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PubMed1979

Anaphylactic release of a basophil kallikrein-like activity. I. Purification and characterization.

These studies describe the IgE-mediated relase of a basophil kallikrein-like enzyme that is an arginine esterase and is inhibited by plasma, diisopropylphosphofluoridate, and Trasylol. The substrate specificity for the synthetic amino acid ester substrates p-toluenesulfonyl-L-arginien methyl ester, benzoyl-arginine methyl ester, and acetyl-tyrosine methyl ester is similar for the basophil enzyme and plasma kallikrein. The interaction of arginine esterase-active fractions from ion-exchange (DEAE-Sephacel) and gel filtration (Sepharose 6B) chromatography, with human plasma kininogen, generates immunoreactive kinin. The basophil arginine esterase and kinin-generating activities co-chromatograph on Sepharose 6B and the quantity of kinin generated is, in general, proportional to the arginine esterase activity of the column fractions, suggesting that these two activities are subserved by the same protease. The ability of this protease to generate kinin equally well from heat- and acid-treated plasma, as from fresh human plasma, suggests that this protease has kallikrein-like activity. These data suggest that kallikrein-like activity can be generated from human basophils as a direct result of a primary IgE-mediated immune reaction, thus providing a potential link between reactions of immediate hypersensitivity and the plasma and(or) tissue kinin-generating systems.

Anaphylaxis↗

PubMed1983

Stimulation of histamine release from human basophils by human platelet factor 4.

Human basophils were stimulated to release histamine noncytotoxically by purified human platelet factor 4 (PF4) and the synthetic substituent peptide PF4(59-70). Histamine release was augmented significantly by 10(-7) M PF4 and 10(-5) M PF4(59-70), increased in a concentration-dependent manner, and attained a maximum at 3 X 10(-5) M PF4 and 3 X 10(-4) M PF4(59-70) similar to that achieved by goat anti-human myeloma IgE. PF4 (1-60) failed to initiate the release of histamine, which confirmed that the critical determinant of activity is in the carboxy-terminal sequence. Histamine release from basophils by optimally effective concentrations of PF4 and PF4(59-70) reached a plateau by 1-3 min, as contrasted with 10 min or longer for anti-IgE. The elimination of calcium and magnesium from the buffer suppressed the release of histamine by anti-IgE by 79-83%, but had no effect on that elicited by PF4(59-70). The rate of uptake of [125I]PF4 by purified basophils was similar on a molar basis to the rate of release of histamine by the same concentrations of PF4. The noncytotoxic release of histamine from human basophils by PF4 thus is temporally and biochemically distinct from that mediated by IgE and may be similar to that evoked by other polycationic stimuli.

Antibodies, Anti-Idiotypic↗

PubMed1990

Early expression of high-affinity receptor for immunoglobulin E (Fc epsilon RI) during differentiation of mouse mast cells and human basophils.

Immediate hypersensitivity is due to the release of mediators from mast cells and basophils after the crosslinking of Fc epsilon RI. The appearance of such receptors was examined during differentiation of human and mouse bone marrow cells cultured in the presence of IL-3. As already reported, mouse bone marrow yield cultures of greater than 95% mast cells by 3 wk, whereas human bone marrow develop into cultures comprising 25% basophils by 3 wk. Here we show that transcripts for Fc epsilon RI subunits and membrane-associated receptors are apparent by 1 wk in both human and murine IL-3-dependent bone marrow cells. These cells contain few, if any, granules. The expression of transcripts and the number of receptor-positive cells continue to increase over 3 wk of culture. In parallel, a progressively larger number of cells become increasingly granulated to finally resemble either basophils or mast cells. Mature peripheral human basophils also contain transcripts for Fc epsilon RI and, therefore, may have the potential to synthesize de novo receptors. The early appearance of Fc epsilon FI during cell differentiation may be important for these cells to respond to IgE-mediated stimuli before granulation. The physiologic role of Fc epsilon RI could be to mediate lymphokine production (IL-3, IL-4, IL-6, and granulocyte/macrophage colony-stimulating factor) without inducing cellular degranulation.

Animals↗

PubMed1992

Monocyte chemotactic and activating factor is a potent histamine-releasing factor for basophils.

