Yoji Iikura

Exercise-Induced Late Asthmatic Reactions with Neutrophil Chemotactic Activity

Two adults and 13 children with exercise-induced asthma had both immediate and late reductions in forced expiratory volume in one second (FEV1) after treadmill exercise. The late reactions developed 4 to 10 hours after exercise and in each instance were associated with wheezing or chest tightness (or both). Increases in neutrophil chemotactic activity, measured in the 2 adults and in 11 of the children, accompanied the reductions in FEV1 in all these subjects. In contrast, four other adults with only an immediate fall in FEV1 after exercise had only an initial elevation in neutrophil chemotactic activity, with no subsequent increase for the remaining 24-hour period. The agent responsible for the neutrophil chemotactic activity released during exercise-induced late reactions appeared to be identical to that released during immediate reactions. These observations suggest that some patients with exercise-induced asthma have late reactions that, as in the case of antigen-induced bronchoconstriction, are accompanied by the release of neutrophil chemotactic activity.

The frequency of food allergy in Australia and Asia

A review of the development of food allergy in a birth cohort of 620 Australian infants at high risk for development of atopic disease has recently been completed. Extrapolating to a random community population showed that at the age of two, egg appears the most frequent food allergen (3.2%), while cow milk (2.0%), and peanut are of similar frequency (1.9%). The prevalence of hypersensitivity to wheat and soy appears similar to sesame seed, cashew nut, hazelnut and walnut, but allergy to fish, brazil nut and shell fish are uncommon. Despite a different methodology, reports from several Asian centres suggest a similar frequency of hypersensitivity to these foods in young children although hypersensitivity to shellfish and seafood was more common than for nuts, peanut and wheat, if seafoods are part of the staple infant diet. Rice hypersensitivity was rare in both Australia and Asian countries.

Characterization of cord-blood-derived human mast cells cultured in the presence of Steel factor and interleukin-6.

We generated > 10(7) mast cells by culturing 10(7) cord blood mononuclear cells for > 10 weeks in the presence of Steel factor, interleukin-6 and prostaglandin E2. 99% of the cultured cells had tryptase-positive granules, while 18% had chymase-positive granules. Cultured mast cells contained 3.6 micrograms histamine and 3.5 micrograms tryptase per 10(6) cells. Cells sensitized with 1 microgram/ml human IgE released 58.5% histamine and 1.55 ng tumor necrosis factor (TNF)-alpha per 10(6) cells when challenged with 1 microgram/ml antihuman IgE, whereas the control cells spontaneously released 3.7% histamine and 0.18 ng TNF-alpha. Analysis for surface antigens revealed that cultured mast cells expressed the following CD molecules: 9, 13, 14, 29, 33, 38, 43, 44, 45RA, 45RB, 46, 47, 48, 49d, 50, 51, 53, 54, 55, 58, 59, 60, 61 and 117 (c-Kit). Taken together, these cultured cells seem to be functionally mature mast cells.

Factors predisposing to exercise-induced late asthmatic responses

Seventeen children developed reproducible early and late asthmatic responses (dual reactions) after cycle ergometer exercise. There was a significant correlation between the magnitude of their early and late reactions, emphasizing the direct relationship of these events. No significant differences were observed in the clinical severity of asthma, diurnal variations in FEV1, and extent of the early reaction after exercise between children with dual responses and 19 children with single reactions. These findings suggest that the occurrence of late reactions after exercise is not determined by differences in severity of disease or baseline airway reactivity in the asthmatic subjects. This view is supported by the finding that there was no significant difference in the dose of acetylcholine necessary to elicit a 20% decrease in FEV1 between eight children with dual response and seven children with single early response after exercise. The rate of spontaneous recovery from early reactions was slower in children with dual responses, suggesting that this variable may predict development of late-phase reactions in exercise-induced asthma.

Pepsin-resistant 16-kD buckwheat protein is associated with immediate hypersensitivity reaction in patients with buckwheat allergy.

Background: Buckwheat is becoming popular in many countries as a health food and the incidence of buckwheat allergy is increasing in Asia. The ingestion of small amounts sometimes provokes an anaphylactic reaction. However, it remains controversial which is the major allergen responsible for such reactions. Methods: The patients whose sera are positive for buckwheat-specific IgE antibody measured by the CAP system fluorescein-enzyme immunoassay (CAP-FEIA) were classified into two subgroups depending on the history of immediate hypersensitivity reactions (IHR). Major buckwheat allergens were identified with immunoblotting, ELISA and N-terminal amino acid sequencing. Various treatments such as pepsin digestion were added to characterize the proteins. Results: We found that the 24-kD protein that had previously been reported to be a major allergen reacted to IgE antibodies present in sera from almost all subjects (19/20) regardless of symptoms. On the other hand, 16- and 19-kD proteins were bound with IgE antibodies present in sera from 9 of the 10 patients with IHR including 8 patients with anaphylaxis but not in sera from buckwheat-specific IgE-positive subjects without IHR. After pepsin treatment, the 16-kD protein but not the 19- and 24-kD proteins remained undigested and preserved the capacity of IgE binding. This pepsin-resistant 16-kD protein had no homology with the 24-kD protein by the N-terminal amino acid sequencing. Conclusions: The 16-kD buckwheat protein was resistant to pepsin digestion and appeared to be responsible for IHR including anaphylaxis, while the pepsin-sensitive 24-kD protein was responsible for CAP-FEIA but not IHR.

FREQUENCY OF IMMEDIATE-TYPE FOOD ALLERGY IN CHILDREN IN JAPAN

The prevalence of allergy in children in Japan is increasing because of the changes in their life-style and diet caused by a strong western influence. Especially in the pediatric field, allergic diseases including food allergy are a growing problem. Many problems are related to food allergy but in the pediatric field, it is especially important to control the immediate-type reactions. The purpose of this study was to estimate the percentage of children in Japan with immediate-type reaction due to food allergy and the common types of food allergens.

