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)

Cytokine release at the cartilage/pannus junction (CPJ) may be involved in cartilage destruction and tissue repair in rheumatoid arthritis (RA). Tissue samples of CPJ from 12 RA patients were examined for the presence of cytokines using immunohistochemical techniques with immunoaffinity purified F(ab')2 antibodies raised against recombinant human cytokines. Twenty-four areas of distinct CPJ at which a discrete junction between cartilage and overlying pannus exists were observed. In all specimens, tumour necrosis factor (TNF)-alpha, interleukin (IL)-1 alpha. IL-6, granulocyte-macrophage colony-stimulating factor (GM-CSF) and transforming growth factor (TGF)-beta 1 were detected in cells in pannus particularly along the surface of cartilage and at the site of cartilage erosion. Double immunofluorescence staining showed that most cytokine containing cells also labelled with a macrophage marker (CD68). About 50% of blood vessel endothelial cells stained for GM-CSF. Twelve areas of diffuse fibroblastic CPJ, at which an indistinct margin is seen between cartilage and pannus were examined. At this site, TGF-beta 1 was the only cytokine detected in fibroblast-like cells. None of these cytokines were detected in synovial tissue at the normal synovium/cartilage junction. Chondrocytes from all 11 normal specimens as well as those from RA patients stained for IL-1 alpha, TNF-alpha, IL-6, GM-CSF and TGF-beta 1, especially those close to subchondral bone. However, IL-1 beta, interferon-gamma and lymphotoxin were not detected in either the normal synovium/cartilage junction or rheumatoid CPJ.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Detection of cytokines at the cartilage/pannus junction in patients with rheumatoid arthritis: implications for the role of cytokines in cartilage destruction and repair. 139 70

Most autoimmune diseases are HLA-associated which supports the notion that they are dependent upon specific immune activation of a limited set of T cell clones. Findings which imply that induction of autoimmune reactivity probably does not differ from normal immune responses are discussed. The possibility of transferring autoimmune disease using T cell clones indicates that target structures for auto-immune attack are also present in healthy individuals. In the present article, it is argued that autoimmune reactions and immunity against nominal conventional antigens in principle are effected and regulated by similar mechanisms. It is assumed that persistent tissue damage occurs if immune attack is directed against tissues that cannot be regenerated, such as in diabetes, or are only slowly reconstituted, such as in rheumatoid arthritis. Normal immune responses are regulated by various inflammatory mediators and cytokines/interleukins. The joint of patients with rheumatoid arthritis is discussed as a model for propagation of immune reactions and tissue destruction in autoimmune disease. Of the different cytokines which are present in the synovial fluid or produced by cells in the synovial tissue, most are presumed to have originated in macrophages/monocytes such as IL-1, IL-6, IL-8, TNF-alpha and TGF-beta. Even so, T cells are believed to have an important role for the continued reactivity associated with autoimmune disease. This discrepancy can be explained in different ways. T cell products might escape detection because they are short-lived, they are immediately consumed or they are produced only during short time intervals.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Specific and non-specific autoreactive immunity. 150 34

This study reports on leukemia inhibitory factor (LIF) in human articular connective tissues. Biologically active LIF is present in synovial fluids from patients with osteoarthritis and at higher titers in samples from patients with rheumatoid arthritis. Cultured human synoviocytes and articular chondrocytes produced biologically active LIF and synthesized and secreted LIF proteins that migrated in SDS PAGE at approximately 43 kD. This was increased after stimulation with IL-1 beta. Chondrocytes in serum-containing cultures expressed the 4.2-kb LIF mRNA. IL-1 beta, LPS, and to a lesser extent tumor necrosis factor-alpha induced LIF gene expression. LIF autoinduced its mRNA and this provides evidence for an effect of this cytokine on function of joint tissue cells. Among a series of growth factors tested, transforming growth factor (TGF beta), including the isoforms TGF-beta1, TGF-beta 2, and TGF-beta 3, platelet-derived growth factor, basic fibroblast growth factor, and insulin-like growth factor induced this cytokine gene but differed with respect to the duration of their effects. Cultured synoviocytes expressed the LIF gene in response to the same set of peptide regulatory factors. Analysis of signal transduction pathways showed that PMA increased LIF mRNA, whereas calcium ionophore and cAMP had no detectable effects. Cycloheximide was a potent LIF mRNA inducer and dexamethasone inhibited LIF induced by PMA or IL-1 beta. Cartilage organ cultures and synovial tissues stimulated with IL-1 expressed high levels of LIF mRNA as demonstrated by in situ hybridization. These results identify LIF as a new cytokine that is produced by joint tissue cells and is overexpressed in arthritis. The induction of this cytokine by factors that are present during joint inflammation and the effects of LIF on connective tissue cells suggest that LIF is a mediator that can contribute to the pathogenesis of arthritis.
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PMID:Leukemia inhibitory factor is expressed in cartilage and synovium and can contribute to the pathogenesis of arthritis. 152 40