Monocyte chemotactic and activating factor (MCAF) is a recently cloned cytokine that causes chemotaxis of basophils. In our pursuit of cytokines affecting basophil function, we studied the effect of MCAF on histamine secretion from basophils. Leukocytes from 20 donors, 10 allergic and 10 normal subjects, were studied. MCAF caused dose-dependent release of histamine at concentrations of 10(-8) and 10(-7) M, and the mean release was 31.25 +/- 2.9% at the highest concentration. In the same experiments the mean histamine release by anti-IgE and histamine releasing factor (HRF) was 27.05 +/- 4% and 32.70 +/- 2.7%, respectively. All 20 subjects responded to MCAF with significant histamine release. Allergic subjects released significantly more histamine than normals in response to anti-IgE (P less than 0.01) but not to MCAF (P = 0.2) and HRF (P = 0.1). The histamine release was significantly correlated between MCAF and HRF (P less than 0.01), but not between MCAF and anti-IgE (P greater than 0.05). The histamine release by MCAF was complete within the first 3 min. MCAF-induced degranulation was a calcium-dependent process. Leukocytes depleted of monocytes responded equally well to MCAF. Using an anti-MCAF affinity column we determined that greater than 50% of HRF activity of crude PBMC supernatant could be attributed to MCAF. Thus, we established that MCAF is a potent secretagogue for basophils.

Basophils↗

PubMed2004

Leukocyte immunoglobulin-like receptors: novel innate receptors for human basophil activation and inhibition.

Basophils, recruited from the blood to tissues, have been implicated by their presence in diverse allergic disorders including bronchial asthma, allergic rhinitis, and cutaneous contact hypersensitivity. We hypothesized that like other leukocytes involved in inflammatory responses, basophils would express members of the leukocyte immunoglobulin-like receptor (LIR) family of immuno-regulatory molecules on their cell surface. We identified LIR7, an activating member coupled to the common Fc receptor gamma chain, and LIR3, an inhibitory member containing cytoplasmic immunoreceptor tyrosine-based inhibitory motifs, on these cells from human peripheral blood. Cross-linking of LIR7 resulted in the concentration-dependent net release of histamine (29.8 +/- 10.8%) and cysteinyl leukotrienes (cysLTs) (31.4 +/- 8.7 ng/10(6) basophils) that were maximal at 30 minutes, and of interleukin-4 (IL-4) (410.2 +/- 61.6 pg/10(6) basophils) that was maximal at 4 hours and comparable with the response initiated by cross-linking of the high-affinity receptor for immunoglobulin E (FcepsilonRI). Coligation of LIR3 to LIR7 or to FcepsilonRI by means of a second monoclonal antibody significantly inhibited net histamine release, cysLT production, and IL-4 generation. That LIR3 is profoundly counter-regulatory for both adaptive and innate receptors suggests a broad role in containment of the inflammatory response.

Antibodies, Monoclonal↗

PubMed2001

The basophil activation marker defined by antibody 97A6 is identical to the ectonucleotide pyrophosphatase/phosphodiesterase 3.

It has recently been shown that monoclonal antibody (MoAb) 97A6 detects a surface antigen expressed on basophils and their CD34(+) precursor cells, as well as the basophil cell line KU-812. In this report the partial amino acid sequence of affinity chromatography- and sodium dodecyl sulfate-polyacrylamide gel electrophoresis-separated 97A6 antigen(s) from KU-812 lysates was determined. Sequence alignment of high-performance liquid chromatography-selected tryptic peptides from the resulting 130- and 150-kd bands revealed a 100% identity with amino acids 393 to 405 of ectonucleotide pyrophosphatase/phosphodiesterase-3 (E-NPP3; CD203c) but not of the related ectoenzyme PC-1 (E-NPP1). Moreover, MoAb 97A6 selectively recognized 293 cells transfected with human E-NPP3, but did not react with cells transfected with PC-1 or parental 293 cells. In addition, E-NPP3 messenger RNA expression was detected in basophils but not other peripheral blood cells. Finally, MoAb 97A6 immunoprecipitated phosphodiesterase activity from KU-812 cells and peripheral blood basophils, but not from other cell populations. These data demonstrate that MoAb 97A6 recognizes the functionally active type II transmembrane ectoenzyme E-NPP3.

