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PubMed1993

Development of human mast cells from umbilical cord blood cells by recombinant human and murine c-kit ligand.

Both human and mouse c-kit ligand induced differentiation of human mast cells in a long-term culture of the mononuclear cells of umbilical cord blood. Growth factor activity for human mast cells present in conditioned medium of BALB/3T3 fibroblasts was due to mouse c-kit ligand. Recombinant c-kit ligand induced differentiation and proliferation of mast cell progenitors in early stages of culture. However, apparent selective growth of mast cells by c-kit ligand in cord blood cell cultures is mainly due to the effect of the cytokine to selectively maintain survival of immature mast cells. Electron microscopic analysis indicated that human mast cells developed by c-kit ligand were similar to human mast cells in the lung and gut mucosa, while those developed in coculture of cord blood cells with Swiss albino/3T3 fibroblasts were similar to skin mast cells. This conclusion was supported by the fact that the majority of mast cells developed by c-kit ligand contained only tryptase in their granules, whereas those developed in the cocultures contained both tryptase and chymase. It was also found that mast cells developed by c-kit ligand were immature even after culture for 14 weeks. Nevertheless, these cells express Fc epsilon RI, and could be sensitized with human IgE for anti-IgE-induced release of histamine, prostaglandin D2, and leukotriene C4.

Animals↗

PubMed2002

Mast cell infiltration in the wall of varicose veins.

Varicose veins of the lower extremities are abnormally dilated, tortuous and elongated. The exact cause of vein dilatation has still not been established. Mast cells produce, store and release various types of vasoactive compounds (histamine, tryptase, prostaglandins, leukotrienes, and cytokines). Histamine enhances local vasopermeability and smooth muscle cell proliferation, leading to thickening of the intima. Tryptase can contribute to local vascular injury and subsequent weakness of the vascular wall causing varix formation. The aim of the present study was the comparison of mast cell infiltration in the wall of varicose and non-varicose veins. The mean mast cell density in the wall of varicose veins was 0.86 mast cell per mm2 and in healthy non-dilated vein walls, density was 1.23 mast cell per mm2. This difference was not statistically significant, therefore we could not confirm our hypothesis. Nevertheless, we suggest that mast cells could play an important role in the development of varices and the factor released by the mast cells should be further examined.

Adult↗

PubMed2002

Mast cell heterogeneity in B-cell non-Hodgkin's lymphomas: an ultrastructural study.

Mast cells (MC) are critical for a number of pathological conditions, including acute and chronic inflammation and tumor angiogenesis. We have previously demonstrated that in B-cell non-Hodgkin's lymphoma (B-NHL) angiogenesis is correlated with total methachromatic and tryptase-positive MC and that both counts increase in step with the increase in malignancy, whereas the role of MC in malignant lymph nodes is not fully clear. An extensive ultrastructural study has been made of representative samples of 30 B-NHL and 10 benign lymphadenopathies. A heterogeneous population of MC characterized by the presence of granules with a semilunar aspect and containing scrolls was observed. The former are the expression of a slow but progressive release of angiogenic factors due to chronic, progressive stimulation of MC degranulation, while the latter contain tryptase, an angiogenic factor. These two ultrastructural data confirm the important role played by MC in the angiogenesis associated with progression in B-NHL.

Cell Degranulation↗

PubMed1999

T helper cell type 2 cytokine-mediated comitogenic responses and CCR3 expression during differentiation of human mast cells in vitro.

