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PubMed1987

Studies on the human basophil IgE receptor. Generation and characterization of monoclonal antibodies against the receptor.

Anti-human basophil IgE receptor (Fc epsilon R) monoclonal antibodies (McAbs) were generated and characterized. The production of these antibodies was facilitated by both a single step procedure for the enrichment of basophils using Ficoll-Paque centrifugation and a double staining technique combining the APAAP with alcian blue. By the double staining technique we could recognize the specific anti-basophil antibodies because the cells binding the antibody--APAAP positive cells--also had alcian blue-stained basophil granules. Blocking experiments showed that the McAb was directed against the Fc epsilon R since preincubation with human IgE blocked the binding of the McAb and preincubation with the antibody blocked the binding of IgE to basophils and inhibited the formation of IgE rosettes.

Animals↗
PubMed1995

Purification of human basophils and mast cells by multistep separation technique and mAb to CDw17 and CD117/c-kit.

Basophils and mast cells represent distinct cell lineages within the hemopoietic system. Based on the unique cell surface antigen profile of both cells, we have established methods which allow the reproducible purification to homogeneity (> 99%) of normal human basophil granulocytes from the peripheral blood and of mast cells from human dispersed tissues. Basophils (n = 9) were purified by current counterflow elutriation followed by depletion of monocytes with CD14 mAb conjugated to magnetic beads, and subsequent cell sorting for CD217+ cells. Basophil purity was 99.5 +/- 0.4% (range 98.7-99.9%). Mast cells were obtained from lung (n = 6), uterus (n = 1), mastocytosis bone marrow (n = 2), and human foreskin (n = 2). Mast cells were purified by collagenase digestion followed by current counterflow elutriation and sorting with CD117/c-kit mAb. Mast cell purity was 99.4 +/- 0.7% (range: 97.5-99.9%). Purified cells were more than 90% viable and were able to release histamine on induction with IgE plus anti-IgE. Furthermore, the PCR technique could be applied on pure cells and confirmed expression of high affinity IgE receptor (Fc epsilon R1) alpha chain mRNA. Thus, by combining isolation techniques including elutriation, magnetic cell depletion and cell sorting with mAb, functionally intact normal human basophils and mast cells can be enriched to homogeneity.

Antibodies, Monoclonal↗
PubMed1986

Possible role of calmodulin in the control of histamine release from human basophil leukocytes.

We investigated the possible role of calmodulin (CaM) in the control of histamine release from human basophil leukocytes using several CaM antagonists. Trifluoperazine (TFP) (10(-6)-2 X 10(-5) M), pimozide (10(-6)-1.5 X 10(-5) M), chlorpromazine (CPZ) (10(-5)-10(-4) M) and promethazine (PMZ) (2 X 10(-5)-10(-4) M) inhibited in vitro histamine secretion from human basophils induced by several immunological (antigen, anti-IgE, and formyl-L-methionyl-L-leucyl-L-phenylalanine: f-met peptide) and nonimmunological (Ca2+ ionophore A23187 and the tumor promoter 12-0-tetradecanoyl-phorbol-13-acetate: TPA) stimuli. Trifluoperazine sulfoxide (TFP-S) and chlorpromazine sulfoxide (CPZ-S), which have very low affinity to CaM, had practically no inhibitory effect on histamine release from human basophils. The inhibitory effect of TFP could be made irreversible by irradiating the cells with UV light. A sulfonamide derivative, the compound N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide hydrochloride (W-7) (2.5 X 10(-5)-2 X 10(-4) M), which selectively binds to CaM, inhibited the release of histamine from basophils. In contrast, the chloride deficient analogue, W-5, which interacts only weakly with CaM, had practically no inhibiting effect. The IC50 for enzyme release by a series of eight CaM antagonists was closely correlated (r = 0.91; p less than 0.001) with the CaM specific binding, supporting the concept that these agents act by binding to CaM and thereby inhibiting histamine release. TFP and W-7 inhibited histamine release in the absence and in the presence of increasing concentrations of extracellular Ca2+. These results emphasize the possible role of CaM in the control of histamine secretion from human basophils.

