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PubMed2002

Altered storage of proteases in mast cells from mice lacking heparin: a possible role for heparin in carboxypeptidase A processing.

Heparin-deficient mice, generated by gene targeting of N-deacetylase/N-sulfotransferase-2 (NDST-2), display severe mast cell defects, including an absence of stored mast cell proteases. However, the mechanism behind these observations is not clear. Here we show that NDST-2+/+ bone marrow-derived mast cells cultured in the presence of IL-3 synthesise, in addition to highly sulphated chondroitin sulphate (CS), small amounts of equally highly sulphated heparin-like polysaccharide. The corresponding NDST-2-/- cells produced highly sulphated CS only. Carboxypeptidase A (CPA) activity was detected in NDST+/+ cells but was almost absent in the NDST-/- cells, whereas tryptase (mouse mast cell protease 6; mMCP-6) activity and antigen was detected in both cell types. Antigen for the chymase mMCP-5 was detected in NDST-2+/+ cells but not in the heparin-deficient cells. Northern blot analysis revealed mRNA expression of CPA, mMCP-5 and mMCP-6 in both wild-type and NDST-2-/- cells. A approximately 36 kDa CPA band, corresponding to proteolytically processed active CPA, as well as a approximately 50 kDa pro-CPA band was present in NDST-2+/+ cells. The NDST-2-/- mast cells contained similar levels of pro-CPA as the wild-type mast cells, but the approximately 36 kDa band was totally absent. This indicates that the processing of pro-CPA to its active form may require the presence of heparin and provides the first insight into a mechanism by which the absence of heparin may cause disturbed secretory granule organisation in mast cells.

Actins↗
PubMed2003

Mast cell subsets and neuropeptides in leprosy reactions.

The immunohistochemical identification of neuropeptides (calcitonin gene-related peptide, vasoactive intestinal polypeptide, substance P, alpha-melanocyte stimulating hormone and gamma-melanocyte stimulating hormone) quantification of mast cells and their subsets (tryptase/chymase-immunoreactive mast cells = TCMC and tryptase-immunoreactive mast cells = TMC) were determined in biopsies of six patients with leprosy reactions (three patients with type I reaction and three with type II). Biopsies were compared with those taken from the same body site in the remission stage of the same patient. We found a relative increase of TMC in the inflammatory infiltrate of the reactional biopsies compared to the post-reactional biopsy. Also, the total number of mast cells and the TMC/TCMC ratio in the inflammatory infiltrate was significantly higher than in the intervening dermis of the biopsies of both periods. No significant difference was found regarding neuroptide expression in the reactional and post-reactional biopsies. The relative increase of TMC in the reactional infiltrates could implicate this mast cell subset in the reported increase of the immune response in leprosy reactions.

Adolescent↗
PubMed1997

Morphology of endogenous flare-up reactions in contact allergy to gold.

In a double-blind study, 20 patients with contact allergy to gold were given an intramuscular injection of gold sodium thiomalate or placebo, inducing a clinical and histological flare-up of healed patch test sites in the gold-injected but not in the placebo group. The test area of the placebo group showed some perivascular lymphocytic foci (UCHL-1+) and vascular endothelial ELAM-1 staining. The gold group, with flare-up, showed larger and more extensive lymphocytic foci with ELAM-1+ endothelium as well as lymphocytic epidermotropism. CD1a+ LC cells were downgraded, tryptase+ mast cells accumulated and CD68+ monocytes/macrophages markedly increased. Probably, a significant part of the tissue priming as a result of patch testing comprises memory T-cells and endothelial ELAM-1 upgrading, but blood-borne CD68+ monocytes may also be instrumental in the flare-up.

Antigens, CD↗
PubMed2001

Quantitative assessment of mast cells and expression of IgE protein and mRNA for IgE and interleukin 4 in the gastrointestinal tract of healthy dogs and dogs with inflammatory bowel disease.

