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ID PMID Title PublicationDate abstract
18625620 Severe alterations in expression and localisation of {alpha}6{beta}4 integrin in salivary 2009 Jun OBJECTIVES: In salivary glands from patients with Sjögren syndrome, overexpression of laminins 1 and 5 and disorganisation of the acinar basal lamina have been reported. Laminin 5 mediates association of the basal lamina with epithelial cells by forming adhesion complexes upon interaction with alpha6beta4 integrin. In the present work, mRNA and protein levels of alpha6beta4 integrin were determined and its localisation in salivary glands evaluated in patients with Sjögren syndrome. METHODS: Salivary glands of 12 patients with Sjögren syndrome and 8 controls were studied. The mRNA and protein levels of alpha6beta4 were determined by semiquantitative reverse transcriptase (RT)-PCR and western blot analysis, respectively. The subcellular localisation of alpha6beta4 and laminin were evaluated by confocal microscopy. RESULTS: In patients, no significant differences in alpha6 and beta4 mRNA levels were detected. However, beta4 integrin protein levels were significantly lower, whereas, changes in alpha6, were highly variable. In controls, alpha6beta4 was detected in the basolateral and basal surface of serous and mucous acini, respectively. In patients, alterations in alpha6beta4 distribution were particularly dramatic for acini with strong basal lamina disorganisation. alpha6beta4 was also detected in the cytoplasm and lateral plasma membrane in serous and mucous acini. CONCLUSION: Mild alterations in the basal lamina correlated with lateral redistribution of alpha6beta4 integrin and the formation of new cell-cell adhesions that help maintain acinar organisation and promote cell survival. Conversely, in cases with severe basal lamina alterations, lateral alpha6beta4 redistribution was no longer sufficient to maintain acinar cell survival. Thus, maintenance of equilibrium between cell-cell and cell-basal lamina attachment is required to sustain gland cell survival.
20736143 Characterization of serum interleukin-15 in healthy volunteers and patients with early 2010 Sep As interleukin-15 (IL-15) has been implicated in the pathophysiology of rheumatoid arthritis, we analysed the serum IL-15 (sIL-15) levels in healthy subjects and patients with early arthritis to establish a cut-off point that might serve to define elevated sIL-15. This is an initial step to determine whether sIL-15 has the potential for use as a biomarker for patients with early arthritis. The IL-15 concentration was measured in serum obtained from 161 healthy controls and from 174 patients with early arthritis, and the relationship between the expression of the two IL-15 mRNA variants and the sIL-15 levels was also assessed. In healthy controls, the median sIL-15 value was 0.83 [interquartile range (IQR) 0-8.68] pg/mL; there was no significant difference in the sIL-15 values according to gender [median level in males was 1.99 (IQR: 0-8.68) pg/mL and in females 0.50 (0-8.25) pg/mL: p = 0.821]. Moreover, sIL-15 levels did not correlate with age (r = 0.033, p = 0.685), and they did not display a clear circadian rhythm in healthy donors, with the median values for IL-15 close to zero at each time tested. In the light of these findings, we considered that sIL-15 was elevated if its concentration was above 20 pg/mL, since this cut-off point corresponded to the 90th percentile for this healthy population. We found that 30% of the patients with early arthritis had sIL-15 values > 20 pg/mL. The levels of sIL-15 did not correlate with disease duration in early arthritis patients, nor did they fluctuate with changes in disease activity over the follow-up period. In addition, the high level of sIL15 in patients was not associated with alterations in the alternative splicing of the IL-15 mRNA, favouring the variant that produces the protein with a long signal peptide for secretion. Serum IL-15 levels were increased in a subpopulation of patients with early arthritis, indicating that this measure may serve as a biomarker for this condition. Further studies will be necessary to determine whether the clinical evolution or response to treatment of patients with high sIL-15 levels differs.
