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)

Antineutrophil cytoplasmic autoantibodies with specificity for myeloperoxidase (MPO) were found in 53 patient sera that were routinely submitted for antineutrophil cytoplasmic antibody determination. Based on clinical and histologic criteria, 15 of these 53 patients were classified as having systemic necrotizing vasculitis of the polyarteritis group, 11 patients were classified as having Wegener's granulomatosis (WG), and 14 were classified as having idiopathic crescentic glomerulonephritis. The remaining 13 patients did not fulfill the diagnostic criteria for these disorders, although most of these patients had clinical symptoms compatible with these disorders. While all patients with WG had renal involvement, only 4 of the 15 patients with systemic necrotizing vasculitis of the polyarteritis group had glomerulonephritis. The sensitivity of autoantibodies to MPO for either systemic necrotizing vasculitis of the polyarteritis group, WG, or idiopathic crescentic glomerulonephritis was further tested in all our patients with these disorders (n = 104). Twenty-seven of 104 patients had autoantibodies to MPO. Furthermore, 69 of the remaining 77 patients had autoantibodies specific for the 29-kd serine protease, which has been reported to be specifically associated with WG. Sera from 8 patients were negative for either of these antibodies (92% sensitivity of autoantibodies to MPO and/or the 29-kd serine protease). The specificity of autoantibodies to MPO for either systemic necrotizing vasculitis of the polyarteritis group, WG, or idiopathic crescentic glomerulonephritis was also tested in selected groups of patients who had closely related diseases. Two of 144 patients had autoantibodies to MPO (specificity 99%).(ABSTRACT TRUNCATED AT 250 WORDS)
Arthritis Rheum 1990 Aug
PMID:Association of autoantibodies to myeloperoxidase with different forms of vasculitis. 165 Feb 23

Activation of human neutrophils (PMN) is accompanied by rapid upregulation of CR1, the C3b receptor, and CR3, the iC3b receptor, which also serves as the PMN's major adherence protein. This is necessary for migration and phagocytosis, but the extent of expression of these proteins on PMN at inflammatory sites has not been determined. We used monoclonal antibodies and flow cytometry to assess CR1 and CR3 expression on PMN in bronchoalveolar lavage (BAL) fluid of cystic fibrosis (CF) patients chronically infected with pseudomonas and in sterile joint fluid of arthritis patients. Resting peripheral blood PMN from these patients and normals expressed similar low levels of CR1 and CR3, and the patients' PMN increased CR1 and CR3 expression normally when stimulated in vitro. CR3 expression on CF BAL PMN was 90 +/- 12% of that on the same patient's blood cells stimulated in vitro with FMLP. In contrast, CR1 expression on BAL PMN was only 27 +/- 8% of that on stimulated blood cells. Similar results were obtained for joint PMN. This pattern could be reproduced in vitro by treating FMLP-stimulated blood cells with BAL supernatants or with pseudomonas or PMN elastase. The serine protease inhibitors, PMSF and alpha 1-antitrypsin prevented the lavage supernatant from reducing CR1 expression, while metalloprotease inhibitors had no effect. Treatment of PMN with elastase in vitro decrease their ability to kill opsonized Pseudomonas aeruginosa. These results suggest that PMN at inflammatory sites have maximally upregulated expression of their complement receptors, but that CR1 is then cleaved by proteolysis in situ. Although not related to the basic defect in CF, this may interfere with efficient phagocytosis and contribute to the CF patient's inability to eradicate chronic lung infection.
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PMID:Complement receptor expression on neutrophils at an inflammatory site, the Pseudomonas-infected lung in cystic fibrosis. 250 78

