Strong induction of members of the chitinase family of proteins in atherosclerosis: chitotriosidase and human cartilage gp-39 expressed in lesion macrophages.
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Atherosclerosis is initiated by the infiltration of monocytes into the subendothelial space of the vessel wall and subsequent lipid accumulation of the activated macrophages. The molecular mechanisms involved in the anomalous behavior of macrophages in atherogenesis have only partially been disclosed. Chitotriosidase and human cartilage gp-39 (HC gp-39) are members of the chitinase family of proteins and are expressed in lipid-laden macrophages accumulated in various organs during Gaucher disease. In addition, as shown in this study, chitotriosidase and HC gp-39 can be induced with distinct kinetics in cultured macrophages. We investigated the expression of these chitinase-like genes in the human atherosclerotic vessel wall by in situ hybridizations on atherosclerotic specimens derived from femoral artery (4 specimens), aorta (4 specimens), iliac artery (3 specimens), carotid artery (4 specimens), and coronary artery (1 specimen), as well as 5 specimens derived from apparently normal vascular tissue. We show for the first time that chitotriosidase and HC gp-39 expression was strongly upregulated in distinct subsets of macrophages in the atherosclerotic plaque. The expression patterns of chitotriosidase and HC gp-39 were compared and shown to be different from the patterns observed for the extracellular matrix protein osteopontin and the macrophage marker tartrate-resistant acid phosphatase. Our data emphasize the remarkable phenotypic variation among macrophages present in the atherosclerotic lesion. Furthermore, chitotriosidase enzyme activity was shown to be elevated up to 55-fold in extracts of atherosclerotic tissue. Although a function for chitotriosidase and HC gp-39 has not been identified, we hypothesize a role in cell migration and tissue remodeling during atherogenesis. (+info)
Serum YKL-40 and colorectal cancer.
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YKL-40 is a mammalian member of the chitinase protein family. Although the function of YKL-40 is unknown, the pattern of its expression suggests a function in remodelling or degradation of extracellular matrix. High serum YKL-40 has been found in patients with recurrent breast cancer and has been related to short survival. In the present study we analysed YKL-40 in preoperative sera from patients with colorectal cancer and evaluated its relation to survival. Serum YKL-40 was determined by RIA in 603 patients. Survival after operation was registered, and median follow-up time was 61 months. Three hundred and forty patients died. Sixteen per cent of the patients with Dukes' A, 26% with Dukes' B, 19% with Dukes' C and 39% with Dukes' D had high serum YKL-40 levels (adjusted for age). Analysis of serum YKL-40 as a continuous variable showed an association between increased serum YKL-40 and short survival (P < 0.0001). Patients with high preoperative serum YKL-40 concentration had significantly shorter survival than patients with normal YKL-40 (HR = 1.7; 95% CI: 1.3-2.1, P < 0.0001). Multivariate Cox analysis including serum YKL-40, serum CEA, Dukes' stage, age and gender showed that high YKL-40 was an independent prognostic variable for short survival (HR = 1.4; 95% CI: 1.1-1.8, P = 0.007). These results suggest that YKL-40 may play an important role in tumour invasion. (+info)
T cell responses to a human cartilage autoantigen in the context of rheumatoid arthritis-associated and nonassociated HLA-DR4 alleles.
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OBJECTIVE: To analyze the CD4+ T cell responses to the human cartilage antigen glycoprotein-39 (HCgp-39) in the context of rheumatoid arthritis (RA)-associated (DRalphabeta1*0401) and nonassociated (DRalphabeta1*0402) HLA class II molecules. METHODS: Large numbers of HCgp-39-specific T cell hybridomas were generated following immunization of HLA-DR4/human CD4 transgenic, murine major histocompatibility complex class II deficient mice with native HCgp-39. Fine epitope mapping of DRalphabeta1*0401-and DRalphabeta1*0402-restricted T cell hybridomas was performed using overlapping synthetic peptides. Antigen-specific cytokine production by lymph node T cells was evaluated after immunization with native antigen. Proliferative T cell responses of healthy human subjects were compared with the T cell responses of patients with active RA using HCgp-39 epitopes defined in HLA-DR4 transgenic mice. RESULTS: CD4+ T cells from DRalphabeta1*0401 and DRalphabeta1*0402 transgenic mice identified completely different immunodominant peptide epitopes of HCgp-39, and this was not explained by known DR4-binding motifs or direct peptide-binding studies. DRalphabeta1*0401-restricted, antigen-specific T cells produced significantly more interferon-gamma and tumor necrosis factor a in response to HCgp-39 than did T cells from DRalphabeta1*0402 transgenic mice. Finally, HCgp-39 peptides defined in DRalphabeta1*0401 transgenic mice stimulated T cells from HLA-DR4 positive human subjects and RA patients, but not T cells from HLA-DR4 negative individuals. CONCLUSION: T cell epitopes of HCgp-39 that were defined in HLA-DR4 transgenic mice stimulated T cells from human subjects carrying RA-associated HLA-DR4 alleles. HLA-DR4 molecules may influence the disease process in RA both by presentation of selected peptide epitopes and by promoting the production of proinflammatory cytokines in synovial joints. (+info)
Serum YKL-40 concentrations in patients with rheumatoid arthritis: relation to disease activity.
