Hippocrates is often credited with first recognizing that food could be responsible for adverse symptoms and even death in some individuals, but it was not until the seminal observations by Prausnitz that the investigation of food allergy was viewed on a more scientific basis. In the first half of the 20th century, there were periodic reports in the medical literature describing various food allergic reactions. In the mid- to late- 1970's, the studies of Charles May and colleagues began to penetrate the medical world's skepticism about the relevance of food allergy and how to diagnose it, since standard skin testing was known to correlate poorly with clinical symptoms. With May's introduction of the double-blind placebo- controlled oral food challenge, the study of food allergy became evidence-based and exponential strides have been made over the past four decades in the study of basic immunopathogenic mechanisms and natural history, and the diagnosis and management of food allergies. Today IgE- and non-IgE-mediated food allergic disorders are well characterized and efforts to treat these allergies by various immuno- therapeutic strategies are well under way.

The prevalence of food allergy has increased over the last 30 years and remains a disease, which significantly impacts on the quality of life of children and their families. Several hypotheses have been formulated to explain the increasing prevalence; this review will focus on the hypothesis that dietary factors may influence the development of food allergy. Historically, the prevention of food allergy has focused on allergen avoidance. However, recent findings from interventional studies have prompted a shift in the mind set from avoidance to early introduction of potentially allergenic foods. This review aims to facilitate a better understanding of contemporary research studies that make use of early introduction of common allergenic foods into infant diets as a preventative strategy against the devel- opment of food allergy.

Due to the high prevalence of food allergic diseases globally there are increasing demands in clinical practice for managing IgE-mediated conditions. During the last decade, component resolved diagnostics has been introduced into the field of clinical allergology, providing information that cannot be obtained from extract-based tests. Component resolved data facilitate more precise diagnosis of allergic diseases and identify sensitizations attributable to cross-reactivity. Furthermore it assists risk assessment in clinical practice as sensitization to some allergenic molecules is related to persistence of clinical symptoms and systemic rather than local reactions. The information may also aid the clinician in pre- scription of oral immunotherapy (OIT) in patients with severe symptoms, and in giving advice on food allergen avoidance or on the need to perform food challenges. The use of allergen components is rapidly evolving and increases our possibility to treat food allergic patients with a more individual approach. Using molecular allergology, we can already now better diagnose, prognose and grade the food allergy. In summary, daily routine molecular allergy diagnostics offers a number of benefits that give us a higher diagnostic precision and allow for better management of the patient.

Food allergy has grown in rapidly in prevalence, currently affecting 5% of adults and 8% of children. Management strategy is currently limited to 1) food avoidance and 2) carrying and using rescue intra- muscular epinephrine/adrenaline and oral antihistamines in the case of accidental ingestion; there is no FDA approved treatment. Recently, oral, sublingual and epicutaneous immunotherapy have been developed as active treatment of food allergy, though none have completed phase 3 study. Efficacy and safety studies of immunotherapy have been variable, though there is clearly signal that immunotherapy will be a viable option to desensitize patients. The use of bacterial adjuvants, anti-IgE monoclonal an- tibodies, and Chinese herbal formulations either alone or in addition to immunotherapy may hold promise as future options for active treatment. Active prevention of food allergy through early intro- duction of potentially offending foods in high-risk infants will be an important means to slow the rising incidence of sensitization.