Amino Acid Sequence↗

PubMed2006

Identification of basogranulin (BB1) as a novel immunohistochemical marker of basophils in normal bone marrow and patients with myeloproliferative disorders.

In myeloproliferative disorders (MPDs), basophils typically increase in number in the bone marrow (BM) and blood. In chronic myeloid leukemia (CML), basophilia is a diagnostic and prognostic variable. However, no reliable approach for routine detection and enumeration of basophils in BM sections is available. We applied the antibasogranulin antibody BB1 on paraffin-embedded BM sections in 21 control samples (normal BM), 45 patients with CML, 9 with chronic idiopathic myelofibrosis, 11 with polycythemia vera, 19 with essential thrombocythemia, and 7 with indolent systemic mastocytosis. As assessed by immunostaining of serial BM sections, BB1+ cells coexpressed myeloperoxidase, histidine decarboxylase, and leukosialin but did not express B- or T-cell-restricted antigens. BB1+ BM cells were found to be highly elevated in patients with CML compared with normal BM or other MPDs, with maximum counts found in accelerated phase CML (median, 160 cells/mm(2)). In summary, BB1 (basogranulin) is a new immunohistochemical basophil marker that should allow quantification of basophils in CML at diagnosis and during therapy.

Adult↗

PubMed2005

Ultrastructural studies of human basophils and mast cells.

Ultrastructural studies of human mast cells (HMCs) and basophils (HBs) are reviewed. Sources of HMCs include biopsies of tissue sites and in situ study of excised diseased organs; isolated, partially purified samples from excised organs; and growth-factor-stimulated mast cells that develop de novo in cultures of cord blood cells. Sources of HBs for study include partially purified peripheral blood basophils, basophils in tissue biopsies, and specific growth factor-stimulated basophils arising de novo from cord blood cells. The ultrastructural studies reviewed deal with identity, secretion, vesicles, recovery, and synthesis issues related to the biology of these similar cells.

Animals↗

PubMed1985

The calcium antagonist, nicardipine, inhibits antigen-stimulated and anti-IgE-induced histamine release from basophilic leucocytes of atopic asthmatics.

The inhibitory effect of nicardipine, a calcium antagonist, on the antigen- and anti-IgE-induced histamine release from basophilic leucocytes of patients with bronchial asthma was examined. The agent significantly inhibited both antigen-stimulated and anti-IgE-induced histamine release from basophils (the maximum percent inhibition was 57.8 +/- 7.2% and 56.0 +/- 8.8%, respectively). Pre-incubation of basophils with nicardipine for periods of up to 120 min did not alter the inhibitory effect. These results suggest that nicardipine modifies the histamine release from basophils which closely participate in an attack of bronchial asthma.

Antibodies, Anti-Idiotypic↗

PubMed1985

Comparison of basophil histamine release induced by the cross-linking of IgE receptors.

Basophil histamine release induced by allergens (house dust and Candida albicans) and anti-IgE was examined in 31 patients with bronchial asthma in relation to patient age, age at onset of the disease and serum IgE levels. Basophils from patients under 40 years of age generally released a significantly large amount of histamine by stimulation with house dust and anti-IgE. On the other hand, histamine release from patients over 41 years of age was generally not marked when the cells were incubated with house dust and anti-IgE, although, in some cases, the release induced by C. albicans was fairly marked. Basophils from patients under 30 years of age at onset were reactive to house dust and anti-IgE, while the cells from patients over 41 years of age at onset tended to be reactive only to C. albicans. Basophils from patients with low serum IgE levels were less reactive than the cells from patients with high levels of IgE to house dust and anti-IgE. C. albicans-induced release of histamine did not correlate with serum IgE levels.

Adult↗

PubMed1999

Establishment of a new cell line (MTT-95) showing basophilic differentiation from the bone marrow of a patient with acute myelogenous leukemia (M7).

