LTB4, a proinflammatory lipid mediator generated from arachidonic acid through the action of 5-lipoxygenase, has been known for over two decades and is implicated in a wide variety of inflammatory disorders. BLT1, a G-protein-coupled receptor, has recently been identified as a high affinity receptor specific for LTB4. Recent studies in allergen-induced airway hyperresponsiveness and inflammation using mice lacking BLT1 have shown crucial new roles for leukotriene B4 and BLT1 in Th2 cytokine IL-13 production from lung T cells and recruitment of antigen-specific effector CD8+ T cells, suggesting novel mechanisms for their actions. The leukotriene B4-BLT1 pathway is an important target for the treatment of bronchial asthma.

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

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Basophils and mast cells are effecter cells in allergen/IgE-mediated immune responses. They induce type 1 immediate immune response in airway or other organ, resulting in bronchial asthma and other allergic diseases. However, they also play a critical role in host defense against infection with helminthes. Upon linkage of FcεRI with a complex of allergen and IgE, basophils and mast cells release a large amount of Th2 cytokines and chemical mediators. Therefore these responses are "acquired allergic responses" and induce allergic diseases, such as bronchial asthma. However, basophils and mast cells derived from cultured bone marrow cells with IL-3 for 10 days express IL-18Rα chain and produce Th2 cytokines in response to the stimulation with IL-3 and IL-18 without FcεRI cross-linkage. Furthermore, they produce Th2 cytokines upon stimulation with several TLR ligands, such as LPS. This finding may suggest the presence of allergen/IgE-independent allergic responses, which we would like to designate as "innate allergic response". However, in vivo treatment with IL-18 and IL-2 protects against gastrointestinal nematode infection by activating intestinal mucosal mast cells in STAT6-independent manner, suggesting the importance of innate allergic response against helminth infection. Here we discuss the functional role of IL-18-induced "innate allergic response" in disease and host defense.

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Omenn syndrome (OS) is a form of severe combined immunodeficiency (SCID) characterized by erythrodermia, hepatosplenomegaly, lymphadenopathy, and alopecia. In patients with OS, B cells are mostly absent, T-cell counts are normal to elevated, and T cells are frequently activated and express a restricted T-cell receptor (TCR) repertoire. Thus far, inherited hypomorphic mutations of the recombination activating genes either 1 or 2 (RAG1/2) have been detected in most OS patients. We have recently experienced a rare case of OS showing the revertant mosaicism due to multiple second-site mutations leading to typical OS clinical features with RAG1-deficient SCID. In this review, we will focus on the variation of several phenotypes of OS.

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Vernal keratoconjunctivitis (VKC), a severe form of ocular allergic disease, is characterized by the formation of giant papillae at the upper tarsal conjunctiva and corneal lesions that threaten vision. Recent evidence indicates that resident fibroblasts function as immune modulators in the pathogenesis of the chronic allergic inflammation associated with VKC. The T helper 2 (Th2) cell-derived cytokines interleukin (IL)-4 and IL-13 stimulate the migration and proliferation of conjunctival fibroblasts as well as protecting these cells from apoptotic cell death, effects that likely underlie the hyperplasia of fibroblasts that contributes to the formation of giant papillae. Conjunctival fibroblasts also synthesize extracellular matrix proteins and tissue inhibitors of metalloproteinases as well as down-regulate the expression of matrix metalloproteinases in response to these cytokines, effects that likely contribute to the excessive deposition of extracellular matrix that is characteristic of giant papillae. Stimulation of fibroblasts in the corneal stroma with the combination of a proinflammatory cytokine and either IL-4 or IL-13 results in up-regulation of the expression of the chemokine eotaxin and thymus- and activation-regulated chemokine as well as of vascular cell adhesion molecule-1, which together mediate the infiltration and activation of eosinophils and Th2 cells. Fibroblasts therefore appear to play a central role in the induction and amplification of ocular allergic inflammation and the consequent development of giant papillae and corneal disorders in individuals with VKC. Fibroblasts and fibroblast-derived factors thus represent new and potentially important therapeutic targets for treatment of the giant papillae and corneal disorders associated with VKC.

