Lack of role for mononuclear cell-derived histamine releasing factors in occupational asthma due to western red cedar

Occupational asthma due to Western Red Cedar (WRCA) is attributed to sensitization to plicatic acid (PA), but does not appear to be dependent on PA-specific IgE antibodies. Exposure to PA induces histamine release in vivo and in vitro, so if IgE is not important, other mechanisms of histamine release must presumably operate in WRCA. To explore the possible role of histamine-releasing factors in WRCA, peripheral blood mononuclear cells were obtained and cultured with PA, PA-albumin conjugate plicatic acid-human serum albumin (PA-HSA), grass pollen or Concanavalin A using a standard histamine releasing factor (HRF) generation protocol. Supernatants were dialysed to remove endogenous histamine and then assayed for histamine releasing activity using human basophils as targets and a Con A-induced bulk supernatant as an internal HRF standard. In contrast to some previous reports, spontaneous HRF release from the peripheral blood mononuclear cells (PBMC) of WRCA patients (n=9) and atopic asthmatic subjects (n=5) was not elevated compared with the non-asthmatic controls (n=11; five atopic and six non-atopic). Both PA and PA-HSA induced the production of small amounts of HRF by PBMC of WRCA patients, but a similar degree of HRF generation was also observed in PBMC from the atopic asthmatic, atopic nonasthmatic, and non-atopic subjects. In contrast, grass pollen induced the production of HRF by PBMC from the subjects with positive skin tests to grass pollen but not by PBMC of non-atopic subjects, confirming that our methods and assay were capable of detecting antigen-specific HRF production. Since neither PA nor PA-HSA induced significantly elevated HRF production from PBMC of WRCA patients, it seems unlikely that PA-induced HRFs play a substantial role in the pathogenesis of WRCA.     

Enhancement of basophil histamine release by interleukin-3: reduced effect in atopic subjects

The inducing and enhancing effects of interleukin-3 (IL-3) on basophil histamine release in patients with respiratory allergy ( n = 28) and in normal subjects ( n = 22) were compared. Leukocyte suspensions, prepared by dextran sedimentation, were stimulated with anti-IgE (1/5000), N-formyl-methionyl-leucyl-phenylalanine (FMLP, 1 μM), and IL-3 (0.1–10 ng/ml), and histamine concentration was measured by an automated fluorometric method. A trend toward higher histamine release after challenge with anti-IgE, FMLP, and IL-3 was found in atopic subjects. Preincubation of basophils with IL-3 resulted in a dose-dependent increase of anti-IgE- and FMLP-induced histamine release, with a more marked effect in nonatopic than in atopic subjects. Mean net enhancement of anti-IgE-induced histamine release by 10 ng/ml IL-3 was 2.5±5% in atopic subjects and 29.6±4.2% in nonatopic subjects ( P < 0.001). The enhancement of FMLP-induced histamine release by IL-3 was 10.3 ±3.9% in atopic patients and 29±2.4% in nonatopic subjects ( P < 0.01). In atopic subjects, a negative correlation was found between anti-IgE- or FMLP-induced histamine release and net enhancement by IL-3 ( r = -0.45, P < 0.02; r = 0.48, P < 0.01, respectively). The results of this study indicate that in atopic subjects IgE-mediated histamine release can scarcely be enhanced by a basophil response modifier such as IL-3. It is conceivable that the frequent basophil stimulation in atopic patients leads to a reduced sensitivity to the enhancing effect of IL-3.     

Potato lectin activates basophils and mast cells of atopic subjects by its interaction with core chitobiose of cell-bound non-specific immunoglobulin E

