. Our findings showed that increased BAFFR expression has a regulatory effect on the activation of B cells and the generation of memory B cells, which may be one of the mechanisms of the therapeutic effects of etanercept.
25065010 The active metabolite of spleen tyrosine kinase inhibitor fostamatinib abrogates the CD4⁠2015 Jan OBJECTIVES: Spleen tyrosine kinase (SYK) is a core signalling protein that drives inflammatory responses and is fundamental to the propagation of signals via numerous immune receptors, including the B cell receptor and Fc receptors (FcRs). Fostamatinib, a small molecule SYK inhibitor, has shown evidence of ameliorating inflammation in RA patients. We sought to understand how the active metabolite of fostamatinib, R406, affects the inflammatory response at the cellular level. METHODS: Antigen-specific in vivo systems and in vitro fluorescence microscopy were combined to investigate the effects of fostamatinib on antigen-specific interactions between dendritic cells (DCs) and CD4(+) T cells. RESULTS: Although it has previously been shown that R406 reduces the response of DCs to immune complexes (ICs), we found that fostamatinib failed to reduce specific CD4(+) T cell proliferation in mice after immunization with ICs. However, we observed in vitro that R406 reduces both the area and duration of cellular interactions between IC-activated DCs and specific CD4(+) T cells during the initial phase of cellular crosstalk. This led to diminished proliferation of antigen-specific CD4(+) T cells after R406 treatment compared with vehicle controls. This decreased proliferative capacity of CD4(+) T cells was accompanied by reduced expression of the co-stimulatory molecules, inducible T cell co-stimulator (ICOS) and PD-1, and abrogation of the production of inflammatory cytokines such as IFN-γ and IL-17. CONCLUSION: Our findings indicate a potential mechanism by which this compound may be effective in inhibiting FcR-driven CD4(+) T cell responses.
23190454 The pharmacology study of a new recombinant TNF receptor-hyFc fusion protein. 2013 Mar TNF-α-blocking agents such as infliximab, adalimumab and etanercept are widely used for the treatment of severe inflammatory diseases including rheumatoid arthritis and psoriasis. The currently used TNF-α blockers have Fc regions of the human IgG1 subtype, which is advantageous in terms of in vivo half-life but also raise the potential for unwanted effector-mediated effects, such as antibody dependent cellular cytotoxicity (ADCC) or complement-dependent cytotoxicity (CDC). To address this issue, we constructed a novel hybrid protein by fusing the TNF receptor (TNFR) with a hybrid Fc (hyFc) consisting of the CH2 and CH3 regions of IgG4 and the highly flexible hinge regions of IgD which would not have ADCC and CDC activity. The resulting fusion protein, TNFR-hyFc, was over-expressed in CHO and pharmacological characteristics were evaluated in comparison with the structurally similar etanercept. TNFR-hyFc effectively neutralized TNF-α in L929 bioassay and showed a 1.5-fold higher neutralizing activity compared to etanercept. In a pharmacokinetic study in cynomolgus monkeys, TNFR-hyFc showed plasma half-life and AUC comparable to etanercept. In a mouse collagen induced arthritis model, TNFR-hyFc showed significant amelioration of arthritis compared to etanercept or vehicle control. In an LPS-induced septic shock model, TNFR-hyFc showed a similar level of protection against mortality as etanercept. These results confirm the feasibility of the TNFR-hyFc as an effective TNF-α blocker for the treatment of inflammatory diseases.
26096092 The child with joint pain in primary care. 2014 Dec Joint pains are a common reason for children to present to primary care. The differential diagnosis is large including some diseases that do not primarily affect the musculoskeletal system. Although the cause for many patients will be benign and self-resolving, in rare cases the diagnosis is associated with long-term morbidity and mortality if not detected early and appropriately treated. These include primary and secondary malignancies, septic arthritis, osteomyelitis, inflammatory arthritis, slipped upper femoral epiphysis (SUFE) and non-accidental injury. We highlight the importance of a thorough history and directed yet comprehensive examination. A diagnostic algorithm is provided to direct primary care physicians' clinical assessment and investigation with the evidence base where available. In many cases, tests are not required, but if there is suspicion of malignancy, infection or inflammatory conditions, laboratory tests including full blood count, blood film, erythrocyte sedimentation rate, C-reactive protein and lactate dehydrogenase help to support or exclude the diagnosis. Autoimmune tests, such as antinuclear antibodies and rheumatoid factor, have no diagnostic role in juvenile idiopathic arthritis; therefore, we advise against any form of 'rheumatological/autoimmune disease screen' in primary care. Imaging does have a place in the diagnosis of joint pains in children, with plain radiographs being most appropriate for suspected fractures and SUFE, whilst ultrasound is better for the detection of inflammatory or infective effusions. The appropriate referral of children to paediatric rheumatologists, oncologists, orthopaedic surgeons and the emergency department are discussed.
24764059 Correlation between disease severity and presence of ocular autoantibodies in juvenile idi 2014 Apr 24 PURPOSE: The pathogenesis of juvenile idiopathic arthritis-associated uveitis (JIAU) is undefined. This study intended to analyze the presence of antiocular autoantibodies in serum and their correlation with disease course. METHODS: Serum samples from children with JIAU (n = 47); JIA without uveitis (n = 67); idiopathic anterior uveitis (IAU; n = 12); and healthy controls (n = 52) were collected. The binding patterns of serum antibodies to ocular cryosections from swine eyes were analyzed by indirect immunohistochemistry, and were correlated to epidemiological, clinical, and laboratory test results. RESULTS: The patient groups differed with respect to their presence of antibody binding to the sections: JIAU (94%), JIA (75%), IAU (75%), and healthy controls (29%) to uveal and/or retinal structures. Serum antibodies of JIAU patients predominantly bound at iris (74%), and ciliary body (79%). Iris/ciliary body positive staining correlated with the presence of uveitis complications (P < 0.005) in JIAU patients, but not with positivity of serum antinuclear antibodies (ANA), rheumatoid factor (RF), or HLA-B27, and was independent from uveitis activity or type of anti-inflammatory therapy. CONCLUSIONS: In JIAU patients, antiocular serum antibodies can be detected more frequently than in control groups. Binding patterns to ocular tissue correlate with complicated uveitis course but not with uveitis activity and anti-inflammatory treatment. Antibody binding is not specific for this uveitis entity, and does not correlate with ANA positivity.