Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0003873 (rheumatoid arthritis)
 53,068 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Two soluble tumour-necrosis-factor-alpha(TNF)-binding proteins are derived from the extracellular domains of the p55 and p75 TNF receptors. They are considered to play a pivotal regulatory role in TNF-mediated inflammatory processes, including diseases such as rheumatoid arthritis, by competing with the cell surface receptors for TNF and lymphotoxin (LT, tumour-necrosis factor beta). The extracellular domains of the two receptors each contain four similar cysteine-rich repeats of about 40 amino acids, in common with several other cell surface proteins including the p75 nerve-growth-factor receptor and the CD40 and Fas antigens. The aim of this study was to characterize the involvement of the four cysteine-rich repeats of the human p55 TNF receptor in TNF and LT binding by both membrane-bound and soluble forms of the receptor. Individual repeats were systematically deleted by PCR mutagenesis and the variants transiently expressed in COS cells. Immunoprecipitated receptor variants exhibited the expected sizes on SDS/PAGE gels, and bound a panel of conformation-dependent anti-(TNF receptor) antibodies. Binding of TNF by the four soluble derivatives was compared with binding by the wild-type soluble receptor using a TNF-affinity column and a BIAcore Biosensor, by measurement of their ability to inhibit TNF cytotoxicity on WEHI cells, and 125I-TNF binding to U937 cells. delta 4, which lacks the fourth cysteine-rich repeat, bound TNF comparably with the full-length soluble receptor. TNF-binding affinity was unaltered by deletion of the fourth membrane-proximal cysteine-rich repeat, as determined by Scatchard analysis of the transmembrane derivatives. We conclude that the fourth cysteine-rich repeat is not required for TNF binding. In contrast, both the soluble and the transmembrane derivatives lacking any one of the first, second or third repeats failed to bind TNF. Although we cannot entirely exclude the possibility that this may be due to indirect conformational change, rather than the removal of essential epitopes, our results suggest that the first three repeats are each required for TNF binding by both the soluble and the cell-surface receptor.
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PMID:Characterization of ligand binding by the human p55 tumour-necrosis-factor receptor. Involvement of individual cysteine-rich repeats. 805 60

Recent reports revealed that Fas antigen is functionally expressed on human synovial cells and apoptosis can be induced in these cells by anti-Fas antibody. We examined the effect of interleukin 1 beta (IL-1 beta) on Fas antigen-mediated apoptosis on human synovial cells in vitro. Using flowcytometric analysis, IL-1 beta inhibited Fas antigen expression on synovial cells in a dose-dependent fashion. No significant difference of Fas antigen gene expression between IL-1 beta-treated and untreated synovial cells was observed by RT-PCR analysis, suggesting that the inhibitory effect of Fas antigen expression by IL-1 beta is at posttranscriptional level. Apoptosis of synovial cells was easily induced by treatment of these cells with anti-Fas antibody. In contrast, pretreatment of synovial cells with IL-1 beta protected these cells against Fas antigen-mediated apoptosis. The expression of bcl-2 on synovial cells, known to interfere with the apoptotic process mediated by the Fas antigen, was not influenced by IL-1 beta. Our results suggest that IL-1 beta inhibits Fas antigen-mediated apoptosis of synovial cells and may perpetuate the hyperplasia of the synovium in patients with rheumatoid arthritis.
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PMID:Fas antigen expression on synovial cells was down-regulated by interleukin 1 beta. 857 46

Expression of Fas antigen and Fas ligand (-L) were observed in synovial tissue from rheumatoid arthritis (RA) patients, whereas in only a few cells expressed these molecule osteoarthritis synovial tissue. Fas-L was expressed on CD45RO, CD4, CD8 or CD56 positive cells in RA synovial tissue. Moreover, 10 to 30% of synovial cells expressing Fas antigen were observed to be identical with apoptotic synovial cells and Fas expression was closely related to c-fos and c-myc. These findings suggest that activated T cells and natural killer cells infiltrating into the RA synovium may play an important role in the induction of apoptosis of RA synovial cells through Fas/Fas-L interactions.
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PMID:[Expression of Fas/Fas ligand and proto-oncogenes in rheumatoid synovial tissues]. 874 95