20012054 A case of juvenile idiopathic polyarticular arthritis complicated by IgA deficiency in 22q 2011 Aug Chronic arthritis may occur in association with antibody deficiency and chromosomal aberrations. This report presents the case of a 6-year-old girl with chromosome 22q11 deletion syndrome and chronic arthritis. The onset of arthritis occurred at 4 years of age. The chronic arthritis course has been the polyarticular type. Neither antinuclear antibody nor rheumatoid factor was detected. Serum IgA was extremely low. She was diagnosed with juvenile idiopathic polyarticular arthritis (JIA) complicated by IgA deficiency in the 22q11 deletion syndrome. There is an increased prevalence of chronic arthritis in association with 22q11 deletion syndrome with IgA deficiency, but the reasons for this association are unknown. This study evaluated the possible correlation between cytokines and the susceptibility to chronic arthritis in the 22q11 deletion syndrome with IgA deficiency. The expression of pro-inflammatory cytokines such as IL-8, IL-6, MIP-1β, and MCP-1 suggests that T and B cells, macrophages and neutrophils modulate joint inflammation by an immune response. And the presence of IL-10 and IL-5 might suggest that the synovitis is associated with JIA and IgA deficiency.
20190141 An LFA-1 (alphaLbeta2) small-molecule antagonist reduces inflammation and joint destructio 2010 Apr 1 LFA-1 appears to play a central role in normal immune responses to foreign Ags. In autoimmune or inflammatory diseases, there is increased expression of LFA-1 and/or its counterligand, ICAM-1. Others have demonstrated that the targeted disruption of LFA-1:ICAM interactions, either by gene deletion or Ab treatment in mice, results in reduced leukocyte trafficking, inflammatory responses, and inhibition of inflammatory arthritis in the K/BxN serum transfer model. However, there has been little success in finding a small-molecule LFA-1 antagonist that can similarly impact rodent models of arthritis. In this paper, we present the first reported example of an LFA-1 small-molecule antagonist, BMS-587101, that is efficacious in preclinical disease models. In vitro, BMS-587101 inhibited LFA-1-mediated adhesion of T cells to endothelial cells, T cell proliferation, and Th1 cytokine production. Because BMS-587101 exhibits in vitro potency, cross-reactivity, and oral bioavailability in rodents, we evaluated the impact of oral administration of this compound in two different models of arthritis: Ab-induced arthritis and collagen-induced arthritis. Significant impact of BMS-587101 on clinical score in both models was observed, with inhibition comparable or better than anti-mouse LFA-1 Ab. In addition, BMS-587101 significantly reduced cytokine mRNA levels in the joints of Ab-induced arthritis animals as compared with those receiving vehicle alone. In paws taken from the collagen-induced arthritis study, the bones of vehicle-treated mice had extensive inflammation and bone destruction, whereas treatment with BMS-587101 resulted in marked protection. These findings support the potential use of an LFA-1 small-molecule antagonist in rheumatoid arthritis, with the capacity for disease modification.
19950294 Inhibitor of DNA binding/differentiation 2 induced by hypoxia promotes synovial fibroblast 2009 Dec OBJECTIVE: To map hypoxic areas in arthritic synovium and to establish the relevance of low oxygen levels to the phenotype of synovial fibroblasts, with special focus on bone degradation. METHODS: To analyze the distribution of hypoxia in arthritic joints, the hypoxia marker EF5 was administered to mice with collagen-induced arthritis (CIA). To evaluate the effect of hypoxia on rheumatoid arthritis synovial fibroblasts (RASFs), reverse suppression subtractive hybridization and complementary DNA array were used. Real-time polymerase chain reaction, Western blotting, and immunohistochemistry were used to evaluate the expression of inhibitor of DNA binding/differentiation 2 (ID-2). To investigate the function of ID-2 in RASFs, cells were transfected either with ID-2 vector or with ID-2-specific small interfering RNA. RESULTS: EF5 staining showed the presence of hypoxia in arthritic joints, particularly at sites of synovial invasion into bone. Differential expression analysis revealed that ID-2 was strongly induced by hypoxia in RASFs. Immunohistochemical analysis of CIA mouse synovium and human RA synovium showed a strong expression of ID-2 by RASFs at sites of synovial invasion into bone. Overexpression of ID-2 in RASFs significantly induced the expression of several factors promoting osteoclastogenesis. The biologic relevance of the potent osteoclastogenesis-promoting effects was shown by coculture assays of ID-2-overexpressing RASFs with bone marrow cells, leading to an increased differentiation of osteoclasts from bone marrow precursors. CONCLUSION: The data show that hypoxic conditions are present at sites of inflammation and synovial invasion into bone in arthritic synovium. Hypoxia-induced ID-2 may contribute to joint destruction in RA patients by promoting synovial fibroblast-dependent osteoclastogenesis.