A new myeloid cell line, MTT-95, was established from the bone marrow of a patient with acute myelogenous leukemia (AML, M7). MTT-95 cells differentiate into mature basophilic cells in culture medium with no chemical component or cytokine. Surface phenotypes were as follows: CD11b 79.3%, CD13 92.4%, CD33 99.8%, CD34 87.9%, CD41a 77.6% and HLA-DR 0.3%. MTT-95 cells were strongly positive for glycoprotein IIb/IIIa by immunohistochemical staining and revealed metachromatic granules. MTT-95 cells seem to possess characteristics of both megakaryocytes and basophils. These findings suggest that MTT-95 cells are basophil progenitors. MTT-95 cells might be useful in the study not only of the biological aspects of basophils, but also of the diversities of AML (M7).

Antigens, CD↗

PubMedDate not supplied

Release of heparin-like substance and histamine from basophilic leucocytes separated by counterflow centrifugation elutriation.

Separation of basophilic granulocytes from peripheral blood was carried out by counterflow centrifugation elutriation using a JE-6B roter. The release of histamine and heparin-like substance from basophilic leucocytes was estimated in healthy and asthmatic subjects. 1. The number of basophils was maximal (0.74 x 10(5] at a flow rate of 4.5 ml/min, and the purity reached a peak (11.8 +/- 2.0%) at a flow rate of 9 ml/min. 2. The content of histamine paralleled the number of basophils in each fraction. 3. The release mechanism of histamine induced by anti-IgE was similar to that of the heparin-like substance. 4. The release of histamine and the heparin-like substance was significantly higher in atopic asthmatics than in non-atopic cases.

Adolescent↗

PubMed2006

Basophils: a potential liaison between innate and adaptive immunity.

Activation of innate immunity is closely associated to development of protective adaptive immune response. Significant advances have been made to reveal such links between innate immunity and Th1 type adaptive immune responses. By contrast, the role of innate immunity in the development of Th2 type adaptive immune responses is still not well understood. Production of IL-4, a key cytokine in the induction of Th2 immunity, by innate type cells represents an attractive mechanism for such an innate link to Th2 immunity. We have recently reported that in the course of infection with the intestinal nematode, Nippostrongylus brasiliensis, a robust basophil accumulation in the liver/spleen occurs and that these basophils display enhanced IL-4 production. Thus, the basophils is an attractive candidate to mediate the innate-adaptive link for Th2 responses and understanding the control of the tissue homing patterns and cytokine responses of basophils in the course of infections may shed important light on the in vivo induction of Th2 adaptive immunity.

Animals↗

PubMedDate not supplied

Basophil-mast cell response syndromes: a unified clinical approach.

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.

Antigens↗

PubMed2000

Basophil responses to chemokines are regulated by both sequential and cooperative receptor signaling.

To investigate human basophil responses to chemokines, we have developed a sensitive assay that uses flow cytometry to measure leukocyte shape change as a marker of cell responsiveness. PBMC were isolated from the blood of volunteers. Basophils were identified as a single population of cells that stained positive for IL-3Ralpha (CDw123) and negative for HLA-DR, and their increase in forward scatter (as a result of cell shape change) in response to chemokines was measured. Shape change responses of basophils to chemokines were highly reproducible, with a rank order of potency: monocyte chemoattractant protein (MCP) 4 (peak at <1 nM) >/= eotaxin-2 = eotaxin-3 >/= eotaxin > MCP-1 = MCP-3 > macrophage-inflammatory protein-1alpha > RANTES = MCP-2 = IL-8. The CCR4-selective ligand macrophage-derived chemokine did not elicit a response at concentrations up to 10 nM. Blocking mAbs to CCR2 and CCR3 demonstrated that responses to higher concentrations (>10 nM) of MCP-1 were mediated by CCR3 rather than CCR2, whereas MCP-4 exhibited a biphasic response consistent with sequential activation of CCR3 at lower concentrations and CCR2 at 10 nM MCP-4 and above. In contrast, responses to MCP-3 were blocked only in the presence of both mAbs, but not after pretreatment with either anti-CCR2 or anti-CCR3 mAb alone. These patterns of receptor usage were different from those seen for eosinophils and monocytes. We suggest that cooperation between CCRs might be a mechanism for preferential recruitment of basophils, as occurs in tissue hypersensitivity responses in vivo.

Basophils↗

PubMed2001

Localizing a control region in the pathway to leukotriene C(4) secretion following stimulation of human basophils with anti-IgE antibody.