Mast cells (MCs) arise in situ from circulating stem cell factor (SCF)-dependent committed progenitors (PrMCs) and accumulate at sites of allergic mucosal inflammation. We hypothesized that human (h)PrMCs and their mature counterparts might share overlapping patterns of chemokine and cytokine receptor utilization with eosinophils, basophils, and T helper type 2 (Th2) lymphocytes for their homing and allergy-associated hyperplasia. We have characterized committed hPrMCs and fully mature hMCs derived in vitro from cord blood for their functional responses to chemokine and cytokine agonists germane to allergic inflammation and for their maturation-related expression of the corresponding receptors. After 4 wk of culture in the presence of recombinant stem cell factor (SCF), interleukin (IL)-6, and IL-10, the cells were characterized as hPrMCs based upon their uniform surface expression of c-kit and CD13, low-level expression of FcinRIalpha, absence of CD14 and CD16 expression, and immunoreactivity for MC chymase in >80%, and about half were immunoreactive for tryptase and metachromatic with toluidine blue. By week 9, the cells had matured into hMCs, identified by higher levels of c-kit, continued expression of CD13 and low-level FcinRIalpha, uniform toluidine blue metachromasia, and uniform immunoreactivity for both tryptase and chymase. The 4-wk-old hPrMCs expressed four chemokine receptors (CXCR2, CCR3, CXCR4, and CCR5). Each receptor mediated transient rapid calcium fluxes in response to its respective ligand. Both recombinant human eotaxin and stromal cell-derived factor 1alpha elicited chemotaxis of hPrMCs. Only CCR3 was retained on the mature 9-wk-old hMCs from among these chemokine receptors, and hMCs responded to eotaxin with a sustained calcium flux but without chemotaxis. The Th2 cytokines IL-3, IL-5, IL-6, IL-9, and granulocyte/macrophage colony-stimulating factor each augmented the SCF-dependent proliferation of hPrMCs and hMCs. In contrast, the prototypical Th1 cytokine, interferon gamma, suppressed SCF-driven proliferation of both hPrMCs and hMCs. Thus, throughout their development in vitro, hMCs obey SCF-dependent, cytokine-driven mitogenic responses that reflect a Th2-type polarization characteristic of allergy and asthma. Furthermore, committed hPrMCs have a unique profile of chemokine receptor expression from among reported hematopoietic cells, including CCR3, which is shared with the other cells central to allergic inflammation (eosinophils, basophils, and Th2 lymphocytes).

Cell Differentiation↗

PubMed2006

Endometrial chemokines, uterine natural killer cells and mast cells in long-term users of the levonorgestrel-releasing intrauterine system.

OBJECTIVE: The objective was to assess endometrial chemokines in users of the levonorgestrel-releasing intrauterine system (LNG-IUS) and correlate them with leucocyte populations, uterine natural killer cells (uNK) and mast cells (MCs). MATERIALS AND METHODS: Endometrium was obtained from two groups of women who had been using LNG-IUS for 3 years or more: 11 amenorrhoeic women formed the non-bleeding group and 15 women who maintained some form of cyclic bleeding comprised the bleeding group. Specific antibodies were used for the assessment of neutrophils, uNK cells and MCs. Immunohistochemistry was performed to locate the chemokines 6Ckine and interleukin-8 (IL-8). RESULTS: Neutrophils were few and without differences between the two groups. uNK cells were significantly higher in the bleeding group (P < 0.0001). There was no difference between the total number of MCs and activated MCs, but there was a greater extracellular area stained for MC tryptase (P < 0.05). Chemokines 6CKine and IL-8 were abundant in the stroma and in the epithelium, and there was no difference between the groups. CONCLUSIONS: We observed more uNK cells in users with bleeding and a greater extracellular area stained for MC tryptase, although there were no differences between the number of MCs and activated MCs or the chemokines 6CKine and IL-8. uNK cells and MC products may play a role in provoking breakthrough bleeding in long-term users of the LNG-IUS.

Chemokines↗

PubMed1998

Nasal challenge test in the diagnosis of allergic respiratory diseases in subjects occupationally exposed to a high molecular allergen (flour).

The objective of this study was the evaluation of the usefulness of the nasal challenge test in the diagnosis of allergic respiratory diseases in subjects occupationally exposed to flour. A single-blind, placebo controlled study was conducted in 100 subjects with occupational atopic asthma with rhinitis. The control groups consisted of 20 atopic subjects not sensitized to investigated allergens and 20 healthy subjects. A 'nasal pool' technique was used to evaluate the changes of the cellular response and protein level in nasal washings after topical provocation with allergen or placebo. The concentrations of eosinophil cationic protein and mast cell-derived tryptase in nasal fluid were evaluated in 60 cases. There were significant increases in eosinophil and basophils number, albumin/total protein ratio, eosinophil cationic protein and tryptase levels in occupationally sensitized patients challenged with specific allergens. There were neither severe bronchial reactions or an increase of bronchial hyperreactivity in occupationally sensitized patients after the nasal provocation with flour. The nasal challenge test appears to be a very useful and safe tool for diagnosing occupational allergy.