Background: Studies show that immunoglobulin E (IgE) is produced in the local nasal mucosa in allergic rhinitis patients. However, no study involved the measurement of IgE levels in the local nasal mucosal tissue in allergic rhinitis patients. This study aimed to measure the local IgE levels in the nasal mucosal tissue and to compare the levels of total IgE and specific IgEs in the serum and the inferior turbinate nasal mucosa in allergic rhinitis patients using the AlaSTAT 3gAllergy assay (Siemens Healthcare Diagnostics AG, Erlangen, Germany). Methods: Total IgE antibodies and allergen-specific IgE antibodies in each sample of nasal mucosal tissue from 11 allergic rhinitis patients were measured with the AlaSTAT 3gAllergy assay. We compared the levels of total IgE and IgEs specific for house dust (HD), mites, and cedar pollen in the serum and the inferior turbinate. Results: The total IgE levels and the cedar pollen-specific IgE levels in the inferior turbinate mucosal tissue correlated significantly with their respective levels in serum. The HD- and mite-specific IgE levels in the inferior turbinate mucosal tissue did not correlate significantly with their respective levels in the serum. Conclusions: Our results evaluating the correlations between nasal mucosal and serum levels of antigen- specific IgE indicate that IgE produced in the nasal mucosa affects the IgE levels in the serum, especially the cedar pollen-specific IgE.

Background: There is no curative treatment for wheat-dependent exercise-induced anaphylaxis (WDEIA). ω-5 Gliadin is one of the dominant allergens affecting WDEIA patients. The use of ω-5 gliadin- free wheat flour in the regular diet is considered one of the prophylactic approaches against the elici- tation of allergic symptoms and sensitization to ω-5 gliadin. We sought to find hypoallergenic bread wheat (or common wheat) that lacked the genes encoding ω-5 gliadin and to evaluate its in vitro allergenicity. We also aimed to evaluate the sensitization ability of one of the selected hypoallergenic wheat lines by using a possible animal model of wheat allergy. Methods: We screened the deletion lines of bread wheat by western blotting to ascertain common wheat lines lacking the ω-5 gliadin locus. The deletion lines we used have partial deficiency of chromosome 1B (Endo and Gill, 1996). To assess sensitization ability of gluten from the selected deletion line, guinea pigs were fed with either the gluten from the selected deletion line or commercially available gluten, and allergic score was evaluated after challenging the same gluten preparations. Results: We found that a deletion line 1BS-18 had the least deficiency of chromosome 1B among the deletion stocks lacking the ω-5 gliadin locus. The challenge test using the guinea pigs revealed that the symptoms induced by application of the 1BS-18 gluten were much less than that of commercially available gluten. Conclusions: The deletion line 1BS-18, which lacked the ω-5 gliadin locus, is likely to have a low sensitization capacity in the guinea pig. The use of the wheat products of the 1BS-18 line in daily life may provide a feasible solution for the onset of wheat allergy.

Background: Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a cytokine that mediates eosinophilic differentiation, migration and survival, causing respiratory tract inflammation. GM-CSF is also known to be secreted from respiratory tract structural cells. However, the mechanisms of GM-CSF secretion have not been well established. Methods: Human fetal lung fibroblasts and human primary asthmatic lung fibroblasts were used for the study of tumor necrosis factor alpha (TNF-α)-induced GM-CSF secretion. GM-CSF secretion and mRNA expression were measured by enzyme-linked immunosorbent assay and quantitative real-time reverse transcription polymerase chain reaction, respectively. Knockdown of cAMP response element-binding protein (CREB) in fibroblasts was carried out by using specific small interfering RNAs of CREB. Results: Among respiratory tract structural cells, pulmonary fibroblasts exhibited increased GM-CSF secretion and mRNA expression after stimulation with TNF-α in a concentration-dependent manner. Moreover, a p38 mitogen-αctivated protein kinase (MAPK) inhibitor controlled TNF-α-induced GM-CSF secretion, and roflumilast and rolipram, inhibitors of phosphodiesterase-4, suppressed TNF-α-induced GM-CSF secretion. Consistent with this, forskolin also completely blocked GM-CSF secretion, and similar results were observed in response to cAMP treatment, suggesting that cAMP signaling suppressed TNF-α- induced GM-CSF secretion in human lung fibroblasts. Furthermore, CREB was phosphorylated through p38 MAPK but not cAMP signaling after TNF-α stimulation, and GM-CSF secretion was inhibited by CREB knockdown. Finally, these effects were also demonstrated in human primary lung fibroblasts in a patient with asthma. Conclusions: CREB signaled independent of cAMP signaling and was phosphorylated by p38 MAPK following TNF-α stimulation, playing a critical role in GM-CSF secretion in human lung fibroblasts.

