Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0003864 (arthritis)
 69,039 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Human autoimmune diseases share the common feature of an imbalance between the production and destruction of various cell types including lymphocytes (SLE), synovial cells (RA), and fibroblasts (scleroderma). Patients with SLE have increased levels of soluble Fas that inhibit proper apoptosis of lymphocytes. In animal models of autoimmune diseases, mutations of genes involved in apoptosis including Fas, Fas ligand, and the hematopoietic cell phosphatase gene have been identified. Oncogenes, including bcl-2, p53, and myc, that regulate apoptosis are also expressed abnormally. Potent inducers of apoptosis including steroids, azathioprine, cyclophosphamide, and methotrexate are the most efficacious therapies for autoimmune disease currently known. Specific therapies that induce apoptosis without incurring side effects should improve treatment of autoimmune disease.
Arthritis Rheum 1994 Oct
PMID:Autoimmune disease. A problem of defective apoptosis. 752 7

Although autoreactive T cells are thought to play a prominent role in autoimmune disease in MRL-lpr/lpr mice, it has been difficult to directly determine if autoreactive T cells escape from the thymus and react with self-antigens in the periphery. Defective expression of the Fas apoptosis antigen in MRL-lpr/lpr mice results from the insertion of the ETn retrotransposon. The fas defect can be partially corrected in CD2-fas transgenic mice in which the expression of fas is corrected in T cells. To identify a possible defect in clonal deletion or clonal anergy induction of auto-specific T cells, we have studied C57BL/6-lpr/lpr transgenic mice that express TcR genes that recognize a known self-antigen, the male H-Y antigen. In addition, we have analyzed clonal deletion and tolerance induction after neonatal tolerance induction and superantigen-induced arthritis with the class II MHC reactive superantigen staphylococcal enterotoxin B (SEB) in V beta 8 TcR transgenic and non-transgenic MRL-lpr/lpr mice. Neonatal tolerance induction to SEB was normal in lpr/lpr mice. However, over time a loss of tolerance (thymic or peripheral) was observed in lpr/lpr mice but not in +/+ TcR transgenic mice. This defect in lpr/lpr mice was thymic-dependent and was due to increased CD28/CTLA4 signaling. These results suggest that an apoptosis defect involving both thymocytes and peripheral lymphoid cells leads to autoimmune disease in lpr/lpr mice. The challenge in the future will be to determine the role of defective apoptosis in other autoimmune diseases.
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PMID:Apoptosis defects analyzed in TcR transgenic and fas transgenic lpr mice. 752 63

RA synovial tissue (ST) was studied to determine if and where apoptosis occurs in situ. Genomic DNA was extracted from 5 RA and 1 osteoarthritis ST samples. Agarose gel electrophoresis demonstrated DNA ladders characteristic for apoptosis from each tissue. In situ and labeling (ISEL) was used to identify DNA strand breaks consistent with apoptosis in frozen sections. 12 RA and 4 osteoarthritis ST were studied by ISEL and all were positive, but only 2 of 4 normal tissues were positive. The primary location of apopotic cells was the synovial lining. Some sublining cells were also positive, but lymphoid aggregate staining was conspicuously absent. Immunohistochemistry and ISEL were combined and showed that the lining cells with DNA strand breaks were mainly macrophages, although some fibroblastlike cells were also labeled. Sublining cells with fragmented DNA included macrophages and fibroblasts, but T cells in lymphoid aggregates, which expressed large amounts of bcl-2, were spared. DNA strand breaks in cultured fibroblastlike synoviocytes was assessed using ISEL. Apoptosis could be induced by actinomycin D, anti-fas antibody, IL-1, and TNF-alpha but not by IFN-gamma. Fas expression was also detected on fibroblast-like synoviocytes using flow cytometry. Therefore, DNA strand breaks occur in synovium of patients with arthritis. Cytokines regulate this process, and the cytokine profile in RA (high IL-1/TNF; low IFN-gamma) along with local oxidant injury might favor induction of apoptosis.
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PMID:Apoptosis in rheumatoid arthritis synovium. 765 32