Basophils↗
PubMed1989

Pathophysiology of human basophils and mast cells in allergic disorders.

Basophil leukocytes and tissue mast cells are inflammatory cells that are found in virtually all human tissues. They appear to be involved in the pathogenesis of such allergic diseases as allergic rhinitis, bronchial asthma, anaphylaxis, atopic and contact dermatitis, chronic urticaria, and hypersensitivity pneumonitis. By releasing a variety of chemical mediators, they could also play a role in the pathophysiology of a wide range of inflammatory disorders of the joints, and of intestine, lung, coronary, and myocardial diseases. Although these two cell types are similar in several aspects, striking differences have also been observed. Moreover, human mast cells from different anatomical sites and within an individual tissue synthesize different mediators and have different release mechanisms. The recent advent of techniques that yield highly purified basophils and mast cells from diverse tissues will probably lead to major advancements in understanding the biochemical and pharmacological mechanisms that control the release process of these cells. The release of mediators from these cells is also controlled by a series of largely undefined biochemical steps that represent the basis of the concept of basophil and mast cell releasability. Alterations of basophil or mast cell releasability have already been detected in patients with allergic rhinitis, bronchial asthma, atopic dermatitis, and chronic urticaria. Taken together, these findings demonstrate that basophils, mast cells, and their chemical mediators play a pivotal role in several inflammatory disorders.

Animals↗
PubMed1977

Complement-mediated release of histamine from human basophils. III. Possible regulatory role of microtubules and microfilaments.

The release of histamine by normal human leukocytes (basophils) following in vitro challenge with activated complement (zymosan-treated serum) was previously reported. In this study, the effects of various pharmacologic agents on this release mechanism were compared with allergen-induced release of histamine. Colchicine and vinblastine antagonize the polymerization of tubulin to form microtubules, and both agents inhibited complement-and allergen-triggered release of histamine from basophils. Finally, treatment with cytochalasin B, a fungal product known to interfere with microfilament formatin, resulted in enhanced release of histamine from complement-treated basophils but no significant change in the percentage of histamine released from allergen-treated basophils. These findings suggest that microtubules and/or microfilaments are involved in complement-induced secretion of histamine by human basophils.

Allergens↗
PubMed1989

Comparison between number of basophils, blood histamine, and histamine release in cancer and noncancer patients.

In cancer patients with primary tumor with or without metastasis or metastasis alone, by comparison with healthy subjects and noncancer patients, the decrease in blood histamine levels is due to a decrease in total basophil number. These basophils have a normal content of histamine (1 to 2 pg per basophil) and are able to release histamine. The percentage of anti IgE-induced histamine release is not significantly different than in noncancer patients. The scarcity of basophils in cancer patients is not due to a leukopenia. Blood histamine levels and total basophil number are normal in patients after successful excision of their primary tumor without metastasis.

Adult↗
PubMed1992

The effect of inhaled allergen on circulating basophils in atopic asthma.

There is increasing evidence for the role of basophils in the allergen-induced late asthmatic response (LAR). To study the effect of inhaled allergen on basophil function in subjects with asthma, ex vivo basophil spontaneous histamine release (SHR) in peripheral blood and plasma histamine was measured before and 2, 5, 10, and 15 minutes, and 2, 4, 6, and 8 hours after allergen bronchial challenge (allergen study day) in six subjects with atopic asthma. Allergen inhalation induced an early response and LAR consisting of a mean (+/- SD) 32.5% (+/- 7.9%) and 28.8% (+/- 7.7%) fall in FEV1, respectively. As a control for the effects of bronchoconstriction, on another occasion, methacholine challenge was performed to produce a mean 33.4% (+/- 3.4%) fall in FEV1 during the early response and no LAR, and blood was obtained to measure basophil histamine release (HR) and plasma histamine. There was a small, but significant (p less than 0.05), rise in median SHR from 4.6% to 6.1% of total basophil histamine after allergen but not after methacholine inhalation. HR remained high after allergen inhalation during the 8 hours of study, whereas it demonstrated a steady, significant, decrease between 4 to 8 hours after methacholine inhalation. No significant changes in plasma histamine were recorded on either allergen or methacholine study days. On a third occasion, SHR was measured after challenge with physiologic saline to control for any effects of methacholine on SHR, and a decrease in HR was recorded during the day similar to HR observed after methacholine challenge. These studies suggest an enhancing effect of inhaled allergen on SHR.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1989

