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Allergy is a life-threatening, acute disease mainly caused by mediators released from immunoglobulin E and allergen-activated mast cells. Syk, an intracellular signaling molecule important for cancer development, was supposed to have a critical role in mast cell activation. Thus, we clarified the anti-allergic effect of potent Syk inhibitor entospletinib in vivo mouse allergic model and in vitro cell cultures. Immunoglobulin E and allergen-mediated degranulation of rat basophilic leukemia RBL2H3 cells was suppressed by quite low concentrations of entospletinib (10 nM or more) occurring in 20 min without affecting cell viability. The drug treatment (3 nM or more) also inhibited cytokine secretion from the immunoglobulin E and allergen-activated RBL2H3 cells within 4 h. Rectal temperature decrease caused by passive systemic anaphylaxis in mice was diminished obviously by oral administration of a small amount of entospletinib (0.3 mg/mouse). Increase of the concentration of mouse mast cell protease-1, an indicator of mast cell activation, in serum of mice upon the passive systemic anaphylaxis induction was also attenuated by the oral administration of entospletinib, similar to its inhibitory effect on RBL2H3 activation observed in vitro. These findings indicated that Syk inhibitor entospletinib inhibited allergic reaction via blunting mast cell activation. Syk inhibitor entospletinib and its derivatives might be good candidates as anti-allergic drugs. [ABSTRACT FROM AUTHOR]

An allergic reaction, which is classified as the type I allergy by Gell and Cooms, is recognized as a pathological reaction with unpleasant symptoms. Many of therapeutic agents have been developed to relieve the symptoms. Antihistamines, the first type of the anti-allergic drugs, which became available in 1940's, has been used to treat acute allergic responses until now After histamine in the central nervous system was reported to play important roles on wakefulness, antihistamines without sleepiness have been developed. The findings that immunoglobulin E and mast cells are important players to trigger allergic reactions led to the development of therapeutic agents to suppress these functions. A series of metabolites derived from arachidonic acid were characterized in the type I allergy. Leukotriene receptor antagonists and inhibitors of production and functions of thromboxane A2 are used to treat allergic asthma. Further research in immunology clarified that immune reactions driven by Th2 cells have pivotal roles on the development of allergic diseases. Th2 cytokines produced by immune cells such as interleukin (IL)-4, IL-5 and IL-13 are the targets of anti-allergic therapies by means of specific antibodies. The therapeutic antibodies can reduce amounts of Th2 cytokines and IgE, and a number of eosinophils, all of which concern the development of allergic diseases. Research on the signal transduction in immune cells led to the development of inhibitors of Janus kinases, key enzymes for cytokine signaling. Taken together, much more therapeutic options are now available in addition to antihistamines for the treatment of allergic diseases. [ABSTRACT FROM AUTHOR]

Tezepelumab (TEZSPIRE ® Subcutaneous Injection 210 ‍mg), a biologic medicine with a novel mechanism, was approved in Japan in September 2022 for the treatment of bronchial asthma. Tezespire auto-injector was approved in Japan in August 2023 as an additional dosage. It is indicated for severe or refractory patients whose asthmatic symptoms cannot be controlled by currently available treatment. Tezepelumab binds to the epithelial cytokine thymic stromal lymphopoietin (TSLP) and disrupts TSLP signaling via the heterodimeric receptor. In the Phase 3 NAVIGATOR trial, the annual asthma exacerbation rate was significantly reduced by tezepelumab when administered subcutaneously every 4 weeks over a 52-week period to patients with uncontrolled, severe asthma who had received medium- or high-dose inhaled glucocorticoids. Its efficacy in reducing asthma exacerbations was observed regardless of blood eosinophil (bEOS) count, fractional exhaled nitric oxide (FeNO) levels, or serum total IgE at baseline. Significant improvements were noted in lung function, health-related quality of life, and change from baseline in asthma control. Reductions in the levels of inflammatory biomarkers (bEOS, FeNO, and IgE) was also noted. Clinical pharmacology trials demonstrated the efficacy of tezepelumab in improving airway hyperresponsiveness. In this article, we reviewed pharmacological characteristics, pharmacokinetics, clinical efficacy, and the safety profile of tezepelumab.

