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)

To understand the role of cytolytic lymphocytes in the pathogenesis of rheumatoid arthritis, we investigated the expression of lymphocyte cytotoxicity mediators, perforin, and serine esterases, in lymphocytes derived from the synovial fluid of 15 patients with rheumatoid arthritis. Previous work has shown that CD8+ lymphocytes that possess markers of activation appear to be present in rheumatoid arthritis (RA). By means of in situ hybridization techniques and immunohistochemical analysis, the authors show that perforin and two serine esterases (serine esterase 1/Hanukah factor/granzyme A, and serine esterase 2/granzyme B) are expressed by subpopulations of CD8+ and CD56+ lymphocytes obtained from synovial fluid. The presence of these cytotoxic mediators suggests a possible mechanism for tissue damage, and provides evidence implicating cytolytic lymphocytes in the pathogenesis of RA.
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PMID:Expression of cytolytic mediators by synovial fluid lymphocytes in rheumatoid arthritis. 158 Mar 35

Cartilage degradation, a hallmark of rheumatoid arthritis, is attributed to serine and metalloproteases secreted by neutrophils, synovial lining cells, macrophages, and chondrocytes. A large proportion of synovial fluid lymphocytes contains the granule-associated serine proteases granzymes A and B. We report that lysates of IL-2-stimulated lymphocytes contain an enzymatic activity (ECMase; cartilage extracellular matrix 35S release assay; extracellular matrix degrading activity) that solubilizes matrix synthesized by chondrocyte monolayers. ECMase activity is inactivated by the serine protease inhibitor diisopropylfluorophosphate, is stored in dense granules and cleaves aggrecan proteoglycans but not free glycosaminoglycans, hyaluronic acid, or type II collagen. ECMase is mediated by a cationic protein with biochemical properties identical to granzyme B, inasmuch as it preferentially hydrolyzes the substrate Boc-Ala-Ala-Asp-SBzl, immunochemically cross-reacts with an antibody that binds to a conserved amino-terminal region of lymphoid-myeloid serine proteases, and has amino-terminal sequence identity with human Q31 granzyme B. Using an agarose gel electrophoresis technique to assess cleavage of the rat sarcoma aggrecan, the catalytic efficiency of granzyme B for the digestion of aggrecan (catalytic efficiency = 1.7 x 10(7) M-1 s-1) was 425-fold faster than the catalytic efficiency reported for human stromelysin-1 at pH 7.5 (catalytic efficiency 4000 M-1 s-1) and 3200-fold faster than granzyme A. Based on these observations, we propose that granzyme B, secreted from cytotoxic lymphocytes within the rheumatoid joint, may contribute to cartilage loss by degrading resident aggrecan.
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PMID:Human granzyme B degrades aggrecan proteoglycan in matrix synthesized by chondrocytes. 825 16

Activated CTLs and NK cells induce apoptosis via multiple mechanisms, including that termed granule exocytosis. The latter pathway consists of vectorial secretion of perforin and a family of granule-associated serine proteases (granzymes) to the target cell. To establish whether granzymes are released extracellularly during cytolytic reactions in vivo, ELISAs that measure the native enzymes were developed and were found to specifically detect granzyme A (GrA) and granzyme B (GrB) at picogram concentrations. Low levels of GrA and GrB were present in plasma of healthy individuals (GrA, 33.5 pg/ml (median); GrB, 11.5 pg/ml (median)), whereas significantly higher levels were present in patients with ongoing CTL response, i.e., patients suffering from infections by EBV or HIV type 1. Markedly elevated levels were also noted in synovial fluid of patients with active rheumatoid arthritis. The measurement of soluble granzymes should be useful to assess clinical disorders associated with activated CTL and NK cells. Furthermore, these results suggest that granzymes mediate biologic effects beyond their described role in apoptotic cell death.
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PMID:Extracellular granzymes A and B in humans: detection of native species during CTL responses in vitro and in vivo. 953 25