Neutrophil attractant/activation protein-1 (NAP-1) causes human basophil histamine release.

Basophils from five of six human donors released histamine in response to neutrophil attractant/activation protein-1 (NAP-1). Histamine release by this protein was concentration-dependent over the range of 3 x 10(-7) M to 4 x 10(-6) M. At 4 x 10(-6) M, the mean agonist-induced release was 16 +/- 3% (SEM) of total basophil histamine. For the same basophil preparations, release by anti-IgE was 35 +/- 6%. The chemotactic protein did not cause release of histamine from basophils at 0 degrees C or in the presence of 10 mM EDTA. The time-course of histamine release was rapid; release was 43% of maximal after 30 s and maximal after 1 min of incubation. Thus, in addition to its previously characterized neutrophil chemotactic and activating properties, this protein activates human basophils.

Basophils↗
PubMed2005

Basophils play a critical role in the development of IgE-mediated chronic allergic inflammation independently of T cells and mast cells.

The recruitment of basophils into the sites of allergic inflammation is often observed. However, no definitive evidence has been provided that basophils are crucially involved in the pathogenesis of chronic allergic disorders. Here, we show that basophils are responsible for the development of IgE-mediated chronic allergic inflammation independently of T cells and mast cells. A single subcutaneous injection of multivalent antigens elicited not only immediate- and late-phase ear swelling but also delayed-onset ear swelling with massive eosinophil infiltration in mice sensitized with antigen-specific IgE. Mast cells were essential for the immediate- and late-phase ear swelling but dispensable for the delayed one. T cells were also dispensable for the latter. Transfer of FcRI-expressing basophils into FcRI-deficient mice restored the development of the delayed-onset allergic inflammation. These findings indicate a novel mechanism of development of chronic allergic inflammation that is induced by basophils through the interaction of antigen, IgE, and FcRI.

Animals↗
PubMed2005

Toll-like receptor 2 ligands activate human basophils for both IgE-dependent and IgE-independent secretion.

BACKGROUND: Toll-like receptor (TLR) molecules play a critical role in directing the course of acquired immunity, including that associated with allergic disease, by recognizing specific microbial products that activate immune cells for effector functions. OBJECTIVE: We investigated whether human basophils express 2 such molecules (TLR2 and TLR4), and assessed whether putative ligands for these receptors activate nuclear factor kappaB (NFkappaB) and modulate mediator release and cytokine secretion either alone or in response to stimulation. METHODS: Toll-like receptor expression was assessed by using RT-PCR and flow cytometry. Immunoblotting detected nuclear NFkappaB. Automated fluorometry, RIA, and ELISA detected concurrent changes in histamine, leukotriene C 4 , and cytokine, respectively, after culture with specific ligands. RESULTS: mRNA and protein for TLR2 and TLR4 were detected in basophils. However, in assessing nuclear localization of NFkappaB as a measure of functional receptor responses, basophils selectively reacted only to peptidoglycan, a TLR2 ligand, and not to LPS, a TLR4 ligand. Likewise, basophils secreted both IL-4 and IL-13 in direct response to peptidoglycan but not to LPS. Although neither ligand induced histamine or leukotriene C 4 release, several TLR2-specific ligands augmented the secretion of these mediators (and cytokine) in response to IgE-dependent activation and of IL-13 in response to IgE-independent stimulation. Finally, a selective inhibitor of NFkappaB did not prevent these enhancing effects mediated by TLR2 ligands. CONCLUSION: These data suggest that innate immune responses mediated through TLR2 play a role in augmenting allergic reactions, in part by modulating basophil cytokine secretion and mediator release independently of NFkappaB activation.