Allergic diseases (e.g., food allergies) are a growing problem, with increasing numbers of individuals experiencing them worldwide. Congruently, the adverse reactions (e.g., anaphylaxis) associated with the administration of vaccines against emerging infectious diseases such as coronavirus disease 2019 (COVID-19) have become a familiar problem. Allergic diseases, which have a wide variety of symptoms, are difficult to prevent or cure; treatment is currently limited to therapeutic drugs or allergen immunotherapy. Therefore, elucidating new allergic regulatory factors that control the allergic (i.e., mast cell) responses is important. While investigating the regulatory mechanisms of the wide range of allergic responses of mast cells, we found that the affinity of allergens to immunoglobin E (IgE) regulates allergic inflammation through the differences in the secretory responses of mast cells and the types and interactions of the cells infiltrating the tissues. Here, we present our recent findings regarding the affinity of allergens to IgE in regulating allergic inflammation, heterogeneous secretory granules inducing diverse secretory responses, and mast cells interacting with neutrophils, thereby regulating the various allergic responses.

Adenosine-5'-triphosphate (ATP) is an important intracellular energy currency, but it is released extracellularly in response to various stimuli and acts as an intercellular signaling molecule by stimulating various P2 receptors. ATP and ADP are stored in synaptic vesicles and secretory granules, and are released extracellularly upon stimulation, playing important roles in neurotransmission and platelet aggregation. Furthermore, considerable amount of ATP is released by mechanical stimuli such as skin scraping or by cell damage, which in turn activates immune cells to promote inflammatory responses. Mast cells (MCs) are derived from hematopoietic stem cells and play a central role in type I allergic reactions. MCs are activated by IgE-mediated antigen recognition, leading to type I allergic reactions. MCs express P2X7 receptors that are activated by high concentrations of ATP (>0.5 ‍mM), and reported to aggravate inflammatory bowel disease and dermatitis. In contrast, role of MC P2 receptors that respond to lower concentrations of ATP remains to be investigated. We investigated in detail the effects of ATP in mouse bone marrow-derived MCs, and found that lower concentrations of ATP (<100 ‍μM) promotes IgE-dependent and GPCR-mediated degranulation via the ionotropic P2X4 receptor. In mouse allergic models, P2X4 receptor signal promote MC-mediated allergic responses through comprehensively increasing the sensitivity of MCs to different stimuli. Since ATP is known to be released from various cells upon mechanical stimuli such as cell damage or scratching, inhibition of P2X4 receptor signaling may represent a novel strategy to abrogate allergic reaction.

Background: The sensitizations to various fungal allergens influence to exacerbation of bronchial asthma. Aspergillus (Asp) and Alternaria (Alt) were one of important fungal allergens for asthma., Aim and Methods: To investigate the influence of sensitization to Asp or Alt in adult asthmatics managed via our asthma coordinated-care system, we recruited 119 patients (91 women) who were measured IgE for Asp (IgE-Asp) and IgE for Alt (IgE-Alt) at three times during two years,Results: In 119 patients, we detected positive IgE for Asp (IgE-Asp(+)) in 19 patients and positive IgE for Alt (IgE-Alt(+)) in 11 patients. 9 patients showed positive both of them. During two years, 7 patients became positive IgE-Asp and 3 cases became negative. And also, 3 cases became positive IgE-Alt and 3 cases became negative. At baseline, serum IgE, IgG 4 , and inhaled corticosteroid (ICS) dose of the group with IgE-Asp (+) or IgE-Alt (+), were significant higher than those of negative group. Among three groups, there was no significant change about other parameters at baseline, exacerbation frequency, or the change of parameters during two years., Conclusion: The sensitizations to Asp or Alt were present in 19 asthmatics (16%) managed via our coordinate-care system. During 2 years, there was not significant change at exacerbation frequency among three groups, but the levels of IgE, IgG 4 , or ICS dose were significantly higher at IgE-Asp (+) or IgE-Alt (+) group than negative group. In the asthma management, it was considered necessary to pay attention to the sensitization to Asp or Alt.

