Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P15088 (mast cell)
 14,925 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1. Although mast cell hyperplasia is a feature of rheumatoid arthritis and osteoarthritis, the extent and nature of mast cell activation in joint disease have not been clearly established. 2. We have investigated the levels of mast cell tryptase and histamine and also of eosinophil cationic protein in synovial fluid collected from 31 patients with rheumatoid arthritis, 14 with seronegative spondyloarthritis and nine with osteoarthritis. Two RIAs for tryptase were employed: one with monoclonal antibody AA5, which was found to bind equally well to both alpha and beta isoforms on Western blots of the recombinant enzyme, and the other with antibody G5, which recognizes predominantly beta-tryptase. 3. alpha-Tryptase, which is likely to be released constitutively from mast cells, appeared to be the major form in synovial fluid, as the assay with antibody AA5 detected appreciably more tryptase than that with antibody G5. beta-Tryptase, which is released on anaphylactic activation of mast cells, was detected in 14 out of 45 synovial fluid samples studied, with concentrations of up to 12 micrograms/l measured by the G5 assay. The apparent levels of beta-tryptase, but not of alpha-tryptase, were closely correlated with those of histamine in the synovial fluid. Patients with osteoarthritis appeared to have a greater proportion of beta-tryptase in the synovial fluid than those with rheumatoid arthritis, as well as higher concentrations of histamine. Eosinophil cationic protein was present at high levels in the synovial fluid, although eosinophil numbers were low, and its concentrations were not correlated with the concentrations of the mast cell products. 4. These data suggest that anaphylactic degranulation of mast cells may have occurred to a greater extent in osteoarthritis than in rheumatoid arthritis, despite the relative lack of synovial inflammation in osteoarthritis. Although the eosinophil cationic protein detected may not reflect eosinophilic inflammation in the joint, the presence in synovial fluid of tryptase of both major forms, and of histamine, appears to indicate that mast cell products are secreted constitutively, as well as by processes of anaphylactic degranulation in rheumatoid arthritis, seronegative spondyloarthritis and osteoarthritis.
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PMID:Mast cell activation in arthritis: detection of alpha- and beta-tryptase, histamine and eosinophil cationic protein in synovial fluid. 940 29

There is an accumulation of evidence to suggest that mast cells may play a key role in gastrointestinal inflammation. We have investigated the numbers and heterogeneity in staining properties of mast cells in biopsies of the duodenum of normal subjects (n = 10), and of normal duodenum from patients with Crohn's disease of the ileum and/or colon (n = 7) or with Helicobacter-associated gastritis of the antrum/corpus (n = 6). In normal donors, two subsets of mast cells, one located in the duodenal mucosa and the other in the submucosa, were clearly distinguished by their morphology and dye-binding properties. Whereas submucosal mast cells stained metachromatically with Toluidine Blue after neutral formalin fixation and emitted a yellow fluorescence after staining with Berberine sulphate, those in the mucosa were invisible using these stains. In patients with gastritis or Crohn's disease, there were marked changes in the numbers of mucosal mast cells compared with control subjects even though the duodenal biopsies were from apparently uninvolved tissue. Gastritis was associated with increased mucosal mast cell numbers (controls: 187 +/- 23 cells mm-2; gastritis: 413 +/- 139 cells mm-2; p = 0.0004), but mean mucosal mast cell counts in the uninvolved duodenum of Crohn's patients were actually decreased (34 +/- 30 cells mm-2, p = 0.0147). The clear differentiation between mucosal and submucosal mast cells on the basis of metachromasia with Toluidine Blue was not seen in biopsies from the patients with gastritis or Crohn's disease. Previous studies which have suggested that there are no distinct mucosal and submucosal mast cell subsets in the human intestine may, therefore, have been affected by the use of tissue from diseased subjects. Heterogeneity in the expression of mast cell tryptase and chymase was seen by immunohistochemistry using specific antibodies, but the relative numbers of mast cell subsets were critically dependent on the methods used. Using a sensitive staining procedure, the majority of mucosal mast cells stained positively for chymase as well as for tryptase, an observation confirmed by immunoelectron microscopy and immunoabsorption studies. Our findings suggest that early stages in intestinal inflammation may be reflected in changes in mast cell numbers and in their staining properties, and call for a reappraisal of mast cell heterogeneity in the human intestinal tract.
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PMID:Number, fixation properties, dye-binding and protease expression of duodenal mast cells: comparisons between healthy subjects and patients with gastritis or Crohn's disease. 942 79

