The clinical relevance of basophil releasability
1994; Elsevier BV; Volume: 94; Issue: 6 Linguagem: Inglês
10.1016/0091-6749(94)90345-x
ISSN1097-6825
AutoresGianni Marone, Giuseppe Spadaro, Vincenzo Patella, Arturo Genovese,
Tópico(s)Urticaria and Related Conditions
ResumoIn contrast to many words used in allergy (e.g., atopy, asthma, apoptosis) that derive from ancient Greek, the term releasability, recently introduced in the English-language literature, does not exist in most dictionaries. It was first used by Lichtenstein and Conroy1Lichtenstein LM Conroy MC The "releasability" from human basophils and granulocytes.in: Allergy and clinical immunology. : Excerpta Medica, Amsterdam1976: 109-115Google Scholar in 1976 to define an event that many investigators and clinicians had probably implicitly already recognized. Initially the concept of releasability was essentially applied to the in vitro study of the release of chemical mediators from human basophils, and this has been reviewed.2Marone G Poto S Giugliano R Bonini S Studies on human basophil releasability.Int Arch Allergy Appl Immunol. 1985; 77: 103-106Crossref PubMed Scopus (18) Google Scholar, 3Marone G Modulation of basophil/mast cell functions in vivo: the 'releasability' concept.in: Progress in allergy and clinical immunology. : CV Mosby, St Louis1985: 175-181Google Scholar, 4Plaut M Kazimierczak W Lichtenstein LM Abnormalities of basophil 'releasability' in atopic and asthmatic individuals.J ALLERGY CLIN IMMUNOL. 1986; 78: 968-973Abstract Full Text PDF PubMed Scopus (19) Google Scholar, 5Marone G Poto S Giugliano R Celestino D Bonini S Control mechanisms of human basophil releasability.J ALLERGY CLIN IMMUNOL. 1986; 78: 974-980Abstract Full Text PDF PubMed Scopus (23) Google Scholar, 6Marone G Casolaro V Cirillo R Stellato C Genovese A Pathophysiology of human basophils and mast cells in allergic disorders.Clin Immunol Immunopathol. 1989; 50: S24-S40Crossref PubMed Scopus (44) Google Scholar, 7MacGlashan Jr, DW Releasability of human basophils: cellular sensitivity and maximal histamine release are independent variables.J ALLERGY CLIN IMMUNOL. 1993; 91: 605-615Abstract Full Text PDF PubMed Scopus (135) Google Scholar The concept of basophil and mast cell releasability is of practical importance because under appropriate conditions these cells synthesize several proinflammatory mediators6Marone G Casolaro V Cirillo R Stellato C Genovese A Pathophysiology of human basophils and mast cells in allergic disorders.Clin Immunol Immunopathol. 1989; 50: S24-S40Crossref PubMed Scopus (44) Google Scholar, 8Stellato C de Paulis A Ciccarelli A et al.Anti-inflammatory effect of cyclosporin A on human skin mast cells.J Invest Dermatol. 1992; 98: 800-804Abstract Full Text PDF PubMed Scopus (143) Google Scholar and cytokines,9Brunner T Heusser CH Dahinden CA Human peripheral blood basophils primed by interleukin 3 (IL-3) produce IL-4 in response to immunoglobulin E receptor stimulation.J Exp Med. 1993; 177: 605-611Crossref PubMed Scopus (351) Google Scholar, 10Bradding P Feather IH Howarth PH et al.Interleukin 4 is localized to and released by human mast cells.J Exp Med. 1992; 176: 1381-1386Crossref PubMed Scopus (513) Google Scholar, 11Möller A Lippert U Lessmann D et al.Human mast cells produce IL-8.J Immunol. 1993; 151: 3261-3266PubMed Google Scholar, 12MacGlashan Jr, DW White JM Huang S-K Ono SJ Schroeder JT Lichtenstein LM Secretion of IL-4 from human basophils: the relationship between IL-4 mRNA and protein in resting and stimulated basophils.J Immunol. 1994; 152: 3006-3016PubMed Google Scholar thus playing a central role in the pathogenesis of immune disorders. This article focuses on the concept of basophil and mast cell releasability, mostly from the clinical viewpoint. The need to invoke releasability derives from a number of clinical observations. Every clinician is aware of persons with positive skin test reactions to various inhalants, who have no symptoms during the appropriate season, whereas other patients with similarly positive skin reactions show a wide spectrum of allergies. This apparent discrepancy has been carefully documented in patients allergic to insect venoms. Patients with identical serum concentrations of IgE and/or IgG antivenom antibodies and similar skin test reactions