Chronic inflammatory diseases are a major health problem with global dimension. Particularly, the incidence of allergic diseases has been increased tremendously within the last decades. This world-wide trend clearly indicates the demand for new approaches in the investigation of early allergy development. Recent studies underlined the basic postulate of the hygiene hypothesis that early exposure to microbial stimuli plays a crucial role in the prevention of chronic inflammatory conditions in adulthood. There is ample evidence that, both, exogenous microbes and endogenous microbial communities, the human microbiota, shape the developing immune system and might be involved in prevention of pathologic pro-inflammatory trails. According to the Barker hypothesis, epidemiological studies pointed to transmaternal transmission from the mother to the offspring already in prenatal life. Experimental data from murine models support these findings. This state of the art review provides an overview on the current literature and presents new experimental concepts that point out to future application in the prevention of allergic diseases.

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It is time to bring our imagination, creativity and passion to the fore in solving the global challenges of our age. Our global health crisis and the pandemic of noncommunicable diseases (NCDs) is clearly rooted in complex modern societal and environmental changes, many of which have effects on developing immune and metabolic responses. It is intimately related to wider environmental challenges. And it is unsurprising that many NCDs share similar risk factors and that many are associated with a rising predisposition for inflammation. Allergy is one of the earliest signs of environmental impact on these biological pathways, and may also offer an early barometer to assess the effects of early interventions. There is dawning awareness of how changing microbial diversity, nutritional patterns, sedentary indoor behaviours and modern pollutants adversely affect early metabolic and immune development, but still much to understand the complexity of these interactions. Even when we do harness the science and technology, these will not provide solutions unless we also address the wider social, cultural and economic determinants of health - addressing the interconnections between human health and the health of our environment. Now more than ever, we need a wider vision and a greater sense of collective responsibility. We need long-range approaches that aim for life long benefits of a ‘healthier start to life', and stronger cross-sectoral collaborations to prevent disease. We need to give both our hearts and our minds to solving these global issues.

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Background: Forestry and field workers who work outdoors are at high risk for Hymenoptera stings and may develop occupation-related allergies from being stung. However, clinical and immunological surveys of Hymenoptera stings in the occupational setting have rarely been reported. We surveyed the natural history of Hymenoptera stings in Japanese forestry workers (FWs) and electrical facility field workers (EFFWs), and we assessed the utility of measuring specific (s)IgE Ab to Hymenptera venom.
Methods: Questionnaires on hornet and paper wasp stings were completed by 999 FWs, 354 EFFWs, and 365 office workers as controls between July and November 2009. Sera from these participants were tested for sIgE Ab levels to Hymenptera venom with a CAP system using a fluoroenzyme immunoassay.
Results: Of the participants who had experienced Hymenoptera stings, 914 (91.5%) were FWs, 293 (82.8%) were EFFWs, and 295 (80.8%) were controls. Of the participants who had experienced systemic reactions, 210 (21.0%) were FWs, 51 (14.4%) were EFFWs, and 39 (10.7%) were controls. sIgE Ab in response to hornet and wasp venom was positive (≥ class 2) in 42.4% and 41.4% of FWs, 30.1% and 31.4% of EFFWs, and 15.1% and 18.1% of controls, respectively. The likelihood of being sIgE-positive to wasp and hornet venom was significantly higher in FWs and EFFWs than in controls (P < 0.05).
Conclusions: 21% of FWs and 14% of EFFWs had experienced systemic reactions to Hymenoptera stings with a higher frequency compared with office workers in the same area. 40% of FWs and 30% of EFFWs had sera that were sIgE positive to Hymenoptera venom.