Background: Vascular endothelial growth factor (VEGF) is known to be associated with the pathogenesis of chronic rhinosinusitis with nasal polyps (CRSwNP). VEGF is produced by a variety of cells including fibroblasts. It was recently reported that prostaglandin (PG) E2 induces VEGF release by nasal polyp fi- broblasts. However, little is known regarding possible regulation of VEGF by other PGs. We have reported that molecules that regulate PGD2 metabolism play roles in the pathogenesis of CRS including in local eosinophilia and type 2 cytokine production. In the present study, we sought to determine whether PGD2 regulates VEGF release by nasal polyp fibroblasts. Methods: Nasal polyp fibroblasts were established from nasal polyps. These fibroblasts were stimulated with serial dilutions of PGD2 or PGD2 receptor (DP/CRTH2)-selective agonists in the presence or absence of receptor-selective antagonists. The concentration of VEGF in the culture supernatants was determined using ELISA. Results: 5 mM of PGD2 significantly induced VEGF release by nasal polyp fibroblasts. VEGF release was also obtained by stimulation with a DP receptor-selective, but not with a CRTH2 receptor-selective agonist. In addition, PGD2-induced VEGF release was significantly inhibited by pre-treatment with DP receptor-selective antagonists. In contrast, pre-treatment with a CRTH2 receptor-selective antagonist significantly enhanced PGD2-induced VEGF release. Conclusions: PGD2 stimulates VEGF production via DP but not CRTH2 receptors in nasal polyp fibroblasts.

Background: Genetic and environmental factors are known to be related to the development of child- hood eczema. Our aim was to assess the environmental factors associated with the prevalence of eczema among children using a web-based survey. Methods: In June 2012, we conducted a nation-wide web-based survey to identify the prevalence and characteristics of allergic diseases among Japanese children. The prevalence of allergic diseases including eczema was assessed using the International Study of Asthma and Allergies in Childhood core ques- tionnaire. The associations between eczema prevalence and environmental factors, as well as those between background characteristics and comorbid allergic diseases among 6-12 year old children were assessed. Results: A total of 28,348 children were included in the analysis. The prevalence of current eczema was 13.0%. Current eczema was significantly associated with a higher prevalence of wheeze, rhinitis, and food allergy. In multiple logistic regression models, birth during autumn (aOR: 1.18 95%CI: 1.06-1.31) or winter (aOR: 1.21 95%CI: 1.08-1.34), duration of exclusive breastfeeding for at least 6 months (aOR:1.14 95%CI: 1.06-1.23), and ownership of a pet from infancy (aOR: 2.61 95%CI: 1.68-4.07) were also associated with a higher prevalence of eczema. The prevalence was lower in those with a high annual household income (aOR: 0.90 95%CI: 0.81-0.99) and 2 or more siblings (aOR: 0.86 95%CI: 0.76-0.97). Conclusions: Duration of breastfeeding, season of birth, pet ownership, household income, and the number of siblings were associated with the prevalence of childhood eczema in a nationwide web survey.

Background: Lung sound analysis is useful for objectively evaluating airways even in children with asymptomatic asthma. However, the relationship between lung sounds and morphological changes in the airways has not been elucidated. We examined the relationship between lung sounds and chronic morphological changes in the airways during the progression of asthma from onset in guinea pigs. Methods: Eleven male guinea pigs were examined; of these, seven were used as asthma models and four as controls. The asthma models were sensitized and repeatedly challenged by inhaling albumin chicken egg. We measured lung sounds and lung function twice a week for 21 weeks. After the final antigen challenge, the lungs were excised for histological examination. We measured the ratio of airway wall thickness to the total airway area and the ratio of the internal area to the total airway area in the trachea, third bronchi, and terminal bronchioles. Results: Among the lungs sounds, the difference between the two groups was greatest with respect to inspiratory sound intensity. The ratio of airway wall thickness to the total airway area of the terminal bronchioles was greater in the asthma models than in the controls, and it correlated best with the changes in inspiratory sound intensity in the 501e1000-Hz range (r = 0.76, p < 0.003). Conclusions: Lung sound intensity in the middle frequency range from 501 to 1000 Hz correlated with peripheral airway wall thickness. Inspiratory sound intensity appeared to be an indicator of morpho- logical changes in small airways in asthma.