can be stung, with opposite clinical results: one patient can have anaphylaxis whereas the other is completely unaffected.13Hunt KJ Valentine MD Sobotka AK Benton AW Amodio FJ Lichtenstein LM A controlled trial of immunotherapy in insect hypersensitivity.N Engl J Med. 1978; 299: 157-161Crossref PubMed Scopus (612) Google Scholar A similar condition is found in persons with positive skin reactions to food allergens. Approximately 50% of subjects with positive skin reactions have no reaction when the culprit food is ingested, whereas the other 50% have local or systemic reactions.14Sampson HA Albergo R Comparison of results of skin tests, RAST, and double-blind, placebo-controlled food challenges in children with atopic dermatitis.J ALLERGY CLIN IMMUNOL. 1984; 74: 26-33Abstract Full Text PDF PubMed Scopus (523) Google Scholar These observations suggested that the serum concentrations of IgE and IgG antibodies against various allergens and the in vivo sensitivity of skin mast cells to allergens were not sufficient to predict the extent of an allergic response in vivo. Thus the releasability of primary effector cells (basophils and mast cells) was proposed to explain the complex array in symptoms in allergic persons. The term releasability implies that several biochemical events, not only the surface density of IgE molecules, control the release of mediators from basophils and mast cells in response to different activating stimuli, independent of the IgE molecules themselves. The first evidence of this was provided in the basophil system by Conroy et al.,15Conroy MC Adkinson Jr, NF Lichtenstein LM Measurement of IgE on human basophils: relation to serum IgE and anti-IgE-induced histamine release.J Immunol. 1977; 118: 1317-1321PubMed Google Scholar who reported a significant correlation between the serum IgE level and the number of IgE molecules per basophil. However, they found no relationship at all between the serum IgE level and the concentration of anti-IgE required for 30% histamine release. In fact, basophils with 5000 IgE molecules responded to anti-IgE just as well as cells with 500,000 molecules. However, in basophils from different patients with 100,000 IgE molecules per cell, the maximum histamine release induced by anti-IgE ranged widely, from 10% to 75%. Thus it was concluded that the response of these different cells to anti-IgE was influenced by something in addition to the antigen-antibody interaction. Although the concept of releasability hasremained biochemically elusive,7MacGlashan Jr, DW Releasability of human basophils: cellular sensitivity and maximal histamine release are independent variables.J ALLERGY CLIN IMMUNOL. 1993; 91: 605-615Abstract Full Text PDF PubMed Scopus (135) Google Scholar information obtained during the last few years has confirmed the existence of this biologic parameter.2Marone G Poto S Giugliano R Bonini S Studies on human basophil releasability.Int Arch Allergy Appl Immunol. 1985; 77: 103-106Crossref PubMed Scopus (18) Google Scholar, 3Marone G Modulation of basophil/mast cell functions in vivo: the 'releasability' concept.in: Progress in allergy and clinical immunology. : CV Mosby, St Louis1985: 175-181Google Scholar, 4Plaut M Kazimierczak W Lichtenstein LM Abnormalities of basophil 'releasability' in atopic and asthmatic individuals.J ALLERGY CLIN IMMUNOL. 1986; 78: 968-973Abstract Full Text PDF PubMed Scopus (19) Google Scholar, 5Marone G Poto S Giugliano R Celestino D Bonini S Control mechanisms of human basophil releasability.J ALLERGY CLIN IMMUNOL. 1986; 78: 974-980Abstract Full Text PDF PubMed Scopus (23) Google Scholar, 6Marone G Casolaro V Cirillo R Stellato C Genovese A Pathophysiology of human basophils and mast cells in allergic disorders.Clin Immunol Immunopathol. 1989; 50: S24-S40Crossref PubMed Scopus (44) Google Scholar Basophil and mast cell releasability can be assessed by (1) measuring spontaneous histamine release in normal buffers or in buffers containing deuterium oxide (D2O) in place of water, (2) stimulating FcϵRI+ cells with increasing concentrations of secretagogues, or (3) measuring the density of antigen-specific IgE required to release of 30% of the total cellular histamine content on challenge with an optimal concentration of antigen or anti-IgE. It is now clear that releasability must be defined in relation to the stimulus employed.16Marone G Poto S di Martino L Condorelli M Human basophil releasability. I. Age-related changes in basophil releasability.J ALLERGY CLIN IMMUNOL. 