In recent years, the consumption of edible insects has gained attention, and the potential allergic risks associated with their ingestion have been pointed out, though there are limited case reports. A 3-year-old boy exhibited an immediate allergic reaction, showing symptoms of sneezing, nasal discharge, coughing, and eyelid edema after ingesting two cricket crackers. He had previously consumed shrimp but had never eaten edible insects. Given his lack of a history of allergic diseases, the onset of this allergy was unexpected. Subsequent prick tests and oral food challenge tests confirmed that the Two-spotted cricket (Gryllus bimaculatus) was the allergen responsible for his symptoms. The IgE inhibition test indicated that the cricket significantly suppressed the specific IgE levels for moth, shrimp, and mite (Dermatophagoides pteronyssinus). This incident marked the first time in the patient's life that he exhibited allergic symptoms, and it serves as a significant case highlighting the risks of allergies from edible insects. Known allergens in insects include tropomyosin and arginine kinase, which are common in arthropods, but there are reports of other allergens as well, suggesting potential sensitization from cross-reactions. As the consumption of insects becomes more widespread, the number of allergic cases may increase, and food labeling and preventive measures should be considered.

Background: The reagent which is available for single allergenic tests is Oriton IgE, ImmnoCAP, Alastat in Japan. No study has investigated the correlations of Oriton IgE and ImmnoCAP or Alastat, and, used for specific IgE antibody testing., Method: Six frequently tested allergens (dust mite, cedar pollen, dog dander, egg white, milk, and candida) were measured by three methods, and Spearman rank correlation coefficient and class-judged agreement were evaluated. Furthermore, we did the evaluation like other 2 methods when we made small short sample volumes of Oriton IgE., Result: As for the examination result of Oriton IgE and ImmnoCAP or Alastat, constant correlation was confirmed. However, the tendency was a different result by assay method and an allergenic item. No significant differences were observed in the results of the Oriton IgE test when standard sample volumes and small short sample volumes were used., Conclusion: These comparison results help us to understand each characteristic and select an optimal test method. In addition, it can be inferred that it is beneficial to choose tests requiring small sample volumes in pediatric patients.

Background: Biologics are an important treatment option for patients with severe asthma. Four biologics are available in Japan, and an overlapping eligibility has been observed. The eligibility and availability of drugs depend on the local regulations of different countries. However, there is no precise information about the eligibility for biologics, including dupilumab, in Japan. The aim of the study was to investigate the overlapping eligibility and to analyze the phenotypes of patients with multiple eligibility., Methods: In this observational study, a retrospective chart review of patients was performed. The eligibility criteria for omalizumab were IgE 30-1500IU/mL and positive IgE for perennial aeroallergen. The eligibility criteria for IL-5-targeted biologics (mepolizumab and benralizumab) were eosinophil counts (Eos) > 150μL, while those for dupilumab were Eos > 150μL or fraction of exhaled nitric oxide (FeNO) > 150ppb or IgE > 167IU/mL. Severe asthma was defined by the severity criteria under treatment based on Japanese guidelines for adult asthma., Results: One hundred patients with severe asthma were identified. The eligibility for omalizumab, IL-5-targeted therapies, and dupilumab was 43%, 69%, and 82%, respectively. Thirty percent of the patients were eligible for all the four biologics and showed the lowest FEV1, frequent exacerbation history, and the highest levels of Eos, FeNO, and serum periostin. Only 11% of the patients were not indicated for any biologics., Conclusion: A considerable portion of patients was eligible for all the biologics. Asthma control was poor, and type 2 inflammation was prominent in such patients.

