Neutrophils and mast cells. Comparison of neutrophil-derived histamine-releasing activity with other histamine-releasing factors.
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Human neutrophil-derived histamine-releasing activity (HRA-N) was partially purified and found to contain a heat-stable 1400 to 2300-Da fraction which caused human basophils and rat basophil leukemia cells (RBL) to degranulate. The capacity of HRA-N to activate basophils was not related to the gender or atopic status of the basophil donor, but was related to anti-IgE responsiveness. Several lines of evidence suggest that HRA-N and anti-IgE induce histamine release through distinctly different mechanisms: 1) the time course of HRA-N- and anti-IgE-induced RBL histamine release are different; 2) HRA-N causes histamine release from RBL with and without surface-bound IgE; 3) lactic acid stripping of IgE from human basophils reduces anti-IgE-induced histamine release, but has no consistent effect on HRA-N-induced histamine release; and 4) passive sensitization of lactic acid-stripped basophils with IgE restores anti-IgE-induced histamine release but not HRA-N-induced histamine release. Several histamine-releasing factors (HRF) were compared with HRA-N. Human nasal HRF (HRF-NW, crude and partially purified fractions of 15 to 30, 3.5 to 9, and less than 3.5 kDa), like HRA-N, caused equal histamine release from both native and IgE-sensitized RBL. However, only the 15- to 30-kDa fraction caused histamine release from human basophils in the doses tested. Mononuclear cell HRF (HRF-M, crude and a partially purified 25 kDa Mr fraction) and platelet HRF (HRF-P, crude preparation) failed to cause histamine release from either native or IgE-sensitized RBL but caused 30 +/- 5.5% and 20 +/- 10% net histamine release from human basophils, respectively. HRA-N and HRF-NW were both stable to boiling. These data, taken together, suggest that the capacity of HRA-N to induce RBL and human basophil histamine release and of HRF-NW to stimulate RBL histamine release is independent of IgE. The data further suggest that HRA-N and HRF-NW can be distinguished by size, and that they both differ from mononuclear cell HRF and platelet HRF. Thus, it appears that inflammatory cells generate a family of distinct HRF.Keywords:
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We studied immunoglobulin E (IgE)- and non-IgE-mediated releasability in basophils from 31 patients with hydatidosis. Histamine release to non-IgE-dependent stimuli did not differ significantly between normal individuals and patients with hydatidosis. On the contrary, an increased histamine liberation was obtained by challenging basophils from hydatid patients with anti-human IgE. It is concluded that <i>Echinococcus granulosus</i> infection induces an enhanced sensitivity of basophils to IgE-dependent stimuli.
Basophil activation
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BackgroundNaturally occurring IgE-specific IgG autoantibodies have been identified in patients with asthma and other diseases, but their spectrum of functions is poorly understood.ObjectiveAddress the hypothesis that: (i) IgG anti-IgE autoantibodies are detectable in the serum of all subjects but elevated in asthmatic patients regardless of atopic status as compared with controls; (ii) some activate IgE-sensitized basophils; and (iii) some inhibit allergen-induced basophil activation.MethodsIgE-specific IgG autoantibodies were detected and quantified in sera using ELISA. Sera were examined for their ability to activate IgE-sensitized human blood basophils in the presence and absence of allergen using a basophil activation test, and to inhibit allergen binding to specific IgE on a rat basophilic cell line stably expressing human FcεRI.ResultsIgG autoantibodies binding to both free and FcεRI-bound IgE were detected in patients with atopic and non-atopic asthma, as well as controls. While some were able to activate IgE-sensitised basophils, others inhibited allergen-induced basophil activation, at least partly by inhibiting binding of IgE to specific allergen.ConclusionNaturally occurring IgG anti-IgE autoantibodies may inhibit, as well as induce, basophil activation. They act in a manner distinct from therapeutic IgG anti-IgE antibodies such as omalizumab. They may at least partly explain why atopic subjects who make allergen-specific IgE never develop clinical symptoms, and why omalizumab therapy is of variable clinical benefit in severe atopic asthma. Naturally occurring IgE-specific IgG autoantibodies have been identified in patients with asthma and other diseases, but their spectrum of functions is poorly understood. Address the hypothesis that: (i) IgG anti-IgE autoantibodies are detectable in the serum of all subjects but elevated in asthmatic patients regardless of atopic status as compared with controls; (ii) some activate IgE-sensitized basophils; and (iii) some inhibit allergen-induced basophil activation. IgE-specific IgG autoantibodies were detected and quantified in sera using ELISA. Sera were examined for their ability to activate IgE-sensitized human blood basophils in the presence and absence of allergen using a basophil activation test, and to inhibit allergen binding to specific IgE on a rat basophilic cell line stably expressing human FcεRI. IgG autoantibodies binding to both free and FcεRI-bound IgE were detected in patients with atopic and non-atopic asthma, as well as controls. While some were able to activate IgE-sensitised basophils, others inhibited allergen-induced basophil activation, at least partly by inhibiting binding of IgE to specific allergen. Naturally occurring IgG anti-IgE autoantibodies may inhibit, as well as induce, basophil activation. They act in a manner distinct from therapeutic IgG anti-IgE antibodies such as omalizumab. They may at least partly explain why atopic subjects who make allergen-specific IgE never develop clinical symptoms, and why omalizumab therapy is of variable clinical benefit in severe atopic asthma.