A major factor in non-allergic food hypersensitivity could be the interaction of dietary lectins with mast cells and basophils. Because immunoglobulin E (IgE) contains 10-12% carbohydrates, lectins can activate and degranulate these cells by cross-linking the glycans of cell-bound IgE. The present objective focuses on the effect of potato lectin (Solanum tuberosum agglutinin; STA) for its ability to release histamine from basophils in vitro and mast cells in vivo from non-atopic and atopic subjects. In this study, subjects were selected randomly based on case history and skin prick test responses with food, pollen and house dust mite extracts. Skin prick test (SPT) was performed with STA at 100 microg/ml concentration. Histamine release was performed using leucocytes from non-atopic and atopic subjects and rat peritoneal exudate cells. SPT on 110 atopic subjects using STA showed 39 subjects positive (35%); however, none showed STA-specific IgE; among 20 non-atopic subjects, none were positive by SPT. Maximal histamine release was found to be 65% in atopic subjects (n = 7) compared to 28% in non-atopic subjects (n = 5); the release was inhibited specifically by oligomers of N-acetylglucosamine and correlates well with serum total IgE levels (R(2) = 0.923). Binding of STA to N-linked glycoproteins (horseradish peroxidase, avidin and IgG) was positive by dot blot and binding assay. As potato lectin activates and degranulates both mast cells and basophils by interacting with the chitobiose core of IgE glycans, higher intake of potato may increase the clinical symptoms as a result of non-allergic food hypersensitivity in atopic subjects.     

No release of histamine and substance P in capsaicin-induced neurogenic inflammation in intact human skin in vivo: a microdialysis study

Background Studies in rodents ‘skin have indicated substance P to be the main inflammatory mediator involved in neurogenic inflammation, acting partly by release of histamine from skin mast cells. The mediators released in neurogenic inflammation in human skin remain to be determined. Objectives To determine the effects of intradermally injected and topically applied capsaicin on the release of histamine and substance P and skin responses in intact human skin in vivo. Methods Extracellular skin levels of histamine and substance P were measured by microdialysis technique and assayed by enzyme and radio immunoassays. Two kinds of dialysis fibres (210μm, 2 kDa, and 500 μm, 20 kDa) were inserted intradermally into forearm skin for studies of histamine release to topically administered capsaicin and intradermally injected capsaicin and substance P. Results Baseline histamine skin levels were 8.0 ± 0.7 nM. Intradermally injected capsaicin (0.3–30μM, 7.5–750 pmol) caused significantly and dose-related flare and pain reactions, but no significant histamine release or weals. Intradermally injected substance P (1 and 3 μM, 25 and 75 pmol) released significant amounts of histamine (peak levels being 90 and 475 nM), evoked weal-and-flare reactions, but did not cause pain. Capsaicin 2% ointment, applied on the skin for 2.5 h, increased skin blood flow by 300–400% as measured by laser Doppler flowmetry, elicited a longstanding burning sensation, but did not release histamine. Substance P-like immunoreactivity (SP-LI) was below the 1.8 pM detection limit following insertion of 20 kDa dialysis fibre and after intradermal injection of capsaicin 3μM. Intradermal injection of injection of 1 μM of substance P increased SP-LI levels to values greater than 4500 pM, confirming the ability of the dialysis fibre to recover this peptide. Conclusions Capsaicin-induced neurogenic activation does not involve the release of histamine from mast cells or detectable amounts of substance P release from sensory nerves in normal human skin in vivo.     

Decreased natural killer cell activity in atopic eczema.

We have studied NK cell activity in atopic and non-atopic subjects using a standard 51Cr-release assay and K562 target cells. In atopics (AT) with allergic rhinitis and/or asthma, NK cell activity was similar to that in non-atopic (N) subjects, whilst patients with severe atopic eczema (AE) had depressed NK cell activity compared to AT or N subjects. In addition, circulating T-cell numbers and Con A responsiveness was decreased in AE, although neither parameter was correlated with decreased NK cell activity. However, decreased NK cell activity in atopic eczema was positively correlated with decreased numbers of Fc gamma + lymphocytes (P = 0.01) and decreased effector: target cell binding (P = 0.05), and negatively correlated with increased monocytes in AE (P = 0.09). AE NK cell activity was equally or more sensitive to the inhibitory effects of drugs such as dibutyryl cyclic AMP, prostaglandins (PG) D2,E2 and histamine. The relative percentage increase in NK cell activity by the interferon inducer poly I:C was similar in AE patients and controls. The results suggest that reduced numbers of circulating NK cells and pre-NK cells account for the depressed level of NK cell activity in subjects with severe atopic eczema.     