Background: There is reportedly a difference in the diameter of the skin reaction induced by different types of skin prick test (SPT) devices. We compared the SPT diagnostic accuracy and wheal size between a Bifurcated Needle ® (BN) and SmartPractice ® Prick Lancet (PL), which are commercially available in Japan., Methods: An SPT was performed on 15 adults with and 10 without subjective symptoms of cedar pollinosis who wished to be examined for Japanese cedar pollen (JCP) sensitization. The SPT was performed blindly with a BN or PL with 10mg/ml of histamine dihydrochloride, 50% glycerosaline control, and JCP extract solution (TORII PHARMACEUTICAL CO., LTD., Tokyo, Japan). The wheal sizes induced by the BN and PL were then compared. The JCP-specific IgE antibody titer was measured to compare the sensitivity and specificity of the SPT., Results: Histamine wheal diameters were 6.0 (5.5-6.5) mm by BN and 6.0 (5.5-6.5) mm by PL (p=0.67), and none of the negative control solutions induced wheal. The respective sensitivity and specificity for cedar sensitization were 100% and 86% for BN, 100% and 79% for PL, and the areas under the ROC curve were 0.72 and 0.69 (p=0.32)., Conclusion: The diagnostic accuracy of cedar pollen extract based on specific IgE-JCP sensitization and the diameter of the wheal produced by a BN and PL were considered equivalent.

A-55-year-old man who have been working in a Sake (Japanese rice wine) brewer for 27 years, came to the outpatient clinic because cough, dyspnea, and wheeze gradually worsen. These symptoms occurred immediately after exposure to Aspergillus oryzae in the brewing process since age 43. A dust mask was required to reduce these symptoms, but that work was interrupted by exacerbation of these symptoms. These symptoms disappeared when he was away from the on-site work. The SMART therapy using combined inhaler of budesonide (ICS) with formoterol (LABA) was effective to reduce these symptoms. In serological test total IgE antibody and Aspergillus specific IgE antibodies increased, whereas Aspergillus precipitating antibody and Asp f 1 (a major allergen of Aspergillus fumigatus) specific IgE antibody were negative. Eosinophilia in peripheral blood was not observed, and FeNO was not increased. Values of peak expiratory flow was reduced by 20.8% after exposure to Aspergillus oryzae in that work. Lung function test including reversibility test was intact, but FEV 1 was fluctuated up to 400mL (15.9%) in the clinical course. Based on these variable clinical manifestations, laboratory data, and lung function test findings, this case was diagnosed as adult-onset atopic (Aspergillus-sensitized) bronchial asthma without allergic bronchopulmonary aspergillosis. Involvement of eosinophilic inflammation is unknown. Allergen may be considered to be Aspergillus oryzae, because these symptoms do not occur in any environment without exposure to Aspergillus oryzae. This patient is the first case of occupational asthma related to Aspergillus oryzae in a Japanese rise wine brewer.

The case involved a man in his forties. While working at the restaurant that the patient runs, the patient experienced a stab-like pain on the left shoulder and developed systemic pruritic eruptions. He was diagnosed with anaphylaxis upon visiting our emergency department. Conjunctival hyperemia, lip swelling, cold sweats, and nausea presented later. A cap fluorescence enzyme immunoassay using the serum of the patient showed specific immunoglobulin E (IgE) positivity for wasps; therefore, we hypothesized that he had anaphylaxis caused by the insect's sting. Insects of the same species as that by which the patient had been stung were collected and finally identified as the Asian needle ant (Brachyponera chinensis). The freeze-dried insects' bodies were sonicated into powders and stored for following examinations. Next, a basophil activation test was performed using the patient's whole blood treated with the reagent above, which showed positivity. Furthermore, a skin prick test using the same reagent showed a positive result, and the reaction increased in a concentrationdependent manner. Based on these results, the patient was diagnosed with anaphylaxis after a sting by the ant. Based on the results of the allergen component specific IgE test, we speculated that the pathogens in this case was group5 allergen of the Asian needle ant. Anaphylaxis following insect stings by this ant has been reported frequently in South Korea. However, it is quite rare in Japan, although the ant is native to Japan. Clinicians should consider that this allergy can occur indoors, unlike allergies to other types of venom.