20875348 Genomics of ankylosing spondylitis. 2010 Sep Ankylosing spondylitis (AS) is the prototypic and most prevalent and debilitating spondyloarthropathy, a group of arthritides where the spine and pelvis are specifically targeted. Unlike many other forms of arthritis in which joint damage is mediated through tissue destruction, in AS uncontrolled bone formation occurs, frequently resulting in joint fusion and consequently significant disability. It is estimated that there are 2.4 million spondyloarthritis sufferers in the U.S., twice as many as rheumatoid arthritis. The pathogenesis of AS is very poorly understood and both genetics and gene expression profiling approaches have been utilized to elucidate the underlying mechanisms and pathways that drive the disease. Using powerful genome-wide association study approaches a number of candidate genes have been found to be associated with AS. However, although such approaches can identify genes that can contribute to the disease process, they do not inform us of the actual changes in gene/cell activity at any point in the disease process. Expression profiling allows us to take a "snapshot" of cellular activity and what gene activity changes are underlying those changes. A number of expression profiling studies have been undertaken in AS, looking at both circulating cells and tissues from affected joints. The results to date have been somewhat disappointing with little consensus on gene activity changes due to the low power of the studies undertaken. Some more recent better powered studies have identified diagnostic expression profiles that do point to a possible role for expression profiling in early AS diagnosis. Future studies will require collaborative approaches to target specific disease stages and sites with larger numbers of samples.
20480461 [Pain-specific diagnosis patterns in claims data - Identification by means of classificati 2010 Jun The identification of beneficiaries with persistent, recurrent or chronic pain in claims data by means of individual diagnoses or analgesic prescription is not sufficient and reliable. By using CLASSIFICATION AND REGRESSION TREES (CART) it was possible to identify specific diagnosis patterns for patients suffering from pain. Diagnosis patterns are considered as specific if they occur more frequently among beneficiaries with at least two opioid prescriptions within one year compared with beneficiaries who did not receive any analgesic therapy. Diagnosis and prescription data of 2006 were provided by the German sickness fund DAK. As a result, 65 diagnosis patterns occurred more frequently among beneficiaries treated with opioids than among the control group. These 65 patterns can be classified as follows: cancer-related pain (4), specific back pain/osteoporosis (8), spine-related pain (6), arthritis-related pain/rheumatoid arthritis (22), pain after traumatic fractures (5), pain in multimorbid, dependent patients (3), neuropathic pain (7), headache (5), non-specific back pain (5). The derived diagnosis patterns showed high predictive values (sensitivity: 78%, specificity: 66%) and are suitable for the identification of beneficiaries suffering from pain - the first step towards health services research in pain-based on claims data.
20128799 Substance P and glutamate receptor antagonists improve the anti-arthritic actions of dexam 2010 Feb BACKGROUND AND PURPOSE: Current single drug treatments for rheumatoid arthritis have problems of limited efficacy and/or high toxicity. This study investigates the benefits of individual and combined treatments with dexamethasone and substance P and glutamate receptor antagonists in a rat model of arthritis. EXPERIMENTAL APPROACH: Arthritis was induced in rats by unilateral intra-articular injection of Freund's complete adjuvant. Separate groups of rats were subjected to the following treatments 15 min before induction of arthritis: (i) control with no drug treatment; (ii) single intra-articular injection of a NK(1) receptor antagonist RP67580; (iii) single intra-articular injection of a NMDA receptor antagonist AP7 plus a non-NMDA receptor antagonist CNQX; (iv) daily oral dexamethasone; and (v) combined treatment with dexamethasone and all of the above receptor antagonists. Knee joint allodynia, swelling, hyperaemia and histological changes were examined over a period of 7 days. KEY RESULTS: Treatment with dexamethasone suppressed joint swelling, hyperaemia and histological changes that include polymorphonuclear cell infiltration, synovial tissue proliferation and cartilage erosion in the arthritic rat knees. Treatment with RP67580 or AP7 plus CNQX did not attenuate hyperaemia or histological changes, but reduced joint allodynia and swelling. Co-administration of dexamethasone with these receptor antagonists produced greater inhibition on joint allodynia and swelling than their individual effects. CONCLUSIONS AND IMPLICATIONS: The data suggest substance P and glutamate contribute to arthritic pain and joint swelling. The efficacy of dexamethasone in reducing arthritic pain and joint swelling can be improved by co-administration of substance P and glutamate receptor antagonists.