Basophil activation
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In order to clarify the pathogenetic role of basophils and mast cells in chronic urticaria, histamine and leukotriene (LT)C 4 release was examined in washed mixed leukocytes ( n = 8) and skin mast cells ( n = 5) from patients with chronic urticaria and compared with the same cells from normal controls ( n = 9). Anti‐IgE‐stimulated basophil histamine release was significantly reduced in urticaria patients (median 2.9% vs 15.1% in normal controls), whereas histamine release to A23187. FMLP, and PAF, as well as anti‐IgE‐induced LTC 4 release, showed no differences in both groups. In contrast, anti‐IgE‐stimulated skin mast cells from urticaria patients reacted similarly to those of controls (median histamine release 11.4% vs 14.2% in normal controls). Pretreatment of the cells with interleukin (IL)‐3 upregulated responsiveness of basophil histamine release to anti‐IgE in urticaria patients (median histamine release 14.3%), but pretreatment with the H 2 ‐antagonist cimetidine showed no effect. These data show that reduced basophil histamine releasability in chronic urticaria is not H 2 mediated. It is a stimulus, mediator‐, and cell type‐restricted phenomenon that can, at least partially, be reversed in the presence of the cytokine IL‐3.
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Summary Background Results from several studies indicate that the magnitude of immediate symptoms of type I allergy caused by allergen‐induced cross‐linking of high‐affinity Fcɛ receptors on effector cells (mast cells and basophils) is not always associated with allergen‐specific IgE levels. Objective To investigate the association of results from intradermal skin testing, basophil histamine release and allergen‐specific IgE, IgG1–4, IgA and IgM antibody levels in a clinical study performed in birch pollen‐allergic patients ( n =18). Methods rBet v 1‐specific IgEs were measured by quantitative CAP measurements and by using purified FcɛRI‐derived α‐chain to quantify IgE capable of binding to effector cells. Bet v 1‐specific IgG subclasses, IgA and IgM levels were measured by ELISA, and basophil histamine release was determined in whole blood samples. Intradermal skin testing was performed with the end‐point titration method. Results Our study demonstrates on the molecular level that the concentrations of allergen‐specific IgE antibodies capable of binding to FcɛRI and biological sensitivities are not necessarily associated. A moderate association was found between cutaneous and basophil sensitivity. Conclusion Our results highlight the quantitative discrepancies and limitations of the present diagnostic tools in allergy, even when using a single allergenic molecule. The quantity of allergen‐specific serum IgE is only one component of far more complex cellular systems (i.e. basophil‐based tests, skin tests) used as indirect diagnostic tests for IgE‐mediated allergic sensitivity.
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<i>Background:</i> For the detection of allergen-specific IgE in serum, IgE-binding assays such as the radioallergosorbent assay (RAST) are commonly used. In this study, the applicability and sensitivity of the stripped basophil histamine release bioassay was investigated and compared to the RAST. <i>Methods:</i> Basophils were stripped of their IgE by an acidic buffer, sensitized by human serum and stimulated by allergen with or without interleukin (IL)-3. The histamine release was determined by fluorometric analysis. <i>Results:</i> We showed that for enhancement of the maximal histamine release and the sensitivity of the stripped basophil assay, the priming cytokine IL-3 can be added to the basophils simultaneously to the stimulus. Preincubation of the cells with IL-3, as described in other studies, was not necessary. The bioassay can be used to study the specificity of IgE-mediated reactions. Basophils sensitized by serum absorbed to a particular allergen did not respond to this allergen anymore. This method is very suitable to study cross-reactivity between allergens. The results obtained in the bioassay were comparable to those obtained in the RAST. Using the RAST, lower concentrations of allergen-specific IgE were detected than in the bioassay. However, sera containing IgE against minor allergenic components were negative in the RAST, but strongly positive in the basophil assay. <i>Conclusions:</i> The stripped basophil histamine release bioassay is useful to complement and extend serological detection of allergen-specific IgE. Especially with sera containing IgE against minor components, this assay is more suitable than the RAST. Furthermore, in this assay, the dependency of IgE and of allergen-specific IgE in reactions can be studied in more detail.
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In order to clarify the pathogenetic role of basophils and mast cells in chronic urticaria, histamine and leukotriene (LT)C4 release was examined in washed mixed leukocytes (n= 8) and skin mast cells (n= 5) from patients with chronic urticaria and compared with the same cells from normal controls (n= 9). Anti-IgE-stimulated basophil histamine release was significantly reduced in urticaria patients (median 2.9%vs 15.1% in normal controls), whereas histamine release to A23187. FMLP, and PAF, as well as anti-IgE-induced LTC4 release, showed no differences in both groups. In contrast, anti-IgE-stimulated skin mast cells from urticaria patients reacted similarly to those of controls (median histamine release 11.4%vs 14.2% in normal controls). Pretreatment of the cells with interleukin (IL)-3 upregulated responsiveness of basophil histamine release to anti-IgE in urticaria patients (median histamine release 14.3%), but pretreatment with the H2-antagonist cimetidine showed no effect. These data show that reduced basophil histamine releasability in chronic urticaria is not H2 mediated. It is a stimulus, mediator-, and cell type-restricted phenomenon that can, at least partially, be reversed in the presence of the cytokine IL-3.