OBJECTIVE: To characterize the mucosal IgE network in dogs affected with inflammatory bowel disease (IBD) and compare it with that for healthy dogs. ANIMALS: 9 healthy dogs and 20 dogs with IBD. PROCEDURE: In situ hybridization of mRNA specific for IgE and interleukin 4 (IL-4) and immunohistochemical analysis for IgE protein and 2 markers of mast cells (ie, tryptase and chymase) were performed on tissue sections obtained from the gastrointestinal (GI) tract and lymph nodes of dogs. RESULTS: Dogs with IBD had significantly more cells positive for IgE protein and more mast cells in the GI mucosa than healthy dogs. Despite this significant increase in number of cells positive for IgE, cells positive for IgE mRNA were rarely detected in the GI mucosa; most cells positive for IgE mRNA were found in mesenteric lymph nodes. Signal pattern of IL-4 mRNA was similar to that of IgE mRNA. CONCLUSIONS AND CLINICAL RELEVANCE: The increased numbers of cells positive for IgE and mast cells in dogs with IBD suggest hypersensitivity such as hypersensitivity to bacterial or dietary-derived antigens in the intestinal lumen. Future studies need to elucidate whether this represents a cause of inflammation or is a result of the inflammatory process of IBD.

Animals↗
PubMedDate not supplied

Clinical and nasal irrigation fluid findings in perennial allergic rhinitis.

Ten patients with perennial allergic rhinitis and 10 healthy subjects were studied to determine most discriminative nasal irrigation fluid marker(s) and to compare samples that were collected at baseline and over a 1-hour period, every 15 minutes. The latter were pooled and designated 1-hour sample. In the nasal irrigation we investigated the following inflammatory cells and soluble mediators: eosinophils, neutrophils, granulocyte-macrophage colony-stimulating factor, interleukin-4, interleukin-6, interleukin-8, ECP, EPX, MPO, leukotriene C4, leukotriene B4, prostaglandin E2, tryptase and fibrinogen. Patients with PAR were then treated for 2 weeks with the topical nasal steroid. The only marker that discriminated patients with perennial allergic rhinitis and healthy subjects was eosinophil count (EO%): correspondingly 14.01 +/- 5.8 and 0.18 +/- 0.09, (M +/- SD). Difference between the studied groups did not depend on the time of irrigation, baseline or 1-hour. EO% was also the only marker of a clinically successful treatment with the nasal steroid, 14.01 +/- 5.8 and 0.87 +/- 0.4, before and after treatment respectively. We conclude that EO% is the most sensitive inflammatory marker of perennial allergic rhinitis, and that baseline nasal irrigation can be used to study nasal mucosal inflammation.

Administration, Intranasal↗
PubMedDate not supplied

Determination of inflammatory markers in allergic reactions to drugs.

Serum tryptase (Tryp) and eosinophil cationic protein (ECP) and urine N-methylhistamine (N-MH) were quantitated in a group of 13 subjects who had experienced immediate allergic reactions to different drugs. Results indicated that both Tryp and N-MH were involved and the levels were related to the severity of the reaction. Results of serum ECP levels failed to provide relevant information concerning the participation of eosinophils in immediate reactions to drugs.

Adolescent↗
PubMed1994

Concentrations of chemical mediators in nasal secretions of patients with hay fever during natural allergen exposure.

By using the microsuction technique, quantitative determination of the chemical mediators in nasal secretions was performed in 40 patients with seasonal allergic rhinitis during the pollen season. The aim of this study was to investigate the actual concentrations of these important mediators in nasal secretions during natural allergen exposure so as to better understand the pathophysiology of allergic rhinitis. The median concentrations of four mediators, were histamine: 51.5 ng/g (range: 4-146 ng/g); tryptase: 0 (range: 0-84 microU/g); leukotriene C4 (LTC4): 23 ng/g (range: 11-77 ng/g); and eosinophil cationic protein (ECP): 410 ng/g (range: 6-2380 ng/g). The authors compared these concentrations with those of the same mediator found in a previous study of seasonal allergic rhinitis patients after nasal challenge outside the pollen season. The present study demonstrates that during the season allergic rhinitis reflects a chronic state of allergic inflammation of the nasal mucosa involving various inflammatory mediators induced by one or more episodes of early type allergic reaction.

Adolescent↗
PubMed2001

Angiogenesis and mast cells in non-Hodgkin's lymphoma: a strong correlation in angioimmunoblastic T-cell lymphoma.

Mast cells are likely to play a role in angiogenesis under pathological conditions. Solid tumor growth is dependent on angiogenesis, but the influence of mast cells on angiogenesis in non-Hodgkin's lymphoma, (NHL) is not clear. We investigated mast cell number and vessel count in 61 cases of NHL. We also evaluated expression of vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF), both important cytokines for angiogenesis. The number of mast cells was greater in T-cell lymphomas than in B-cell lymphomas. Of the T-cell lymphomas, the greatest number of mast cells was observed in the angioimmunoblastic T-cell lymphoma (AIL). In all NHLs, significant correlation was found between vessel count and the number of mast cells (p < 0.0001) and between vessel count and the number of VEGF-expressing cells (p < 0.05) but not between vessel count and bFGF-expressing cells. Strong correlation was detected between the number of mast cells and the number of VEGF-expressing cells (p < 0.0001) in all NHLs. Double fluorescence staining of VEGF mRNA and mast cell tryptase revealed that mast cells expressed VEGF mRNA. Our data suggest that mast cells play a very important role in angiogenesis by expressing VEGF in NHL, especially in AIL.