Administration, Intranasal↗

PubMed1989

Inhibitory effects of GMCHA-OPhBut on phospholipid methylation and histamine release in mast cells activated by concanavalin A, anti-IgE, and antigen.

[3H]Methyl group incorporation and histamine secretion in rat mast cells induced by anti-IgE and con A were strongly inhibited by trans-4-guanidinomethylcyclohexanecarboxylic acid 4-tert-butylphenyl ester (GMCHA-OPhBut), a strong and specific inhibitor for pH 7 tryptase (Muramatsu et al. (1988) Biol. Chem. Hoppe-Seyler 369, 617-625) which is present in rat mast cells. The IC50s for these events were of the order of 10(-6) M. Addition of GMCHA-OPhBut after the maximal increase in [3H]methyl group incorporation in rat mast cells activated by con A and anti-IgE induced rapid reduction of the methylated phospholipid, and the later histamine release was strongly suppressed. Mast cells were prepared with Mg2+-free Tyrode-HEPES solution, and challenged with anti-IgE with or without Mg2+. With Mg2+, [3H]methyl group incorporation was enhanced, and histamine was secreted time-dependently. Without Mg2+, [3H]methyl group incorporation fell to one-third, whereas histamine secretion was not affected. These results were incompatible with the above results. From these results it was strongly suggested that a trypsin-like protease, probably pH 7 tryptase, is involved not only in the early events, such as activation of phosphatidylethanolamine methyltransferase I and/or II, but also in the late events such as histamine release, and phospholipid methylation is not associated with histamine secretion.

Animals↗

PubMed1997

The lack of histamine release with cisatracurium: a double-blind comparison with vecuronium.

A prospective, randomized, double-blind study was performed in 62 patients (ASA Classes I and II) treated with either 0.15 or 0.25 mg/kg cisatracurium or 0.15 mg/kg vecuronium administered as a rapid bolus. We wished to determine whether the muscle relaxants caused cutaneous, systemic, or chemical evidence of histamine release. Six minutes after induction of anesthesia with thiopental, patients received one of the muscle relaxants over 5 s. Plasma histamine levels were measured by radioimmunoassay after thiopental administration and 3 and 5 min after the administration of the relaxant. Additionally, plasma was assayed for tryptase, a marker of mast cell release. Cutaneous manifestations to both thiopental and the muscle relaxant were graded by an independent observer. Arterial blood pressure and heart rate were measured every minute. Although systolic and diastolic blood pressure decreased and heart rate increased significantly after thiopental administration (P < 0.0001), there were no further hemodynamic changes after either cisatracurium or vecuronium. One patient who received 0.25 mg/kg cisatracurium exhibited a slight elevation in plasma histamine level 5 min after hemodynamic changes. Cutaneous signs of histamine release were noted in five patients after thiopental administration (flush in four, erythema in one), but no further cutaneous reactions were observed after administration of either cisatracurium or vecuronium. We conclude that cisatracurium and vecuronium do not cause systemic or cutaneous histamine release. Tryptase levels showed no evidence of mast cell degranulation.

Atracurium↗

PubMed1999

Effect of steroids on nasal inflammatory cells and cytokine profile.

OBJECTIVES: To assess the cellular and humoral effects of unilateral topical steroid application on the nasal mucosa of chronic sinusitis patients. STUDY DESIGN: Cohort study with randomized grouping. METHODS: Chronic sinusitis patients awaiting endonasal sinus surgery were randomly divided into a study group and a control group. All patients underwent allergy studies and categorized as allergic or nonallergic. Patients in the study group were exposed unilaterally to fluticasone propionate nasal spray, 100 microg/day for 4 to 6 weeks before the planned surgery. The control group was not exposed to steroids. At the time of surgery, anterior ethmoid mucosa specimens were obtained. The samples were immunostained for CD3, MBP, CD68, elastase, and tryptase. In situ hybridization was used for the detection of interleukin (IL)-4, IL-5, and interferon gamma (IFN-gamma) mRNA. The results were compared between the treated and untreated sides of exposed patients, as well as with nontreated controls. RESULTS: Twenty-one patients consented to participate in the study. The number of CD3-, MBP-, and tryptase-positive cells was significantly less in the treated and untreated sides of exposed patients, compared with unexposed controls. IL-4 and IL-5 mRNA were significantly downregulated in the treated side of allergic patients, as compared with nontreated patients. This effect could not be shown for IL-4 in nonallergic patients. CONCLUSIONS: Topical steroid therapy had an anti-inflammatory effect on both allergic and nonallergic chronic sinusitis patients. The unilateral application of the steroid spray affected the contralateral side as well.