We have recently demonstrated Fas-mediated apoptosis in the synovium, of patients with rheumatoid arthritis (RA) and suggested that it may be one factor responsible for the regression of RA. To examine whether the induction of apoptosis caused by anti-Fas mAb may play a potential role as a new therapeutic strategy for RA, we investigated the effect of anti-Fas mAb (RK-8) on synovitis in an animal model of RA, the human T cell leukemia virus type I (HTLV-1) tax transgenic mice. We report here that administration of anti-Fas mAb into mice intra-articularly improved the paw swelling and arthritis within 48 h. Immunohistochemical study and in vitro culture studies showed that 35% of synovial fibroblasts, 75% of mononuclear cells, and some of polymorphonuclear leukocytes infiltrating in synovium underwent apoptosis by anti-Fas mAb. In situ nick end labeling analysis and electron microscope analysis clearly showed that many cells in synovium were induced apoptosis by anti-Fas mAb administration. However, local administration of anti-Fas mAb did not produce systemic side effects. Results demonstrated that administration of anti-Fas mAb in arthritic joints of the HTLV-1 tax transgenic mice produced improvement of arthritis. These findings suggest that local administration of anti-Fas mAb may represent a useful therapeutic strategy for proliferative synovitis such as RA.
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PMID:Therapeutic effect of the anti-Fas antibody on arthritis in HTLV-1 tax transgenic mice. 875 34

To understand the role of apoptosis through Fas/Fas ligand (Fas-L) interaction in the pathogenesis of rheumatoid arthritis (RA), we examined the expression of Fas antigen, Fas-L, and apoptosis in synovial tissue obtained from eight patients with RA and five patients with osteoarthritis (OA). Immunohistochemical staining demonstrated the significant expression of Fas antigen and Fas-L in RA synovial tissue compared with that in OA synovial tissue. Immunohistochemical staining and the DNA nick end labeling (TUNEL) method were combined and revealed that approximately 10 to 30% of Fas antigen-expressing cells in the RA synovium showed DNA fragmentation characteristic for apoptosis. In double-staining analysis, Fas-L was expressed on up to 10% of CD45RO-, CD4-, CD8-, or CD56-positive mononuclear cells in RA synovial tissue. Our results suggest that activated T cells and natural killer cells infiltrating into the RA synovium may contribute to the induction of apoptosis of RA synovial and mononuclear cells through Fas/Fas-L interaction.
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PMID:Expression of Fas antigen and Fas ligand in the rheumatoid synovial tissue. 880 38

In this study, we investigated the IL-1 beta converting enzyme (ICE) family cysteine proteases responsible for the Fas-mediated apoptosis of rheumatoid arthritis (RA) synoviocytes and their involvement in proinflammatory cytokine production. CPP32 inhibitor, but not ICE inhibitor, was capable of inhibiting the Fas-mediated apoptosis of RA synovial cells. CPP32, but not ICE, was activated in response to anti-Fas stimulation. IL-8, but not IL-1 beta, was secreted from the anti-Fas-stimulated RA synoviocytes even in the presence of CPP32 inhibitor. These results demonstrated that CPP32, but not ICE, is the predominant cysteine protease that mediates the Fas-mediated apoptosis of RA synovial cells. We also demonstrated that anti-Fas stimulation of RA synoviocytes leads to IL-8 secretion independently of the CPP32-mediated apoptosis, which would accelerate inflammation.
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PMID:Fas-mediated stimulation induces IL-8 secretion by rheumatoid arthritis synoviocytes independently of CPP32-mediated apoptosis. 891 30

Apoptosis is a feature of the synovium of rheumatoid arthritis (RA). We have recently shown that RA synoviocytes were susceptible to anti-Fas mAb and undergo apoptosis in vitro. To investigate whether infiltrating mononuclear cells also undergo Fas-dependent apoptosis, double-labeling techniques combined with immunohistochemical examination with anti-CD3 mAb and the TdT-mediated dUTP-blotin nick end labeling (TUNEL) method to detect apoptotic cells, or in situ RT assay to detect Fas mRNA, were performed using frozen tissue sections. We also examined the in vitro induction of Fas-dependent apoptosis in freshly isolated synovium infiltrating mononuclear cells (SIM), synovial stromal cells (SSC) and peripheral blood lymphocytes (PBL) using tissues from nine patients with RA and three with osteoarthritis (OA). The results showed expression of Fas antigen and apoptotic cells in a number of CD3-bearing cells in RA synovial tissues. In vitro treatment with anti-Fas mAb produced a significant apoptosis of RA SIM and SSC, while none of PBL, and neither SIM nor SSC from OA exhibited apoptosis. Moreover, approximately 50% of CD4+, CD3+ and CD45RO+ cells, and > 90% of Fas-expressing cells of RA SIM underwent apoptosis in response to anti-Fas mAb, as detected by flow cytometry. Our results suggest that RA synovial infiltrating lymphocytes acquire high susceptibility to anti-Fas mAb and undergo apoptosis. Such a phenomenon of infiltrating T cells in RA synovium may play an important pathophysiological role and suggest a possible therapeutic effect for anti-Fas mAb in RA.
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PMID:Induction of Fas-dependent apoptosis in synovial infiltrating cells in rheumatoid arthritis. 892 39