Cell Count↗
PubMed2003

IL-1 induces vesicular secretion of IL-6 without degranulation from human mast cells.

Fc epsilon RI cross-linkage in mast cells results in release of granule-associated mediators, such as histamine and proteases, as well as the production of numerous cytokines, including IL-6. Mast cells have been increasingly implicated in inflammatory processes where explosive degranulation is not commonly observed. Here, we show that IL-1 stimulates secretion of IL-6 without release of the granule-associated protease tryptase in normal human umbilical cord blood-derived mast cells (hCBMCs). IL-6 secretion stimulated by IL-1 in hCBMCs is potentiated by priming with IL-4 and reflects the higher levels of IL-6 secreted from human leukemic mast cell line (HMC-1). Stimulating HMC-1 cells by both IL-1 and TNF-alpha results in synergistic secretion of IL-6. IL-6 is de novo synthesized, as its secretion is blocked by inhibitors of transcription or protein synthesis. IL-1 does not increase intracellular calcium ion levels in either hCBMCs or HMC-1 cells, and IL-6 stimulation proceeds in the absence of extracellular calcium ions. Ultrastructural Immunogold localization shows that IL-6 is excluded from the secretory granules and is compartmentalized in 40- to 80-nm vesicular structures. Selective secretion of IL-6 from mast cells appears distinct from degranulation and may contribute to the development of inflammation, where the importance of IL-6 has been recognized.

Calcium↗
PubMed2005

Human mast cells express corticotropin-releasing hormone (CRH) receptors and CRH leads to selective secretion of vascular endothelial growth factor.

Mast cells are critical for allergic reactions, but also for innate or acquired immunity and inflammatory conditions that worsen by stress. Corticotropin-releasing hormone (CRH), which activates the hypothalamic-pituitary-adrenal axis under stress, also has proinflammatory peripheral effects possibly through mast cells. We investigated the expression of CRH receptors and the effects of CRH in the human leukemic mast cell (HMC-1) line and human umbilical cord blood-derived mast cells. We detected mRNA for CRH-R1alpha, 1beta, 1c, 1e, 1f isoforms, as well as CRH-R1 protein in both cell types. CRH-R2alpha (but not R2beta or R2gamma) mRNA and protein were present only in human cord blood-derived mast cells. CRH increased cAMP and induced secretion of vascular endothelial growth factor (VEGF) without tryptase, histamine, IL-6, IL-8, or TNF-alpha release. The effects were blocked by the CRH-R1 antagonist antalarmin, but not the CRH-R2 antagonist astressin 2B. CRH-stimulated VEGF production was mediated through activation of adenylate cyclase and increased cAMP, as evidenced by the fact that the effect of CRH was mimicked by the direct adenylate cyclase activator forskolin and the cell-permeable cAMP analog 8-bromo-cAMP, whereas it was abolished by the adenylate cyclase inhibitor SQ22536. This is the first evidence that mast cells express functional CRH receptors and that CRH can induce VEGF secretion selectively. CRH-induced mast cell-derived VEGF could, therefore, be involved in chronic inflammatory conditions associated with increased VEGF, such as arthritis or psoriasis, both of which worsen by stress.

Blotting, Western↗
PubMed1995

Aspirin idiosyncrasy in systemic mast cell disease: a new look at mediator release during aspirin desensitization.