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OBJECTIVE: YKL-40, also called human cartilage glycoprotein-39, is secreted by chondrocytes, synovial cells, macrophages and neutrophils. Studies have shown that YKL-40 is an autoantigen in rheumatoid arthritis (RA). We evaluated whether serum YKL-40 was related to disease activity in patients with RA. METHODS: Serum YKL-40 was determined by radioimmunoassay in 156 patients with RA during a 1 yr longitudinal study. RESULTS: Serum YKL-40 was increased in 54% of the patients with clinically active disease. Patients with clinically active disease initially who became inactive after 12 months had a significant decrease in serum YKL-40 (-30%, P < 0.002) and patients who changed from inactive to active disease had an increase in serum YKL-40. Patients who remained active had unchanged serum YKL-40 during the study. Serum YKL-40 decreased rapidly (-24% after 7 days, P < 0.01) during prednisolone therapy, and more slowly in patients treated with methotrexate only (-15% after 60 days, P < 0.01). Patients with early RA (disease duration < 3 yr, n = 50) and a persistently elevated serum YKL-40 were at risk of radiological disease progression as determined by Larsen score. CONCLUSION: Serum YKL-40 varies according to disease activity in RA, but provides in some respect information different from conventional markers. Our previous studies are consistent with a local release of YKL-40 in the arthritic joint followed by a secondary increase in serum YKL-40. YKL-40 may prove to be a new tool for the study of disease activity and pathophysiology of RA. (+info)
YKL-40, a matrix protein of specific granules in neutrophils, is elevated in serum of patients with community-acquired pneumonia requiring hospitalization.
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The serum concentration of YKL-40, a matrix protein of specific granules in neutrophils, was determined by RIA in 90 patients hospitalized with pneumonia of suspected bacterial origin. Of these, 64 were followed prospectively during antibiotic treatment with blood samples taken on day 0 (on admission and the start of treatment) and on days 1, 3, 5, 7, 10, and 21. Serum YKL-40 at admission was increased in patients with Streptococcus pneumoniae pneumonia (median, 893 microgram/L; 95% confidence interval [CI], 704-1560), compared with healthy subjects (median, 102 microgram/L; 95% CI, 64-247 microgram/L; P<.001) and in patients with pneumonia of unknown etiology (median, 448 microgram/L; 95% CI, 334-700; P<.05). Peak YKL-40 serum values were observed on day 1 and thereafter declined steeply to almost normal by day 3. During the first 10 days, there was a close relation between serum YKL-40 and markers of specific granules of neutrophils (serum lactoferrin and neutrophil gelatinase-associated lipocalin), which suggests that serum YKL-40 reflects exocytosis of specific granules of neutrophils in persons with acute bacterial pneumonia. (+info)
YKL-40 in giant cells and macrophages from patients with giant cell arteritis.
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OBJECTIVE: YKL-40, a mammalian member of the family 18 glycosyl hydrolases, is secreted by activated macrophages at a late stage of differentiation. Macrophages are present in inflammation of the arterial wall and are thought to participate in the pathogenesis of giant cell arteritis (GCA). The aim of this study was to evaluate whether macrophages and giant cells of patients with GCA produce YKL-40, and whether serum YKL-40 concentrations are elevated in these patients. METHODS: Serum YKL-40 was determined by radioimmunoassay in 19 patients with GCA and 8 patients with polymyalgia rheumatica (PMR) who were followed up prospectively during 1 year of treatment with prednisolone. Immunohistochemical staining for YKL-40 was performed in temporal artery biopsy samples that were obtained before treatment. RESULTS: In the arteritic vessels of patients with GCA, positive staining for the YKL-40 antigen was found in CD68+ giant cells and mononuclear cells located in the media. Macrophages located in the adventitia and intima were negative for YKL-40. At the time of diagnosis, patients with GCA had an increased median serum level of YKL-40 (256 microg/liter; P<0.01) compared with healthy age-matched controls (median 118 microg/liter), and the serum level of YKL-40 decreased to normal levels during prednisolone treatment (-38% after 1 month; P<0.001). Most patients with PMR had normal serum YKL-40 levels (median 158 microg/liter) and had no changes in the serum YKL-40 levels during prednisolone treatment. The observed changes in serum YKL-40 did not always parallel the changes in serum C-reactive protein levels and erythrocyte sedimentation rate during the 1-year study period. CONCLUSION: YKL-40 is found in CD68+ giant cells and mononuclear cells in the media of arteritic vessels of patients with GCA, and the concentration of serum YKL-40 may reflect the local activity of these cells in the inflamed artery. (+info)
Induction of tolerance with intranasal administration of human cartilage gp-39 in DBA/1 mice: amelioration of clinical, histologic, and radiologic signs of type II collagen-induced arthritis.