The Japan Environment Health and Children's Study (JECS) is an ongoing cohort study designed to evaluate the impact of various environmental factors on children's health. In this study, more than 100,000 pregnant women were recruited in 15 regional centers throughout Japan. Within the University of Occupational and Environmental Health, the departments of Pediatrics, Obstetrics and Gynecology, Environmental Health, and the School of Health Sciences collaborate with the JECS University of Occupational and Environmental Health Subunit Center in advancing research in this study. Several original articles based on JECS and written by our unit members were published in recent years. The aim of this review is to summarize these studies by JECS and University of Occupational and Environmental Health Subunit Center based on the data from JECS. We introduce research articles covering the following categories; environmental health, occupational health, and maternal and child health. Studies found associations between concentrations of metals and maternal health, such as premature birth, placenta previa and placenta accrete, associations between metals and IgE, dietary differences among occupational groups, associations between work-related factors and dietary behaviors, associations between job changes and pregnancy/delivery, mental and physical stress among pregnant women and influence on work, associations between sleep and gestational diabetes, and associations between an ability to push up in the prone position and infant development. This review may promote the development of new research, such as collaborative research projects, including clinical and social medicine, epidemiological studies and laboratory investigations.

A 16-year-old male high-school student experienced generalized itchy wheal and dyspnea during physical exercise after lunch. Each food material of his lunch was examined using a prick-prick test, allergen-specific IgE test (ImmunoCAP ® ), and provocation test. The prick-prick test was positive for black tiger shrimp (raw and heated) and white leg shrimp (heated). Allergen-specific IgE test (ImmunoCAP ® ) showed absolutely negativity for all suspected foods. The food-exercise provocation test using heated black tiger shrimp with additional aspirin intake finally induced anaphylaxis.We studied the IgE-binding molecules from shrimp using a purification procedure and Western blotting, with sera from the patient and several controls. A 40-kDa protein, corresponding to FBA, was found to be the major IgE-binding allergen component in this patient. Currently, the precise history and the prick-prick test using both raw and heated shrimps are useful to diagnose shrimp-induced FDEIA. Because the allergen-specific IgE test is insufficient to diagnose the cause of the symptoms, a component allergen-specific IgE test after the identification of the causative allergenic protein, such as FBA, is required.

Background: One of the strengths of multi-panel IgE testing is that it facilitates screening for IgE antibodies (Abs) in allergic patients by providing data on levels of IgE Abs to multiple allergens at the same time. Nonetheless, its diagnostic sensitivity for clinical use has not been well-studied., Methods: We tested sera from 33 fruit-allergic patients. The sensitivity of determining IgE Abs to fruit allergens using the MAST Immunosystems (MAST) system and the View Allergy 39 (VA) system was calculated separately in patients sensitized to PR-10 or to profilin, and compared with that of single-panel IgE testing (ImmunoCAP system)., Results: In both the PR-10 sensitized and 31 profilin sensitized groups, the sensitivity of the IgE Abs to apple measured by VA (87%, and 83%, respectively) was almost identical to that of ImmunoCAP. On the other hand, the sensitivity of IgE Abs to peach measured by MAST (23% and 25%, respectively) was markedly lower than that of ImmunoCAP., Conclusions: The sensitivity of fruit IgE Abs in the MAST system was remarkably lower than that of the ImmunoCAP system. Caution is necessary in clinical practice when interpreting of the results of some multipanel IgE testing.

Backgrounds: Recently, patients with oral allergy syndrome (OAS) to fruits or vegetables caused by pollenfood allergy syndrome (PFAS) have increased nationwide. We examined effectiveness of SCIT using birch pollen extract for PFAS., Methods: A total of 19 patients (9 male and 10 female) underwent SCIT with birch pollen extract from August 2011 to August 2016. Rush schedule was used for the initial updosing for SCIT in a hospital setting. In maintenance phase, SCIT was administered every 4-8 weeks on an outpatient basis. According to the situation of sensitization, patients underwent SCIT with other extracts at the same time. Oral food challenge (OFC) with fruits and vegetables was performed at baseline and after rush phase. We also investigated about OAS symptoms in maintenance phase., Results: SCIT was remarkably effective in five patients for OAS symptoms just after rush phase, and effective in nine patients. And it was not effective in two patients, and not determined in three patients, but it was confirmed to be effective in four out of these five patients in maintenance phase. There were relapse of OAS symptoms in three patients, then SCIT was remarkably effective or effective in 15 patients (79%) in maintenance phase. No patients dropped off the SCIT protocol., Conclusions: Generally, PFAS can't be expected to remit naturally. SCIT with birch pollen extract effectively reduces OAS symptoms, and it can be expected as a radical therapy for PFAS.