Patients with systemic autoimmune diseases such as SLE and rheumatoid arthritis have increased rates of morbidity and mortality caused by infection. Although this increased risk of infection has been primarily attributed to therapeutic immuno-suppression, some reports exist of defective polymorphonuclear leukocytes (PMN) function in these patients. The purpose of the present work is to investigate the recruitment of PMN phagocytic function in a murine model of autoimmunity, the MRL/lpr mouse. PMN from MRL/lpr, but not from congenic MRL/n mice, exhibit a marked defect in the amplification of FcR-mediated phagocytosis stimulated by various inflammatory mediators. This defect is acquired and correlates with the onset of the autoimmune disease observed in this strain. In addition, MRL/lpr but not MRL/n PMN exhibit a defect in extravasation into the thioglycollate-inflamed peritoneum. Incubation of MRL/n PMN in MRL/lpr serum induces a defect in the amplification of PMN phagocytic function identical to that observed with MRL/lpr PMN. The activity in the serum that induces this defect is neutralized by an antibody to TGF-beta but not by control antibodies. Incubation of murine and human PMN with purified TGF-beta induces an identical defect in stimulated FcR-mediated ingestion. In addition, TGF-beta-treated MRL/n PMN fail to extravasate into the thioglycollate-inflamed peritoneum after injection into normal MRL/n recipient mice. In addition, direct injection of TGF-beta into MRL/n mice also reduces the percentage and number of PMN in the thioglycollate-stimulated peritoneal exudates of these mice. The defect in PMN extravasation and phagocytic function was not caused by failure of the defective PMN to modulate the expression of the adhesion molecules, Mac-1 and Mel-14. These data indicate that defects in PMN function can be observed in a murine model of autoimmunity and that spontaneous production of TGF-beta possibly may play a crucial role in the pathogenesis of the defective PMN function in this animal model.
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PMID:Defective neutrophil function in the autoimmune mouse strain MRL/lpr. Potential role of transforming growth factor-beta. 167 21

Mononuclear cells (MNC) in synovial fluids from patients with rheumatoid arthritis and other arthropathies differ clearly from MNC in peripheral blood. Typically the ratio of CD4(+)-/CD8+ lymphocytes is inverted and the response to mitogens/cytokines (IL-1/IL-2) is impaired. Active TGF-beta (transforming growth factor beta) was found to account for these abnormalities, and the major isoform was identified as TGF-beta 2.
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PMID:[Modulation of immunocompetent cells in the synovial fluid TGF-beta]. 167 45

Transforming growth factor (TGF)-beta has been shown to promote tissue repair and have immunosuppressive actions, and has been proposed to have a role in rheumatoid arthritis (RA). Using immunohistochemical techniques with rabbit F(ab')2 antibodies raised against recombinant human TGF-beta 1, we have detected TGF-beta 1 in the synovial tissue and cartilage/pannus junction (CPJ) from 18/18 patients with RA. TGF-beta 1 was found predominantly in the thickened synovial lining layer in RA, but also detected in a perivascular pattern in the synovial interstitium as well as in occasional cells in the lymphoid aggregates. At the CPJ it was found both in cells at the distinct junction as well as in the transitional region of the diffuse fibroblastic zone. The cells staining for TGF-beta 1 were identified by double immunofluorescence staining as being from the monocyte/macrophage series as well as the type B synovial lining cells. TGF-beta 1 was also detected in the synovial membrane sections from 4/4 patients with systemic lupus erythematosus/mixed connective tissue disease and 5/8 patients with osteoarthritis, in a similar distribution to that seen in RA, and in the lining layer of 1/7 normal synovial membranes. These results add to histological evidence confirming that TGF-beta 1 is present in RA synovial cells and those from other arthritides. The distributions of TGF-beta 1 in RA synovial membrane reflects its known actions, as it can be detected at the CPJ, where it could induce repair, and close to activated cells upon which it may exert an immunosuppressive action.
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PMID:Transforming growth factor-beta 1 in rheumatoid synovial membrane and cartilage/pannus junction. 174 46