Background: Drug reaction with eosinophilia and systemic symptoms (DRESS) is a rare but life- threatening adverse drug reaction. Several criteria have been established to aid the diagnosis. However, patients with DRESS remained underdiagnosis and undertreatment. Methods: Medical records of hospitalized patients at the King Chulalongkorn Memorial Hospital from January 2004eDecember 2014 due to DRESS were enrolled retrospectively using RegiSCAR diagnostic criteria. Results: A total of 52 patients were included. Thirty-seven patients (71.2%) were female. The four most common causative agents were phenytoin (23.1%), nevirapine (17.3%), allopurinol (15.4%), and cotri- moxazole (13.5%). The overall prevalence was 9.63 cases per 100,000 inpatients. Median onset time (IQR) was 16 (9e27) days. Allopurinol was associated with longer onset time than others (p = 0.014). Clinical presentation: skin rash 100%, fever 78.8%, and lymphadenopathy 50%. The majority (84.6%) had single internal organ involvement. The most common internal organ involvement was liver (94.2%). Allopurinol was associated with higher incidence of renal involvement (p = 0.01). Up to 60% of patients had eosinophilia. Allopurinol was associated with higher eosinophilia (p = 0.003). A half of patients received systemic corticosteroids. Two mortality cases were reported (omeprazole-fulminant hepatitis and phenytoin-nosocomial infection). Conclusions: DRESS is associated with severe morbidity and mortality. Phenytoin, nevirapine, allopurinol, and cotrimoxazole were the major causes. Allopurinol-induced DRESS had the longest onset time, and was associated with higher eosinophilia and incidence of renal involvement. Raising awareness among both health care providers and public for early detection and withdrawal of the causative agent is critical to save life and reduce morbidity.

Background: A key therapeutic approach to asthma, which is characterized by chronic airway inflam- mation, is inhaled corticosteroid (ICS). This study evaluated the association of symptom control with changes in lung function, bronchial hyperresponsiveness (BHR), and exhaled nitric oxide (eNO) after ICS treatment in asthmatic children. Methods: A total of 33 children aged between 5 and 12 years with mild to moderate persistent asthma were treated with 160 mg ciclesonide per day for 3 months. At days 0 and 90, the following parameters were assessed: asthma symptom scores; lung function, including forced expiratory volume in one second (FEV1), forced vital capacity (FVC), and forced expiratory flow at 25-75% of forced vital capacity (FEF25 -75%); BHR to methacholine and adenosine 5-monophosphate (AMP); and eNO. Results: Asthma symptom scores, lung function parameters, BHR to methacholine and AMP, and eNO levels at day 90 were significantly improved versus day 0 (all p < 0.001). Symptom scores at day 90 were not correlated with changes in lung function and BHR to methacholine during the follow-up period, whereas those at day 90 were more closely correlated with changes in BHR to AMP (r = 0.511, p = 0.003) than with eNO (r = -0.373, p = 0.035). Additionally, changes in PC20 AMP were correlated with changes in PC20 methacholine (r = 0.451, p = 0.011) and eNO (r = -0.474, p = 0.006). Conclusions: Changes in the BHR to AMP, and to a lesser extent eNO, correlate with asthma symptom control after ICS treatment. BHR to AMP may better reflect the relationship between improved airway inflammation due to ICS treatment and asthma symptoms.