MRL/Mp-lpr/lpr (MRL/lpr) mice carry a mutation in the Fas gene whose product is involved in the regulation of lymphocyte apoptosis. This mutation is associated with the lpr phenomenon, i.e., a massive expansion of phenotypically abnormal CD4-CD8- cells ("double negative," DN) alpha/beta T cells (lpr cells) that becomes manifest at 3-4 months of age. As in normal mice, intravenous SEB injection into 2- or 6-month-old female MRL/lpr mice causes a transient expansion of SEB-reactive V beta 8+ T cells, followed by a deletion of this subset. In contrast, in the same animals, the frequency of abnormal V beta 8+CD4-CD8- cells is not modulated by SEB. Whereas DN T cells are completely resistant to SEB-mediated deletion in vivo, their precursors appear susceptible to SEB-induced deletion. Thus, a single injection of SEB prior to the surge of DN T cells in peripheral lymphoid organs, at 2 months of age, is sufficient to cause a stable long-term (6 months) deletion of DN cells. This is accompanied by a significant amelioration of autoimmune parameters (autoantibody titers, incidence of arthritis and nephritis), thus pointing to the feasibility of employing superantigens for simple manipulations of the immune repertoire that result in the long-term prophylaxis of autoimmune diseases.
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PMID:A single injection of Staphylococcus aureus enterotoxin B reduces autoimmunity in MRL/lpr mice. 818 Nov 86

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

Activation induced cell death (AICD) plays a critical role in eliminating autoimmune cells and limiting inflammation after activation. The two major signaling molecules for AICD are the Fas and TNF-R pathways of apoptosis. Defective Fas apoptosis in lpr/lpr mice results in a compensatory increase in TNF-R/TNF-mediated apoptosis. TNF/TNF-R has been shown to be a compensatory pathway of apoptosis in T cells and macrophages of lpr/lpr mice. Therefore, early production of TNF/TNF-R limit an immune response by inducing AICD in the absence of an intact Fas/Fas ligand apoptosis pathway. However, increased TNF production in lpr mice also lead to increased susceptibility to septic shock and autoimmune disease such as arthritis. Therefore TNF production during an inflammatory response can downmodulate this response, but this also results in the failure to downmodulate TNF production leading to septic shock and arthritis. A second pathway of AICD is mediated by Nur77 after T cell stimulation through the CD3 molecule. Mice with defective Nur77 signaling undergo AICD using the Fas-Fas ligand pathway to eliminate autoreactive T cells. A third defect of AICD is observed in HCP-mutant me/me (motheaten) mice which develop autoimmune disease related to defective Fas apoptosis signaling. Therefore, multiple interactive pathways play a role in limiting development of autoimmunity.
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PMID:Autoimmune disease results from multiple interactive defects in apoptosis induction molecules and signaling pathways. 895 Apr 77

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

Both rheumatoid arthritis and animal models of autoimmune arthritis are characterized by hyperactivation of synovial cells and hyperplasia of the synovial membrane. The activated synovial cells produce inflammatory cytokines and degradative enzymes that lead to destruction of cartilage and bones. Effective treatment of arthritis may require elimination of most or all activated synovial cells. The death factor Fas/Apo-1 and its ligand (FasL) play pivotal roles in maintaining self-tolerance and immune privilege. Fas is expressed constitutively in most tissues, and is dramatically upregulated at the site of inflammation. In both rheumatoid arthritis and animal models of autoimmune arthritis, high levels of Fas are expressed on activated synovial cells and infiltrating leukocytes in the inflamed joints. Unlike Fas, however, the levels of FasL expressed in the arthritic joints are extremely low, and most activated synovial cells survive despite high levels of Fas expression. To upregulate FasL expression in the arthritic joints, we have generated a recombinant replication-defective adenovirus carrying FasL gene; injection of the FasL virus into inflamed joints conferred high levels of FasL expression, induced apoptosis of synovial cells, and ameliorated collagen-induced arthritis in DBA/1 mice. The Fas-ligand virus also inhibited production of interferon-gamma by collagen-specific T cells. Coadministration of Fas-immunoglobulin fusion protein with the Fas-ligand virus prevented these effects, demonstrating the specificity of the Fas-ligand virus. Thus, FasL gene transfer at the site of inflammation effectively ameliorates autoimmune disease.
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PMID:Amelioration of collagen-induced arthritis by CD95 (Apo-1/Fas)-ligand gene transfer. 932 58