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The aim of this study was to evaluate the potential of anti-immunoglobulin E (IgE) and/or anti-IgE-IgE immune complexes to release histamine from peripheral blood basophils. In addition, a potential modulating effect of anti-IgE-IgE complexes on allergen-induced peripheral blood basophil histamine release was evaluated.Whole blood basophil histamine release (WBB-HR) tests done by using glass-fiber-based microtiter plates were performed in 62 patients with allergic rhinitis and/or asthma sensitized to perennial allergens. Evaluation of the direct effects of monoclonal anti-IgEs, including E25, E27, and QGE031, on WBB-HR, and the indirect effects of anti-IgE-serum IgE complexes on spontaneous and allergen-induced WBB-HR were conducted. The tests were performed with and without pretreatment of the basophils with interleukin 3, and the results were expressed as the fraction of total histamine content released.There was no difference between WBB-HR induced by any of the studied anti-IgE antibodies and that induced by isotype antibodies for all blood samples assessed, which, for each patient, was significantly less than that induced by positive anti-IgE control antibodies. Similarly, no effect of any of the studied anti-IgE-IgE complexes on spontaneous or allergen-induced WBB-HR could be demonstrated.There was no evidence that humanized, monoclonal anti-IgE antibodies E25 (omalizumab), E27, or QGE031 directly or indirectly induced histamine release from peripheral blood basophils.
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This study was undertaken to investigate the effect of estrogens on the histamine release mediated by IgE in rat peritoneal mast cells (PMC) and in sensitized human basophils. The estrogens were found to enhance the histamine release of either rat PMC and sensitized human basophils upon stimulation with anti-IgE. The enhancement was estrogens dose-dependent reaching the maximum value of 23% for rat PMC and 41% for sensitized human basophils stimulated with anti-IgE upon preincubation with 10<sup>––</sup><sup>8</sup><i>M </i>estrogens. Moreover, when purified PMC were used, the enhancing effect was still detected, suggesting a direct interaction between estrogens and mast cells. The enhancing effect took place quite rapidly reaching plateau levels in about 60 min. Basophils preincubated at 4 instead of 37 °C did not give any appreciable enhancement, suggesting that it was temperature-dependent and that the effect observed was not due to cytotoxicity. Incubation of PMC or human basophils with estrogens alone, without challenge with anti-IgE, did not give any detectable histamine release. The enhancement of histamine release by estrogens is probably mediated by IgE molecules present on the cell membrane, since this effect was not observed on challenge with substance P or compound 48/80, two segretagogues known to induce histamine release not via IgE.
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Allergic antibodies, now known to be of the IgE class, have been associated with basophil and mast cell activation and thus with histamine release since these cells contain histamine. Common allergen induced diseases such as allergic rhinitis have been correlated with IgE antibody, basophils, mast cells and histamine release and partial control with pharmacologic use of histamine receptor blockade. This report now classifies all immediate-type reactions in reference to basophils and mast cells and activation of these cells. This approach appears particularly important in relation to those immediate-type reactions which simulate IgE mediated responses but in which no allergenic stimulus is present. The mechanisms of pharmacologic control of these basophil-mast cell response syndromes and potential research approaches are emphasized.
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Allergen-induced basophil activation has been associated with the release of several mediators and with an increased expression of CD203c molecules on basophils.To assess the influence of specific allergens on the generation of 15-hydroxyeicosatetraenoic (15-HETE) from peripheral blood leukocytes in relation to basophil activation, on the basis of CD203c molecule expression and histamine release.The study included 15 patients with clinical symptoms of birch pollen allergy confirmed by a positive skin prick test with the birch allergen, and 6 healthy controls. Leukocytes isolated from peripheral blood were incubated with 3 concentrations of the birch pollen allergen (Bet v 1), anti-IgE or with ionophore A23187.In vitro challenge of leukocytes from allergic patients with 1 ng/ml of allergen induced a significant increase in 15-HETE generation. An increase above 30% was observed in almost half the allergic patients, with mean values ranging from 40% to 46%, but not in healthy controls. Anti-IgE antibodies increased 15-HETE generation in 5 patients (termed IgE+), and the allergen induced a significant increase in 15-HETE in all patients who reacted to anti-IgE. The mean CD203c expression on basophils of the allergic patients increased after allergen challenge, but a significant increase (> 30%) was observed only in patients who demonstrated an increased expression after anti-IgE exposure. A significant correlation was seen between 15-HETE generation and histamine release induced by the highest concentration of the allergen (r = 0.95; p < 0.01).Allergen-induced, IgE-mediated activation of basophils is associated with a significant increase in 15-HETE generation.
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