Chronic idiopathic urticaria: Profiles of skin mast cell histamine release during active disease and remission

Chronic idiopathic urticaria (CIU) is characterized by the increased releasability of histamine by mast cells in normal-appearing skin. In active CIU, this abnormality is consistently present. To determine if this finding subsides when the disease goes into remission phase, we analyzed the histamine secretion in patients with CIU in remission (CIUR) compared with that of patients with CIU and in normal control (NC) subjects, with the skin-chamber technique. The profiles of histamine release in sites challenged with compound 48/80 were significantly different in the groups with CIU and CIUR. Furthermore, patients with CIUR did not differ from NC subjects in terms of histamine releasability under compound 48/80 stimulation (p greater than 0.1). These data suggest that the state of excessive skin mast cell sensitivity is a reversible and transient phenomenon in CIU disease.     

The effect of food and exercise on the skin response to compound 48/80 in patients with food-associated exercise-induced urticaria-angioedema

Food-associated, exercise-induced urticaria-angioedema is increasingly being recognized. We studied five atopic individuals in whom ingestion of food was followed by exercise-induced urticaria-angioedema. The combined effect of food and exercise on skin wheal response to compound 48/80 and histamine was studied. Symptoms could be reproduced in only four of the patients who performed strenuous exercise after ingestion of food to which they were skin sensitive. When symptoms appeared, that is, after a combination of food and exercise challenge, there was a marked increase in the wheal response to compound 48/80 (greater than 200%) and not to histamine. Food or exercise challenge alone did not induce any significant change in the skin reactivity to compound 48/80 or to histamine. It was concluded that mast cell releasability could be increased when the patient was subjected to combined factors.     

Increased compound 48/80 induced local histamine release from nonlesional skin of patients with chronic urticaria

Histamine released from skin mast cells in normal skin sites of patients with idiopathic chronic urticaria (CU) and normal volunteers was assessed with the skin chamber technique. Small amounts of histamine were spontaneously and continuously released during the 4-hour observation in both groups but were twofold greater in patients with CU. In addition, histamine levels were significantly more elevated in sites challenged with compound 48/80 than in unstimulated sites. Patients with CU differed from normal volunteers in that histamine release induced by 48/80 compound was significantly greater at 1 and 2 hours after challenge. The number of mast cells and the histamine content of the skin did not differ in the two groups. These observations could suggest a functional defect at the mast cell level rather than a difference in their numbers.     

Skin reactivity to codeine and histamine during prolonged corticosteroid therapy

Corticosteroids, used in low to moderate doses for short time intervals, do not suppress immediate percutaneous skin test responses to allergens, compound 48/80, or histamine. During routine skin testing, in our clinic, intradermal injection of codeine (1 mg/ml) and histamine (0.02 mg/ml) are used as positive controls. We had noted that responses to codeine but not histamine are decreased in some patients with asthma who had been receiving prolonged corticosteroid therapy. Therefore, we retrospectively compared skin test responses to codeine and histamine between 25 adult subjects with asthma receiving steroids (group I) and 25 age-matched control subjects (group II). In group I, the mean wheal diameters, induced by codeine but not histamine, were significantly less than diameters in group II. This decreased skin test reactivity to codeine was not due to effects of theophylline also taken by group I subjects, since the skin test reactions of other subjects with asthma, treated with theophylline but not steroids (group III), were not significantly different from reactions in group II. We conclude that prolonged courses of corticosteroids do not appear to alter histamine-induced vascular reactivity in skin but may affect cutaneous mast cell responses by an undefined mechanism.     

Skin reactivity to histamine and codeine in unselected 9-year-old children from Italy, Poland and Libya