Toluene diisocyanate (TDI) is the most prevalent agent in occupational asthma (OA) in Korea. The immuno-pathologic mechanism for TDI-induced bronchoconstriction remains to be clarified. We studied the immunohistochemical finding of inflammatory cells in bronchial mucosa in subjects with TDI-induced asthma. Fiberoptic bronchial biopsy specimens were obtained from nine subjects with TDI-induced asthma. Six allergic asthma sensitive to house dust mite were enrolled as controls. Bronchial biopsy specimens were examined by immunohistology with a panel of monoclonal antibodies to mast cell tryptase (AA1), secretary form of eosinophil cationic protein (EG2), pan T-lymphocyte (CD3) and neutrophil elastase (NE). There was a significant increase in the number of AA1+, EG2+ and NE+ cells in TDI-induced asthma compared to those of allergic asthma (p=0.02, p=0.04, p=0.03, respectively). No significant differences were observed in the number of CD3+ cells (p=0.27). These findings support the view that neutrophil recruitment together with eosinophil and mast cell, may contribute to the bronchoconstriction induced by TDI.
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PMID:Immunohistochemical characterization of the cellular infiltrate in airway mucosa of toluene diisocyanate (TDI)-induced asthma: comparison with allergic asthma. 953 14

Mastocytosis is a term used for a spectrum of disorders characterized by abnormal growth and accumulation of mast cells. The cutaneous variants of the disease have to be distinguished from systemic mastocytosis (SM), in which at least one extracutaneous organ is involved. In contrast to cutaneous mastocytosis, SM is often associated with another hematologic neoplasm. In most cases clonal myeloid malignancies such as a myeloproliferative or myelodysplastic syndrome occur. In a few cases of SM, however, clonal lymphoid disorders have been described. We here report on a case of SM associated with multiple myeloma. At first presentation, the 48-year old female patient showed monoclonal IgGlambda gammopathy and bone marrow (BM) mastocytosis, but no BM plasma cell infiltrates. Eight years later, the patient presented with BM mastocytosis and overt multiple myeloma. The co-existence of myeloma and mastocytosis was demonstrable by staining serial BM sections with antibodies against mast cell tryptase, CD68R, and the plasma cell marker VS38c. Interphase FISH analysis of BM sections revealed a numeric gain of chromosome 5 and chromosome 7 in the plasma cells but not in the mast cell infiltrates, thereby confirming the presence of two different neoplastic cell populations. To our knowledge, this is the first report describing the co-existence of multiple myeloma and mastocytosis.
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PMID:A case of bone marrow mastocytosis associated with multiple myeloma. 961 35

Mast cells can be distinguished according to various characteristics: rodent mast cells have been subtyped by histochemical criteria, whereas canine and human mast cells have been classified according to their proteases. Comparisons of mast cells from different species have therefore resulted in contradictory and confusing opinions on mast cell heterogeneity. Thus, it is essential to obtain species-specific data on mast cell density and heterogeneity. The present study was carried out to determine the physiological distribution of mast cell numbers and types in bovines according to tissue location, staining, and fixation methods. Samples were fixed in formalin or Carnoy's fluid. The average number of mast cells was determined by using a metachromatic staining method. Protease content of mast cells was examined with a double-enzyme-immunohistochemical staining technique. Three mast cell subtypes were distinguished: T-, TC-, and C-mast cells. The T-mast cell was the predominant subtype in nearly all investigated organs and tissue locations. Only tryptase-positive mast cells could be demonstrated in bovine skin and uterus. No chymase activity was found in these organs, regardless of the fixation type. A larger number of mast cells was observed after fixation in Carnoy's fluid. The three different mast cell subtypes were only demonstrated in formalin-fixed tissue; chymase-positive mast cells were not found after fixation in Carnoy's fluid. Increasing experimental data suggest that mast cell subtypes have different functions in promoting and modulating inflammation and in remodeling the extracellular matrix. Since mast cell tryptase and chymase have different functional properties, these results may clarify the different reaction patterns observed in various organs and species.
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PMID:Bovine mast cells: distribution, density, heterogeneity, and influence of fixation techniques. 963 3