21130134 The CCN family: a new class of inflammation modulators? 2011 Mar Uncontrolled or sustained inflammation is the underlying cause of or actively contributes to the progression of many chronic pathologies such as atherosclerosis, arthritis, or neuroinflammatory diseases. Matricellular proteins of the CCN family (CYR61/CTGF/NOV) have emerged as localized multitasking signal integrators. These structurally conserved secreted proteins specifically interact with and signal through various extracellular partners, in particular integrins, which enable them to play crucial roles in various processes including development, angiogenesis, wound healing and diseases such as fibrosis, vascular disease and cancer. In this review, we discuss the possibility that the CCN family members could represent a putative new class of modulators of inflammation. In this context, we focused on their relationship with cytokines and chemokines. In vitro, CCN expression is finely regulated by diverse inflammatory mediators including cytokines (TNFα, IL1β, TGF-β), small factors such as prostaglandins, nitric oxide, histamine and serotonin, and extracellular matrix enzymes. In addition, CCN proteins acting alone or in concert with their specific partners appear to be potent regulators of the production of cytokines and chemokines in a context-dependent manner. Finally, emerging studies suggest a potential role for CCN proteins in chronic inflammatory diseases such as atherosclerosis, rheumatoid arthritis, inflammatory kidney diseases and neuroinflammatory pathologies such as Alzheimer's disease. CCN members could therefore represent new potential therapeutic targets for drug development against such diseases.
20393640 Efficacy and safety of biologicals against immune-mediated diseases: do benefits outweigh 2010 Feb The success of molecular biology in identifying molecular pathways underlying chronic immune-mediated diseases and the rapid development of gene/cell engineering biotechnologies has resulted in the development of a number of targeted biological drugs, which have revolutionized the therapy of these diseases. Numerous data published over the last 10-15 years demonstrate a dramatic improvement in the clinical efficacy of biologics compared with conventional drugs. However, professional and public concern about serious biological drug-associated adverse events has also been growing steadily. We critically analyze recent literature on the efficacy and safety of biologics in the management of rheumatoid arthritis, psoriasis, psoriatic arthritis and immune thrombocytopenia. Our analysis of benefits, resistance to the therapy, risk of infections, tumors and other serious complications related to chronic administration of biologics is based on the molecular/cellular mechanisms of their interaction with the immune system. We also address whether it is feasible to attenuate the risks associated with biologics without limiting their benefits.
19719397 Progressive multifocal leukoencephalopathy in patients on immunomodulatory therapies. 2010 Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease of the white matter of the human brain caused by lytic infection of oligodendrocytes with the human polyomavirus JCV. Although the majority of PML cases occur in severely immune-suppressed individuals, with HIV-1 infection as the predominant factor, PML has been increasingly diagnosed in patients treated with biological therapies such as monoclonal antibodies that modulate immune system functions. Monoclonal antibodies that target the cell adhesion molecules VLA-4 (natalizumab; Tysabri for multiple sclerosis and Crohn's disease) or LFA-1 (efalizumab; Raptiva for severe forms of plaque psoriasis) to prevent extravasation of inflammatory T cells into tissues, or target the cell surface marker CD20 (rituximab; Rituxan for hematologic malignancies and rheumatoid arthritis) to deplete peripheral circulating B cells, have all been associated with PML. The link between the effects of these therapies on the immune system and the occurrence of PML has prompted investigations on JCV sites of latency in the bone marrow, the migration of bone marrow derived cells into the circulation, and intracellular virus entry into the brain.