BACKGROUND: Previous studies have shown that histamine skin reactivity (the dimensions of a skin wheal elicited by a prick with histamine 10 mg/ml) in unselected school children has increased in Italy during the past two decades and is higher in Italy than in Poland. Hence this variable can probably be influenced by a changing or different lifestyle. The aim of this study was to compare skin reactivity to histamine and codeine (a marker of histamine releasability from mast cells) in schoolchildren from countries with different lifestyles. METHODS: Six previously unstudied unselected populations of 9-year-old schoolchildren (two each from Poland, Italy, and Libya; n = 863 subjects; 49.0% males) were pricked with two concentrations of histamine (10 and 1 mg/ml) and codeine (90 and 9 mg/ml). RESULTS: The higher concentrations of both pharmacologic agents tested yielded significantly different wheal areas in the three countries: Poland < Italy < Libya (histamine, 11.8, 16.1 and 20.7 mm2; codeine, 9.2, 13.2 and 16.2 mm2; p < 0.001 for all comparisons). The lower concentrations elicited almost matching results. Histamine wheal areas correlated closely with areas elicited by codeine in the same individual: angular coefficients of the histamine to codeine regression lines were 0.535, Italy; 0.551, Libya; 0.612, Poland; and 0.581 for the whole population. More histamine was needed to produce a wheal in Poland than in Libya: a 20-mm2 wheal required an injected histamine concentration of about 8.8 mg/ml in Libya, 29.5 mg/ml in Italy and 102.1 mg/ml in Poland. CONCLUSION: More studies are necessary to explain the observed international differences in skin histamine reactivity and their effect on the prevalence of positive allergen skin tests.     

Dopamine inhibition of histamine-mediated cutaneous responses

Several patients receiving dopamine for hypotension were skin tested for possible penicillin sensitivity. Not only were the penicillin skin tests negative but also the histamine control. On the possibility that dopamine might affect cutaneous histamine responses, we examined the effect of dopamine on histamine, antigen, morphine, and compound 48/80 skin responses. Both intradermal and intravenous dopamine selectively inhibited histamine but not antigen, morphine, or compound 48/80 skin responses, and the inhibition was in a dose-related fashion. This observation indicates that histamine should not be used to demonstrate dermal reactivity in patients receiving dopamine. The results of this study also suggest that histamine may not be the sole mast cell-derived mediator involved in the wheal-and-flare reaction characteristic of immediate-type skin tests since dopamine did not affect skin reactions caused by endogenous mast cell degranulation. Finally, the possible use of dopaminergic drugs in diseases with histamine-associated symptoms is discussed.     

Effects of infused histamine on asthmatic and normal subjects: comparison of skin test responses

The effect of histamine infused intravenously at sequentially increasing concentrations (0.05, 0.1, 0.25, 0.5, and 1 μ/kg/min) on the wheat responses to intradermal histamine and compound 48/80 in eight normal and five asthmatic subjects and to allergen skin tests in five asthmatic subjects was measured. These measurements were repeated following pretreatment with the H-1 antagonist hydroxyzine or the H-2 antagonist cimetidine, either alone or in combination. Histamine infused in progressively increasing concentrations had no effect on histamine, compound 48/80, or allergen skin tests either before or after H-1 or H-2 antihistamine treatment. No significant differene was found in the concentration of histamine or compound 48/80 required to elicit a 10-mm wheat in normal or asthmatic patients. Pretreatment with the H-2 antagonist alone had no effect on histamine or compound 48/80 skin tests in either group. However, the H-1 antagonist significantly reduced the wheat response to histamine (p < 0.05 normal; p < 0.025 asthmatics) and compound 48/80 (p < 0.05 normal; p < 0.025 asthmatics) in both groups. The combination of H-1 and H-2 histamine antagonists was not significantly different from the H-1 antagonist alone. Antigen skin testing was suppressed 82% by the hydroxyzine alone; no significant suppression was induced by cimetidine alone, and the combination of hydroxyzine plus cimetidine was only slightly more effective than hydroxyzine alone. The results indicate that blockade of histamine H-2 receptors with cimetidine has little or no additive effect on H-1 antagonist-suppressed skin test responses to histamine, compound , or antigen. Furthermore, the capacity of histamine to suppress histamine release in vitro from basophils was not demonstrated in vivo assessing skin mast cell responses. This observation combined with earlier studies on the human lung mast cell, which also failed to demonstrate that histamine had an inhibitory action, suggests that the human mast cell may not respond to histamine like the basophil and that this discrepancy may represent a fundamental difference in the cell types.     

Plasma histamine in patients with chronic renal failure and nephrotic syndrome.