Recent clinical articles have suggested that amniotic fluid embolism (AFE) may be the result of anaphylactic reactions to fetal antigens and that the major part of this clinical syndrome is the result of mast cell degranulation and of the release of histamine, tryptase and other mediators. Tryptase, a neutral protease, is known to be the dominant protein component of the secretory granules of T and TC mast cells. In this paper we have examined the presence and the pulmonary distribution of mast cell tryptase utilizing specific immunohistochemical studies and morphometric evaluation in six cases of fatal amniotic fluid embolism compared to six subjects who died following anaphylactic shock and two control groups (five and six cases respectively) of traumatic death. The results demonstrate a numerical increase of pulmonary mast cells in the subjects who died of AFE (average cell number 54.095) with values corresponding to those encountered in cases of death due to anaphylactic shock (average cell number 51.378) compared with that of the traumatic control groups (average cell number 24.477 and 9.995 respectively). These results can shed light on additional criteria for the diagnosis of amniotic fluid embolism.
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PMID:The diagnosis of amniotic fluid embolism: an immunohistochemical study for the quantification of pulmonary mast cell tryptase. 972 49

Human mast cell tryptase beta (EC 3.4.21.59) is a trypsin-like serine protease that is stored in and released from mast cell granules. This enzyme has been expressed in Pichia pastoris via homologous recombination of the cDNA coding for the mature active tryptase with the addition of a KEX 2 processing site into the Pichia genome. Cells producing recombinant human tryptase (rHT) were selected by screening with antibodies. Induction with methanol resulted in the secretion of rHT into the Pichia growth medium; tryptase activity was stabilized by the addition of heparin to the culture medium. Increasing levels of enzyme were detected in the medium for up to 3 days. Fully active enzyme was purified from the culture medium with a 100% yield of activity via a simple two-step procedure, with hydrophobic interaction chromatography followed by affinity chromatography on immobilized heparin. Bands of 33 (faint), 34.2, 35.9 and 50 kDa (diffuse) were observed on SDS/PAGE. These multiple forms were due to differences in post-translational glycosylation of asparagine residues, because enzymic deglycosylation resulted in only one band at 33 kDa. A single symmetrical peak with an estimated size of 197 kDa was obtained on gel filtration. Kinetic analyses in comparison with native human lung mast cell tryptase (HLT) yielded similar Km values, but the kcat of rHT was more than twice that of HLT.
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PMID:Recombinant human mast cell tryptase beta: stable expression in Pichia pastoris and purification of fully active enzyme. 975 42

We have previously shown that fibroblast and keratinocyte supernatants up-regulate expression of mast cell characteristics in the human immature mast cell line HMC-1. This effect could not be induced in HMC-1 cells by the well-known mast cell growth factor stem cell factor (SCF), probably due to mutations of the SCF receptor c-Kit in these cells. Here we report the effects of several known fibroblast- and keratinocyte-derived growth factors, namely nerve growth factor (NGF), basic fibroblast growth factor, platelet-derived growth factor and transforming growth factor-beta, on mast cell differentiation, using HMC-1 cells as a model. NGF, at 0.1-50 ng/ml concentrations, caused a marked, dose-dependent up-regulation of tryptase, Fc epsilon RI and histamine within 10 days of culture, associated with an enhanced expression of mRNA for Fc epsilon RI and mast cell tryptase. On restriction analysis, only mast cell beta-tryptase, but not alpha-tryptase, could be demonstrated. Furthermore, the high-affinity NGF receptor (TrkA) was found at both the transcriptional and protein levels, while expression of the low-affinity NGF receptor was detectable at the mRNA level only. None of the other growth factors caused a significant alteration of the mast cell markers studied when added to HMC-1 cells at concentrations known to be biologically active in other culture systems. Immature human mast cells are thus induced to assume a more mature phenotype in vitro in response to NGF, most probably via stimulation of the high-affinity NGF receptor expressed on these cells. Besides SCF, NGF should therefore be considered as an additional mast cell growth factor that contributes to human mast cell maturation at tissue sites.
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PMID:Effects of nerve growth factor (NGF) and other fibroblast-derived growth factors on immature human mast cells (HMC-1). 977 35