Background: There is no systematic analysis to identify problems involved with instruction on inhalation therapy for elderly patients. We conducted a nationwide questionnaire survey for patients and medical professionals. Methods: A questionnaire survey was conducted of adult patients on inhaled drugs (ages 18e92 years, 820 individuals) and medical professionals (pharmacists or nurses) who provided instruction on inha- lation therapy to these patients in 23 institutions in Japan to investigate the technique and the level of understanding (knowledge) of the inhalation therapy. Changes in the recognition of performance of inhalation technique and inhalation knowledge with increasing age were analyzed. Results: According to patients' subjective assessment, there was no deterioration in the performance of the inhalation technique or loss of the knowledge with increasing age. On the other hand, medical professionals' objective assessment revealed a significant loss of both inhalation technique and knowl- edge with increasing age. Not many elderly patients noticed their own problems themselves, revealing a great perception gap between elderly patients and medical professionals. Thus, there was concern that patients would unconsciously practice the inhalation procedure improperly. On the other hand, in comparison with non-elderly patients, elderly patients were less resistant to continuation of therapy, suggesting that they would be more likely to accept instruction on inhalation therapy.

Background: Parvalbumin was identified as a major fish allergen, and has been well investigated. Collagen was identified as a second allergen; however, its allergenic properties remain uncharacterized. Although fish is an important staple in coastal countries, its thermostability is unknown. Therefore, we aimed to determine the thermostability of fish collagen as an allergen. Methods: Meat of seven bony and four cartilaginous fishes was heated at various temperatures and times, and extracts were analyzed using SDS-PAGE, IgE-ELISA, and SPTs. Results: Collagen was dissolved from heated meat of Pacific mackerel into a crude extract. Collagen in the extracts was degraded at a high heating loadd140 °C (10 min) or 100 °C (320 min). However, ELISA revealed the IgE reactivities of patients' sera with the extracts were unchanged even after heating the samples. Patients strongly reacted to extract proteins of other bony fish, which were detected by patients' IgE even after heating at 100 °C (320 min). In contrast, reactivities of the extracts of cartilaginous fish were lower than those of bony fish. SPTs in one patient revealed that all bony and cartilaginous fish extracts prepared from heated meat elicited allergic reactions. Conclusions: The IgE reactivity of patients' sera to fish collagen in extracts was retained even when fish meat was treated by a high heating load. As for the fish collagen, the IgE reactivities to cartilaginous fish were lower than that to bony fish. Reducing IgE reactivity to fish meat using heat is difficult, and other modalities will be required to produce hypoallergenic fish meat.

Background: T cell immunoglobulin domain and mucin domain-containing molecule 3 (TIM-3), which is preferentially expressed on Th1 cells rather than Th2 cells, is considered to be a negative regulator of Th1 cell function. This suggests that TIM-3 indirectly enhances Th2-type immune responses by suppressing Th1 cell function. Methods: To investigate TIM-3's possible involvement in Th2-type acute and chronic airway inflamma-tion, wild-type and TIM-3-deficient (TIM-3-/-) mice were sensitized and challenged with a house dust mite (HDM) extract. Airway inflammation and the number of inflammatory cells in bronchoalveolar lavage fluids (BALFs) in the mice were determined by histological analysis and with a hemocytometer, respectively. Expression of mRNA in the lungs was determined by quantitative PCR, while the levels of cytokines in the BALFs and IgE in sera were determined by ELISA. Results: Despite constitutive expression of TIM-3 mRNA in the lungs, the number of eosinophils in bronchoalveolar lavage fluids (BALFs) and the score of pulmonary inflammation were comparable be- tween wild-type and TIM-3-/- mice during both acute and chronic HDM-induced airway inflammation. On the other hand, the number of lymphocytes in the BALFs of TIM-3-/- mice was significantly increased compared with wild-type mice during HDM-induced chronic, but not acute, airway inflammation, while the levels of Th2 cytokines in the BALFs and HDM-specific IgG1 and IgG2a and total IgE in the sera were comparable in both groups. Conclusions: Our findings indicate that, in mice, TIM-3 is not essential for development of HDM-induced acute or chronic allergic airway inflammation, although it appears to be involved in reduced lymphocyte recruitment during HDM-induced chronic allergic airway inflammation.