Granzyme B is the prototypic member of the granzymes, a family of trypsin-like serine proteinases localized in the dense cytoplasmic granules of activated natural killer cells and cytotoxic T lymphocytes. Granzyme B directly triggers apoptosis in target cells by activating the caspase pathway, and has been implicated in the etiology of rheumatoid arthritis. Human granzyme B expressed in a baculovirus system has been crystallized without inhibitor and its structure has been determined to 3.1 A resolution, after considerably improving the diffraction power of the crystals by controlled humidity changes. The granzyme B structure reveals an overall fold similar to that found in cathepsin G and human chymase. The guanidinium group of Arg226, anchored at the back of the S1-specificity pocket, can form a salt bridge with the P1-Asp side chain of a bound peptide substrate. The architecture of the substrate binding site of granzyme B appears to be designed to accommodate and cleave hexapeptides such as the sequence Ile-Glu-Thr-Asp-/Ser-Gly present in the activation site of pro-caspase-3, a proven physiological substrate of granzyme B. These granzyme B crystals, with fully accessible active sites, are well suited for soaking with small synthetic inhibitors that might be used for a treatment of chronic inflammatory disorders.
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PMID:Crystal structure of the caspase activator human granzyme B, a proteinase highly specific for an Asp-P1 residue. 1120 55

To identify candidate autoantigens associated with arthritis, a rat chondrocyte cDNA library was immunoscreened with serum from a patient with rheumatoid arthritis. One isolated cDNA encoded part of AHNAK, a 700-kDa phosphoprotein with DNA binding properties, that appears to be involved in several signal transduction pathways. Immunoreactivity against an in vitro translated human AHNAK fragment was detected in 4.6% (5/109) of patients with rheumatoid arthritis, 29.5% (18/61) of patients with systemic lupus erythematosus (SLE), and 1.2% (2/172) of blood donors. Anti-AHNAK antibodies reacted with a recombinant human AHNAK fragment and with native AHNAK from C32 cell lysates. In vitro translated AHNAK fragment could be cleaved by granzyme B and caspase-3. Anti-AHNAK positive SLE patients had a higher frequency of homogeneous antinuclear antibody staining patterns and a lower frequency of recent mucosal ulcerations. This is the first report that AHNAK can be targeted by the immune system in autoimmune disease.
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PMID:Identification of AHNAK as a novel autoantigen in systemic lupus erythematosus. 1186 58

Fractalkine (now also called CX3CL1) is a unique chemokine that functions not only as a chemoattractant but also as an adhesion molecule and is expressed on endothelial cells activated by proinflammatory cytokines, such as interferon-gamma and tumor necrosis factor-alpha. The fractalkine receptor, CX3CR1, is expressed on cytotoxic effector lymphocytes, including natural killer (NK) cells and cytotoxic T lymphocytes, which contain high levels of intracellular perforin and granzyme B, and on macrophages. Soluble fractalkine causes migration of NK cells, cytotoxic T lymphocytes, and macrophages, whereas the membrane-bound form captures and enhances the subsequent migration of these cells in response to secondary stimulation with other chemokines. Furthermore, stimulation through membrane-bound fractalkine activates NK cells, leading to increased cytotoxicity and interferon-gamma production. Recently, accumulating evidence has shown that fractalkine is involved in the pathogenesis of various clinical disease states or processes, such as atherosclerosis, glomerulonephritis, cardiac allograft rejection, and rheumatoid arthritis. In addition, polymorphisms in CX3CR1, which reduce its binding activity to fractalkine, have been reported to increase the risk of HIV disease and to reduce the risk of coronary artery disease. This review will examine new concepts underlying fractalkine-mediated leukocyte migration and tissue damage, focusing primarily on the pathophysiological roles of fractalkine in various clinical conditions, especially in atherosclerosis and vascular injury.
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PMID:Fractalkine in vascular biology: from basic research to clinical disease. 1296 92

Normal gammadelta T-lymphocytes have the morphology of large granular lymphocytes (LGL) and, as the LGL of alphabeta T-cells, they express pan-T antigens, NK-associated antigens and the cytotoxic molecules, perforin and granzime B. In this report we describe an unusual patient with rheumatoid arthritis and neutropenia who has a chronic gammadelta T-cell proliferation with a chronic, indolent clinical course and atypical lymphocytes, lacking the classical LGL morphology, not expressing NK-associated antigens, and not expressing perforin or granzyme B. In spite of the atypical morphological features of the clonal cells, which were suggestive of a more malignant process, the patient has been followed for 4 years without aggressive therapy. It is important to recognize this entity and to distinguish it from other gammadelta T proliferations such as the hepatosplenic gammadelta T-cell lymphoma.
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PMID:Chronic clonal proliferative disease of gamma-delta (gammadelta) T-cells in a patient with rheumatoid arthritis and neutropenia: lack of the morphology and the immunophenotype of large granular lymphocytes. 1522 58

