Histamine‐releasing factors, a heterogeneous group of different activities
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Histamine-releasing factor or HRF is a collective term used for a heterogeneous group of factors with different modes of action. The current review is focussed on IgE-dependent HRF that require the presence of certain types of IgE (designated IgE+) to induce histamine release. IgE+ might be a structurally different IgE molecule, or, alternatively, autoreactive IgE. A subgroup of IgE-dependent HRF does not bind to IgE, such as cloned HRF p23. This factor turned out to be a basophil-priming cytokine. Alternatively IgE-dependent HRF might be an autoallergen. Several groups demonstrated IgE antibodies to human proteins. However, not all IgE autoallergen-containing extracts induce histamine release of appropriately sensitized basophils. In culture supernatants of human mononuclear cells an autoallergenic activity (Agmn) is found, but no binding to IgE+ was found yet. Agmn might be an autoallergen, since it is cross-reactive with a grass pollen allergen in the stripped basophil assay. IgE-dependent HRF and IgE+ may play a role in the late allergic reaction (LAR). However, IgE+ responsiveness to Agmn (IgEmn+) was not required for a bronchial LAR. IgEmn+ is associated with chronic allergic disease, since the prevalence of IgEmn+ is high in the serum of severe asthmatics and atopic dermatitis patients. Our hypothesis is that exogenous allergens induce IgE antibodies cross-reactive with an endogenous protein. During a LAR, these endogenous proteins are released and the subsequent IgE-mediated reaction prolongs and aggravates the allergic and/or asthmatic symptoms. In conclusion, HRF is a confusing term since it is used for different activities. It might be better to avoid this terminology on and just describe the activity of the factors. Autoallergenic activity is likely to explain most, if not all, IgE-dependent activity.Keywords:
Priming (agriculture)
Measurement of IgE on human basophils: relation to serum IgE and anti-IgE-induced histamine release.
The number of IgE molecules bound to human basophils was calculated from direct measurements of the IgE dissociated after exposing leukocytes to pH 3.7 acetate buffer in the cold. In 18 donors studied, cell-bound IgE ranged from 4000 to 500,000 molecules/basophil and correlated with the serum IgE concentration (r = 0.89, p less than 0.001) which ranged from 5 to 3,000 ng/ml. Sensitivity of these cells to anti-IgE was tested to explore the relationship between cell-bound IgE and the concentration of anti-IgE required for histamine release. Cells from some nonatopic donors (4000 to 100,000 IgE molecules/basophil) were as sensitive as cells from allergic donors (100,00 to 500,000 IgE molecules/basophil). Moreover, cells from donors having approximately the same cell-bound IgE concentration varied widely in their sensitivity to anti-IgE. We conclude that an intrinsic property of human basophils ("releasability") is an important parameter in determing mediator release.
Basophil activation
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Abstract The number of IgE molecules bound to human basophils was calculated from direct measurements of the IgE dissociated after exposing leukocytes to pH 3.7 acetate buffer in the cold. In 18 donors studied, cell-bound IgE ranged from 4000 to 500,000 molecules/basophil and correlated with the serum IgE concentration (r = 0.89, p < 0.001) which ranged from 5 to 3,000 ng/ml. Sensitivity of these cells to anti-IgE was tested to explore the relationship between cell-bound IgE and the concentration of anti-IgE required for histamine release. Cells from some nonatopic donors (4000 to 100,000 IgE molecules/basophil) were as sensitive as cells from allergic donors (100,000 to 500,000 IgE molecules/basophil). Moreover, cells from donors having approximately the same cell-bound IgE concentration varied widely in their sensitivity to anti-IgE. We conclude that an intrinsic property of human basophils (“releasability”) is an important parameter in determining mediator release.
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)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.
Cimetidine
Leukotriene C4
Histamine H4 receptor
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Abstract Human blood was fractionated by differential centrifugation on a Hypaque-Ficoll layer, followed by chromatography on a glass-bead column. Analysis of subfractions of leukocytes thus obtained indicated that essentially all histamine in human leukocytes was associated with basophil granulocytes. Histamine release experiments from the subfractions by anti-IgE and by allergen showed that histamine release was induced by IgE-anti-IgE or allergen-IgE antibody reaction on basophil granulocytes. None of the neutrophils, eosinophils and lymphocytes is involved in the mechanisms of histamine release. It was confirmed that anti-IgG-released histamine from leukocytes of some atopic patients. In spite of the presence of IgG on neutrophils, none of the neutrophils, eosinophils and lymphocytes is essential for anti-IgG-induced histamine release. A minute amount of IgG was demonstrated on basophil granulocytes from both atopic and normal individuals by autoradiography, and evidence was obtained that the reaction of the basophil-bound IgG with anti-IgG is accompanied by histamine release from the cells.