Administration, Intranasal↗

PubMed2002

Epidemiology of Hymenoptera allergy.

PURPOSE OF REVIEW: Epidemiology and especially the natural history of Hymenoptera allergy form the background that is essential to improving the clinical management of insect venom allergic patients. This review focuses on the emergence of recent data which could help provide further enlightenment in this field. RECENT FINDINGS: The latest data on the extent of the disease, the risk factors for sensitization and for local, systemic and fatal reactions after a hymenoptera sting are reviewed. The emerging problems concerning asymptomatic sensitization, the meaning of constitutively elevated tryptase serum levels and the persisting widespread poor awareness of available therapies in Hymenoptera allergic patients are particularly emphasized. SUMMARY: The assessment of the risk for systemic reaction in skin-positive subjects with a negative case history, and the suggestion of the baseline serum tryptase level as a risk factor for reaction severity after a sting, are the most important clinical implications of the latest studies. The genetic and environmental factors involved in the persistence of venom specific immunoglobulin E after a sting and the factors which orient towards a systemic or a large local reaction after apparently the same sting remain open questions.

Animals↗

PubMed2005

Cardiovascular aspects of anaphylaxis: implications for treatment and diagnosis.

PURPOSE OF REVIEW: Anaphylactic cardiovascular collapse can be resistant to treatment with epinephrine (adrenaline) and, in some cases, diagnostic uncertainty compromises follow-up care. The purpose of this review is to examine recent studies relevant to the management and diagnosis of this condition. RECENT FINDINGS: Nausea, vomiting, incontinence, diaphoresis, dyspnoea, hypoxia, dizziness and collapse are associated with hypotension. Relative bradycardia (falling heart rate despite hypotension) is a consistent feature of hypotensive insect sting anaphylaxis and may represent a non-specific physiological response to severe hypovolaemia in conscious individuals. Upright posture has been found to be associated with death from anaphylaxis. Animal studies have found the intramuscular route for epinephrine is ineffective, intravenous boluses temporarily effective, but intravenous infusions of epinephrine are able to reverse anaphylactic shock. In one animal model, antihistamines were found to be harmful. A prospective human study provides evidence for the efficacy of treatment with intravenous epinephrine infusion and fluid (volume) resuscitation. Case reports support the use of the vasoconstrictors metaraminol, methoxamine and vasopressin if adrenaline is ineffective. Repeated measurements of mast cell tryptase are more sensitive and specific than a single measurement for the diagnosis of anaphylaxis. SUMMARY: Current evidence supports use of the supine/Trendelenburg position, epinephrine by intravenous infusion and aggressive volume resuscitation. If these fail, atropine should be considered for severe bradycardia and potent vasoconstrictors may be useful. To confirm the diagnosis of anaphylaxis, serial measurements of mast cell tryptase may be preferable to a single measurement.

Adolescent↗

PubMed2006

Mastocytosis and Hymenoptera venom allergy.