1986; 77: 377-383Abstract Full Text PDF PubMed Scopus (40) Google Scholar, 17Casolaro V Galeone D Giacummo A Sanduzzi A Melillo G Marone G Human basophil/mast cell releasability. V. Functional comparisons of cells obtained from peripheral blood, lung parenchyma, and from bronchoalveolar lavage in asthmatics.Am Rev Respir Dis. 1989; 139: 1375-1382Crossref PubMed Scopus (97) Google Scholar Different stimuli induce the release of histamine either by interacting with cell-bound IgE or by acting on surface or intracellular targets independent of the IgE receptor. IgE-mediated secretagogues may in turn induce degranulation of basophils and mast cells either by direct anaphylaxis, that is, by inducing IgE crosslinking at the F(ab′)2 regions (specific antigen), or by "reverse" anaphylaxis, that is, crosslinking IgE by polyclonal anti-IgE antibodies or a monoclonal antibody against the α chain of FcϵRI. The latter mechanisms, frequently exploited for experimental purposes, are of clinical relevance because anti-IgE autoantibodies18Nawata Y Koike T Yanagisawa T et al.Anti-IgE autoantibody in patients with bronchial asthma.Clin Exp Immunol. 1984; 58: 348-356PubMed Google Scholar, 19Quinti I Brozek C Wood N Geha RS Leung DYM Circulating IgG autoantibodies to IgE in atopic syndromes.J ALLERGY CLIN IMMUNOL. 1986; 77: 586-594Abstract Full Text PDF PubMed Scopus (85) Google Scholar and anti-α-chain autoantibodies20Hide M Francis DM Grattan CEH Hakimi J Kochan JP Greaves MW Autoantibodies against the high-affinity IgE receptor as a cause of histamine release in chronic urticaria.N Engl J Med. 1993; 328: 1599-1640Crossref PubMed Scopus (842) Google Scholar have been detected in a certain percentage of atopic patients. Some bacterial immunoglobulin-binding proteins, such as protein A from Staphylocccus aureus Cowan I (Staph A) and protein L from Peptostreptococcus magnus, also induce the release of mediators from basophils and mast cells by interacting with IgE molecules.21Marone G Poto S Petracca R et al.Activation of human basophils by staphylococcal protein A. I. The role of cyclic AMP, arachidonic acid metabolites, microtubules and microfilaments.Clin Exp Immunol. 1992; 50: 661-668Google Scholar, 22Marone G Tamburini M Giudizi MG Biagiotti R Almerigogna F Romagnani S Mechanism of activation of human basophils by Staphylococcus aureus Cowan 1.Infect Immun. 1987; 55: 803-809PubMed Google Scholar, 23Patella V Casolaro V Björck L Marone G Protein L: a bacterial Ig-binding protein that activates human basophils and mast cells.J Immunol. 1990; 145: 3054-3061PubMed Google Scholar Among non-IgE-mediated secretagogues, the formylated tripeptide, N-formyl-methionyl-leucyl-phenylalanine (FMLP), complement-derived anaphylatoxins C3a and C5a, and platelet-activating factor activate basophils by interacting with specific cell-surface receptors, independent of the IgE receptor.24Glovsky MM Hugli TE Ishizaka T Lichtenstein LM Erickson BW Anaphylatoxin-induced histamine release with human leukocytes: studies of C3a leukocyte binding and histamine release.J Clin Invest. 1979; 64: 804-811Crossref PubMed Scopus (84) Google Scholar, 25Marone G Columbo M Soppelsa L Condorelli M The mechanism of basophil histamine release induced by pepstatin A.J Immunol. 1984; 133: 1542-1546PubMed Google Scholar, 26Columbo M Casolaro V Warner JA MacGlashan Jr, DW Kagey-Sobotka A Lichtenstein LM The mechanism of mediator release from human basophils induced by platelet-activating factor.J Immunol. 1990; 145: 3855-3861PubMed Google Scholar Ca2+ ionophores such as compound A23187, and tumor-promoting phorbol esters such as 12-o-tetradecanoylphorbol-13-acetate do not interact with surface receptors, therefore bypassing some of the early stages of signal transduction, and induce degranulation by allowing transmembrane Ca2+ influx or by directly activating protein kinase C, respectively.27Lichtenstein LM The mechanism of basophil histamine release induced by antigen and by the calcium ionophore A23187.J Immunol. 