Poor association between allergen‐specific serum immunoglobulin E levels, skin sensitivity and basophil degranulation: a study with recombinant birch pollen allergen Bet v 1 and an immunoglobulin E detection system measuring immunoglobulin E capable of binding to FcɛRI
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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.Keywords:
Basophil activation
We have examined the use of 3 H‐histamine for evaluating in vitro basophil responses. Incubation of 3 H‐histainine for 4 h with basophil‐enriched mononuclear fractions containing autologous plasma, resulted in the best incorporation of the label. Even so, less than 3 % of the added label was actually recovered and other leukocytes also bound or incorporated 3 H‐histamine. Labeled mononuclear preparations failed to release 3 H‐histamine when challenged with zymosan‐activated serum or anti‐IgE, but endogenous histamine released under the same experimental conditions could be determined fluorometrically. The calcium ionopbore, A23187, however, did cause a dose‐dependent release of 3 H‐histamine. We conclude that 3 H‐histamine is not preferentially incorporated into basophil granules, and that this technique cannot be used for assessing allergen and/or IgE‐mediated basophil responses.
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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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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.
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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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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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The aim of the present investigation was to study the dose response relationship of allergen, histamine and histamine releasers in skin prick test (SPT) and the precision of the SPT method. In one experiment timothy allergen, histamine HCl, rabbit anti-human-IgE and compound 48/80 were studied in seven patients. In a second experiment timothy allergen and histamine and dog allergen and histamine were investigated in two groups of 10 patients. Histamine HCl 1 and 10 mg/ml induced weals about 15 and 25 mm2 (4.5 and 5.5 mm in diameter), respectively. The precision as expressed by the coefficient of variation was about 25% for histamine and 40% for allergen for weal areas greater than 10 mm2. Calculations of the regression lines to test the dose response relationships were based on the method of least squares. The best fit was to a log/log model. The slopes of allergen, histamine and histamine releasers were essentially parallel within patients. The median slope of allergen was estimated to about 0.4 based on weal areas and 0.2 based on mean weal diameters. Furthermore, no significant differences were found between the lower and upper parts of the dose response curves of allergen and histamine, although there was a tendency towards steeper slopes at lower concentrations. These results show that histamine concentrations greater than or equal to 1 mg/ml should be used as positive control in SPT and that histamine releasers do not offer advantages over histamine as reference substances in SPT. A common slope for the dose response relationship of allergen and histamine can be used for the estimation of skin sensitivity.
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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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