20572813 A peptide from the beta-strand region of CD2 protein that inhibits cell adhesion and suppr 2010 Sep 1 Cell adhesion molecules play a central role at every step of the immune response. The function of leukocytes can be regulated by modulating adhesion interactions between cell adhesion molecules to develop therapeutic agents against autoimmune diseases. Among the different cell adhesion molecules that participate in the immunologic response, CD2 and its ligand CD58 (LFA-3) are two of the best-characterized adhesion molecules mediating the immune response. To modulate the cell adhesion interaction, peptides were designed from the discontinuous epitopes of the beta-strand region of CD2 protein. The two strands were linked by a peptide bond. beta-Strands in the peptides were nucleated by inserting a beta-sheet-inducing Pro-Gly sequence with key amino acid sequences from CD2 protein that binds to CD58. Using a fluorescence assay, peptides that exhibited potential inhibitory activity in cell adhesion were evaluated for their ability to bind to CD58 protein. A model for peptide binding to CD58 protein was proposed based on docking studies. Administration of one of the peptides, P3 in collagen-induced arthritis in the mouse model, indicated that peptide P3 was able to suppress rheumatoid arthritis in mice.
20229261 Anti-agalactosyl IgG antibody in ankylosing spondylitis and psoriatic arthritis. 2010 Aug Anti-agalactosyl IgG antibody (anti-Gal(0) IgG) has been regarded as a useful serological marker for rheumatoid arthritis (RA). It is unknown whether it is also elevated in serum and implicated in the pathogenesis of joint inflammation in seronegative spondyloarthropathy (SpA) such as ankylosing spondylitis (AS) and psoriatic arthritis (PsA). Sera were collected from 43 patients with AS or PsA with axial joint involvement, 22 patients with RA, and 25 healthy normal individuals for the detection of anti-Gal(0) IgG with a cup-type lectin enzyme immunoassay (Eitest CA(.)RF). The disease activity of the AS/PsA was evaluated by Bath Ankylosing Spondylitis Disease Activity Score (BASDAI), the serum C-reactive protein (CRP) and IgA were measured by nephelometry, and erythrocyte sedimentation rate (ESR) was measured by Westergren's method. The median titers of anti-Gal(0) IgG were significantly elevated in patients with RA (167.85, 15.73 approximately 797.58 AU/mL) and AS/PsA (186.15, 34.71 approximately 651.19 AU/mL), compared to those of the normal controls (13.04, 12.00 approximately 202.43 AU/mL). The titers of the anti-Gal(0) IgG in patients with AS/PsA were correlated to the BASDAI scores (r (2) = 0.422, SEE = 1.443, p < 0.001) and serum CRP (r (2) = 0.345, SEE = 2.434, p < 0.001) but not to IgA (r (2) = 0.0259, SEE = 126.30, p < 0.001) or ESR (r (2) = 0.171, SEE = 31.053, p = 0.0059). Collectively, the anti-Gal(0) IgG is elevated and vaguely correlated with the disease activity of AS/PsA although its titers in these patients were erratic. The result of the present investigation has suggested that anti-Gal(0) IgG may be more ubiquitously present in inflammatory arthritides including RA or SpA.