Basophils↗
PubMed2005

Interleukin-18 primes human basophilic KU812 cells for higher leukotriene synthesis.

The human basophilic cell line KU812 that is an established tool for studying the function of human basophils, is differentiated into mature basophils by interleukin (IL-3) or other agents. However, whether leukotrienes (LTs)-synthesis is affected by cytokines in KU812 cells remains unknown. KU812 cells were incubated with IL-3, IL-4, IL-6, IL-13 or IL-18 for up to 14 days. The A23187 stimulated- and IgE cross-linked-synthesis of LTC(4) and LTB(4) were measured using an enzyme immunoassay (EIA). The expression of messenger RNA (mRNA) for LT-synthesizing enzymes was examined by reverse transcriptase polymerase chain reaction (RT-PCR), and the expression of 5-lipoxygenase (5-LO) was examined by immunostaining. Incubation with IL-3 (10 ng/ml) and IL-18 (10 ng/ml) induced the expression of 5-LO. A23187stimulated LT-synthesis and IgE cross-linked LT-synthesis were enhanced after incubation with IL-3 or IL-18. These results indicated that IL-3 and IL-18 primed human basophils for higher LT-synthesis. Thus, both IL-3 and IL-18 might be important factors for regulating LT-synthesis during the differentiation of human basophils.

5-Lipoxygenase-Activating Proteins↗
PubMed1998

Histamine content and secretion in basophils and mast cells.

Biochemical determinations of the histamine content and secretion from basophils and mast cells have been available for some time, and much of the complex anatomy of these cellular populations and their release reactions has been documented using the electron microscope. The ultrastructural analyses led to the description of vesicular transport between secretory granules and the plasma membrane as a mechanism for secretion from basophils and mast cells--a process termed piecemeal degranulation. Proof of concepts incorporated in a general degranulation model put forth in 1975 (DVORAK, H.F. and DVORAK, A.M.) requires high magnification imaging of a granule constituent in trafficking vesicles in the process of a stimulated release reaction in which the constituent release is monitored biochemically. Development and application of a new enzyme-affinity method to detect histamine at high magnifications in well-preserved ultrastructural samples have provided the necessary means to establish proof that appropriate secretagogues can stimulate the vesicular transport of histamine in basophils and mast cells during release reactions monitored biochemically. The background information necessary to the understanding of this result is presented here, as well as the development and verification of the diamine oxidase-gold method to image histamine in human mast cell granules as the test system. Also presented are applications using this technology to examine histamine stores and secretion in vitro, in vivo, and ex vivo in human basophils and mast cells and in mouse mast cells. Specifically examined are histamine stores developing in maturing mast cells induced to develop de novo from cultured human cord blood cells, secretagogue-stimulated release and recovery of histamine stores from isolated, purified human lung mast cells ex vivo, cytokine-stimulated degranulation of human skin mast cells and their histamine stores in vivo, piecemeal degranulation of human gut mast cells and their histamine stores in inflammatory bowel disease in vivo, piecemeal degranulation of mouse skin mast cells and their histamine stores in inflammatory eye disease in an interleukin-4 transgenic mouse model in vivo, and the stimulated secretion and recovery of histamine from human basophils ex vivo.

Animals↗
PubMed1990

Sensitivity of basophils to histamine releasing factor(s) of various origin: dependency on allergic phenotype of the donor and surface-bound IgE.