Mediators in exercise-induced asthma

Circulating concentrations of the mast cell-associated mediators, histamine and neutrophil chemotactic factor (NCF) of high molecular weight, were measured in atopic and nonatopic asthmatics after treadmill exercise. Elevations in the concentrations of both mediators accompanied the development of exercise-induced asthma (EIA). Normal individuals did not release mediators or develop bronchoconstriction after an identical exercise. The elaboration of mediators was not due to the onset of airflow obstruction, the postexercise basophilia, or the exercise task per se. A treadmill exercise undertaken while inhaling fully conditioned air inhibited EIA and NCF release; in contrast the same exercise undertaken while breathing cold, dry air elicited EIA and the production of mediators. This suggests that the stimulus for EIA and mediator release may be identical. Late-phase asthmatic reactions occur 3 to 9 hr after exercise in some asthmatics and are accompanied by the appearance of circulating NCF, as previously reported in allergen-induced late responses. In addition to the contribution of mediators to the spasmogenic reaction in EIA, mediators may contribute to bronchial inflammation by activating circulating leukocytes. There was a kinetic increase in the expression of neutrophil C3b receptors in EIA (+) asthmatics for up to 60 min after treadmill exercise. The enhancement of C3b receptors, as evidence of neutrophil activation, was preceded by release of NCF and reductions in peak expiratory flow rates. The prior administration of cromolyn inhibited EIA, NCF release, and enhancement of C3b receptors. These changes were not observed in EIA (-) asthmatics after an identical exercise task. These findings support the view that mediators are released in EIA and may play an important role in its pathogenesis.

Altered eosinophil levels as a result of viral infection in asthma exacerbation in childhood

Respiratory viral infection is known to be a significant cause of asthma exacerbation. Eosinophils have been considered to play an important role in the pathogenesis of virus‐induced asthma exacerbations. To determine how often asthma exacerbation is caused by virus infections and to examine the relationship between eosinophilia and asthma episode, we investigated 64 children who experienced asthma attacks between October 1999 and March 2000. We used rapid enzyme immunoassays to detect antigens of respiratory syncytial virus (RSV), influenza A virus, and adenovirus in nasopharyngeal secretions (NPS) of these children, and enumerated eosinophils in the blood and NPS. We detected RSV in 27% and influenza A virus in 17% of the patients. No adenovirus infection or RSV/influenza A co‐infection was detected. RSV‐infected children were younger (3.85 ± 0.83 years old) than influenza A virus‐infected patients (5.23 ± 1.34 years old). Eighty‐two per cent of patients in the RSV group and 36% of patients in the influenza A virus group had moderate‐to‐severe asthma episodes (p < 0.05). In RSV‐infected children, the eosinophil counts in NPS were higher in the ‘severe’ group, and younger patients had a greater number of eosinophils in their NPS than older patients (p < 0.05). These trends were not found in influenza A virus patients. In conclusion, our results indicate that, compared with influenza A virus‐induced asthma attacks, RSV infection had a higher probability of being associated with asthma exacerbation in infants and younger children and induced attacks of greater severity. The increase in the number of eosinophils in the NPS of RSV‐infected children may be responsible, in part, for these differences.

Influence of SNPs in cytokine-related genes on the severity of food allergy and atopic eczema in children

Although many single nucleotide polymorphism (SNP) studies have reported an association of atopy, allergic diseases and total serum immunoglobulin E (IgE) levels, almost all of these studies sought risk factors for the onset of these allergic diseases. Furthermore, many studies have analyzed a single gene and hardly any have analyzed environmental factors. In these analyses, the results could be masked and the effects of other genes and environmental factors may be decreased. Here, we described the correlation between four genes [interleukin (IL)‐4 (C‐590T), IL‐4 receptor (A1652G), FCER1B (G6842A) and STAT6 (G2964A)] in connection with IgE production; the role of IL‐10 (C‐627A) as a regulatory cytokine of allergy; and the severity of food allergy (FA) and atopic eczema (AE) in 220 Japanese allergic children. In addition to these SNPs, environmental factors, i.e., patients attitude, indoor envirmonment, and so on, were also investigated in this study.

Interferon-gamma promotes the survival and Fc epsilon RI-mediated histamine release in cultured human mast cells.

We examined the effects of interferon‐γ (IFN‐γ) on 100% pure human mast cells generated in suspension cultures of umbilical cord blood mononuclear cells in the presence of stem cell factor (SCF) and interleukin‐6 (IL‐6). When mast cells were suspended in serum‐free medium without any cytokine after the withdrawal of SCF and IL‐6, they died over a period of 5 days because of apoptosis. IFN‐γ in the cultures suppressed apoptosis and prolonged their survival in a dose‐dependent manner. This survival‐promoting effect of IFN‐γ was blocked by neutralizing antibodies to IFN‐γ or to IFN‐γ receptor (IFN‐γR). When mast cells were incubated with IFN‐γ in serum‐free medium for more than 4 hr during sensitization, immunoglobulin E (IgE)/anti‐IgE antibody‐induced histamine release was effectively enhanced. Polymerase chain reaction (PCR) amplification of the α‐chain of IFN‐γR (IFN‐γRα) yielded products of the correct size predicted from the sequence of the receptor. In addition, flow cytometry using anti‐IFN‐γR monoclonal antibodies (mAbs) indicated that these mast cells bear IFN‐γR on their surface. These findings suggested that IFN‐γ activates human mast cells via specific receptors in certain aspects of inflammatory reactions.