OBJECTIVE: To report the clinical responses and mediator-release profiles of an aspirin-sensitive man with systemic mast cell disease during aspirin desensitization. MATERIAL AND METHODS: We quantified the release of six mediators during aspirin desensitization. RESULTS: Although aspirin was administered cautiously with an initial dose of 20 mg, successful aspirin desensitization necessitated complete monitoring and resuscitation capabilities of a medical intensive-care unit for 4.5 days because of frequent, severe anaphylactoid responses. To our knowledge, this is the first report of a pronounced increase in plasma levels of the vasodilator peptide calcitonin gene-related peptide during episodes of aspirin-induced hypotension. Increases in plasma levels of calcitonin and serum levels of tryptase paralleled those of calcitonin gene-related peptide, but plasma levels of calcitonin remained increased for up to 18 hours. Urinary excretion of histamine and 1-methyl-4-imidazoleacetic acid also showed precipitous, although delayed, increases. Excretion of the prostaglandin D2 metabolite 11 beta-prostaglandin F2 alpha followed a bimodal pattern during aspirin desensitization; after severe hypotensive responses, the maximal value was more than 490,000 pg/mL, but the level decreased to less than 100 pg/mL after therapeutic serum levels of salicylate were attained. CONCLUSION: These data suggest that the hypotensive responses to aspirin in some patients with systemic mast cell disease may result from the combined effects of several mediators.

Adult↗
PubMed1999

Deficient transcription of mouse mast cell protease 4 gene in mutant mice of mi/mi genotype.

The mi locus encodes a member of the basic-helix-loop-helix-leucine zipper (bHLH-Zip) protein family of transcription factors (hereafter called MITF). We reported that expression of the mouse mast cell protease 5 (MMCP-5) and MMCP-6 genes were deficient in cultured mast cells (CMC) derived from mutant mice of mi/mi genotype. Despite the reduced expression of both MMCP-5 and MMCP-6, their regulation mechanisms were different. Because MMCP-5 is a chymase and MMCP-6 a tryptase, there was a possibility that the difference in regulation mechanisms was associated with their different characteristics as proteases. We compared the regulation mechanisms of another chymase, MMCP-4, with those of MMCP-5 and MMCP-6. The expression of the MMCP-4 gene was also deficient in mi/mi CMC. The overexpression of the normal (+) MITF but not of mi-MITF normalized the poor expression of the MMCP-4 gene in mi/mi CMC, indicating the involvement of +-MITF in transactivation of the MMCP-4 gene. Although MMCP-4 is chymase as MMCP-5, the regulation of MMCP-4 expression was more similar to MMCP-6 than to MMCP-5. We also showed the deficient expression of granzyme B and cathepsin G genes in mi/mi CMC. Genes encoding granzyme B, cathepsin G, MMCP-4, and MMCP-5 are located on chromosome 14. Because all these genes showed deficient expression in mi/mi CMC, there is a possibility that MITF might regulate the expression of these genes through a locus control region.

Animals↗
PubMedDate not supplied

Nasal provocation and immunotherapy.

Nasal mucosa is heavily exposed to inflammatory and allergic stimuli, rhinitis being the most common form of allergic respiratory disease. The nose is an easily accessible organ and a good model for the study of allergies as it makes it possible to monitor the effects of specific challenges as well as therapeutic interventions, namely specific immunotherapy (SIT). Injectable, nasal or sublingual SIT are useful therapeutic strategies in the management of allergic rhinitis patients. Monitoring the evolution of parameters such as clinical scores, nasal peak flow variation or drug requirements during SIT provides important information on its clinical efficacy. Laboratory measurement of tryptase and eosinophil cationic protein in the target organ after specific nasal provocation makes it possible to record changes in the release of mast cell and eosinophil mediators, thus providing objective evidence of the immunological efficacy of this therapy on these cell populations and providing data which eventually will contribute to a better understanding of the multiple mechanisms of action of allergen desensitization therapy.

Asthma↗
PubMed1999

Anaphylactoid and anaphylactic reactions to iodinated contrast material.

Some adverse reactions to iodinated contrast material (ICM) are considered allergy-like, with cutaneous, cardiovascular, respiratory, and digestive symptoms. Allergy-like reactions are usually unpredictable. Reactions are more frequent with ionic than with nonionic material, but the frequency of deaths is almost identical. In a recent study, 20 severe unexpected reactions to ICM, including 10 life-threatening reactions and one death, were investigated by measuring mediators in blood, within the first minutes or hours of reaction. The responsible ICMs were mostly ionic materials. Histamine and tryptase release correlated with the severity of the reaction. Specific IgE against the responsible ICM was significantly higher in reactors than in controls. A few patients had positive skin tests to the administered ICM, suggesting type-I allergic reaction. Only 2.4% and 3.1% of the cases yielded a positive IgE-RIA, in a second retrospective study which included 165 patients recruited during a 4-year period. In conclusion, IgE-mediated anaphylaxis is rare, but it may be one of the possible mechanisms of severe adverse reactions to ICM.