PURPOSE OF REVIEW: Mastocytosis is a rare disease characterized by increased mast cells in skin and/or internal organs. We evaluate the impact of mastocytosis on diagnosis and treatment of Hymenoptera venom allergy. RECENT FINDINGS: Patients with Hymenoptera venom allergy who suffer from mastocytosis develop life-threatening sting reactions more often than those who do not. When patients with Hymenoptera venom allergy were systematically examined for mastocytosis, it was found to be represented to an abnormally high extent. Most patients with mastocytosis tolerate venom immunotherapy with no or only minor systemic symptoms. Venom immunotherapy was found to be marginally less effective in patients with mastocytosis than in those without evidence of mast cell disease (defined as absent cutaneous mastocytosis combined with a serum tryptase concentration of <11.4 microg/l). Several deaths from sting reactions were reported in patients with mastocytosis after venom immunotherapy was stopped. These patients should have venom immunotherapy for the rest of their lives. SUMMARY: Patients suffering from mastocytosis and Hymenoptera venom allergy are at risk from a particularly severe sting anaphylaxis. They need optimal diagnosis and treatment. In patients presenting with Hymenoptera venom allergy, screening tests by measurement of serum tryptase concentration, and a careful skin examination, are highly recommended.

Animals↗

PubMed2006

Assessment of immunologic mechanisms for flare reactions to Synvisc.

Intraarticular injection of Synvisc for treatment of knee pain sometimes results in an acute local reaction (flare). We tested the hypothesis that the flare was a Type-1 hypersensitivity reaction as manifested by the presence of Synvisc antibodies in the synovial fluid and serum and by an increase in the concentration of the mast-cell enzyme tryptase in the synovial fluid. Our second objective was to determine whether the ratio of CD4+ to CD8+ lymphocytes in the synovial fluid was increased, as would be expected in a Type-4 hypersensitivity reaction. The study population was a prospective, consecutive series of 16 patients who had a flare, and 20 control patients. We found no differences in product-specific antibodies in the synovial fluid or serum between patients with flares and patients without flares. The mean tryptase level in the synovial fluid of patients with flares, 3.8 +/- 0.8 microg/L, was not different from the corresponding level in the control patients. The CD4+/CD8+ ratio in the synovial fluid was more than eight times greater in patients with flares. Flares that sometimes occur after treatment with Synvisc are probably not Type-1 (antibody-mediated) hypersensitivity reactions, but may be Type-4 (cell-mediated) hypersensitivity reactions.

Aged↗

PubMed2004

Is urine methylhistamine a useful marker for interstitial cystitis?

PURPOSE: We determined whether urine methylhistamine (MH) is associated with other clinical features and bladder biopsy findings in interstitial cystitis (IC). MATERIALS AND METHODS: Urine MH and University of Wisconsin symptom scores were measured before and 1 month after bladder distention for IC. Bladder biopsies were done at the time of distention. In new patients with IC who met cystoscopic criteria urine MH was compared before and after distention, and changes in urine MH were compared with changes in symptom scores. Pre-distention urine MH was tested for associations with the results of a symptom questionnaire, symptom response after distention, cystoscopic findings and bladder biopsy findings. RESULTS: There were no significant associations between urine MH and symptom scores, response to bladder distention, cystoscopic findings or bladder biopsy features, including mast cell count by tryptase staining. Urine MH was similar in new patients with IC who did vs did not meet cystoscopic criteria. Urine MH was similar in new vs chronically treated patients with IC. CONCLUSIONS: Urine MH is unlikely to be useful as an objective marker of the response to bladder distention, as a method to predict which patients will respond to bladder distention or as a noninvasive substitute for bladder biopsy and mast cell counts by tryptase staining.

Adult↗

PubMed2006

Allergic eosinophilic gastroenteritis with protein-losing enteropathy: intestinal pathology, clinical course, and long-term follow-up.

OBJECTIVES: A subset of patients with allergic eosinophilic gastroenteritis (AEG) has anemia and hypoalbuminemia caused by protein-losing enteropathy (PLE). Our goals were to describe the response to therapy and the long-term outcome of patients in this subgroup and to evaluate their gastric and intestinal biopsies for distinguishing features that might explain their protein and blood loss. METHODS: Patients with AEG + PLE were identified retrospectively and compared with controls and with patients with AEG only. Immunohistochemical staining for tryptase, a mast cell mediator, was performed on gastric and duodenal tissues. Eosinophils identified by hematoxylin/eosin stain and mast cells identified as tryptase-positive cells were counted in one high-power field area with maximal cell infiltration. RESULTS: Although all patients had excellent response to therapy with amino acid-based formula and tolerated gradual introduction of some foods with time, food-responsive disease persisted in all patients over 2.5 to 5.5 years of follow-up. Routine histological evaluation did not show any features differentiating AEG + PLE from AEG. When eosinophils and mast cells were counted in intestinal biopsies, however, significantly more mast cells were found in biopsies of the AEG + PLE group despite comparable numbers of eosinophils. In contrast, in gastric biopsies, eosinophils were more prominent in AEG + PLE, but mast cell numbers were similar in all groups. CONCLUSIONS: Patients with AEG + PLE responded well to therapy with amino acid-based formula. Food hypersensitivities did not completely resolve over up to 5.5 years. Intestinal mast cells were significantly increased in maximally infiltrated areas of the intestine, possibly causing increased intestinal permeability and protein loss.