Plasma histamine concentrations were measured using a commercially available monoclonal antibody radioimmunoassay in 38 patients with nephrotic syndrome, end stage renal failure, those receiving haemodialysis, and those receiving continuous ambulatory peritoneal dialysis to determine whether histamine may mediate damage to glomerular capillaries and arterial endothelium. Plasma histamine concentrations were significantly increased in all four patient groups when compared with those of controls and were the highest in two patients with pruritus. Raised plasma histamine concentrations in such patients are consistent with the hypothesis that histamine may contribute to the damage to glomerular capillaries and to arterial endothelium. These effects may be relevant to the pathogenesis of glomerular disease and atherosclerosis. Histamine may also contribute to the pathogenesis of pruritus in patients with chronic renal failure.     

Histamine release from isolated rat mast cells: effect of morphine and related drugs and their interaction with compound 48/80

Morphine, codeine, and pethidine induced histamine release from isolated rat mast cells in the same concentration range. The histamine release induced by morphine and by codeine occurred rapidly, in contrast to the release induced by pethidine. The effect of morphine was reduced by the presence of calcium, enhanced by magnesium, and unaffected by phosphatidyl serine. Pretreatment of the cells with the ionophore A23187 inhibited the response to morphine, indicating a requirement for intracellular calcium.The release induced by morphine and by codeine was inhibited by antimycin A, but the release induced by pethidine was unaffected. The effect of morphine was inhibited by both naloxone and codeine, and naloxone also reduced the release induced by codeine. The effect of pethidine was inhibited by codeine, whereas the influence of naloxone was less pronounced.Preincubation of cells with lower concentrations of morphine reduced the response to a subsequent exposure to morphine. The release induced by compound 48/80 was similarly inhibited after preincubation with morphine as well as after preincubation with codeine and with pethidine. In contrast, preincubation with pethidine enhanced the effect of subsequent incubation with pethidine. Preincubation with low concentrations of compound 48/80 reduced the response to compound 48/80 in the absence of calcium, but was without effect in the presence of calcium.It is suggested that morphine, codeine, pethidine, and naloxone act on common or closely related sites on the mast cell and that these sites may account for the action of compound 48/80 as well. The results indicate similar mechanisms for the histamine release induced by morphine and by codeine, whereas pethidine clearly has a different mode of action.     

Discrimination between urticaria-prone and other allergic patients by intradermal skin testing with codeine

To study the ability of cutaneous mast cells to degranulate in urticaria-prone patients, subjects were skin tested with the known mast cell degranulator, codeine sulfate. Sensitivity to codeine as determined by the concentrations of codeine necessary to cause a net wheal of 5 mm was compared between urticaria-prone subjects, allergic subjects, and normal control subjects. Urticaria-prone subjects were more sensitive to codeine at every concentration tested and exhibited a mean reactivity to codeine that was almost 100 times that of the other allergic individuals and normal control subjects. This difference could not be explained by an increased sensitivity to histamine in 71% of urticaria-prone patients nor by any dermatographic tendencies or increased relative allergic reactivity. These findings suggest that codeine skin testing can be used to identify a distinct population of patients with urticaria.     

Human mast cell heterogeneity: histamine release from mast cells dispersed from skin, lung, adenoids, tonsils, and colon in response to IgE-dependent and nonimmunologic stimuli

We have compared the ability of anti-IgE, calcium ionophore A23187, substance P, compound 48/80, poly-L-lysine, and morphine to release histamine from mast cells of human skin, lung, adenoids, tonsils, and colon. Use of a single collagenase/hyaluronidase dispersion technique for all tissues has allowed comparisons of reactivity to be made that are free from methodological variations. Mast cells from all tissues examined secreted histamine in response to anti-IgE and calcium ionophore A23187. However, only skin mast cells were responsive to substance P, compound 48/80, poly-L-lysine, and morphine. Activation of human skin mast cells by these nonimmunologic stimuli clearly distinguishes them from the mast cells of human lung, adenoids, tonsils, and colon and is indicative of functional heterogeneity within the human mast cells population. We propose that the presence of functional receptor sites for neuropeptides and basic compounds on skin mast cells that are not present in mast cell populations from mucosal or lymphoid sources reflects a specialized role for these cells in vascular homeostasis.     

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.     