Certain species of histamine-releasing factor (HRF) have been demonstrated to distinguish a select group of allergic patients from healthy subjects. An IgE-dependent mechanism of action has been suggested. The donor and IgE dependency of HRF produced by peripheral blood mononuclear cells (PBMCs) has not been clearly demonstrated. In this study, we have compared the response of basophils from normal subjects versus allergic patients with and without asthma. In addition, we have addressed the IgE dependency of HRF recovered from cultures of PBMCs, T cells, B cells, macrophages, and bronchoalveolar lavage fluid. We have demonstrated that basophils from allergic as well as normal subjects respond to PBMC-HRF. The response of basophils from allergic patients with asthma is significantly increased. This heightened response to HRF does not correlate with the severity of disease as assessed by baseline spirometry, medication, and skin test scores. Stripping of the membrane-bound IgE by incubating basophils with lactic acid causes a significant loss of sensitivity to HRF generated by PBMCs, T cells, B cells, and macrophages, as well as to HRF recovered from bronchoalveolar fluid. The loss of response can be restored by sera from patients with asthma but not from normal subjects or by myeloma IgE. In addition, poorly responsive basophils from normal subjects can be rendered sensitive by incubating with sera from patients with asthma. The capacity of a given serum from a patient with asthma to restore the response to HRF is not correlated with the total concentration of IgE in the serum.(ABSTRACT TRUNCATED AT 250 WORDS)

Asthma↗
PubMed1992

Regulation of human basophil activation. III. Impairment of the inhibitory effect of Na+ on IgE-mediated histamine release in patients with allergic rhinitis.

We recently observed that external Na+ inhibited the IgE-dependent human basophil histamine release (HR) in normal subjects. In this article we report differences in the Na+ effect on basophil HR between normal subjects (n = 16) and age matched patients with allergic rhinitis (AR) (n = 18). As expected, in vitro anti-IgE-stimulated basophils from the group with AR released greater amounts of histamine than basophils from the normal group. However, removal of external Na+ (and replacement by N-methyl-D-glucamine) abolished this difference between the two groups. HR in the normal group increased to the same high level as that of the group with AR. By contrast, the release of histamine in the group with AR was not further increased by Na+ removal. Although high releasers were more frequent in the group with AR, the absence of effect after Na+ removal was not due to the high basal release level (in the presence of Na+) because no effect after Na+ removal was also observed with medium releasers. These results strongly suggest that increased basophil HR in populations with AR, and possibly in other allergic populations, is linked to a defect in the inhibitory effect of Na+.

Adult↗
PubMed1997

Late allergic airway response to segmental bronchopulmonary provocation in allergic subjects is related to peripheral blood basophil histamine release.

BACKGROUND: Basophil histamine release has been found to correlate with the presence and severity of allergic disease. However, it remains to be established whether airway response to antigen is related to basophil involvement and its release of histamine. OBJECTIVE: The purpose of this study was to investigate whether the intensity of airway response to an inhaled antigen challenge in allergic subjects is related to IgE-dependent peripheral blood basophil histamine release. METHODS: The response to segmental bronchoprovocation with antigen was examined in 34 subjects with allergic rhinitis. Bronchoalveolar lavage samples were obtained 5 minutes (immediate response) and 48 hours (late response) after allergen challenge. Peripheral blood maximal basophil histamine release (MBHR) in response to in vitro antigen stimulation was determined in each subject before segmental bronchoprovocation. RESULTS: Bronchoalveolar lavage samples obtained during immediate response showed an increase in histamine, whereas the late response was noted for a marked enhancement in airway cells, particularly eosinophils. Interestingly, a significant correlation (r = 0.73, p < 0.0001, Spearman Rank test) was noted between MBHR and intensity of bronchoalveolar lavage eosinophilia at 48 hours. Furthermore, subjects with high (> or = 20%) MBHR had significantly higher total cells and eosinophils in bronchoalveolar lavage fluid 48 hours after antigen segmental bronchoprovocation when compared with subjects with low (< 20%) MBHR. CONCLUSION: Our data suggest that the intensity of airway eosinophilia in response to antigen challenge is correlated with the magnitude of basophil mediator release in allergic subjects.