20087751 Guidelines on the use of etanercept for juvenile idiopathic arthritis in Japan. 2010 Apr Etanercept is a dimeric fusion protein consisting of the extracellular domain of human tumor necrosis factor receptor II (TNFR II, molecular weight 75 kDa) coupled to the Fc region of human immunoglobulin (IgG1). It is produced by recombinant DNA technology by first introducing the gene into Chinese hamster ovarian cells and then purifying the protein from the culture supernatant. The mechanism of action of etanercept consists of binding to serum TNF-alpha and lymphotoxin (LT)-alpha (TNF-beta), which prevents TNF-alpha and LT-alpha from binding to the TNF-alpha receptor on the plasma membrane of the target cell. Etanercept is currently approved for treating adult rheumatoid arthritis (RA) in more than 70 countries worldwide. In Japan, it was approved for this target group in January 2005. The USA and Europe were the first to approve entanercept for use in treating juvenile idiopathic arthritis (JIA), initially for the treatment of active polyarticular JIA in patients not responding to disease-modifying antirheumatic drugs (USA in May 1999, followed by the EU in February 2000). Thereafter, the drug received approval for the treatment of JIA in many other countries. In Japan, children who have been diagnosed and treated according to Yokota et al. (Mod Rheumatol 17:353-363, 2007), but who have responded poorly to treatment must move onto the next stage of treatment. Such treatments include biological drugs, which, however, should be used with strict adhesion to the indications and exclusion criteria and should be used, for the time being, only by physicians trained on how to use them. In Japan, etanercept was approved in July 2009 for use in children. Although this drug has brought about a revolutionary advance in the treatment of JIA, it is our task to maximize its therapeutic effects and minimize its toxic effects. The guidelines presented here define the indications, exclusion criteria, usage, and evaluation criteria of etanercept for the treatment of polyarticular JIA.
20558268 Effects of compounds from bi-qi capsule on the expression of inflammatory mediators in lip 2011 Jul 14 AIM OF THE STUDY: The Bi-Qi Capsule (Bi-Qi) has been used in clinic as prescribed drug for the treatment of rheumatic arthritis, rheumatoid arthritis and other osteoarticular diseases about 20 years in China. Pharmacological and clinical studies have confirmed the anti-inflammatory and analgesic action of Bi-Qi in vivo. However, its anti-inflammatory molecular mechanism is still unclear. The objective of the study is to reveal the anti-inflammatory molecular mechanism of Bi-Qi which would form an additional proof to the traditional experience of Bi-Qi in clinical administration. MATERIALS AND METHODS: The aqueous extract of Bi-Qi was used to evaluate the anti-inflammatory action in murine macrophage cell line RAW 264.7 treated with lipopolysaccharide (LPS). Cell viability was evaluated by MTT assay. Production of nitric oxide (NO) and prostaglandin E(2) (PGE(2)) were measured by the Griess colorimetric method and enzyme-linked immunosorbent assay (ELISA), respectively. Protein expression levels of cyclooxygenase 2 (COX-2) were monitored by cell-based ELISA. Proteome profiler array was analyzed to evaluate 40 cytokines at protein level. In addition, interleukin 6 (IL-6) and tumor necrosis factor-alpha (TNF-α) synthesis were analyzed using ELISA to confirm the result of the Proteome profiler array. The gene expression levels of inducible nitric oxide synthase (iNOS), COX-2, TNF-α, IL-6, and interleukin 1β (IL-1β) were detected by quantitative real-time reverse-transcription polymerase chain reaction (real-time RT-PCR). RESULTS: Bi-Qi significantly decreased the production of NO, PGE(2), and inhibited the protein expression of COX-2. The Proteome profiler array showed that eight protein cytokines were down-regulated and six protein cytokines were up-regulated by Bi-Qi. Furthermore, the results of TNF-α and IL-6 protein expression analyzed by ELISA were similar to those of Proteome profiler array. The results of real-time RT-PCR demonstrated that iNOS, COX-2, TNF-α, IL-6 and IL-1β gene expression were also significantly reduced by Bi-Qi. CONCLUSION: These results suggested that the anti-inflammatory molecular mechanism of Bi-Qi might be the results from modulating the LPS-mediated NO-iNOS pathway, COX-2 pathway via inhibition of iNOS, COX-2, TNF-α, IL-6 and IL-1β expression in activated macrophages. In addition, these results provided evidence to understand the therapeutic effects of Bi-Qi on various inflammatory diseases, e.g. rheumatoid arthritis, rheumatic arthritis and other osteoarticular diseases.