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OBJECTIVE: Human cartilage glycoprotein 39 (HC gp-39) was recently identified as a candidate autoantigen in the pathogenesis of rheumatoid arthritis. In the present studies, we investigated the capacity of HC gp-39 to interfere in clinical disease induced by an unrelated autoantigen, type II collagen (CII), by the induction of cross-tolerance. METHODS: DBA-1j/Bom mice were immunized with bovine CII/complete Freund's adjuvant and were given intraperitoneal booster injections of CII on day 21. Tolerance was induced via the intranasal pathway with either the disease-inducing antigen (CII), a control antigen (ovalbumin), or HC gp-39 either before priming with CII or near the day of the booster injection. Arthritis was monitored visually, and joint pathology was examined histologically and radiologically. In addition, CII antibody levels in serum were analyzed by enzyme-linked immunosorbent assay. RESULTS: In contrast to treatment before priming, intranasal application of HC gp-39 after immunization markedly suppressed disease activity and prevented joint destruction, whereas application of ovalbumin or CII was ineffective. Interference of HC gp-39 with the immune response to CII was demonstrated by decreased anti-CII antibody levels. The combined data indicate that intranasal treatment with HC gp-39 may trigger modulatory or regulatory mechanisms that interfere with the expression of disease in murine collagen-induced arthritis. CONCLUSION: HC gp-39 is the first cross-tolerance-inducing protein in arthritis that down-modulates a spectrum of disease features when given in a semitherapeutic protocol. (+info)
Human cartilage glycoprotein 39 (HC gp-39) mRNA expression in adult and fetal chondrocytes, osteoblasts and osteocytes by in-situ hybridization.
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OBJECTIVE: To examine the expression pattern of human cartilage glycoprotein 39 (HC gp-39) mRNA in human cartilage and bone. DESIGN: In-situ hybridization analysis was used to examine the expression pattern of human cartilage glycoprotein 39 (HC gp-39) mRNA in adult human osteoarthritic articular cartilage from various stages of disease, as well as in human osteophytic tissue and in human fetal bone. RESULTS: In cartilage from patients with mild osteoarthritic cartilage degeneration, HC gp-39 was expressed at moderate to high levels only in chondrocytes of the superficial zone. In advanced OA cartilage, cloning chondrocytes of the superficial zone expressed high levels of HC gp-39 and chondrocytes of the mid- and deep zones were also positive. HC gp-39 was undetectable in the chondrocytes of normal articular cartilage. In osteophytic tissue, the expression of HC gp-39 mRNA was intense in flattened, end-stage osteoblasts and in primary osteocytes in both endochondral and intramembranous bone formation. Proliferating osteoblasts expressed low to moderate levels. Notably, mature osteocytes were negative for HC gp-39 expression. Chondrocytes in the secondary ossification center of developing fetal cartilage demonstrated high expression while growth plate and mineralized cartilage chondrocytes had lower expression. Osteoblasts at sites of endochondral and intramembranous bone formation were positive for expression of HC gp-39. CONCLUSIONS: The stage-specific expression of HC gp-39 in fetal development and adult remodelling bone and cartilage provides evidence for a specific functional or structural role for HC gp-39 in bone and cartilage tissue. HC gp-39 is expressed in diseased human osteoarthritic cartilage and osteophyte, but not in non-diseased tissue, and its distribution within the tissue changes as disease progresses. OA is characterized not only by cartilage degeneration, but by increased subchondral bone formation and osteophytosis. The results from this study indicate that the increased HC gp-39 expression in OA serum and synovial fluid may reflect not only cartilage degeneration but increased osteogenesis. (+info)