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Background: Chronic rhinosinusitis (CRS), which is clinically classified into CRS without nasal polyps (CRSsNP) and CRS with nasal polyps (CRSwNP), shows considerable geographic differences and heterogeneity. Eosinophilic (E) CRS with nasal polyps (ECRSwNP) has a higher degree of disease severity and higher frequency of comorbid asthma. Epidemiologic studies in different ethnic populations have improved understanding of the pathophysiology of the disease. Here we report the clinical characteristics of Japanese patients with medically refractory CRS undergoing endoscopic sinus surgery (ESS).
Methods: We recruited a total of 210 CRS patients and assessed them by nasal endoscopy, the Lund-Mackay score using computed tomography (CT), peripheral eosinophilia and smoking status. We also examined the comorbidity of asthma, effects of age and lung functions in the patients.
Results: In this study, 13% of CRSwNP patients and 20% of CRSwNP patients with peripheral blood eosinophilia exhibited obstructive lung dysfunction (FEV₁/FVC <70%) despite the absence of an asthma diagnosis. Among elderly nonsmoker patients (≥ 60 years) who had never been diagnosed with asthma, 50% of CRSwNP patients with peripheral blood eosinophilia showed decreased FEV₁/FVC <70%.
Conclusions: Our findings suggest that asthma is under-diagnosed in CRS patients who undergo ESS, especially the elderly. Although the association between CRS and asthma has been recognized, increased attention to the comorbidity of obstructive airway diseases such as asthma is still needed for management of medically refractory CRS.

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Background: It is known that idiopathic chronic urticaria occasionally develops with Helicobacter pylori (H. pylori) infection, but the association between urticaria and H. pylori remains unknown.
Methods: We focused on the relationship between the titer of anti H. pylori IgG antibodies and urticaria. Sixty-five patients with idiopathic urticaria were divided into 3 groups by a difference of their titers. All patients in the high titer (≥40U/ml) group underwent endoscopy of the upper gastrointestinal tract with antral biopsy for the Rapid Urease Test (RUT) or a culture test. We investigated the relationship between the efficacy of eradication therapy against H. pylori and urticaria.
Results: The positive rate for H. pylori was 100% (20/20) by RUT or culture test in the high titer group. A CR using antihistamines alone was 0% (0/20) in the high titer group, 27.2% (3/11) in the low titer group and 38.2% (13/34) in the negative group respectively. A CR or PR using antihistamines was 70% (14/20) in the high titer group, 81.8% (9/11) in the low titer group and 97.1% (33/34) in the negative group. After successful eradication therapy, the CR was increased to 56% (9/16) in the high titer group.
Conclusions: Regardless of acute or chronic urticaria, a high titer of anti H. pylori IgG antibody can be an indicator for undergoing upper endoscopy, and eradication therapy is strongly recommended. It will be necessary to develop diagnostic criteria for urticaria associated with H. pylori.

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Background: An environmental challenge chamber (ECC), which we refer to as the α-chamber, was built at Chiba University in 2008. The aim of this study was to validate the functionality of the ECC.
Methods: The stability of the pollen distribution and concentration in the ECC and symptoms of patients with Japanese cedar pollinosis induced by cedar pollen exposure were examined. Carryover effects of symptoms induced by different exposure protocols and correlations between symptoms induced in the ECC and those in the natural cedar pollen season were also determined. All the studies using the α-chamber were conducted out of the cedar pollen season.
Results: The severity of symptoms in the chamber reached a peak about 2 hours after the start of pollen exposure and plateaued thereafter. After subjects left the chamber, the symptoms persisted for several days. There was no significant difference between the severity of symptoms at exposure levels of 8000 and 12000 grains/m³. The symptoms were significantly increased by exposure for 3 consecutive days; however, there were no carryover effects in a study performed with a two-week interval. The total nasal symptom score (TNSS) in the natural pollen season showed a weak correlation with the mean TNSS on the day of exposure and the following 3 days. Symptoms in the ECC also had weak correlations with those in the early natural pollen season.
Conclusions: The ECC under well-controlled conditions is suitable for clinical studies and might accelerate development of treatment for seasonal allergic rhinitis. A complete evaluation requires inclusion of the persistent reaction after subjects leave the ECC.