Adult↗
PubMed1998

Complementation of Der P 2-induced histamine release from human basophils sensitized with monoclonal IgE: not only by IgE, but also by IgG antibodies directed to a nonoverlapping epitope of Der p 2.

The interaction of free allergen with two (or more) IgE molecules bound to the high-affinity receptor for IgE (FcepsilonRI) on mast cells and basophilic granulocytes results in the release of inflammatory mediators. The role of allergen-specific IgG antibodies in the allergic reaction in human beings is less clear. We produced two chimeric IgE antibodies, hIgE-Dp2A and hIgE-Dp2B, directed to two nonoverlapping epitopes (A and B) of the house dust mite allergen Der p 2. Chimeric IgG1 and IgG4 variants of these antibodies were produced also. Basophil activation by the house dust mite allergen Der p 2 was induced after sensitization of basophils with a mixture of chimeric hIgE-Dp2A and hIgE-Dp2B antibodies but not after sensitization by the individual IgE antibodies alone. Basophil activation was also shown after sensitization with hIgE-Dp2A and stimulation with Der p 2 incubated with hIgG1-Dp2B or hIgG4-Dp2B antibodies. Both IgE and IgG antibodies directed to the other nonoverlapping epitope complemented the sensitization by the hIgE-Dp2A antibody. Nonsensitized basophils were not activated by the Der p 2/hIgG-Dp2 mixtures. These results indicate that allergen-specific IgG can complement an IgE-dependent reaction and therefore under certain conditions can act as an anaphylactic antibody.

Anaphylaxis↗
PubMed2002

Association of the Src homology 2 domain-containing inositol 5' phosphatase (SHIP) to releasability in human basophils.

During the study of the biology of the Human recombinant Histamine Releasing Factor (HrHRF), we uncovered a hyperreleasable phenotype of basophils from HrHRF-responder donors. Basophils from these donors released histamne to HrHRF, IL-3 and D(2)O. While there has been a significant amount of work elucidating signal transduction events in human basophils, the reason for this hyperreleasable phenotype remained illusive. A clue to the releasability of these highly allergic, asthmatic HrHRF-responder donor basophils was demonstrated in studies using SHIP knockout mice. Bone marrow-derived mast cells from the SHIP knockout mice demonstrated hyperreleasability to stimuli through the IgE receptor and alteration of subsequent signal transduction events. We have demonstrated a highly significant negative correlation between the amount of SHIP protein per cell equivalent and maximum histamine release to HrHRF. These results provide a clue to the hyperreleasable phenotype and implicate SHIP as an additional regulator of secretion in human basophils.

Basophils↗
PubMed2000

FK506 inhibition of histamine release and cytokine production by mast cells and basophils.

Histamine release and cytokine production by mast cells and basophils are thought to be closely involved in the pathogenesis of allergic diseases. Some reports show that FK506 (tacrolimus hydrate) inhibited histamine release and cytokine production by mast cells and basophils. However, as the effects of FK506 has not been compared with those of clinically used drugs in those reports, the clinical relevancy of FK506 inhibition remained unclear. In this paper, we compared the actions of FK506 with those of steroids or disodium cromoglycate (DSCG) which has been clinically used. FK506 inhibited histamine release by Brown-Norway rat peritoneal mast cells more potently than steroids and especially DSCG. FK506 also inhibited histamine release by a mast rat basophilic leukemia (RBL)-1 cell line and human peripheral blood basophils, whereas steroids failed to inhibit histamine release by human basophils. FK506 as well as steroids inhibited TNF-alpha and IL-4 production by RBL-1 cells. FK506 was therefore more effective than steroids and DSCG in inhibiting histamine release, and it also had the ability of inhibiting cytokine production by mast cells as steroids do. We concluded that FK506 might regulate allergic diseases via these actions, judging from the viewpoint of clinical relevancy.

Animals↗