Fixation and staining conditions for rat mast cell tryptase and its histochemical distribution in different rat tissues were investigated. Prostate, skin, lung, gut, stomach and salivary glands were fixed in either aldehyde or Carnoy fixatives and then frozen or embedded in paraffin wax. Preservation of tryptase enzymic activity against peptide substrates required aldehyde fixation and frozen sectioning. Of the peptide substrates examined, z-Ala-Ala-Lys-4-methoxy-2-naphthylamide and z-Gly-Pro-Arg-4-methoxy-2-naphthylamide proved the most effective for the demonstration of tryptase. Double staining by enzyme cytochemistry followed by immunological detection of tryptase showed that, in all tryptase-containing mast cells, the enzyme is at least in part active. Conventional dye-binding histochemistry was used to confirm the identity of mast cells. Aldehyde-fixed mucosal mast cells required a much shorter staining time with Toluidine Blue if tissue sections were washed directly in t-butyl alcohol. Double staining by enzyme cytochemistry and dye binding showed that tryptase is absent from mucosal and subepidermal mast cells, which are also smaller in size and appear to contain fewer granules than connective tissue mast cells. This study demonstrates that rat mast cell tryptase, unlike tryptases in other species, is a soluble enzyme. It is stored in an active form and is absent from some mast cell subpopulations in mucosa, skin and lung.
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PMID:Enzyme histochemistry of rat mast cell tryptase. 1019 50

Human tryptase is a structurally unique and mast cell specific trypsin-like serine protease. Recent biological and immunological investigations have implicated tryptase as a mediator in the pathology of numerous allergic and inflammatory conditions including rhinitis, conjunctivitis, and most notably asthma. A growing body of data further implicates tryptase in certain gastrointestinal, dermatological, and cardiovascular disorders as well. The recent availability of potent, and selective tryptase inhibitors, though, has facilitated the validation of this protease as an important therapeutic target as well. Herein, we describe the design and potency of four classes of selective tryptase inhibitors, of which the first three types are synthetic and the fourth is natural in origin: 1) peptidic inhibitors (e.g., APC-366), 2) dibasic inhibitors (i.e., pentamidine-like), 3) Zn(2+)-mediated inhibitors (i.e., BABIM-like), and 4) heparin antagonists (e.g., lactoferrin). These inhibitors have been tested in the airways and skin of allergic sheep. Aerosol administration of tryptase inhibitors from each structural class 30 minutes before, and 4 hours and 24 hours after allergen challenge, abolishes late phase bronchoconstriction and airway hyperresponsiveness in a dose-dependent manner. Moreover, intradermal injection of APC-366 blocks the cutaneous response to antigen. These studies provide the essential proof-of-concept for the further pursuit of tryptase inhibitors for the treatment of asthma, and perhaps other allergic diseases. Results from clinical studies with the first generation tryptase inhibitor APC-366, currently in phase II trials for the treatment of asthma, provide additional support for a pathological role for tryptase in this disease. Notable advances in the area of tryptase inhibitor design at Axys Pharmaceuticals, Inc. include a novel, zinc-mediated, serine protease inhibitor technology (described herein), and the discovery of a unique class of extremely potent and selective dibasic tryptase inhibitors. Independently, an X-ray crystal structure of active tryptase tetramer complexed with 4-amidinophenyl pyruvic acid has been reported. It is anticipated that these discoveries will further accelerate the design of structurally novel tryptase inhibitors as well as the development of new drugs for the treatment of mast cell tryptase-mediated disorders.
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PMID:Inhibitors of tryptase for the treatment of mast cell-mediated diseases. 1019 50


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