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Background: Anaphylaxis after the ingestion of foods contaminated with mites has recently been recognized. Case series and case reports thus far have shown that mite-contaminated wheat flour is the major cause of oral mite anaphylaxis. However, we have found 8 cases of oral mite anaphylaxis which were caused by mite-contaminated okonomiyaki-mix, a savory Japanese style pancake mix, in our hospital.
Methods: In addition to our 8 cases, the databases of MEDLINE and ICHUSHI were systematically searched for patients with oral mite anaphylaxis in Japan.
Results: Thirty-six patients including our 8 cases with oral mite anaphylaxis were identified. Thirty-four out of 36 cases (94%) ingested okonomiyaki or takoyaki, prepared at home using okonomiyaki-mix or takoyaki-mix which was previously opened and stored for months at ambient temperature. Microscopic examination of culprit mixes of 16 cases including our 1 case revealed contamination of mites such as Dermatophagoides farina (Der f) (5 cases), Tyrophagus putrescentiae (Tyr p) (4 cases), and Dermatophagoides pteronyssinus (Der p) (3 cases). The specific IgE to each mite is generally upregulated in these patients. Especially, the titers of specific IgE to Der p and Der f were more than class 2 in all cases.
Conclusions: Mite-contaminated flavored flour is the major cause of oral mite anaphylaxis in Japan.

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Background: Thrombomodulin treatment modulates the properties of dendritic cells (DCs) converting them from immunogenic to tolerogenic and inducing its own expression on DCs. Thrombomodulin binds to the inflammatory mediator, high mobility group protein B1 (HMGB1), antagonizing signalling through its receptor, receptor for advanced glycation end products (RAGE).
Methods: To test if soluble thrombomodulin could antagonize HMGB1 signaling via RAGE on DCs. DCs were prepared from mouse bone marrow cells or human monocytes. In some experiments dendritic cells were sorted into thrombomodulin⁺ and thrombomodulin^- populations. Expression of surface maturation markers was determined by flow cytometry following treatment with thrombomodulin in the presence or absence of HMGB1.
Results: Thrombomodulin⁺ dendritic cells secrete less HMGB1 into the medium. HMGB1 reduces the effects of thrombomodulin on expression of DC maturation markers. Treatment with thrombomodulin reduces the expression of maturation markers such as CD80 and CD86 and increases the expression of thrombomodulin on the DC surface. Treatment of DCs with neutralizing anti-HMGB1 antibody acted synergistically with thrombomodulin in increasing thrombomodulin expression on DCs. Treatment with thrombomodulin can still reduce the expression of surface markers on DCs derived from mice that are deficient in RAGE showing that thrombomodulin can affect DCs by an alternative mechanism.
Conclusions: The results of this study show that thrombomodulin modulates DCs both by antagonizing the interaction of HMGB1 with RAGE and by an independent mechanism.

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Background: Influenza infection is known to be an exacerbating factor in the control of asthma, therfore its prevention is critical in managing asthma. The aim of this study was to investigate the influenza A H1N1 2009 pandemic virus (H1N1 pdm09) infection in adult asthmatic patients.
Methods: Data were obtained from a questionnaire-based survey of asthmatic patients conducted from September to October 2010 in Niigata Prefecture. Patient background, H1N1 pdm09 infection, vaccination status, and asthma exacerbation due to influenza infection were analyzed.
Results: In total, 2,555 cases were analyzed. The incidence of the infection was 6.7% (95% confidence interval [CI]: 5.7-7.6), and the rate of vaccination was 63.9% (95% CI: 62.1-65.8). The odds ratio (OR) for vaccination against the infection among adult patients and younger patients (≤ the median age) were 0.61 (95% CI: 0.45-0.84) and 0.62 (95% CI: 0.42-0.90), respectively. However, OR among the older patient (> median age) were 1.38 (95%CI: 0.66-2.89). The rate of infection-induced asthma exacerbation was 23.2% (95% CI: 18.6-29.6), and the OR for vaccination against the infection-induced asthma exacerbation was 1.42 (95% CI: 0.69-2.92).
Conclusions: The effectiveness of the vaccination against the H1N1 pdm09 virus was confirmed during the first pandemic season, but it was limited. Further investigation on H1N1 pdm09 virus infection in asthmatics will be required.