Effect of hypo- and hyper-osmolarity on basophil histamine release

The pattern of histamine release from peripheral white blood cells in response to hyper-(sodium chloride, mannitol) and hypo-osmolar (water) stimuli was studied in order to determine the differences between non-atopic control and atopic asthmatic patients in histamine release caused by osmolar changes. All subjects showed histamine release to both hyper- and hypo-osmolar stimuli and this response was reproducible. Viability studies and the effect of time and temperature indicated that, at the extremes of hypo- and hyper-osmolality, histamine release was associated with cell cytotoxicity. Asthmatics and controls showed no differences either in their level of spontaneous or hyper-osmolar sodium chloride induced histamine release, but asthmatics' cells were more responsive to mannitol over 600–800 mOsm/kg and less responsive to a hypo-osmolar stimulus under 80 mOsm/kg. This suggests that asthmatics' cells may differ from controls in the manner in which they respond to osmotic stimuli and this may be relevant in certain clinical situations.     

Histamine release from mast cells of various species induced by histamine releasing factor from human lymphocytes

The aim of our work was to investigate the effect of histamine releasing factor (HRF), producedin vitro by lymphocytes obtained from atopic and non-atopic asthmatics, on mast cells of various species (mouse—peritoneal mast cells, hamster and rat—peritoneal and pleural mast cells, guinea-pig — mesenteric and pulmonary mast cells). We found that human HRF is able to release histamine from the examined mast cell populations in a dose-dependent fashion. Mast cells from various species differed in their susceptibility to the action of HRF; rat pleural and guinea-pig mesenteric and pulmonary mast cells were the most susceptible, while mouse and hamster peritoneal mast cells —the least susceptible. The presence of 50% D₂O in the medium significantly increased HRF-induced histamine release from rat mast cells, while the addition of phosphatidylserine did not change it. HRF-induced histamine release from guinea-pig mesenteric mast cells was not related to sensitization of these cells.We also compared histamine release from guinea-pig pulmonary and mesenteric mast cells induced by human HRF producedin vitro by lymphocytes obtained from atopic and non-atopic asthmatics. We have found that supernatant from atopic asthmatics lymphocyte cultures released significantly more histamine than supernatant from non-atopic asthmatics lymphocyte cultures.Our studies give evidence that human HRF acts across the species barrier and induces histamine release from mast cells of various species. The mechanism of HRF action on mast cells seems to be different from that of allergen.This work was supported by Polish academy of Sciences (Grant CPBP 06.01).     

In vivo effects of corticosteroids on human allergic responses. I. Effects of systemic administrations of steroids

In order to better understand the effects of corticosteroids in allergic disease, the relative degrees of allergen-induced cutaneous histamine release and granulocyte accumulation were evaluated in atopic volunteers following intravenous placebo or methylprednisolone administration. In nine subjects, a single intravenous dose of methylprednisolone (1 mg/kg) did not inhibit histamine release but did significantly reduce granulocyte accumulation at both allergen and buffer-challenged sites during five and one-half to six and one-half hours following steroid injection. These findings suggest that the corticosteroid-induced anti-inflammatory effects at allergic reaction sites do not include inhibition of local mediator release. Furthermore, the steroid-induced inhibition of inflammatory cell accumulation is not specific for the allergic reaction.     

Intradermal challenge with interleukin-8 causes tissue oedema and neutrophil accumulation in atopic and non-atopic human subjects

Background Interleukin-8 (IL-8) is a cytokine with potent neutrophil chemotactic and activating properties and is active in inflammatory conditions in man. It has been identified in human inflammatory skin conditions where it is likely to be responsible for both neutrophil recruitment from the circulation and possibly T-lymphocyte chemoattraction. Studies in animals also suggest that IL-8 may augment skin oedema. Objective To study the effects of intradermally administered IL-8 in humans on tissue oedema and cellular recruitment in atopic and non-atopic volunteers. Method Interleukin-8 (1.2 ± 10^?7M) in the presence and absence of histamine was administered by intradermal injection. Wheal and erythema area were measured at regular intervals and 3 h following challenge punch biopsies were taken for immunocytochemistry. Cellular infiltrate was measured by immunocytochemical identification of neutrophils, eosinophils and T-lymphocytes in glycol-methacrylateembedded sections. Results In the presence of histamine, IL-8 provoked a significantly greater wheal area when compared to that produced by histamine alone (P < 0.001). In the presence of histamine, IL-8 produced a significantly greater neutrophil infiltrate (P < 0.05); however, neither lymphocyte or eosinophil infiltration was found to be increased with IL-8 challenge. There was no difference observed between atopic and non-atopic subjects, nor were any effects of IL-8 demonstrated in the absence of histamine. Conclusion This study demonstrates that in human skin, IL-8 induces increased microvascular permeability and neutrophil infiltration, but not eosinophil or T-lymphocyte chemoattraction.     