19493438 Inhibition of collagen-induced arthritis by DNA vaccines encoding TCR Vbeta5.2 and TCR Vbe 2009 May 5 BACKGROUND: Arthritogenic T lymphocytes with common T cell receptor (TCR) Vbeta clonotypes, infiltrating in the articulars of rheumatoid arthritis (RA) patients, play a central role in the pathogenesis of RA. TCR Vbeta5.2 and TCR Vbeta8.2 are the main pathogenic T cell clonotypes in the course of collagen-induced arthritis (CIA) progression in Lewis rats. To investigate a TCR-based immunotherapy for RA, we constructed recombinant DNA vaccines encoding TCR Vbeta5.2 and TCR Vbeta8.2, and evaluated the inhibitive effects of the two vaccines on CIA rats. METHODS: Genes encoding TCR Vbeta5.2 and TCR Vbeta8.2 were amplified by RT-PCR from spleen lymphocytes of Lewis rats and cloned into the eukaryotic expression vector pTargeT. The expression of vaccines was confirmed by RT-PCR and immunohistochemistry. The inhibitive effects of the vaccines on articulars of CIA rats were assessed with arthritis index evaluation and histology. Interferon gamma (IFN-gamma) and interleukin (IL)-4 production by spleen lymphocytes were tested with enzyme-linked immunospot assay (ELISPOT) technique, the changes in peripheral CD4(+) and CD8(+) lymphocyte populations were tested by flow cytometry, and the level of anti-CII antibody in serum was assayed by enzyme-linked immunosorbent assay (ELISA). RESULTS: Recombinant DNA vaccines pTargeT-TCR Vbeta5.2 and pTargeT-pTCR Vbeta8.2 were successfully constructed. Both vaccines inhibited CIA, which alleviated the arthritis index score (P < 0.05), decreased the level of IFN-gamma (P < 0.05), and reduced the ratio of CD4(+)/CD8(+) lymphocytes (P < 0.05) and the anti-CII antibody in serum (P < 0.05). In addition, the histological change in DNA-vaccinated rats was less serious than CIA rats. Compared to pTCR Vbeta 8.2 and pTCR Vbeta 5.2 groups, the group that was injected with a combination of the two vaccines showed stronger inhibitive effects on CIA than either individual vaccine. CONCLUSION: The recombinant plasmids pTargeT-TCR Vbeta5.2 and pTargeT-TCR Vbeta8.2 have obvious inhibatory effects on CIA rats and better effects could be achieved when the vaccines were used in combination.
19356238 Vasoactive intestinal peptide inhibits TNF-alpha-induced apoptotic events in acinar cells 2009 INTRODUCTION: The role of apoptotic secretory epithelium as a pro-inflammatory triggering factor of exocrine dysfunction is currently explored in Sjogren's syndrome patients and in the nonobese diabetic (NOD) mouse model. Vasoactive intestinal peptide (VIP) has anti-inflammatory effects in various models of chronic inflammation. Our goal was to analyse the effect of TNF-alpha on apoptotic mediators in isolated acinar cells from NOD submandibular gland and their modulation by VIP. METHODS: Acinar cells were isolated from submandibular glands of 16-week-old NOD females with salivary flow decline. Age-matched BALB/c females or eight-week-old NOD females were used as controls. Apoptotic mediators and TNF-alpha receptor expression were assessed by immunoblotting and RT-PCR, caspase 3 activity was assessed by optical density at 405 nm with Ac-DEVD-pNA as a substrate and chromatin condensation by Hoechst stain. They were evaluated in resting conditions and after a 3.5 or 6 hours of culture with TNF-alpha. VIP effects in acinar cells were assessed at 100 nM in TNF-alpha-treated cultures and VIP receptor functional assays by radio immunoassay (cAMP) or enzymatic detection (amylase). RESULTS: NOD acinar cells at 16 weeks present an increased expression of TNF-alpha receptor1 together with increased Bax, tumour protein 53-induced nuclear protein1alpha (TP53INP1alpha), caspase 3 activity and chromatin condensation. Acini from NOD mice were more sensitive to TNF-alpha-induced increases of apoptotic mediators than control cells. VIP inhibited TNF-alpha-induced apoptotic events through functional VPAC1 receptors coupled to the protein kinase A (PKA) signalling pathway. CONCLUSIONS: Our results indicate that acinar cells isolated from submandibular glands of NOD mice with salivary dysfunction are more sensitive to apoptosis induced by TNF-alpha which could be prevented by VIP through a PKA-mediated pathway.