Rheumatoid factor (RF) B cells proliferate during secondary immune responses to immune complexed antigen and antigen specific T cells, but higher affinity RFs are not detected except in patients with rheumatoid arthritis and other autoimmune diseases. Consequently, there must exist highly efficient mechanisms for inactivation of these higher-affinity RF B cell clones under normal circumstances. Exposure of transgenic mice expressing a human IgM RF to soluble human IgG in the absence of T cell help causes antigen specific B cell deletion in 2-3 days. The deletion is independent of the Fas/Fas ligand (FasL) pathway of apoptosis and is preceded by a phase of partial activation involving increase in cell size and expression of B7 and ICAM-1, and transient release of low levels of immunoglobulin. Complete B cell activation involving the formation of germinal centers and sustained high level RF secretion only occurs if T cell help is provided simultaneously. RF B cells exposed to tolerogen remain competent to secrete RF in vitro if provided with an appropriate antigenic stimulus and T cell help. Consequently, death of these cells is not preceded by anergy. Abortive activation/deletion of B cells by antigen in the absence of T cell-derived survival signals may represent the major mechanism for maintaining peripheral tolerance in B cells expressing higher affinity RF. The lack of anergy, and the potential for reactivation before death, provide a means for maintaining RF production under pathologic circumstances, such as may occur in the inflamed rheumatoid synovium.
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PMID:Peripheral deletion of rheumatoid factor B cells after abortive activation by IgG. 901 38

Synovial T cells in rheumatoid arthritis are highly differentiated and express a phenotype suggesting susceptibility to apoptosis (CD45RB dull, CD45RO bright, Bcl-2 low, Bax high, Fas high). However, no evidence of T cell apoptosis was found in synovial fluid from any of 28 patients studied. In contrast, synovial fluid from 10 patients with crystal arthritis showed substantial levels of T cell apoptosis. The failre of apoptosis was not an intrinsic property of rheumatoid synovial T cells, as they showed rapid spontaneous apoptosis on removal from the joint. Synovial T cells from rheumatoid arthritis and gout patients could be rescued from spontaneous apoptosis in vitro either by IL-2R gamma chain signaling cytokines (which upregulate Bcl-2 and Bcl-XL) or by interaction with synovial fibroblasts (which upregulates Bcl-xL but not Bcl-2). The phenotype of rheumatoid synovial T cells ex vivo (Bcl-2 low, Bcl-xL high) suggested a fibroblast-mediated mechanism in vivo. This was confirmed by in vitro culture of synovial T cells with fibroblasts which maintained the Bcl-xL high Bcl-2 low phenotype. Synovial T cells from gout patients were Bcl-2 low Bcl-xL low and showed clear evidence of apoptosis in vivo. Inhibition experiments suggested that an integrin-ligand interaction incorporating the Arg-Gly-Asp motif is involved in fibroblast-mediated synovial T cell survival. We propose that environmental blockade of cell death resulting from interaction with stromal cells is a major factor in the persistent T cell infiltration of chronically inflamed rheumatoid synovium.
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PMID:Inhibition of T cell apoptosis in the rheumatoid synovium. 902 77

Apoptosis is found in synoviocytes and CD3+ T cells in the synovium of patients with rheumatoid arthritis (RA). To analyze the pathogenesis of apoptosis in rheumatoid synovium, we examined the expression of Fas Ag, Fas ligand (Fas-L), and TCR on T cells susceptible to anti-Fas mAbs. Fas Ag is expressed on 40 to 60% of CD3+ T cells in the synovium as measured by immunohistochemical and flow cytometry methods. It was observed by the reverse transcription-PCR method that Fas-L is overexpressed on T cells infiltrating the rheumatoid synovium. These results suggest that apoptosis in RA synovium is mediated by the Fas/Fas-L pathway. PCR-single-strand conformation polymorphism clearly demonstrated that more than 50% of T cells that accumulate in synovium are removed by incubation with anti-Fas mAbs for 24 h in vitro, indicating that these cells are Fas sensitive. Junctional sequence analysis revealed several conserved amino acids motifs (ERxxxSMNTE, IAAEGLLG, QxEGxD, VPD, TLAGxYNEQ, EPSE, LTNxGEL, QGK, NIP, GLL, and KWT) in the CDR3 region of accumulated Fas-sensitive T cell clones, whereas these motifs were not detected in Fas-resistant clones. In conclusion, our findings support the notion that Fas-sensitive T cells in rheumatoid synovium are generated by Ag stimulation and recognize relatively limited T cell epitopes on autoantigens, suggesting that susceptibility to anti-Fas mAbs might be a selection marker for activated autoreactive T cells in RA.
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PMID:T cell receptor of Fas-sensitive T cells in rheumatoid synovium. 902 39


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