Background: Japanese cypress pollen is a major causative allergen of seasonal allergic rhinitis in Japan. Although ImmunoCAP-specific immunoglobulin E (IgE) reagent Japanese cypress pollen has been widely used as a diagnostic aid, its sensitivity requires enhancement. This study evaluated an improved version of this reagent., Methods: Serum samples from 61 subjects who underwent Japanese cypress pollen exposure testing in an environmental challenge chamber in Chiba University were assessed using the conventional ImmunoCAPspecific IgE Japanese cypress pollen product and the improved product. In addition, specific IgE for Cha o 1 and Cha o 2, the primary allergen components of Japanese cypress pollen, was evaluated and their reactivity to specific IgE was compared between the conventional and improved products., Results: The antibody titer of the improved product was approximately 1.8-fold that of the conventional product. In addition, higher correlations with Cha o 1 and Cha o 2 were observed for the improved product than for the conventional product. The clinical sensitivity (≥class 2) in 56 exposure test-positive subjects was better for the improved product (80.4%) than for the conventional product (71.4%)., Conclusions: An improvement of the ImmunoCAP-specific IgE reagent Japanese cypress pollen resulted in enhanced Japanese cypress pollen-specific IgE sensitivity. The primary reason for this appeared to be an improved Cha o 1- and Cha o 2-specific IgE detectability.

Background: This study aimed to evaluate the clinical accuracy of specific IgE (sIgE) to Ara h 2 in the diagnosis of peanut allergy (PA). We also investigated the prevalence of complications with other nut allergies in PA patients., Methods: The Ara h 2-sIgE titer was examined in patients with positive results for sIgE to peanut from April 2014 to March 2015. The presence or absence of PA was diagnosed based on an oral food challenge or a convincing clinical history. The characteristics of 217 patients (including 90 PA patients) were retrospectively evaluated., Results: At ≥0.35U A /mL, Ara h 2 showed 85.6% sensitivity in the diagnosis of PA. At the clinically-designated positive cut-off value (≥4.0U A /mL), the positive predictive value was 93.1% and the specificity was 96.9%. However, the Ara h 2-sIgE levels were not correlated with the threshold dose or the severity of the symptoms that were provoked in the peanut challenge (n=42). Nine (10%) of the PA patients also had allergies to other tree nuts., Conclusion: The re-evaluation of the clinically-designated positive Ara h 2-sIgE cut-off value revealed that the cut-off value was appropriate. The differential diagnosis of tree nut allergies was suggested to be important in PA patients.

Three stages of the pathogenic mechanism of drug allergies can be considered: antigen formation, immune reaction and inflammation/disorder reaction. Drugs are thought to form 4 types of antigens: drug only, polymers, drug-carrier conjugates, and metabolite-carrier complexes. Antigens are recognized by B cell receptors and T cell receptors. Helper T cells (Th) are differentiated into four subsets, namely, Th1, Th2, Th17 and regulatory T cells (Treg). Th1 produces interleukin (IL)-2 and interferon (IFN)-γ, and activates macrophages and cytotoxic T cells (Tc). Macrophages induce type IV allergies, and Tc lead to serious type IV allergies. On the other hand, Th2 produces IL-4, IL-5, and IL-6, etc., and activates B cells. B cells produce IgE antibodies, and the IgE antibody affects mast cells and induces type I allergies. Activated eosinophil leads to the chronic state of type I allergy. Diagnostic testing for allergenic drugs is necessary for patients with drug allergies. Because in vivo diagnostic tests for allergenic drugs are associated with a risk and burden to the patient, in vitro allergy tests are recommended to identify allergenic drugs. In allergy tests performed in vitro, cytological tests are more effective than serological tests, and the leukocyte migration test (LMT) presently has the highest efficacy. An LMT-chamber is better than LMT-agarose in terms of usability and sensitivity, and it can detect about 80% of allergenic drugs.