Mediator release from human basophils is a self-limited process, but down-regulation of the signaling cascades leading to secretion of leukotriene C(4) (LTC(4)) is controlled independently of the pathway leading to IL-4 secretion. In the current studies, we have explored the regulation of upstream signaling events leading to activation of extracellular signal-related kinases (ERKs; previously shown to be required for LTC(4) generation) in human basophils. IgE-, but not FMLP-mediated activation, induced sustained tyrosine phosphorylation of syk, of shc, and an association of shc to the Grb2/son of sevenless 2 complex. In contrast, IgE-mediated activation resulted in transient activation of p21(ras) and mitogen-activated protein/ERK kinase 1, which were kinetically associated with phosphorylation of ERKs. The canonical Shc/Grb2/son of sevenless pathway to activation of p21(ras) is therefore sustained, while p21(ras) activity is not. We have previously shown that phosphatidylinositol 3 kinase activity is required for p21(ras) activity and, in the current studies, we show that of the p85-sensitive forms of p110 possible, basophils express only p110 delta and that there are no changes in association between p21(ras) and p110 delta in stimulated basophils. We used the generation of phospho-Akt as a marker of the presence of phosphatidylinositol-3,4,5-trisphosphate and found that phospho-Akt is transient on a time scale consistent with p21(ras) activity. On the basis of information obtained in these and other studies, we localize down-regulation of IgE-mediated LTC(4) secretion to a region of the signaling cascade antecedent to p21(ras) activation, downstream of phosphatidylinositol 3 kinase activity and probably involving regulation of phosphatidylinositol-3,4,5-trisphosphate levels.

Adaptor Proteins, Signal Transducing↗

PubMed2005

Down-regulation of basophil function by human CD200 and human herpesvirus-8 CD200.

Human and rodent CD200 are recognized by the inhibitory CD200R, and these molecules play an important role in the regulation of the immune system. Several viruses, such as human herpesvirus-6 (HHV-6), HHV-7, and HHV-8, possess a CD200 homologue, suggesting that these viruses regulate the immune response via CD200R. In this study, we analyzed the effect of human CD200 and the viral CD200 homologues on human CD200R-expressing cells. We found that human CD200R is predominantly expressed on basophils in amounts higher than on other human peripheral blood leukocytes. Furthermore, the viral CD200 homologues as well as human CD200 were recognized by human CD200R, and the activation of basophils was down-regulated by these CD200 proteins. These results suggested that CD200R is an important regulatory molecule of basophil activation. In addition, the presence of CD200 homologues on several viruses suggests a potentially unique relationship between basophil function and viral infection.

Animals↗

PubMed1999

Extracellular signal-regulated kinases regulate leukotriene C4 generation, but not histamine release or IL-4 production from human basophils.

Human basophils secrete histamine and leukotriene C4 (LTC4) in response to various stimuli, such as Ag and the bacterial product, FMLP. IgE-mediated stimulation also results in IL-4 secretion. However, the mechanisms of these three classes of secretion are unknown in human basophils. The activation of extracellular signal-regulated kinases (ERKs; ERK-1 and ERK-2) during IgE- and FMLP-mediated stimulation of human basophils was examined. Following FMLP stimulation, histamine release preceded phosphorylation of ERKs, whereas phosphorylation of cytosolic phospholipase A2 (cPLA2), and arachidonic acid (AA) and LTC4 release followed phosphorylation of ERKs. The phosphorylation of ERKs was transient, decreasing to baseline levels after 15 min. PD98059 (MEK inhibitor) inhibited the phosphorylation of ERKs and cPLA2 without inhibition of several other tyrosine phosphorylation events, including phosphorylation of p38 MAPK. PD98059 also inhibited LTC4 generation (IC50 = approximately 2 microM), but not histamine release. Stimulation with anti-IgE Ab resulted in the phosphorylation of ERKs, which was kinetically similar to both histamine and LTC4 release and decreased toward resting levels by 30 min. Similar to FMLP, PD98059 inhibited anti-IgE-mediated LTC4 release (IC50, approximately 2 microM), with only a modest effect on histamine release and IL-4 production at higher concentrations. Taken together, these results suggest that ERKs might selectively regulate the pathway leading to LTC4 generation by phosphorylating cPLA2, but not histamine release or IL-4 production, in human basophils.

Antibodies, Anti-Idiotypic↗