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Basophil activation
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IgE antibody specific for AgE (IgE—AgE) was eluted from human basophils at acid pH and quantified by its binding of 125I AgE in antigen excess. The quantity of Ige—AgE recovered from 30 ml of blood ranged from 0.08 ng to 10.3 ng representing 500 to 56,000 molecules IgE—AgE per basophil. The number of molecules of IgE—AgE per basophil was compared to plasma IgE—AgE, total plasma IgE and leucocyte histamine release in response to AgE.
The ratio of plasma IgE—AgE to basophil bound IgE—AgE ranged from 100 to 4000, indicating that there are a limited number of IgE receptors on the basophil surface as contrasted to the concentration of IgE in the plasma. There was no correlation between IgE—AgE in plasma and the number of molecules of IgE—AgE per basophil. However there was a significant correlation between the ration of IgE—AgE to total IgE in plasma and the number of IgE—AgE molecules per basophil.
Two measures of leucocyte histamine release in response to AgE, cell reactivity (maximum per cent histamine release attainable) and sensitivity (lowest antigen dose leading to 50% release), were compared to the number of IgE—AgE molecules per basophil. Cell reactivity was dependent on the number of IgE—AgE molecules per basophil. Only 2500 molecules IgE—AgE per basophil were required to reach a cellular reactivity of 50%. Cell sensitivity to AgE was not correlated with the number of molecules IgE—AgE per basophil which indicated that other factors played a role in determining the sensitivity of a population of basophils to antigenic stimulation by AgE.
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We evaluated the clinical significance of the spontaneous histamine release ratio (SHR/T) and low responders in the automated basophil histamine release test (AllerportⓇ HRT).This study analyzed the outcomes of 101 oral food challenges (OFC) with egg, milk or wheat (challenge-positive: n=79) in relation to the SHR/T. The traditional HRT low responders (n=27) were separated into two groups:"LOW"responders (n=10), who showed a ≥10% concentration-dependent maximum histamine release in response to the anti-human IgE stimulation, and"NON"responders who did not fulfill the criteria (n=17).Among the 34 patients with ≥20% SHR/T, 32 patients (94%) had a positive OFC with a low threshold dose which provoked severe symptoms. Among the"LOW"responders, four cases showed ≥10% allergen-specific maximum histamine release. On the other hand, concentration-dependent histamine release was not seen in the"NON"responders, suggesting the basophil function was not detected in this subgroup.The present study suggested that SHR/T could be an indicator of basophil activation and hypersensitivity in vivo. We also suggested that significant basophil functions might be detected among the "LOW"responders, but not among the"NON"responders.
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Abstract Human peripheral blood monocytes generated activities during 24-h culture that were capable of triggering histamine release from 17 of 18 human basophil donors. Monocytes and their in vitro transformed macrophages continued to elaborate these basophil histamine-releasing activities for at least 3 wk in culture. In the 18 basophil donors tested, maximum histamine release induced by monocyte supernatants was 33.8 +/- 5.9% (mean +/- SEM) of total basophil histamine content; optimum anti-IgE-induced release was 38.8 +/- 6.2%. Basophil histamine release in response to monocyte activities was optimal at 37 degrees C and at calcium concentrations of 2 to 5 mM. Release was greater than 90% complete 1 min after challenge and was inhibited by anti-allergic drugs. The mechanism of release appeared to be independent of IgE binding. Gel filtration of supernatants derived from both day 1 (monocyte stage) and day 14 (macrophage stage) cultures demonstrated activity peaks with approximate m.w. of 12,000 and 30,000. In contrast to the marked responsiveness of basophils, only 2 of 10 human lung mast cell preparations responded; release in those preparations was low: 3% and 13% histamine release, respectively. Thus, monocytes produce potent histamine-releasing activities with differential actions on basophils and mast cells.
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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.
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IgE-mediated histamine release from whole blood was analyzed in 44 patients with bronchial asthma by observing maximum present release and dose-response curves of histamine release induced by anti-IgE and house dust extract. The maximum histamine release from whole blood induced by anti-IgE correlated with total serum IgE levels. There was a close correlation between allergen-induced release from whole blood and the serum levels of specific IgE antibodies. In the maximum histamine release from whole blood induced by both anti-IgE and allergen, the interaction with a serum factor was not clearly recognized. Effect of a serum factor was shown in the dose-response curves of anti-IgE-induced histamine release, but not in those of allergen-induced histamine release. The dose-response curves caused by anti-IgE showed that basophils from cases with a high serum IgE level require much more anti-IgE to produce maximum histamine release than basophils from cases with a low serum IgE level. The results showed that IgE molecules contained in the serum participate in anti-IgE-induced histamine release from whole blood.
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