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Background: Accurate diagnosis of allergy to specific fungal species is confounded by the variability in allergens occurring with different diagnostic systems. We compared the halogen immunoassay (HIA), which uses allergens expressed by freshly germinated spores that are bound to protein binding membranes (PBM), with the commercial Pharmacia UniCap^® assay (CAP) and with skin prick tests (SPT).
Methods: Serum from 60 subjects was used; 30 were SPT positive and sensitized to at least one of Alternaria alternata or Aspergillus fumigatus and the other 30 were SPT negative to these fungi but known to be sensitized to non-fungal allergens. All sera were analyzed by CAP against A. alternata, A. fumigatus, Cladosporium herbarum and Epicoccum purpurascens. For HIA, spores from reference cultures belonging to these four species were germinated on PBM, laminated and then probed with each serum. Two independent observers using an ordinal ranking system quantified the intensity and occurrence of the resultant immunoglobulin E (IgE) immunostained haloes around spores and this was statistically compared with the results of the two conventional immunodiagnostic techniques.
Results: Germinated conidia of each species expressed detectable allergen in the HIA. The agreement between the ordinal rank scores assigned by the pair of observers was very good (k ≥ 0.8) and only differed for A. fumigatus (k = 0.66) . Between 3% and 7% of SPT negative sera was identified by HIA to have specific IgE towards A. fumigatus and A. alternata. For all four species tested there were strong correlations between HIA and CAP (P < 0.0001). However the correlation of both HIA and CAP to SPT was weaker for A. alternata (r_s = 0.44, P < 0.0153) and absent for A. fumigatus.
Conclusions: Overall, the HIA is a new immunodiagnostic technique for the detection of sensitization to fungal allergens that correlates significantly with CAP and to a lesser extent with SPT. This may be due to extract variability and system differences. The significance of this derives from the unique ability of the HIA to measure IgE antibodies to the undegraded allergens that are actively secreted by germinating conidia and hyphae. These are the natural agents of exposure to fungi, and as such, are most likely to be relevant to clinical disease.

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Background: Although allergen avoidance is known to be important for treating atopic diseases, there is a very limited amount of time for clinical education of patients on this topic.
Methods: We compared the effect of the thorough home visit counseling (>60 minutes per visit) for avoiding house dust mites (HDMs) with that of regular guidance in our clinics (10 minutes per patient). We enrolled 36 children with asthma (7 years of age or younger; mean, 3.8) in this study under an informed consent. After enrolling the 24 patients for the home visit, 12 families were enrolled as controls for the regular clinical guidance. Between June 1995 and June 1996, we visited the homes of 24 children with asthma enrolled in this study every month and performed a thorough HDM-avoidance counseling of more than 60 minutes (home visit counsel) at each visit. We compared the effects of this counseling with those of the regular clinical guidance given (10 minutes per patient) to the remaining 12 children with asthma. We also evaluated the effect of home visit counseling on children of two subgroups, i.e., an atopic (with positive IgE antibody against HDM) and a non-atopic (without detectable IgE antibodies against 8 common allergens) subgroup.
Results: Home visit counseling markedly reduced the frequencies of asthma attacks (p < 0.000001), the required theophylline dosages (p < 0.0005), and the levels of HDM allergens (p < 0.0005) in the atopic subgroups, whereas the effect of regular counseling on these 3 items was relatively less (p < 0.05 or not significant). Surprisingly, home visit counseling also markedly reduced the asthma attacks (p < 0.00001) and theophylline dosages (p < 0.00001) of children with non-atopic asthma.
Conclusions: These results suggest that thorough allergen avoidance counseling is effective for children with non-atopic asthma as well as atopic asthma.