Levels of soluble IL-2 receptor in plasma from asthmatics. Correlations with blood eosinophilia, lung function, and corticosteroid therapy.

Evidence now suggests that eosinophils and T lymphocytes infiltrating bronchial tissues may play a key role in the pathophysiology of asthma. Circulating eosinophils, lung function, and plasma soluble IL-2 receptor (sIL-2R) were measured in 42 asthmatic patients referred for symptomatic asthma. The patients were divided into two groups based on the presence or absence of atopy. The group of non-atopic asthmatics was further divided according to the patients' requirement for long term oral corticosteroids. The mean sIL-2R +/- s.d. was 36.3 +/- 9.9 pM in the control group, 28.9 +/- 9.2 pM in the atopic asthmatics, 43.3 +/- 18.07 pM in the non-atopic asthmatics without oral steroid therapy, but was increased in the steroid-treated group (62.2 +/- 19.3 pM, P less than 0.01). A significant correlation was found between FEV1 and circulating eosinophils in atopic asthmatics and in non-atopic asthmatics without oral corticosteroid therapy, but not in the steroid-treated group. Furthermore, significant correlations were found between sIL-2R and FEV1, and between sIL-2R and blood eosinophils, in the group of non-atopic asthmatics not on oral steroid therapy. No such correlations were evidenced in the other groups of asthmatics. Similar results were obtained during the clinical course of three non-atopic patients followed for more than 1 year. These data suggest that T cell activation appears more prominent in non-atopic asthma than in atopic asthma. Moreover, it appears that T cell activation can occur in severe forms of asthma despite steroid treatment. Finally, the results suggest a possible link between T cell activation, eosinophils, and lung function, which may reflect a particular pathogenetic mechanism involved in non-atopic asthma.     

A clinical study of concanavalin A-induced histamine release utilizing a single isotopic enzymatic assay of histamine.

Concanavalin A (Con A)-induced histamine release from cells of subjects with extrinsic asthma, intrinsic asthma or urticaria and normal individuals was examined utilizing a single isotopic enzymatic assay for histamine. Maximum histamine release by Con A occurred with 0.9 to 4.5 microgram/ml. The mean percentage of maximum histamine release by Con A from cells of donors with extrinsic asthma was 36(+/- 19.3)% while that from cells of normal individuals was 21.4(+/- 23.7)%. However, there was no significant difference between the two groups. The higher reactivity to Con A of cells from individuals with intrinsic asthma or urticaria was not observed compared to that of the normal group. The histamine release by Con A was not correlated with IgE level in the plasma (r = 0.35). It was observed that compound 48/80 inhibited the enzymatic reaction in the isotopic, enzymatic assay.     

Effect of exercise on isoprenaline-induced lymphocyte cAMP production in atopic asthmatics and atopic and non-atopic, non-asthmatic subjects

The effect of exercise on isoprenaline-induced cyclic adenosine monophosphate (cAMP) production was studied in peripheral-blood lymphocytes obtained from ten patients with atopic asthma, seven subjects who were atopic but did not have asthma and eight non-atopic, non-asthmatic control subjects. The asthma in the atopic subjects was mild only requiring intermittent treatment with inhaled β adrenoceptor agonists, none of which were taken in the 48 hr prior to the study. Exercise consisted of a standardized 6-min run on a treadmill sufficient to raise the subject's pulse rate to > 160 bpm and respiratory function was measured before and at 5,10,15,20,30 and 60 min after the test. Blood samples were taken 5 min before and at 10 and 60 min after exercise, lymphocytes were separated by density gradient centrifugation and cAMP measured by a competitive radioimmunoassay. Exercise led to a significant decrease (27%) in the forced expiratory volume in I sec (FEV₁) in the ten atopic asthmatic subjects but no change (< 3%) in the non-atopic and atopic non-asthmatics. There was no significant difference in the unstimulated cAMP levels before exercise in the three groups, but stimulation with isoprenaline caused a significantly greater rise in cAMP in the non-atopic, non-asthmatic subjects when compared to both the atopic asthmatics and the atopic subjects without asthma. Exercise led to a significant elevation of cAMP in all three groups of subjects, but the same differences between the groups remained. These results suggest that there are differences in lymphocyte β receptor function not between patients who are asthmatic or non-asthmatic but between individuals who are atopic as opposed to non-atopic.     