Mast cells are effector cells in immunoglobulin E (IgE)-mediated immediate hypersensitivity and allergic diseases such as asthma and food allergy. Mast cells are activated by the aggregation of the IgE-bound high-affinity IgE receptor FcεRI with multivalent antigen. Activated mast cells secrete proinflammatory mediators such as histamine, serotonin, and proteases and produce cytokines and chemokines. However, it has been reported that mast cells are activated by crosslinking of FcεRI with monomeric IgE in the absence of antigen. We have recently demonstrated that histamine-releasing factor (HRF) is involved in IgE-mediated mast cell activation both in vitro and in vivo. HRF binds to a subset of IgE and IgG molecules [HRF-reactive antibodies (Abs)]. The Fab, but not Fc, portions of the IgE and IgG molecules are HRF-binding sites, and the N-terminal 19-residue (N19) and H3 portions of HRF are HRF-reactive Ab-binding sites. We observed that both N19 and H3 tagged with glutathione S transferase (GST) (GST-N19 and GST-H3) can inhibit the interaction between HRF and HRF-reactive Abs. Using acute- and late-phase passive cutaneous anaphylaxis mouse models, it was shown that HRF initiates mast cell activation through HRF-reactive, but not HRF-nonreactive, IgE in vivo. Antigen-induced passive cutaneous anaphylaxis was inhibited by pretreatment with GST-N19 and GST-H3. We demonstrated that pretreatment with GST-N19 before antigen challenge inhibited antigen-induced mast cell-dependent airway inflammation. In addition, GST-N19 partially inhibited Aspergillus fumigatus extract-induced IgE-dependent airway inflammation. However, GST-N19 did not inhibit T cell-dependent airway inflammation. These results suggest that mast cells are target cells for HRF to initiate IgE- and mast cell-dependent airway inflammation.

Tissue-resident mast cells are derived from circulating committed progenitors, which are originated from pluripotential hematopoietic stem cells in bone marrow. These progenitors migrate into extravascular tissues, where they undergo differentiation and maturation into tissue-specific mature phenotypes. When activated by IgE/antigen, stem cell factor, neuropeptides, or other stimuli, mature mast cells release three classes of biologically active products, including pre-formed mediators stored in secretory granules, newly transcribed cytokines and chemokines, and de novo synthesized lipid mediators. Therefore, these cells have been implicated as major effector cells in acute and chronic inflammatory diseases. In recent years, it has become clear that lipid mediators including arachidonic acid metabolites (prostaglandins and leukotrienes) and lysophospholipid-derived products play crucial roles in mast cell-associated pathology. In this article, we will provide an overview of the roles of various lipid mediators in allergic diseases fueled by studies of their biosynthetic enzymes or receptors. In the latter part, we will make a particular focus on phospholipase A(2) enzymes, which are placed at the bottleneck (rate-limiting) step of the lipid mediator-biosynthetic pathways.

Basophils represent less than 1% of peripheral blood leukocytes. Under physiological conditions, basophils principally circulate in peripheral blood, while mast cells reside in peripheral tissues. Like mast cells, they express the high-affinity IgE receptor on their cell surface and release chemical mediators. Because of morphological and functional similarities, basophils have long been considered to be redundant "circulating mast cells" and minor (probably negligible) players in inflammation. Mouse and human basophils cannot be stained in routinely processed histological specimens, and thus, our understanding of tissue basophils in allergic inflammation had been limited. However, recent studies in mice have revealed that basopihls play non-redundant roles from mast cells. Basophils function as a source of IL-4, IL-13, and CCL22, thereby contributing Th2 immunity. They are also capable of presenting antigens. Basophils are essential for the development of IgE-mediated chronic allergic skin inflammation in mice. Recent immunohistochemical studies with an basophil-specific antibody revealed that, in humans, varying numbers of basophils infiltrate skin lesions of inflammatory diseases, such as atopic dermatitis, urticaria, prurigo, and eosinophilic pustular folliculitis. Basophils may play important roles in a variety of inflammatory skin diseases than previously thought.

We presented an autopsy case with severe motor and intellectual disabilities (SMID) who showed a severe increase in the serum level of IgE. Although the patient had rarely been exposed to food allergens, the serum level of IgE continued increasing. He developed a high titer of serum IgE against specific antigens to which he had never been exposed. There was no mutation of the STAT3 gene, and no abnormalities in immunological functions including serum levels of cytokines. Death was from a hemorrhage caused by a tracheoinnominate artery fistula. At autopsy, the submucosal area of the colon presented with an increase in the number of mast cells immunoreactive for tryptase, which could have been involved with hyper IgE. Since SMID patients tend to be sensitized by food allergens subsequent to recurrent gastroesophageal reflux, we should pay attention to complications of food allergy even when using an elemental diet.