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Background: Cough variant asthma has recently been described, mainly as airway inflammation in relation to bronchial asthma, but the relationship between the two types of asthma remains unclear. Further studies of cough receptor sensitivity are necessary to fully characterize cough variant asthma.
Methods: We assessed the relevance of testing cough sensitivity using an Astograph^® with continuous capsaicin inhalation, and compared the results with those obtained using intermittent inhalation. We showed the clinical applicability of testing cough sensitivity (0.156—80μM capsaicin; five or more coughs, 1 minute of continuous inhalation at each concentration) using this method. We compared cough sensitivity among patients with pure cough variant asthma who did not develop bronchial asthma after an observation period of at least 1 year, patients with bronchial asthma and healthy individuals.
Results: The continuous cough sensitivity test using the Astograph^® was reproducible and reliable. Cough sensitivity in patients with pure cough variant asthma was significantly higher than that in healthy individuals.
Conclusions: The cough sensitivity of patients with cough variant asthma is not necessarily identical to that of healthy individuals.

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Background: This study was conducted to investigate the efficacy and safety of 0.025% levocabastine hydrochloride in Japanese subjects with seasonal allergic conjunctivitis and its duration of action using the conjunctival allergen challenge (CAC) test.
Methods: Twenty-four asymptomatic subjects were randomized to instill 0.025% levocabastine ophthalmic suspension in one eye and vehicle in the other eye 10 minutes before the CAC test. Signs and symptoms of allergic conjunctivitis were scored 10, 15, and 25 minutes after the CAC test. The duration of drug effects was also evaluated by allergen rechallenge 4 hours after levocabastine administration. The itching score for each eye as the primary efficacy endpoint was assessed 15 minutes after the CAC test using a 5-point scale.
Results: The mean itching score in the levocabastine-treated group was 0.08 ± 0.06, which was significantly lower than the mean score of 1.98 ± 0.16 in the vehicle group (P < 0.0001). The redness and chemosis of the conjunctiva were also improved significantly compared with the vehicle group. Levocabastine showed prolonged efficacy in inhibiting itching (0.42 ± 0.12 vs 0.94 ± 0.17, P < 0.0002) and redness (1.04 ± 0.18 vs 1.42 ± 0.22, P < 0.01) of the conjunctiva upon the rechallenge test. No significant topical or systemic adverse safety findings were observed in the levocabastine group.
Conclusions: The results indicate that 0.025% levocabastine ophthalmic suspension is effective and safe in the treatment of allergic conjunctivitis with a duration of action of at least 4 h.

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Background: A new electronic mesh nebulizer, eMotion^® is known to have higher performance compared to conventional nebulizers. However, there are some concerns about whether too much delivered dose might cause side effects with higher frequency.
Methods: To evaluate the safety and usefulness of the nebulizer, we measured changes in heart rates and lung functions of 73 asthmatic children when they inhaled 1μg/kg of procaterol with eMotion^® or a conventional nebulizer, Junior BOY^®.
Results: In 34 children with mild asthma exacerbation, physical findings, lung function and transcutaneous oxygen saturation levels were improved after inhalation using both nebulizers. No adverse effects including significant increase of heart rate were found. Improvements in the rates of the parameters were comparable. When response to beta2-agonist inhalation was checked in 39 children in stable condition, similar degrees of improvement in lung function were observed, and heart rates did not change after inhalation with either nebulizers.
Conclusions: Safety and efficacy was comparable between eMotion^® and a conventional nebulizer when it was used to administer beta2-agonists in asthmatic children. However, from the fact that eMotion^® needs only 3—4 minutes to inhale 2 mL solution, eMotion^® could be more useful for most children who usually do not prefer longer inhalation time with conventional compressor nebulizers.