Measurements were made of the neutral proteoglycan-digesting protease activity in the cartilage matrix breakdown observed in the rheumatoid arthritic process. Normal knee (tibial plateau) cartilage specimens were obtained from 7 fresh cadavers and 29 cartilage specimens were obtained from 23 patients diagnosed as having rheumatoid arthritis (RA). The total neutral metalloproteoglycan-degrading enzyme (NMPE) activity in RA cartilages exhibited roughly an eightfold elevation over that of control subjects. The active form of the NMPE for diseased cartilage was higher than that observed for normal cartilage, but was not statistically different. A very low level of activity was detected for serine proteases and no variation was observed between normal and diseased cartilages. Data obtained from RA cartilages were also analyzed with respect to the relationship between enzyme activities and the patients' medications. Four groups of patients were then selected according to their drug treatments: S + G patients received steroid and gold therapy; S patients received steroids only; NS + NG patients did not receive steroid or gold therapy; G patients received gold therapy alone. The total NMPE activity for each of these groups remained at a very high level. The active enzyme activity measured in S + G and S patients was decreased to a level not different from that of normal controls. Specimens from NS + NG patients presented a significantly higher level of the active form of the enzyme (P less than 0.05) when compared with either normal controls, S + G, or S patients. No significant difference was noted in the level of serine protease activity between the RA cartilage and normal cartilage.(ABSTRACT TRUNCATED AT 250 WORDS)
Arthritis Rheum 1985 Apr
PMID:Human rheumatoid arthritic cartilage and its neutral proteoglycan-degrading proteases. The effects of antirheumatic drugs. 392 Oct 34

Proteases have been postulated to account for the progressive disappearance of matrix proteoglycans in osteoarthritic (OA) cartilage. The digestion of endogenous proteoglycans by neutral proteases in human OA cartilage homogenates has been measured and compared with that of normal age-matched controls. Cartilage was obtained from 16 patients at the time of knee arthroplasty and from 7 accident victims. Tissue blocks were cut from the tibial plateau; part was used for histologic grading of the severity of OA and part was homogenized for the quantification of neutral metallo- and serine protease activities, based on the release of digested products from endogenous proteoglycans. Total metalloprotease activity (latent plus active forms) was elevated 3- to 10-fold in all diseased cartilage. This elevation was already significant in mild disease, but was greatest in samples of moderate to severe disease. The active form of the enzyme was highest at the center of erosions and decreased in the margins of the plateau. The digestion of proteoglycans, as distinct from their mere release from the tissue, was demonstrated by chromatography on Sepharose-CL2B and by large pore electrophoresis. Serine protease activity on proteoglycans was much lower than that of metalloprotease. The mean activity was highest in mild disease and declined in the severe disease samples, but the difference between these 2 groups and the controls was not statistically significant. The results of this study are consistent with the hypothesis that the neutral metalloproteases of cartilage are involved in the degradation of proteoglycans in osteoarthritis.
Arthritis Rheum 1984 Mar
PMID:Neutral proteases capable of proteoglycan digesting activity in osteoarthritic and normal human articular cartilage. 636 52

Immunization of BALB/c mice with human fetal cartilage proteoglycan (PG) produces progressive polyarthritis, and T cells play key roles in the development of the disease. To gain an understanding of how PG is presented to autoreactive T cells by synovial antigen-presenting cells (APC), we examined the abilities of various syngeneic APC in presenting PG to a specific T cell hybridoma 5/4E8, derived from a mouse with PG-induced arthritis. A20 B lymphoma cells and spleen cells were strong presenters of PG, but synoviocytes and P388D1 macrophages could only present PG effectively after stimulation with interferon-gamma (IFN-gamma). The IFN-gamma exerted its effect by up-regulating both MHC class II and intercellular adhesion molecule-1 (ICAM-1) expression by these cells as neutralizing antibodies to Ia, LFA-1 and ICAM-1 inhibited presentation. Our studies also showed that synoviocytes and spleen cells took up and processed PG more rapidly than the cell lines. Cysteine and serine protease-dependent antigen presentation of PG was blocked at 4 degrees C, 18 degrees C and by chloroquine treatment, indicating that presentation required active uptake and processing in an acidic compartment, probably in lysosomes. Also, keratan sulphate-depleted and cyanogen bromide (CNBr) and 2-nitro-5-thiocyanobenzoic acid (NTCB)-cleaved PG elicited stronger T cell responses, as they were more easily processed than the native molecule. Furthermore, CNBr-generated peptides were presented by fixed APC, indicating that core protein fragments of cartilage PG can be presented directly by APC in context with MHC class II molecules.
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PMID:Presentation of cartilage proteoglycan to a T cell hybridoma derived from a mouse with proteoglycan-induced arthritis. 769 8