The potential ability of surface-linked liposomal antigens for application to vaccine development was investigated. During the course of this investigation, a significant difference, which correlated closely with the adjuvant activity of liposomes, was observed in the recognition of liposomal antigens by APCs between liposomes with different lipid components. In addition to this "quantitative" difference between liposomes with differential lipid components, a "qualitative" difference (i.e., the differential ability to induce cross-presentation) was observed among liposomes with different lipid components. Although the precise mechanism underlying this difference is currently unclear, the significant difference in membrane mobility observed between these liposomes might affect their ability to induce cross-presentation. Thus, surface-linked liposomal antigens are potentially applicable for the development of vaccines with the least allergic side effects and for a novel protocol of allergen immunotherapy. In addition, by the utilization of their ability to induce cross-presentation, surface-linked liposomal antigen might potentially serve as a candidate protocol for virus vaccines which induce CTL response, and for tumor vaccine preparation to present tumor antigens to APCs and induce effective antitumor responses.

Objective: We investigated the usefulness of skin prick test (SPT) for the diagnosis of egg white (EW) allergy in infants with atopic dermatitis who showed negative to EW CAPRAST, and followed up the EW-CAPRAST in this study., Subjects and Methods: Data of negative SPT using Bifurcated needle (BN) were analyzed from the data of 202 atopic dermatitis infants, who had received SPT from January in 2001 to April in 2005. From the negative SPT value (average and standard deviation) positive SPT value was obtained. Among 202 cases, 89 suspected-egg allergy infants with negative IgE CAPRAST against EW at the time of first visit were recruited to examine the usefulness of SPT. Positive conversion of EW-CAPRAST was checked in 78 cases (65: egg allergy+, 13: egg allergy(-)) who had been followed up in our outpatient clinic., Results: Range of negative SPT control value (mean+2SD) using BF among infants could be set as less than 2 mm for wheal and/or 5 mm for erythema. Among 89 suspected-egg allergy infants with negative EW-CAPRAST, 72 infants (80.9%) were diagnosed as egg allergy by the combination of elimination and provocation test, interestingly 39 infants (54.2%) showed positive SPT results. In the follow up study of 78 negative EW-CAPRAST cases, 47 EW-CAPRAST out of 65 egg-allergy cases turned positive later infantile period (mean EW-CAPRAST: 9.6+/-16.7 Ua/ml at 9.9+/-5.6 months old). EW-CAPRAST of 7 cases in 13 non-egg allergies also turned positive in the follow up, however EW-CAPRAST titer was relatively lower compared to that of egg allergies (1.1+/-1.5 Ua/ml at 13.3+/-2.6 months old)., Conclusions: We experienced fairly number of atopic infants with negative EW-CAPRAST at the first outpatient visit, who were later diagnosed as egg allergy. In about half of these cases, SPT egg-allergy infants, three quarter of EW-CAPRAST turned positive around 10 months old. EW-CAPRAST of atopic infants without egg allergy also turned transiently and slightly positive. In the conclusions, SPT seemed to be more useful than EW-CAPRAST for the diagnosis of egg allergy in early infantile period, however provocation test should be required for the definitive diagnosis in suspected-egg allergy infants without any proof of egg-sensitization.

A 6-year-old girl who had been diagnosed as hyper immunoglobulin-E syndrome, was admitted to the department of pediatrics of our institute in May 2006, because of pulmonary aspergillosis. The chest X-ray showed bilateral cavities with niveau and fungus ball in the left middle lung field. In spite of medical treatment by antibiotics and antimycotics, the lesions did not improve. Therefore, bilateral lobectomy was done. After surgery, she needed re-operation twice, because of prolonged air leakage. There are few reports of lung surgery for the patient with the hyper immunoglobulin-E syndrome, and we present our case and review previous 2 case reports in the Japanese literature.