Joints with rheumatoid arthritis are a site for chronic inflammation involving T cells, B cells, macrophages and dendritic cells. When these cells interact cytokines are likely to be produced. The presence of different cytokines in the synovial fluid of patients with rheumatoid arthritis has been studied and the macrophage derived cytokines such as IL-1, IL-6, TNF-alpha, TGF-beta and PDGF have usually been detected in large quantities, whereas T cell produced cytokines (IL-2, IL-4, IFN-gamma) are absent or present in small quantities. IL-1, IL-6 and TNF-alpha have several functions which suggest that they participate in the chronic disease process of rheumatoid arthritis, such as increasing production of eicosanoid, collagenase and prostaglandin E2. Many synovial B cells are activated and produce large amounts of immunoglobulins. We searched for a B cell stimulatory activity in rheumatoid synovial fluid and found a B cell differentiation and helper activity. Cytokines in the joints of patients with rheumatoid arthritis seem central for the propagation of the disease process. Specific intervention in cytokine production or in its effects might help to relieve symptoms in rheumatoid patients.
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PMID:Cytokines in rheumatoid arthritis. 193 Sep 11

Interleukin 1 (IL-1) and tumor necrosis factor alpha are thought to contribute to the inflammatory response associated with autoimmune diseases. Transforming growth factor beta 1 (TGF-beta 1) counteracts many effects of these cytokines and has various immunosuppressive properties. In the present study, it is shown that microgram amounts of TGF-beta 1, injected daily for 1-2 weeks, protect against collagen-induced arthritis (CIA) and relapsing experimental allergic encephalomyelitis (REAE), the animal models for rheumatoid arthritis and multiple sclerosis, respectively. When administered during induction of the disease, TGF-beta 1 prevents CIA but only delays the onset of REAE by 2-3 days. However, when administered during a remission. TGF-beta 1 prevents the occurrence of relapses in REAE. The results suggest that TGF-beta 1 has powerful anti-inflammatory effects, mimicking in some respects the beneficial effects of immunosuppressive drugs in these experimental models of autoimmune disease, but without discernable adverse effects.
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PMID:Protective effect of transforming growth factor beta 1 on experimental autoimmune diseases in mice. 201

Granulocyte-macrophage CSF (GM-CSF) is a potent stimulator of macrophages and neutrophils and is produced by rheumatoid arthritis (RA) synovium. We now report studies that identify some of the synovial cells and cytokines responsible for local GM-CSF production and gene expression in RA. GM-CSF was assayed by ELISA in supernatants from cultured RA fibroblast-like synoviocytes stimulated with various cytokines (IL-1 beta, TNF-alpha, macrophage-CSF, IFN-gamma, IL-6, and TGF-beta). Immunoreactive GM-CSF was detected in IL-1 beta and TNF-alpha-stimulated cultures, but not in cells cultured in medium or stimulated with any of the other cytokines. IL-1 and TNF-alpha had a synergistic effect on GM-CSF production. GM-CSF gene expression by fibroblast-like synoviocytes was analyzed by ribonuclease protection assay, Northern blot analysis, and in situ hybridization. Both IL-1 beta and TNF-alpha induced GM-CSF mRNA accumulation, with a maximum effect after 4 h of stimulation. We then studied GM-CSF production by macrophage-like synoviocytes (MLS) isolated from fresh synovial specimens by flow microfluorimetry. Fresh MLS spontaneously secreted the cytokine and exogenous IL-1 beta or TNF-alpha had no effect. After 1 wk in culture, additional stimulation with IL-1 beta or TNF-alpha was required for GM-CSF production. Finally, in situ hybridization performed on freshly isolated subpopulations of synovial cells, identified GM-CSF RNA transcripts in MLS.
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PMID:Cytokines in chronic inflammatory arthritis. VI. Analysis of the synovial cells involved in granulocyte-macrophage colony-stimulating factor production and gene expression in rheumatoid arthritis and its regulation by IL-1 and tumor necrosis factor-alpha. 202 69

Rheumatoid arthritis (RA), and not osteoarthritis (OA) synovial cells proliferate in serum-free medium, a finding that suggests that, in vitro, RA synovial cells may be stimulated to grow by the continuous autocrine production of at least one polypeptide growth factor. Adding monoclonal antibody 1D11.16, or rabbit polyclonal anti-tumor growth factor beta (anti-TGF-beta) antibodies (both neutralizing antibodies to TGF-beta 1 and TGF-beta 2) to RA synovial cells, in culture, caused a significant reduction in cell growth, an effect not seen when other growth factor antibodies (platelet-derived growth factor [PDGF], epidermal growth factor [EGF], or EGF receptor) were added to the culture medium. Taken together, these data are consistent with the concept that RA synovial cell growth in vitro is driven endogenous TGF-beta. Moreover, when EGF was added to the culture medium, this caused the numbers of RA, and not OA, synovial cells to increase significantly. This finding suggests that RA synovial cells are in G1 phase of the cell cycle; an effect that could be mediated by endogenous TGF-beta.
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PMID:Autocrine regulation of rheumatoid arthritis synovial cell growth in vitro. 210 18


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