Eosinophils↗

PubMed2006

Indolent systemic mastocytosis as the cause of a long history of unexplained hypotensive episodes.

Assessment of patients with unexplained hypotensive episodes in outpatient practice is often challenging, with an extensive differential diagnosis. The prevalence of systemic mast cell disease (MCD) is unknown, and the diagnosis is often elusive because serum and urine markers may become positive only after one of the self-limited, recurrent hypotensive episodes. Nevertheless, MCD is increasingly recognized as a cause of unexplained hypotension, secondary osteoporosis, and anaphylactic reactions to Hymenoptera stings. We describe a 38-year-old man who had a 15-year history of undiagnosed, recurrent hypotensive episodes with stereotypic symptoms. Extensive evaluation during these years was unrevealing. On physical examination, he appeared to be a healthy man with a prominent macular rash. Results of skin biopsy showed tryptase-positive mast cells. He had markedly elevated serum tryptase levels, and results of bone marrow biopsy revealed 10% mast cells; all these findings were consistent with indolent systemic mastocytosis. Key features in his history and physical examination prompted the conclusive testing. The most telling features were hypotension, tachycardia, and the rash (urticaria pigmentosa).

Adult↗

PubMed2006

Anti-CXCR3 staining is useful for detecting human cutaneous and mucosal mast cells.

Human synovial mast cells (MC) can be immunolabelled with antihuman CXCR3 antibody (Ab) (clone 49801). We have investigated whether cutaneous and mucosal MC are stained with anti-CXCR3 Ab in paraffin-embedded sections. Immunohistochemical staining and immunofluorescence double staining assays were performed with anti-CXCR3, anti-tryptase, and anti-chymase Ab using normal skin, psoriatic skin lesions, and normal colon. When compared with tryptase and chymase staining, 100% of the cutaneous and 98% of the mucosal MC were positive for CXCR3. Anti-CXCR3 staining is a useful marker for human cutaneous and mucosal MC in paraffin-embedded sections.

Antibodies, Monoclonal↗

PubMed1994

Mast cells are one major source of interleukin-4 in atopic dermatitis.

Several reports have shown the presence of T-helper lymphocytes with Th2 characteristics in the skin lesions of atopic dermatitis (AD). However, Th2 cells themselves require an exogenous pulse of IL-4 to initiate their differentiation and synthesis of IL-4. As mast cells have recently been shown to contain IL-4, this finding prompted us to investigate IL-4 in mast cells of AD lesions, to determine if they might provide the IL-4 pulse needed by the Th2 cells. In this study, we measured IL-4 immunoreactivity in mast cells of non-lesional and lesional skin sections from 20 patients with AD. Ten patients with nummular eczema (NE) without any atopic features or background, and five healthy subjects, served as the control groups. Mast cells were first identified using an enzyme--histochemical staining method for tryptase. Subsequently, the sections were photographed, the tryptase stain was removed, and IL-4 was demonstrated with a polyclonal antibody. The sections were photographed again, and the percentage of IL-4 positive mast cells was calculated. The percentage of mast cells exhibiting IL-4 immunoreactivity in the upper dermis in lesional vs. non-lesional skin was 66 +/- 18% vs. 37 +/- 18% in AD (P < 0.0001, paired t-test), but only 46 +/- 19% vs. 31 +/- 22% in NE. In the skin of healthy controls, only 23 +/- 25% of the mast cells were positive for IL-4. In addition, a significant difference was found between lesional skin of AD vs. NE patients (P < 0.008, unpaired t-test).(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