Human granzyme B (GrB) released from cytotoxic lymphocytes plays a key role in the induction of target cell apoptosis when internalized in the presence of perforin. Here we demonstrate that GrB also possesses a potent extracellular matrix remodeling activity. Both native and recombinant GrB caused detachment of immortalized and transformed cell lines, primary endothelial cells, and chondrocytes. Cell detachment by GrB induced endothelial cell death (anoikis). GrB also inhibited tumor cell spreading, migration, and invasion in vitro. Investigation into the underlying mechanism revealed that GrB efficiently cleaves three proteins involved in extracellular matrix structure and function: vitronectin, fibronectin, and laminin. In vitronectin, GrB cleaves after an Arg-Lys-Asp (RGD) motif, which is part of the integrin-binding site found in matrix proteins. We propose that targeting of the integrin-extracellular matrix interface by GrB may allow perforin-independent killing of target cells via anoikis, restrict motility of tumor cells, facilitate lymphocyte migration, or directly reduce virus infectivity. It may also contribute to tissue destruction in diseases in which extracellular GrB is evident, such as rheumatoid arthritis and atherosclerosis.
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PMID:Extracellular matrix remodeling by human granzyme B via cleavage of vitronectin, fibronectin, and laminin. 1584 72

Granzyme B is a unique serine protease, which plays a crucial role for target cell death. Several mechanisms of delivery of granzyme B to target cells have been recently identified. Granzyme B directly activates Bid, a specific substrate for granzyme B, resulting in caspase activation. Granzyme B efficiently cleaves many prominent autoantigens, and the hypothesis that autoantibodies arise when cryptic determinants are revealed to the immune system has been proposed. Some autoantibodies directed against granzyme B-specific neoepitopes are present in serum from patients with autoimmune diseases. In the tissues from autoimmune diseases, granzyme B might play an important role for disease progression (i.e., rheumatoid arthritis synovium) or inhibition (i.e., regulatory T cells). We have identified a novel type of activation-induced cell death (granzyme B leakage-induced cell death). Activation-induced natural killer (NK) cell death is accompanied by the leakage of granzyme B from intracellular granules into the cytoplasm, and it triggers apoptosis by directing Bid to mitochondrial membranes. An excess of "leaked" granzyme B over its inhibitor, serpin proteinase inhibitor 9, is a major determinant of cell death. The role of granzyme B in autoimmunity and its influence on NK cell death are discussed.
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PMID:Granzyme B and natural killer (NK) cell death. 1702 86

Granzyme B is a major mediator of the cytotoxic immune response by inducing target cell death when internalized in the presence of perforin. Recently, several studies have focused on another role of granzyme B, which is extracellular matrix (ECM) remodeling through the degradation of ECM proteins. In order to investigate the expression pattern of granzyme B in the lesion areas of atherosclerosis and rheumatoid arthritis, we performed immunohistochemistry and in situ hybridization analyses using human atherosclerotic plaques and the synovial tissues of rheumatoid arthritic- and osteoarthritic-joints. In atherosclerotic plaques, granzyme B was expressed by macrophages in areas such as the boundary regions between media and intima, areas around necrotic cores, and in shoulder regions. In the synovial tissues of rheumatoid arthritic-joints, the expression of granzyme B was strongly observed in the lining layers where the majority of cells are macrophages and also in perivascular areas where macrophages and a small number of lymphocytes were mixed to form diffuse cellular aggregates. Granzyme B-positive cells were not detected in osteoarthritic synovium. Furthermore, the expression of granzyme B has been induced in the human macrophage cell line, THP-1, by ECM proteins or agents which induce macrophage differentiation. These observations indicate that macrophages should be added to the list of cell types that express granzyme B in human inflammatory diseases and that granzyme B may play a role in macrophage functions that are associated with disease progression.
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PMID:Macrophages express granzyme B in the lesion areas of atherosclerosis and rheumatoid arthritis. 1760 48


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