We studied the in vivo effect of long-term doxycycline treatment combined with NSAID on human interstitial collagenases, other matrix metalloproteinases, serine proteinases, tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) and lactoferrin from saliva and serum during the course of acute reactive arthritis (ReA). Collagenase activity and serine proteases (elastase-like, cathepsin G-like and trypsin-like activities) of saliva (n = 10) and gelatinase, lactoferrin and TIMP-1 of saliva (n = 10) and serum (n = 10) samples before and after 2 months doxycycline treatment, combined with NSAID, were studied by quantitative SDS-PAGE assay, ELISA assay and by spectrophotometric assay. The cellular source and molecular forms of salivary collagenase were characterized by immunoblotting using specific antisera. We found that activities of total and endogenously active interstitial collagenase reduced significantly. The salivary collagenase was found to originate from neutrophils. No fragmentation of either pro 75-kD and active 65-kD MMP-8 was detected after 2 months doxycycline treatment. However, during 2 months doxycycline and NSAID treatment no reduction of salivary and serum gelatinase, lactoferrin and TIMP-1-levels and salivary serine protease activities were detected. The in vivo inhibition of collagenase (MMP-8) activity during long-term doxycycline therapy in human saliva containing inflammatory exudate of ReA patients may contribute to the reduced tissue destruction observed in recent clinical and animal model studies in arthritides during long-term doxycycline/tetracycline treatment.
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PMID:In vivo inhibition of human neutrophil collagenase (MMP-8) activity during long-term combination therapy of doxycycline and non-steroidal anti-inflammatory drugs (NSAID) in acute reactive arthritis. 792 79

Antineutrophil cytoplasmic antibodies (ANCA) are important serological markers for the primary systemic vasculitides, including microscopic polyarteritis and necrotizing crescentic glomerulonephritis. Numerous reports have established the clinical utility of ANCA titer in monitoring disease activity, relapses, and response to treatment. ANCA, detected by indirect immunofluorescence (IIF) assays using patient's serum and ethanol-fixed human neutrophils, produce two common fluorescent staining patterns: cytoplasmic (C-ANCA), involving a 29-kD neutral serine protease termed proteinase 3 (PR3), and perinuclear (P-ANCA), the result mainly of myeloperoxidase (MPO), but occasionally by other components of the azurophilic granules including lysozyme, elastase, cathepsins, and lactoferrin. Some sera contain granulocyte-specific antinuclear antibodies (GS-ANA), which require formaldehyde fixation of neutrophils to cross link cytoplasmic antigens for distinguishing between ANCA and the GS-ANA by IIF. Positive IIF is confirmed by Western blot analysis or specific enzyme-linked immunosorbent assay for PR3, MPO, and other neutrophil granule antigens. The C-ANCA pattern is highly specific for Wegener's granulomatosis, a disease characterized by granulomatous inflammation, necrotizing and crescentic glomerulonephritis, and vasculitis; P-ANCA is found in sera of individuals with vasculitis, glomerulonephritis, and several other diseases. ANCA are predominantly immunoglobulin (Ig)G isotype, but may be IgM and IgA. Various pathophysiologic mechanisms have been proposed involving ANCA-mediated neutrophil activation in a hypothetical model of vasculitic diseases: positive signals via the FcgammaRII (CD32) receptor after IgG-ANCA binding to membrane-associated PR3, relevant cytokines, production of adhesion molecules on both activated neutrophils and endothelial cells, and the release of neutrophil reactive oxygen species and degranulation causing endothelial cell damage. Interference of C-ANCA with PR3 proteolysis and PR3 inhibition physiologically by the alpha1-proteinase inhibitor may have a pathogenic role. No convincing data have been reported for the existence of autoreactive T lymphocytes reactive to any degree with the neutrophil azurophilic enzymes. Studies of various drug- and infectious agent-related diseases and ANCA may contribute to understanding the mechanism(s) involved in some vasculitides.
Semin Arthritis Rheum 1995 Dec
PMID:Antineutrophil cytoplasmic antibodies: major autoantigens, pathophysiology, and disease associations. 865 May 85