Immune function in SLE is paradoxically characterized by active T cell help for autoantibody production, along with impaired T cell proliferative and cytokine responses in vitro. To reconcile these observations, we investigated the possibility that the accelerated spontaneous cell death of SLE lymphocytes in vitro is caused by an activation-induced cell death process initiated in vivo. 27 SLE patients, three patients with systemic vasculitis, seven patients with arthritis, and 14 healthy subjects were studied. Patients with clinically active SLE or systemic vasculitis had accelerated spontaneous death of PBMC with features of apoptosis at day 5 of culture. A prominent role for IL-10 in the induction of apoptosis was observed, as neutralizing anti-IL-10 mAb markedly reduced cell death in the active SLE patients by 50%, from 22.3 +/- 5.2% to 11.2 +/- 2.8%, and the addition of IL-10 decreased viability in the active SLE group, but not in the control group, by 38%. In addition, apoptosis was shown to be actively induced through the Fas pathway. The potential clinical relevance of T cell apoptosis in active SLE is supported by the correlation of increased apoptosis and IL-10 levels in vitro with low lymphocyte counts in vivo. We conclude that the spontaneous cell death observed in vitro in lymphocytes from patients with SLE and other systemic autoimmune disorders results from in vivo T cell activation, is actively induced by IL-10 and Fas ligand, and reflects pathophysiologically important events in vivo. Activation-induced cell death in vivo provides a pathogenic link between the aberrant T helper cell activation and impaired T cell function that are characteristic features of the immune system of patients with SLE.
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PMID:Interleukin-10 promotes activation-induced cell death of SLE lymphocytes mediated by Fas ligand. 936 78

Recent studies suggest a protective effect of glucocorticoid against progression of bone erosion and periarticular osteoporosis in patients with rheumatoid arthritis (RA), although this steroid hormone itself is believed to increase bone loss. To understand the antagonistic effect of glucocorticoid for osteopenic process in RA patients, we examined the effect of dexamethasone on Fas-mediated apoptosis of cultured human osteoblasts induced by either anti-Fas IgM or activated peripheral blood mononuclear cells (PBMC). Human osteoblastic cell line MG63 and primary osteoblast-like cells obtained from biopsy specimens were used in this study. PBMC isolated from healthy donors were cultured with or without recombinant interleukin-2 (rIL-2) followed by 12-O-tetradecanoyl-phorbol 13-acetate (PMA) with ionomycin in the presence or absence of dexamethasone. Fas was functionally expressed on MG63 and primary osteoblast-like cells, and treatment of these cells with dexamethasone affected neither Fas expression nor anti-Fas IgM-induced apoptosis. Activated PBMC expressing membrane-type Fas ligand (mFasL) efficiently killed both MG63 and primary osteoblasts-like cells, and the addition of human Fas chimeric protein (hFas-Fc) significantly diminished the cytotoxicity, indicating that interactions between mFasL of activated PBMC and Fas on human osteoblasts induce apoptosis of the latter. Although dexamethasone did not affect apoptosis of MG63 and primary osteoblast-like cells induced by anti-Fas IgM, treatment of activated PBMC with dexamethasone markedly inhibited both mFasL expression and cytotoxicity of these cells against human osteoblasts, suggesting that dexamethasone preferentially acts not on osteoblasts but PBMC. Cultured supernatants from activated PBMC induced apoptosis of human osteoblasts and the addition of hFas-Fc also inhibited the cytotoxicity of the supernatants. In addition, soluble form FasL (sFasL) was detected in the supernatants of activated PBMC. Furthermore, both the cytotoxicity and sFasL concentration of cultured supernatants of activated PBMC incubated with dexamethasone was significantly lower than that in the absence of dexamethasone. Our data suggest that glucocorticoid suppresses the apoptotic process of osteoblasts by inhibiting the expression of both mFasL and sFasL derived from activated PBMC, mediating a protective effect against periarticular bone loss and bone erosion in inflammatory arthritis such as RA.
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PMID:Inhibitory effect of glucocorticoid for osteoblast apoptosis induced by activated peripheral blood mononuclear cells. 952 91


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