Somatostatin and serum gastrin behaviour

The effect of somatostatin (250 mcg. by i.v. bolus injection) on serum gastrin behaviour was studied in 12 dyspeptic subjects. In 6 of them, seven gastrin levels were determined in the basal conditions and after somatostatin injection. In the remaining 6 patients, the gastrinemic profile was evaluated after histamine injection (0.5 mg/i.m.) and after the injection of histamine plus somatostatin (24 h later). Gastric acid secretion was also determined in all the cases. The results obtained demonstrate that somatostatin reduces the gastrin release: this reduction appears 30 minutes after its administration and persists until the 60th minute: after the 75th minute the serum gastrin returns to the basal level. The contemporaneous injection of somatostatin and of histamine does not modify the gastrinemic profile as compared to what was observed in the basal condition or after histamine alone.     

Bronchial inflammation and the common cold: a comparison of atopic and non-atopic individuals

Background Cold virus infections are associated with asthma attacks and with increased bronchial responsiveness even in normal subjects. Possible mechanisms include epithelial damage, interaction with adhesion molecules or with T-helper cell subsets. Objective To determine whether colds increase lower airway inflammation, comparing atopic with non-atopic normal subjects. Methods Thirty healthy volunteers (15 atopic) took part. Basehne tests included viral serology. microbiological culture and polymerase chain reaction for rhinovirus infection (HRV-PCR), histamine bronchial provocation and bronchoscopy. Twenty subjects (eight atopic) underwent repeat tests when they developed a cold. Results Forced expiratory volume in one second (FEV₁) was significantly lower during colds (-0.19L [95% confidence mterval -0.10, -0.29], P= 0,0004) and there was a significant increase in bronchial responsiveness (+0.62 doublings of the dose-response slope [+0.24, +1.00], P=0.003). Eight subjects (two atopic) had a diagnosed viral infection: two HRV. three coronavirus (HCV), one HRV + HCV, one parainfluenza III(PI) and one respiratory syncytial virus (RSV) (also Haemophilus influenzae). In biopsies, during colds, total eosinophils (EG1⁺) increased significantly (geometric mean 6.73-fold [1.12,40.46], P=O.04). Activated eosinophils (EG2⁺) only increased significantly in the subgroup without diagnosed viral infection and particularly in atopic rhinitics. T-suppressor (CD8⁺) cells also increased significantly (median +178.3 cells mm², P= 0.004). Epithelial expression of intercellular adhesion molecule-1 (ICAM-1) expression increased in four atopic rhinitics during colds. Bronchial washings showed a significant increase in neutrophils (GM 1.53-fold [1.04,2.25], P= 0.02). Conclusion Lower airway inflammation was present in atopic and non-atopic normal subjects with colds. Atopic subjects differed in that they were less likely to have positive virological tests and were more likely to show activated eosinophilia in the lower airway, despite a similar spectrum of symptoms.     

Priming and inducing effects of interleukin-3 on histamine release from cord-blood basophils

The effects of inlerleukin-3 (IL-3) on histamine release from cord and adult blood basophils were evaluated. Leukocyte suspensions, obtained from adult patients with respiratory allergy ( n = 15), normal adult subjects ( n = 15), and neonates with ( n = 15) and without ( n = 19) atopic disposition, were stimulated with anti-IgE, fMLP, and IL-3. IgE-mediated histamine release was significantly higher in adult patients, either allergic or normal, than in neonates with or without atopic disposition. A trend toward higher fMLP-induced histamine release was found in allergic adult subjects. IL-3 had a weak direct histamine-releasing activity in allergic adult subjects and in neonates, but not in normal adult donors. A significant enhancing effect of IL-3 on histamine release induced by anti-IgE was observed in neonates with and without atopic disposition and in normal adult subjects, but not in atopic adult patients. IL-3 exerted a priming effect also when basophils were stimulated with fMLP, without any significant difference between neonates and adult subjects. Passive sensitization with IgE-rich serum resulted in a significant increase in anti-IgE-induced, but not in IL-3–induced, histamine release from cord-blood basophils. In conclusion, IL-3 primes cord-blood as well as adult blood basophils for a consecutive anti-IgE- or fMLP-induced histamine release, and its activity is not limited by the low density of membrane IgE in cord-blood basophils.     