1975; 114: 1692-1699PubMed Google Scholar, 28Schleimer RP Gillespie E Lichtenstein LM Release of histamine from human leukocytes stimulated with the tumor-promoting phorbol esters. I. Characterization of the response.J Immunol. 1981; 126: 570-574PubMed Google Scholar Another interesting stimulus is D2O which in vitro potentiates the release of mediators induced by other stimuli but causes little release by itself from cells of normal donors.29Tung R Lichtenstein LM In vitro histamine release from basophils of asthmatic and atopic individuals in D2O.J Immunol. 1982; 128: 2067-2072PubMed Google Scholar, 30Kazimierczak W Plaut M Knauer KA Meier HL Lichtenstein LM Deuterium-oxide-induced histamine release from basophils of allergic subjects. I. Responsiveness to deuterium oxide requires an activation step.Am Rev Respir Dis. 1984; 129: 592-596PubMed Google Scholar In general, there is no correlation between the sensitivity and reactivity of the cells to release with any of these stimuli, and basophil and mast cell releasability must therefore be defined with respect to each stimulus. We studied IgE (anti-IgE) and non-IgE-mediated (FMLP and Ca2+ ionophore A23187) releasability of basophils from 63 normal subjects ranging in age from 1 to 86 years. The maximum histamine release induced by anti-IgE was significantly age related.16Marone G Poto S di Martino L Condorelli M Human basophil releasability. I. Age-related changes in basophil releasability.J ALLERGY CLIN IMMUNOL. 1986; 77: 377-383Abstract Full Text PDF PubMed Scopus (40) Google Scholar The percent histamine secretion of the group less than 20 years of age was significantly lower than that of the older groups at all concentrations of anti-IgE. The groups older than 20 years released the same percentage of histamine release for all concentrations of anti-IgE. These results indicate that when crosslinking of the IgE receptor is the signal for basophil histamine release, the cell donor's age significantly influences the amount of histamine secretion. Studies of IgE-mediated release should therefore take into account the fact that basophil releasability is age related. In the groups examined, we found no correlation between the donor's age and the maximum percentage of histamine release induced by FMLP. Histamine release tended to decline slightly with age and in fact was significantly lower in the group more than 60 years old. The decreased in vitro response to FMLP in these older subjects might reflect long-term in vivo exposure and desensitization to bacterial products. No correlation was found between the age of donors and the maximum A23187-induced histamine release. Finally, we compared the maximum percentage of histamine release with optimal concentrations of these three agents (anti-IgE, FMLP, and A23187). There was no correlation at all between any pair of the three releasing agents, suggesting again that basophil releasability must be defined for each separate stimulus. Heredity has long been suspected of playing a role in the development of allergic disorders,31Marsh DG Meyers DA Bias WB The epidemiology and genetics of atopic allergy.N Engl J Med. 1981; 305: 1551-1559Crossref PubMed Scopus (245) Google Scholar and several early observations report allergy as "running in families."32Bazaral M Orgel HA Hamburger RN Genetics of IgE and allergy: serum IgE levels in twins.J ALLERGY CLIN IMMUNOL. 1974; 54: 288-304Abstract Full Text PDF Scopus (93) Google Scholar, 33Hopp RJ Bewtra AK Watt GD Nair NM Townley RG Genetic analysis of allergic disease in twins.J ALLERGY CLIN IMMUNOL. 1984; 73: 265-270Abstract Full Text PDF PubMed Scopus (237) Google Scholar We assessed the influence of genetic and environmental factors on basophil releasability in 26 sets of twins.34Marone G Poto S Celestino D Bonini S Human basophil releasability. III. Genetic control of human basophil releasability.J Immunol. 1986; 137: 3588-3592PubMed Google Scholar Zygotic status was established by direct observation, detailed examination of various anthropologic markers, and questionnaire answers, with a reliability estimated at 98% through control blood typing on about 15% of sets.35Parisi P Gatti M Prinzi G Caperna G Familial incidence of twinning.Nature. 