Anin vitro model system to evaluate pulmonary macrophage,endothelial cell,and neutrophil interactions

A defective histaminergic dilating system in the digital vasculature has been proposed for the pathophysiology of Raynaud's phenomenon but this is not supported by studies of digital intradermal responses to histamine or agents which cause histamine release. The vascular responses (measured by planimetry and laser Doppler flowmetry) of digital skin over the middle phalanx to intradermal histamine, compound 48/80 and Substance P have now been studied at low temperatures (because it is in the cold that Raynaud's phenomenon occurs) in normal controls and patients with primary Raynaud's phenomenon. A cold-related attenuation of mast cell histamine release by compound 48/80 was observed in both normal and Raynaud's subjects. These results do not support a major histaminergic defect in the pathogenesis of Raynaud's phenomenon.     

Histologic studies of human skin test responses to ragweed, compound 48-80, and histamine

The patterns of mast cell and eosinophil changes at the site of intradermal injection of ragweed, compound $\text{48}\text{80}$, and histamine were studied by histologic techniques. Dermal biopsies of 23 ragweed skin test-positive subjects revealed increasing numbers of eosinophils and decreasing numbers of mast cells over a 240 minute period following injection of antigen. The eosinophil response began in the periappendigeal areas, extended into the interstitium, and occurred in sites with depressed wheal reactions in hydroxyzine-treated subjects. These cellular patterns did not occur at ragweed skin test sites in nonatopic subjects. However, compound $\text{48}\text{80}$ induced similar eosinophilic responses in both atopics and nonatopics. Histamine injection was followed by no eosinophilic or mast cell changes. These findings support the hypothesis that eosinophil responses in reagin-mediated reactions may occur secondary to release of a mediator other than histamine of mast cell origin.     

Effect of Terbutaline, a β2-adrenergic Receptor Stimulating Compound, on Cutaneous Responses to Histamine, Allergen, Compound 48/80, and Trypsin

The beta-adrenoceptor stimulating agent terbutaline (2 ng-2 microgram) injected intradermally in eight atopic subjects produced a dose-dependent inhibition of the skin reactions induced by subsequently injected allergen. After injection of 0.5 microgram terbutaline inhibition of the flare and weal responses was demonstrable throughout the observation period of 90 min. The flare response induced by histamine, the histamine liberator compound 48/80 and the proteolytic enzyme trypsin was not inhibited by terbutaline in the doses used, suggesting a selective action of terbutaline on the allergen-induced response. The weal response elicited by histamine and compound 48/80 was slightly reduced by 2 microgram terbutaline. It is suggested that pretreatment of the skin with terbutaline interferes with the ability of the cutaneous mast cells to respond to challenge with allergen and that terbutaline produces this effect in doses lower than those needed to counteract the permeability increasing effect of released mediator substances.     

Mast cell subtypes from human lung tissue: Their identification,separation, and functional characteristics

The contribution of mast cell subtypes and their different mediators to the pathogenesis of chronic obstructive lung diseases (COLD) has not yet been established. In the present study, enzymatic digestion, centrifugal elutriation and Percoll gradient centrifugation were used to obtain two populations of mast cell subtypes from human lung tissue. Mast cell subtypes were challenged with anti-human IgE, propranolol, compound 48/80, or opsonized zymosan. Both subtypes were able to release histamine, but differed in the amount of the amine released. Only the formalin-sensitive and alcian blue-positive type (FS-AB) released histamine on challenge with opsonized zymosan. The same subtype was able to release leukotriene C₄ (LTC₄) after challenge with anti-human IgE. The other subtype, the formalin-insensitive and alcian blue-positive type (FI-AB), did not respond to opsonized zymosan and did not release LTC₄ after challenge with anti-human IgE. Stimulation with propranolol or compound 48/80 did not release histamine from the FS-AB mast cells while the FI-AB mast cells released only about 10% of their histamine content upon challenge with these secretagogues.     

Acute Stress Modulates the Histamine Content of Mast Cells in the Gastrointestinal Tract Through Interleukin-1 and Corticotropin-Releasing Factor Release in Rats