Increased release of histamine in patients with respiratory symptoms related to perfume

BACKGROUND: Environmental perfume exposure may cause respiratory symptoms. Individuals with asthma and perfume contact allergy report such symptoms more frequently than others. However, immunologic mechanisms have not been demonstrated and the symptoms are not associated with IgE-mediated allergy. The study aimed to investigate whether basophils from patients with respiratory symptoms related to perfume released more histamine in the presence of perfume as compared with healthy volunteers. METHODS: Histamine release was measured by the glass fibre method. Blood was obtained from healthy volunteers (n=20) and patients with respiratory symptoms related to perfume (n=17) attending a dermatological outpatient clinic for patch testing. The effect of an international brand perfume was investigated using the basophil histamine release test with perfume. Furthermore, basophils from a healthy non-atopic donor were incubated with participant's sera and histamine release induced by perfume was measured. RESULTS: In both groups incremental perfume concentrations showed a positive and significant (P<0.001) dose-response effect on the release of histamine. At the highest perfume concentration, the basophils released significantly (P<0.05) more histamine in patients as compared with healthy volunteers. No difference was found between the groups when sera were incubated with basophils from a healthy non-atopic donor. CONCLUSION: Perfume induces a dose-dependent non-IgE-mediated release of histamine from human peripheral blood basophils. Increased basophil reactivity to perfume was found in patients with respiratory symptoms related to perfume.     

Methacholine induces wheal-and-flare reactions in human skin but does not release histamine in vivo as assessed by the skin microdialysis technique

A number of investigations have indicated that cholinergic agonists release histamine from isolated mast cells and suggested that cholinergic stimulation releases histamine in vivo. The purpose of this study was to investigate whether the cutaneous wheal-and-flare reaction induced by methacholine challenge in human skin involves histamine release as measured by the skin microdialysis technique. Five hollow dialysis fibers were inserted intradermally in forearm skin in eight healthy subjects. Each fiber was perfused with Kreb's-Ringer bicarbonate at a rate of 3 μl/min. Dialysates were collected in 2-min fractions before skin challenge and for 20 min after intradermal injection of methacholine 10–^-3 -10^-1 M, the vehicle, and a positive control, codeine phosphate 0.3 mg/ml. Histamine was assayed spectrofluorometrically. Methacholine caused a statistically significant dose-related wheal-and-flare reaction, the flare reaction to methacholine 10^-1 M being comparable with that seen with codeine 0.3 mg/ml. No significant histamine release was observed with methacholine, cumulative histamine release of 16 ± 8nM by methacholine 10^-1 M being similar to vehicle responses of 15 ± 9 nM. Histamine release by codeine was 2524 ± 435 nM. In conclusion, methacholine-induced wheal-and-flare reactions in human skin appeared not to involve histamine release from skin mast cells.     