Anaphylaxis↗
PubMed1999

Immunocytochemical study of giant cell fibroma.

Giant cell fibroma (GCF) is a non-neoplastic lesion of the oral mucosa. The origin of stellate and multinucleate cells of GCF is not well known. The purpose of the present article was to investigate the immunoreactivity of these cells for leukocyte common antigen, vimentin, tryptase, HLA-DR, alpha-smooth muscle actin, CD68, and S-100. The results showed positive staining only for vimentin. This suggests that the stellate and multinucleate cells of GCF have a fibroblast phenotype.

Actins↗
PubMed2000

Mast cell density is associated with angiogenesis and poor prognosis in pulmonary adenocarcinoma.

BACKGROUND: Angiogenesis in individuals with various solid tumors has provided useful information on tumor progression and prognosis, and many examples of mast cell (MC) accumulation coupled with angiogenesis can be found in the literature. METHODS: Utilizing monoclonal antibodies for tryptase that are specific markers for MC and for the endothelial surface marker CD34, the authors quantified MC infiltration in 180 patients with pulmonary adenocarcinoma who underwent curative tumor resection, to investigate the relation between mast cell density (MCD) and microvessel density (MVD), clinicopathologic factors, and prognosis. RESULTS: A significant association was found between MCD and MVD (P < 0.0001). The MC count was significantly related to tumor progression, involving N classification and stage (P = 0.0002 for N classification and P = 0. 0015 for stage). A significant difference in the rate of patient survival was detected between patients whose tumors had an MCD defined as high and those whose tumors had an MCD defined as low (P < 0.0001). Multivariate analysis also showed that MCD was significantly related to survival (P = 0.0378). CONCLUSIONS: These data indicate that MC infiltration may contribute to tumor angiogenesis and tumor progression, and that MCD is a useful prognostic marker in pulmonary adenocarcinoma.

Adenocarcinoma↗
PubMed2000

A functional proteomics screen of proteases in colorectal carcinoma.

BACKGROUND: Proteases facilitate several steps in cancer progression. To identify proteases most suitable for drug targeting, actual enzyme activity and not messenger RNA levels or immunoassay of protein is the ideal assay readout. MATERIALS AND METHODS: An automated microtiter plate assay format was modified to allow detection of all four major classes of proteases in tissue samples. Fifteen sets of colorectal carcinoma biopsies representing primary tumor, adjacent normal colon, and liver metastases were screened for protease activity. RESULTS: The major proteases detected were matrix metalloproteases (MMP9, MMP2, and MMP1), cathepsin B, cathepsin D, and the mast cell serine proteases, tryptase and chymase. Matrix metalloproteases were expressed at higher levels in the primary tumor than in adjacent normal tissue. The mast cell proteases, in contrast, were at very high levels in adjacent normal tissue, and not detectable in the metastases. Cathepsin B activity was significantly higher in the primary tumor, and highest in the metastases. The major proteases detected by activity assays were then localized in biopsy sections by immunohistochemistry. Mast cell proteases were abundant in adjacent normal tissue, because of infiltration of the lamina propria by mast cells. Matrix metalloproteases were localized to the tumor cells themselves; whereas, cathepsin B was predominantly expressed by macrophages at the leading edge of invading tumors. Although only low levels of urinary plasminogen activator were detected by direct enzyme assay, immunohistochemistry showed abundant protein within the tumor. CONCLUSIONS: This analysis, surveying all major classes of proteases by assays of activity rather than immunolocalization or in situ hybridization alone, serves to identify proteases whose activity is not completely balanced by endogenous inhibitors and which may be essential for tumor progression. These proteases are logical targets for initial efforts to produce low molecular weight protease inhibitors as potential chemotherapy.

Biopsy↗
PubMedDate not supplied

Evaluation of selected cytokines and mononuclear cell infiltration in gastric mucosa of children with food allergy.

The authors performed simultaneous evaluation of histological changes in gastric and duodenal mucosa, phenotypic evaluation of mononuclear cells infiltration and the levels of selected cytokines of gastric mucosa in children with diagnosed food allergy. It was determined that IL-4, IL-5, IL-10 and TNF-alpha were produced locally within alimentary tract mucosa; they may play pathogenic role in food hypersensitivity in children. Increase in the number of T lymphocytes (CD3+, CD8+) and B lymphocytes (CD20+) as well as mastocytes with positive reaction to Mast Cell Tryptase-Mastocyte antibody was also observed in gastric and duodenal mucosa of these patients.

Adolescent↗