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Background: Human mast cells (MCs) were classified into at least two subtypes, i.e., tryptase- and chymase-positive MCs (MC_TC) and tryptase-only-positive MCs (MC_T). However, differences in global molecular expression between these subtypes are unknown.
Methods: We analyzed public microarray data of MC subtypes derived from various tissues and those of peripheral blood granulocytes by using hierarchical clustering methods to understand the global gene expression profiles.
Results: All the transcripts subjected to this clustering analysis were classified into two large clusters, i.e., MC-preferential or granulocyte-preferential. In the original works, MCs from tonsil, lung and skin had been cultured for more than several weeks to obtain highly viable and pure cell populations, and these MCs retained their typical profiles such as intensities of chymase protein expression. Most of the transcripts were commonly expressed by these MC subtypes. However, tonsil-derived MCs and skin-derived MCs but not lung-derived MCs expressed high levels of chymase (CMA1) as expected for the properties of MC_TC and MC_T. These CMA1-high MCs and CMA1-low MCs respectively expressed distinct sets of transcripts as small gene clusters as well as CMA-1 even after being cultured in the absence of a tissue environment.
Conclusions: The MC lineage seems to be far from the granulocyte lineages including basophils. CMA1-high MCs (MC_TC) and CMA1-low MCs (MC_T) can be regarded as differentiated MC subtypes. As such, importance of data analysis studies will be increasing along with the accumulation of global molecular data in the public database.

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Background: Since the first report of a dog that developed severe systemic symptoms in response to a second injection of sea anemone toxin by Richet and Portier in 1902, no clear human cases of anaphylaxis related to exposure to sea anemones has been reported in the literature.
Methods: A 24-year-old man with an episode of local urticaria on his first contact with a sea anemone (Stichodactyla haddoni), developed dyspnea, severe urticaria and hypotension on exposure to water containing the dead bodies of the organism. To study whether this reaction was mediated by antigen-specific IgE, we performed a histamine release test with blood, Western blotting with serum and lymphocyte proliferating test with peripheral blood mononuclear cells of the patient, for the homogenate of sea anemones.
Results: The homogenate of sea anemones induced histamine release from the blood of the patient, but it also induced histamine release from the blood of control subjects. Moreover, it also caused hemolysis of blood of all donors. However, Western-blotting demonstrated the presence of an 86 kd protein-specific IgE in the serum of the patient.
Conclusions: Protein antigen(s) in sea anemones may cause anaphylactic shock under the influence of the cytolytic effects and/or lymphocyte-stimulating activity elicited by the toxin of sea anemones.

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Background: Oral administration of enzymatic hydrolysate of cow's milk whey protein (WPH) has been reported to produce an anti-inflammatory effect. Since inflammation plays a role in dermatitis of allergic disease, we examined the influence of WPH on the development of atopic dermatitis (AD)-like skin lesions, induced in NC/Nga mice by the mite antigen Dermatophagoides pteronyssinus (Dp).
Methods: AD-like skin lesions were induced on the pinnae and backs of NC/Nga mice by daily application of Dp for 4 weeks. Mice were fed cow's milk casein (control), WPH or casein protein hydrolysate (CPH) diets for 2 weeks prior to Dp application. Clinical skin conditions were evaluated periodically by a clinical severity score, total serum IgE and soluble E-selectin levels were measured by enzyme linked immunosorbent assay (ELISA).
Results: WPH-fed mice showed significantly less AD-like skin lesions than those fed casein diets at 2 and 4 weeks after Dp application. In contrast, CPH-fed mice had manifestations in a similar manner as casein-fed mice did, and did not show an inhibitory effect. Serum soluble E-selectin levels, known as a marker of disease activity in AD patients, were significantly lower in the WPH diet group.
Conclusions: Our results suggest that in addition to its hypoallergenicity an anti-inflammatory function, dietary WPH might be useful for reducing the severity of AD-like skin lesions.

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Background: The β2-adrenergic receptor gene (ADRB2) is a target molecule of β2-agonists. Single nucleotide polymorphisms (SNPs) in the ADRB2 are related to the effectiveness of β2-agonists. However, there are some discrepancies in the results of pharmacogenetic studies of ADRB2 among different ethnic groups. The aims of this study were to determine the ADRB2 haplotypes and diplotypes in Japanese asthmatic and non-asthmatic subjects and to examine their relation to asthma and to compare these results with previous studies done in other ethnic groups.
Methods: Complete sequences for 3 kb promoter and 1.2 kb structural regions of ADRB2 were analyzed in 48 Japanese asthmatics and 100 controls, and haplotypes and diplotypes of SNPs were analyzed.
Results: Fifteen SNPs including a novel one in -839 were observed. Allele frequencies for all SNPs were similar between asthmatics and controls. We also identified 42 haplotypes and 54 diplotypes of ADRB2 in a Japanese population. The frequencies were similar between the two groups. They were classified into 17 and 23 types, respectively, according to Drysdale's haplotype-organization system, and a significant ethnic difference was observed between the Japanese and Caucasian populations.
Conclusions: The frequencies of SNPs and ADBR2 haplotypes in Japanese are different from those in Caucasians and African Americans. These divergences might imply the need for independent pharmacogenetic studies for ADBR2 in each ethnic group.