Passive sensitization and histamine release of basophils

This study had two purposes. First, to examine a possible functional heterogeneity of IgE regulating basophil histamine release and the effect of using two different donor cells for passive sensitization experiments. Second, to investigate basophils not releasing histamine to anti-IgE by stimulating protein kinase C with the addition of the phorbol-ester, TPA. In consecutive experiments responding donor basophils were passively sensitized with plasma from non-responding subjects. Thus, the first set of experiments included passive sensitization of acid treated donor basophils from one atopic and one non-atopic patient with plasma from 29 children with exogenous asthma to grass pollen, cat dander, or dust mites. Different secretagogues (anti-IgE, Concanavalin A, and N-formyl-methionyl-leucyl-phenylalanine) induced different histamine release responses due to a cellular property of the basophils not related to the type of IgE bound to the cell membrane. It was demonstrated that the allergen-induced histamine release did not depend on the extract or type of IgE when the biological activity of each extract and serum-specific IgE levels were similar. However, the atopic donor cells released significantly (P less than 0.05) more histamine than non-atopic donor cells. Thus, histamine release depends on the type of secretagogues and a cellular property which is maybe influenced by the presence of serum factors and a certain type of IgE in the serum of atopics. The second set of experiments included 10 patients (6 atopics and 4 non-atopics) with non-histamine releasing basophils. In the presence of 10 ng/ml TPA, however, seven of 10 patients released histamine at anti-IgE challenge. Three months later two additional patients became responsive in the presence of TPA. By passive sensitization of responding donor basophils the non-responding patients were shown to possess functionally intact IgE. Thus, the discrepancies sometimes observed between clinical symptoms, serological IgE-antibody measurements and histamine release testing in allergic patients may be related to a cellular property of basophils.     

Relationship between atopy and bronchial responsiveness to histamine in a random population

Although there are theoretical reasons to suggest that atopy might predispose to non-allergic bronchial hyperresponsiveness, previous studies have yielded conflicting results. We assessed this by determining the atopic status and bronchial responsiveness to inhaled histamine in 400 randomly selected college students. An atopy score was determined as the number of "+"s from a standard battery of seven allergy prick skin tests each graded from + to +, and the atopic status was graded as non-atopic (no +'s) mildly atopic (1 to 4 +'s), moderately atopic (5 to 8 +'s), or markedly atopic (greater than 8 +'s). Non-allergic bronchial responsiveness to inhaled histamine was measured with a standardized histamine inhalation test from which the histamine provocation concentration producing a 20% FEV1 fall (PC20) was calculated. The prevalence of bronchial hyperresponsiveness to histamine (PC20 less than or equal to 8 mg/ml) was 10.3% in the entire population. There was a progressive increase from 6.1% in the non-atopic group to 33% in the markedly atopic group (p less than 0.001). In 43 subjects with both measurable atopy score (greater than or equal to 1) and PC20 (less than or equal to 16 mg/ml), a regression of atopy score vs. log PC20 produced a small (r = -0.36) but significant (p less than 0.02) correlation. These data indicate a significant relationship exists between atopic status and increased non-allergic bronchial responsiveness to histamine. Although cause and effect cannot be inferred from this study, it is hypothesized that atopy is one factor, among others, which predisposes to non-allergic bronchial hyperresponsiveness.     

Bronchial responsiveness to methacholine and adenosine 5''-monophosphate in atopic and non-atopic preschool children with recurrent wheezing

BACKGROUND: It is well known that atopy is a major determinant of bronchial hyper-responsiveness (BHR) in both asymptomatic and asthmatic children. However, the relationship between atopy and BHR has not been well studied in preschool children with wheezing. BHR is usually measured by bronchial challenges using direct and indirect stimuli. OBJECTIVE: The aim of this study was to investigate whether atopic and non-atopic preschool wheezers display similar or different BHR profiles for direct and indirect stimuli. METHODS: Methacholine and adenosine 5'-monophosphate (AMP) bronchial challenges were performed in 4 to 6-year-old children with recurrent wheezing, using a modified auscultation method. The end-point was defined as the appearance of wheezing and/or oxygen desaturation. Atopy was determined to be present when a child had at least one positive reaction to a panel of 13 common airborne allergens in the presence of positive and negative controls. RESULTS: A positive response to methacholine (an end-point concentration < or =8 mg/mL) was observed in 89.3% (50/56) of atopic wheezers and in 83.8% (31/37) of non-atopic wheezers (P=0.44) for the difference. By contrast, the frequency of a positive response to AMP (an end-point concentration < or =200 mg/mL) was significantly higher in the atopic group (47/56, 83.9%) compared with the non-atopic group (12/37, 32.4%; P<0.01). CONCLUSION: While a majority of both atopic and non-atopic preschool wheezers were hyper-responsive to methacholine, atopic subjects were more hyper-responsive to AMP than non-atopic subjects. These findings suggest that atopic and non-atopic wheeze in preschool children are related to distinctive pathophysiologic pathways.