21133840 Tumor necrosis factor-α signaling in macrophages. 2010 Tumor necrosis factor-α (TNFα) was cloned over 2 decades ago and its identification in part led to the discovery of a super family of tumor necrosis factors (TNFs) and their receptors. TNFα signals through two transmembrane receptors, TNFR1 and TNFR2, and regulates a number of critical cell functions including cell proliferation, survival, differentiation, and apoptosis. Macrophages are the major producers of TNFα and interestingly are also highly responsive to TNFα. Aberrant TNFα production and TNF receptor signaling have been associated with the pathogenesis of several diseases, including rheumatoid arthritis, Crohn's disease, atherosclerosis, psoriasis, sepsis, diabetes, and obesity. TNFα has been shown to play a pivotal role in orchestrating the cytokine cascade in many inflammatory diseases and because of this role as a "master-regulator" of inflammatory cytokine production, it has been proposed as a therapeutic target for a number of diseases. Indeed anti-TNFα drugs are now licensed for treating certain inflammatory diseases including rheumatoid arthritis and inflammatory bowel disease. In this review we discuss the discovery of TNFα and its actions especially in regulating macrophage biology. Given its importance in several human diseases, we also briefly discuss the role of anti-TNFα therapeutics in the treatment of inflammatory diseases.
20617533 Preclinical validation of salivary biomarkers for primary Sjögren's syndrome. 2010 Nov OBJECTIVE: Sjögren’s syndrome (SS) is a systemic autoimmune disease with a variety of presenting symptoms that may delay its diagnosis. We previously discovered a number of candidate salivary biomarkers for primary SS using both mass spectrometry and expression microarray analysis. In the current study, we aimed to verify these candidate biomarkers in independent patient populations and to evaluate their predictive values for primary SS detection. METHODS: In total, 34 patients with primary SS, 34 patients with systemic lupus erythematosus (SLE), and 34 healthy individuals were enrolled for the validation studies. Salivary protein biomarkers were measured using either Western blotting or enzyme-linked immunosorbent assay, and the messenger RNA (mRNA) biomarkers were measured using quantitative polymerase chain reaction. Statistical analysis was performed using R software, version 2.9. RESULTS: Three protein biomarkers (cathepsin D [CPD], α-enolase, and ß₂-microglobulin [ß₂m]) and 3 mRNA biomarkers (myeloid cell nuclear differentiation antigen [MNDA], guanylate binding protein 2 [GBP-2], and low-affinity IIIb receptor for the Fc fragment of IgG) were significantly elevated in patients with primary SS compared with both SLE patients and healthy controls. The combination of 3 protein biomarkers, CPD, α-enolase, and ß₂m, yielded a receiver operating characteristic (ROC) value of 0.99 in distinguishing primary SS from healthy controls. The combination of protein biomarkers ß₂m and 2 mRNA biomarkers, MNDA and GBP-2, reached an ROC of 0.95 in discriminating primary SS from SLE. CONCLUSION: We have successfully verified a panel of protein and mRNA biomarkers that can discriminate primary SS from both SLE and healthy controls. If further validated in patients with primary SS and those with sicca symptoms but no autoimmune disease, these biomarkers may lead to a simple yet highly discriminatory clinical tool for diagnosis of primary SS.
20069326 Pseudohypercalcaemia in mixed cryoglobulinaemia (IgMkappa/polyclonal IgG): a rare complica 2010 Apr This is the first reported case of pseudohypercalcaemia associated with type 2 cryoglobulinaemia, secondary to primary Sjögren's syndrome. Pseudohypercalcaemia is an asymptomatic syndrome and does not require specific treatment. However, cryoglobulins have been demonstrated to bind to calcium, affecting the cryoprecipitability, and consequently, altering the pathogenicity of the cryoglobulins. This first report highlights potential for further research into this intriguing phenomenon.