1983; 304: 626-628Crossref PubMed Scopus (72) Google Scholar The total sample consisted of 14 monozygotic and 12 dizygotic sets. Fig. 1 shows the significant intraset correlation coefficient of the maximum percentage of anti-IgE-induced histamine release in the 14 monozygotic twins (r = 0.84; p < 0.001) but not in the dizygotic twins. When the mean intraset variance of anti-IgE-induced histamine release was calculated in the monozygotic (VMZ = 85) and dizygotic twins (VDZ = 327) we found an F value of 3.84 (p < 0.01) and a heritability value of 0.74. These results suggest that IgE-mediated releasability is controlled by genetic factors and underline the importance of basophil releasability. No correlation was found between serum IgE levels and anti-IgE-induced histamine release, suggesting that the two parameters (serum IgE level and basophil IgE-mediated releasability) are under separate genetic control. FMLP-induced histamine release from basophils appeared to be influenced mainly by environmental factors. The intratwin correlation coefficient of A23187-induced histamine release was 0.62 (p < 0.01) in the monozygotic sets and 0.38 (not significant) in the dizygotic sets. The difference between monozygotic and dizygotic sets was significant, suggesting that the biochemical steps explored by the Ca2+ ionophore A23187 are at least partly under genetic control. This evidence strongly favors a genetic control of basophil releasability.34Marone G Poto S Celestino D Bonini S Human basophil releasability. III. Genetic control of human basophil releasability.J Immunol. 1986; 137: 3588-3592PubMed Google Scholar, 36Casolaro V Spadaro G Marone G Genetic studies of basophil releasability.in: The genetics of asthma. : Blackwell Scientific Publications, Oxford1993: 291-308Google Scholar Human basophils differ from mast cells morphologically, ultrastructurally, biochemically, immunologically, and pharmacologically.37Dvorak AM Galli SJ Schulman ES Lichtenstein LM Dvorak HF Basophil and mast cell degranulation: ultrastructural analysis of mechanisms of mediator release.Fed Proc. 1983; 42: 2510-2515PubMed Google Scholar, 38Marone G Cirillo R Genovese A Marino O Quattrin S Human basophil/mast cell releasability. VII. Heterogeneity of the effect of adenosine on mediator secretion.Life Sci. 1989; 45: 1745-1754Crossref PubMed Scopus (27) Google Scholar, 39Stellato C Cirillo R de Paulis A et al.Human basophil/mast cell releasability. IX. Heterogeneity of the effects of opioids on mediator release.Anesthesiology. 1992; 77: 932-940Crossref PubMed Scopus (95) Google Scholar It is therefore not surprising that many aspects of releasability in basophils differ from those of mast cells isolated from different anatomic sites. The evidence for different control of releasability in these two primary effector cells derives from the clinical observation that patients with urticarial syndromes have increased releasability of skin mast cells,40Bédard PM Brunet C Pelletier G Hébert J Increased compound 48/80 induced local histamine release from nonlesional skin of patients with chronic urticaria.J ALLERGY CLIN IMMUNOL. 1986; 78: 1121-1125Abstract Full Text PDF PubMed Scopus (62) Google Scholar whereas IgE-mediated releasability of basophils is markedly reduced.41Greaves MW Plummer VM McLaughlan P Stanworth DR Serum and cell bound IgE in chronic urticaria.Clin Allergy. 1974; 4: 265-271Crossref PubMed Scopus (70) Google Scholar, 42Kern F Lichtenstein LM Defective histamine release in chronic urticaria.J Clin Invest. 1976; 57: 1369-1377Crossref PubMed Scopus (124) Google Scholar, 43Casolaro V Cirillo R Genovese A Formisano S Ayala F Marone G Human basophil releasability. IV. Changes in basophil releasability in patients with chronic urticaria.J Immunol Res. 1989; 1: 67-73Google Scholar Casolaro et al.17Casolaro V Galeone D Giacummo A Sanduzzi A Melillo G Marone G Human basophil/mast cell releasability. V. Functional comparisons of cells obtained from peripheral blood, lung parenchyma, and from bronchoalveolar lavage in asthmatics.Am Rev Respir Dis. 1989; 139: 1375-1382Crossref PubMed Scopus (97) Google Scholar compared basophil and lung mast cell releasability from individual donors. The response of basophils from 52 donors to anti-IgE, Staph A, concanavalin A (Con A), FMLP, and A23187 was compared with that of mast cells isolated enzymatically (PMCE) or mechanically (PMCM) from lung parenchyma. The maximum percentage of