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Background: A 47-year-old Japanese woman was suffering from dermatomyositis with progressive interstitial pneumonia, which was resistant to treatment with prednisolone (Pred) and cyclosporine A (CsA). Unfortunately, the opportunistic infection and steroid psychosis made therapeutic intervention using additional immunosuppressive drugs problematic. To overcome these difficulties, we created a regimen of intravenous gammaglobulin (IVIG) and cyclophosphamide (CPM) for the treatment of this patient.
Methods: For the simultaneous treatment, IVIG-CPM was added to Pred/CsA by means of infusion of IVIG on five consecutive days per month, followed by CPM infusion on the ninth day after the last IVIG administration. The treatment was repeated for four months.
Results: This regimen induced almost full remission without exacerbation of the opportunistic infection or mental disturbance.
Conclusions: The outcome reported here suggests that the combination therapy of Pred/CsA and IVIG-CPM appears to be useful for the treatment of dermatomyositis with pulmonary, infectious and mental complications.

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Background: Cases of multiple chemical sensitivities (MCS) have been reported predominantly in adult patients, but pediatric cases have rarely been reported.
Methods: We present a 5-year-old girl who suffered from recurrent reactions accompanied by urticaria, angioedema, headaches, dyspnea, loss of consciousness, and abdominal pain that were not eradicated, but were instead exacerbated, by various treatments with antihistamines and intravenous corticosteroids. Her diet diary revealed that symptoms occurred after ingestion of colorful sweets such as candies and jellybeans. Open challenge tests with food additives and nonsteroidal anti-inflammatory drugs (NSAIDs) were performed after elimination of these items. Skin prick tests using additives and NSAIDs, which were dissolved in saline, and prick- prick tests using candies and jellybeans, were carried out.
Results: Open challenge tests with Tartrazine, aspirin and acetaminophen were positive, whereas skin prick tests using additives and NSAIDs and prick-prick tests using candies and jellybeans were all negative. Consequently, intolerance to azo dyes and NSAIDs such as aspirin was diagnosed. However, she appeared to react to multiple chemical odors such as those of cigarette smoke, disinfectant, detergent, cleaning compounds, perfume, and hairdressing, all while avoiding additives and NSAIDs. On the basis of her history and the neuro-ophthalmological abnormalities, a diagnosis of severe MCS was made and she was prescribed multiple vitamins and glutathione.
Conclusions: The present results suggest that in pediatric MCS, food and drug additives containing azo dyes might play important roles as elicitors.

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Background: We report a neonatal case of cystic periventricular leukomalacia (PVL) in which the hypoxia was considered to have been caused by severe asthma in the mother, who had not taken any medication during pregnancy because she was anxious about its possible effects on her unborn child.
Methods: After the mother had severe exacerbation of asthma for five days, the baby was born at 36 weeks in gestation, weighing 2100g, and with moderate asphyxia. Although the baby had been aggressively treated in a neonatal intensive care unit, at birth, an ischemic area had been formed in the periventricular areas in the brain echogram. We suspected that she had severe brain damage due to prenatal hypoxia.
Results: The baby was found to have cystic PVL by ultrasonography at age 15 days, and diplegia at age 4 months.
Conclusions: The poorly controlled, persistent and severe asthma of the mother may have caused prenatal hypoxia, resulting in the cystic PVL and lower limb palsy. Pregnant patients with poorly controlled asthma should be advised of the great risk of this condition to the fetus. Also, patients should be assured of the safety of modern asthma treatments.

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