The pro-inflammatory cytokines IL-1 and TNF-alpha are primary mediators of the acute phase response, the complex reaction of the mammalian organism to infection and injury. Among the genes activated by TNF-alpha and IL-1 in a variety of cells is TNF-stimulated gene 6 (TSG-6). The TSG-6 cDNA encodes a secreted 35 kDa glycoprotein which is abundant in synovial fluids of patients with various forms of arthritis and detectable in serum of patients with different inflammatory or autoimmune disorders. TSG-6 protein consists of two structural domains: a hyaluronan-binding link module, the characteristic domain of the hyaladherin family of proteins, and a C-terminal CUB domain, present in a variety of diverse proteins. TSG-6 forms a stable complex with components of the plasma protein inter-alpha-inhibitor (I[alpha]I), a Kunitz-type serine protease inhibitor. TSG-6 and I(alpha)I synergize to inhibit plasmin, a serine protease involved in the activation of matrix metalloproteinases which are part of the proteolytic cascade associated with inflammation. Recombinant human TSG-6 protein exerts a potent anti-inflammatory effect in a murine model of acute inflammation. Modulation of the proteolytic network associated with inflammatory processes may be a mechanism whereby TSG-6, in cooperation with I(alpha)I, inhibits inflammation. Activation of the TSG-6 gene by pro-inflammatory cytokines, presence of TSG-6 protein in inflammatory lesions and its anti-inflammatory effect suggest a role for TSG-6 in a negative feed-back control of the inflammatory response.
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PMID:TSG-6: an IL-1/TNF-inducible protein with anti-inflammatory activity. 924 9

Tumor necrosis factor-alpha (TNF-alpha)-stimulated gene-6 (TSG-6) is up-regulated by various cytokines and growth factors. TSG-6 binds to hyaluronan in inflamed synovial tissue and forms a complex with a serine protease inter-alpha-trypsin inhibitor (IalphaI), increasing the protease inhibitory effect of IalphaI >100-fold. The TSG-6/IalphaI complex then blocks serine proteases, including the plasminogen-plasmin activation, probably the most important component in the activation processes of matrix metalloproteinases. To gain insight into the mechanisms of TSG-6 action in arthritis, we have used an autoimmune murine model (proteoglycan-induced arthritis) for systemic, and a monoarticular form of arthritis (antigen-induced arthritis) for local treatment of arthritis with recombinant mouse TSG-6 (rmTSG-6). Intravenous injection of rmTSG-6 induced a dramatic reduction of edema in acutely inflamed joints by immobilizing CD44-bound hyaluronan and, in long-term treatment, protected cartilage from degradation and blocked subchondral and periosteal bone erosion in inflamed joints. The intra-articular injection of a single dose (100 microg) of rmTSG-6 exhibited a strong chondroprotective effect for up to 5 to 7 days, preventing cartilage proteoglycan from metalloproteinase-induced degradation. In contrast, rmTSG-6 did not postpone the onset, nor reduce the incidence of arthritis. We were unable to detect any significant differences between control and rmTSG-6-treated animals when various serum markers (including pro- and anti-inflammatory cytokines, auto- and heteroantibody productions) or antigen-specific T-cell responses were compared, nor when the expressions of numerous cell surface receptors or adhesion molecules were measured. TSG-6 seems to play a critical negative regulatory feed-back function in inflammation, especially in arthritic processes.
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PMID:Anti-inflammatory and chondroprotective effect of TSG-6 (tumor necrosis factor-alpha-stimulated gene-6) in murine models of experimental arthritis. 1169 32

Serine proteases (SP), such as thrombin, factor Xa, elastase, trypsin are implicated in many clinical disorders such as emphysema, arthritis and cardiovascular diseases. These enzymes, in normal physiological conditions, are regulated by naturally occurring serine protease inhibitors, such as anti-thrombin III involved in thromb in inhibition. Primitive parasitic invertebrates have co-evolved highly specific mechanisms to communicate with their hosts for survival purposes, by blocking host processes such as blood coagulation. Thus a battery of new powerful molecules from blood-sucker animals acting at different points of the coagulation cascade such like factor Xa, thrombin, platelets aggregation inhibitors have been isolated and are now at a clinical level. In this review, we focus our attention on thrombin inhitors.
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PMID:Leech thrombin inhibitors. 1194 54


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