anti-IgE-induced histamine secretion was higher in basophils than in PMCE and PMCM. The correlation between the maximum percentage of histamine release induced by anti-IgE and Staph A was positive in basophils, whereas PMCE and PMCM were essentially unresponsive to Staph A and Con A. Similarly, lung mast cells were unresponsive to FMLP. Even more dramatic are the differences between basophils and mast cells from bronchoalveolar lavage (BAL). BAL mast cells do not release histamine in response to FMLP, and anti-IgE induces a significantly higher maximum histamine release in basophils than in BAL mast cells. Striking differences also have been clearly demonstrated between basophils and mast cells and between mast cells from different anatomic sites in response to opioids.39Stellato C Cirillo R de Paulis A et al.Human basophil/mast cell releasability. IX. Heterogeneity of the effects of opioids on mediator release.Anesthesiology. 1992; 77: 932-940Crossref PubMed Scopus (95) Google Scholar The observations discussed so far provide some insight into the concept of basophil and mast cell releasability. However, the study of releasability probably has practical implications, and releasability has been investigated in a variety of allergic disorders. We have carried out experiments to ascertain whether there was any difference in the releasability of basophils from young patients with atopic dermatitis and normal donors.44Marone G Giugliano R Lembo G Ayala F Human basophil releasability. II. Changes in basophil releasability in patients with atopic dermatitis.J Invest Dermatol. 1986; 87: 19-23Abstract Full Text PDF PubMed Scopus (57) Google Scholar Basophils from the young patients released significantly more histamine both spontaneously and in response to D2O, and were significantly more responsive to anti-IgE and A23187. No correlation was found between histamine release with optimal and suboptimal concentrations of the stimuli and the serum IgE level. Interestingly, in a recent study in adult patients with atopic dermatitis, anti-IgE-induced histamine release was the same in patients with atopic dermatitis and in control subjects.45Bull HA Courtney PF Bunker CB Rustin MHA Pearce FL Dowd PM Basophil mediator release in atopic dermatitis.J Invest Dermatol. 1993; 100: 305-309Abstract Full Text PDF PubMed Google Scholar This is a further reminder that basophil releasability is affected by the cell donor's age for normal persons and for atopic patients. Basophil releasability is not always increased in patients with allergic disorders. In patients with chronic urticaria, basophils were significantly less responsive to anti-IgE than the cells of control subjects.41Greaves MW Plummer VM McLaughlan P Stanworth DR Serum and cell bound IgE in chronic urticaria.Clin Allergy. 1974; 4: 265-271Crossref PubMed Scopus (70) Google Scholar, 42Kern F Lichtenstein LM Defective histamine release in chronic urticaria.J Clin Invest. 1976; 57: 1369-1377Crossref PubMed Scopus (124) Google Scholar, 43Casolaro V Cirillo R Genovese A Formisano S Ayala F Marone G Human basophil releasability. IV. Changes in basophil releasability in patients with chronic urticaria.J Immunol Res. 1989; 1: 67-73Google Scholar It was suggested that in vivo desensitization had occurred in response to the same stimulus tested in vitro. Interestingly, in patients with chronic urticaria the de novo synthesis of an eosinophil chemotactic factor was also lower than in normal donors.46Czarnetzki BM Kern F Lichtenstein LM Defective release of eosinophil chemotactic factor from peripheral leukocytes in patients with chronic urticaria.J Invest Dermatol. 1976; 67: 276-278Crossref PubMed Scopus (16) Google Scholar We have confirmed and extended these findings, showing that basophils of patients with chronic urticaria released significantly less histamine than did control subjects and synthesized less leukotriene C4 (LTC4) de novo in response to anti-IgE.43Casolaro V Cirillo R Genovese A Formisano S Ayala F Marone G Human basophil releasability. IV. Changes in basophil releasability in patients with chronic urticaria.J Immunol Res. 1989; 1: 67-73Google Scholar The maximum release of histamine and LTC4 from control subjects and from patients with chronic urticaria presented a significant linear correlation. Thus it appears that releasability of preformed mediators such as histamine correlates with that of de novo synthesized metabolites such as eosinophil chemotactic factor and LTC4. There is compelling evidence that basophils and mast cells play a role in the pathogenesis of respiratory allergy. Metachromatic cells are increased in the sputum before an asthmatic attack,47Kimura I Moritani Y Tanizaki Y Basophils in bronchial asthma with reference to reagin-type allergy.Clin Allergy. 