Stress results in activation of the hypothalamic pituitary adrenal axis and affects illnesses such as neuroinflammatory syndrome. In vivo acute stress (restraint stress) induces gastrointestinal function disturbances through colonic mast cell activation. This study investigated the effect of acute stress in histamine content of colonic mast cells, and the central role of interleukin-1 (IL-1) and corticotropin-releasing factor (CRF) in this effect. After a restraint stress session colonic segments were isolated and submitted to three protocols: (i) determination of histamine levels by radioimmunoassay (RIA) after incubation with 48/80 compound, (ii) evaluation by histology of mucosal mast cell (MMC) number and (iii) determination of histamine immunoreactivity of MMC. These procedures were conducted (1) in sham or stressed rats, (2) in stressed rats previously treated with intracerebroventricular ( i.c.v. ) IL-1ra or α-helical CRF9-41, (3) in naive rats pretreated with i.c.v. rhIL-1β or CRF and (4) in rats treated with central IL-1β and CRF plus α-helical CRF and IL-1ra, respectively (cross-antagonism reaction). Acute stress increases histamine content in colonic mast cells, without degranulation. i.c.v. pretreatment with IL-1ra or α-helical CRF9-41 blocked stress-induced mast cell histamine content increase. Both i.c.v. rhIL-1β and CRF injections reproduced the stress-linked changes. i.c.v. treatment with CRF antagonist blocked i.c.v. rhIL-1β-induced mast cell histamine content increase, whereas central IL-1ra did not affect stress events induced by i.c.v. CRF administration. These results suggest that in rats acute stress increases colonic mast cell histamine content. This effect is mediated by the release in cascade in the brain first of IL-1 and secondly of CRF.     

Increased releasability of skin mast cells after exercise in patients with exercise-induced asthma

The role of lung mast cells in exercise-induced asthma (EIA) is controversial. To investigate whether the skin mast cell releasability is increased after exercise in EIA, 49 young atopic men with or without asthma took part in a free-running test for 6 min and were given skin prick tests using morphine, a mast cell secretagogue, before and after the exercise. The mean diameters of the wheal induced by morphine in patients with EIA were not significantly different from those in patients without EIA before exercise, although the baseline lung function was significantly lower and the airway hyperresponsiveness, the peripheral blood eosinophil count, and the size of the wheal in response to Dermatophagoides pteronyssinus were significantly higher in patients with EIA. However, the differences of the morphine-induced wheal diameter between patients with EIA and those without EIA became significant at 120 min after exercise (p<0.05), while the responses to histamine were not significantly different. These results suggest that exercise increases the releasability of skin mast cells in EIA patients whose asthma/allergy are relatively severe.     

Histamine releasability of basophils and skin mast cells in chronic urticaria

In order to clarify the pathogenetic role of basophils and mast cells in chronic urticaria, histamine and leukotrienes (LT) C₄ release was examined in washed mixed leukocytes (n=8) and skin mast cells (n=5) from patients with chronic urticaria and compared with the same cells from normal controls (n=9). Anti-IgE-stimulated basophil histamine release was significantly reduced in urticaria patients (median 2.9% vs 15.1% in normal controls), whereas histamine release to A23187, FMLP, and PAF, as well as anti-IgE-induced LTC₄ release, showed no differences in both groups. In contrast, anti-IgE-stimulated skin mast cells from urticaria patients reacted similarly to those of controls (median histamine release 11.4% vs 14.2% in normal controls). Pretreatment of the cells with interleukin (IL)-3 upregulated responsiveness of basophil histamine release to anti-IgE in urticaria patients (median histamine release 14.3%), but pretreatment with the H₂-antagonist cimetidine showed no effect. These data show that reduced basophil histamine releasability in chronic urticaria is not H₂ mediated. It is a stimulus-, mediator-, and cell type-restricted phenomenon that can, at least partially, be reversed in the presence of the cytokine IL-3.     

Inhibitory effect of cetirizine 2HCl on eosinophil migration in vivo

The effect of a potent antihistamine, cetirizine, was studied on allergic patients and normal subjects by means of an in-vivo 'skin window' technique. All subjects showed significant inhibition of skin-test responses to grass pollen, compound 48/80, histamine and methacholine, after administration of a single dose (10 mg) of cetirizine. Compared to placebo, cetirizine significantly decreased the eosinophils attraction at skin sites challenged with grass pollen and compound 48/80. In allergic patients no change in eosinophil migration pattern was noted with histamine and methacholine skin-tested sites. In normal subjects, compound 48/80 and histamine did not induce eosinophil accumulation and cetirizine did not modify cellular patterns as compared to placebo. These results suggest that cetirizine acts on eosinophil migration by inhibiting the release of mast cell mediators or inhibiting the eosinophilotactic mediators themselves.