1973; 3: 195-202Crossref PubMed Scopus (189) Google Scholar and basophils are increased in bronchoalveolar lavage (BAL) fluid after antigen challenge.48Liu MC Hubbard CW Proud D et al.Immediate and late inflammatory responses to ragweed antigen challenge of the peripheral airways in allergic asthmatics: cellular, mediator, and permeability changes.Am Rev Respir Dis. 1991; 144: 51-58Crossref PubMed Scopus (333) Google Scholar The presence of basophils in lung tissues obtained from asthma patients who died49Koshino T Teshima S Fukushima N et al.Identification of basophils by immunohistochemistry in the airways of post-mortem cases of fatal asthma.Clin Exp Allergy. 1993; 23: 919-925Crossref PubMed Scopus (94) Google Scholar and the correlation between the annual changes in methacholine airway responsiveness and basophil count50Sparrow D O'Connor GT Rosner B Weiss ST Predictors of longitudinal change in methacholine airway responsiveness among middle-aged and older men: the normative aging study.Am J Respir Crit Care Med. 1994; 149: 376-381Crossref PubMed Scopus (44) Google Scholar support the view that basophils play a major role in the pathogenesis of bronchial asthma. Spontaneous release of histamine from basophils in the presence of D2O is markedly greater than normal in approximately 30% of patients with allergic rhinitis or bronchial asthma.5Marone G Poto S Giugliano R Celestino D Bonini S Control mechanisms of human basophil releasability.J ALLERGY CLIN IMMUNOL. 1986; 78: 974-980Abstract Full Text PDF PubMed Scopus (23) Google Scholar, 29Tung R Lichtenstein LM In vitro histamine release from basophils of asthmatic and atopic individuals in D2O.J Immunol. 1982; 128: 2067-2072PubMed Google Scholar, 30Kazimierczak W Plaut M Knauer KA Meier HL Lichtenstein LM Deuterium-oxide-induced histamine release from basophils of allergic subjects. I. Responsiveness to deuterium oxide requires an activation step.Am Rev Respir Dis. 1984; 129: 592-596PubMed Google Scholar Studies of basophil releasability in response to different IgE-mediated or non-IgE-mediated stimuli in patients with respiratory allergies have yielded apparently contradictory results. Basophil releasability in patients with asthma was increased,51Gaddy JN Busse WW Enhanced IgE-dependent basophil histamine release and airway reactivity in asthma.Am Rev Respir Dis. 1986; 134: 969-974PubMed Google Scholar unchanged,17Casolaro V Galeone D Giacummo A Sanduzzi A Melillo G Marone G Human basophil/mast cell releasability. V. Functional comparisons of cells obtained from peripheral blood, lung parenchyma, and from bronchoalveolar lavage in asthmatics.Am Rev Respir Dis. 1989; 139: 1375-1382Crossref PubMed Scopus (97) Google Scholar and even decreased.52Findlay SR Lichtenstein LM Basophil "releasability" in patients with asthma.Am Rev Respir Dis. 1980; 122: 53-59PubMed Google Scholar In one study in patients with allergic rhinitis, basophil releasability was increased in response to the anti-IgE-related stimulus Con A.53Busse WW Swenson CA Sharp G Koschat M Enhanced basophil histamine release to concanavalin A in allergic rhinitis.J ALLERGY CLIN IMMUNOL. 1986; 78: 90-97Abstract Full Text PDF PubMed Scopus (35) Google Scholar We compared basophil releasability in young adults with severe bronchial asthma or with allergic rhinitis, all of whom were skin test–positive for Dermatophagoides pteronyssinus p I antigen (Der p I), and age-matched control subjects.54Casolaro V Spadaro G Marone G Human basophil releasability. VI. Changes in basophil releasability in patients with allergic rhinitis or bronchial asthma.Am Rev Respir Dis. 1990; 142: 1108-1111Crossref PubMed Scopus (70) Google Scholar Basophils were challenged with increasing concentrations of anti-IgE, Der p I, FMLP, and A2318
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