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Background: Rebamipide, a gastroprotective drug, has been reported to suppress gastric mucosal inflammation. In Japan, rebamipide eyedrops have recently been approved for the treatment of dry eye disease. Some patients with allergic conjunctival diseases such as vernal keratoconjunctivitis (VKC) or atopic keratoconjunctivitis (AKC) manifest dry eye with decreased tear break-up time only. We report patients with VKC/AKC refractory to anti-allergic treatments who responded to the combination of rebamipide eyedrops and conventional anti-allergic treatments with anti-allergic- and/or immunosuppressive/steroid eyedrops.
Methods: Four patients with allergic conjunctival diseases with giant papillae (VKC or AKC) instilled rebamipide eyedrops three or four times a day for varying periods. All had dry eye with decreased tear break-up time. We evaluated changes in the size of their giant papillae using Image J software.
Results: We observed attenuation of the giant papillae in all 4 patients. In 2 patients with severe disease, whose giant papillae had become larger despite the administration of tacrolimus and steroids, the addition of rebamipide contributed to their attenuation. In 2 patients with mild disease, the giant papillae had become larger or remained the same size despite the administration of anti-allergy drugs; the addition of rebamipide eyedrops also resulted in the attenuation of their giant papillae.
Conclusions: Our findings suggest that rebamipide eyedrops might attenuate giant papillae in patients with allergic conjunctival diseases and that these eyedrops may be useful for the treatment of not only dry eye but also of allergic conjunctival diseases.

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Background: MGL_1304 secreted by Malassezia globosa is contained in human sweat and induces histamine release from basophils in patients with atopic dermatitis (AD) at a high positive rate. The aims of this study were to establish the enzyme-linked immunosorbent assay (ELISA) measuring specific immunoglobulins against MGL_1304 and to investigate the levels of these immunoglobulins in sera of patients with various allergic diseases.
Methods: Purified MGL_1304 from human sweat (QRX) and recombinant MGL_1304 (rMGL_1304) were prepared for ELISA. To quantify the amount of MGL_1304-specific immunoglobulins, the standard serum was created by pooling sera of 20 patients with AD whose basophils released histamine in response to QRX. A monoclonal antibody which exhibited the highest neutralizing ability against QRX was established as Smith-2, and used as a capture antibody for the assay of QRX-specific IgE. A total of 156 subjects [normal controls (n = 23), AD (n = 63), cholinergic urticaria (CU) (n = 24), bronchial asthma (n = 32), and allergic rhinitis (n = 14)] were enrolled in this study.
Results: ELISA methods to quantify the specific IgE, IgG and IgG4 against MGL_1304 in sera were successfully established. Levels of QRX-specific IgE in sera of patients with AD and CU were significantly higher than those of normal controls. Moreover, the levels of QRX-specific IgE and rMGL_1304-specific IgE in patients with AD were significantly correlated with their disease severities.
Conclusions: These ELISA methods to quantify the specific immunoglobulins against MGL_1304 are easy and useful means to assess allergy to MGL_1304. MGL_1304 contained in sweat is an important antigen for patients with AD and CU.

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Background: Intra individual longitudinal data has been lacking for IgE-mediated seasonal allergic rhinitis (SAR), especially in young children. Little is known about the development and natural course of SAR in terms of prevalence and incidence rates in schoolchildren.
Methods: In May or June each year from 1994 to 2007, schoolchildren were assessed for serum Japanese cedar pollen (JCP)-IgE and house dust mite (HDM)-IgE levels, and surveyed regarding nasal symptoms.
Results: Among the 220 children initially assessed in the first grade, 69 (31.4%) were already sensitized to JCP at first grade and 119 (54.1%) did not develop JCP sensitivity during the 6-year study at all. In the first grade children who were HDM-sensitized but JCP non-sensitized, JCP-IgE level was significantly elevated compared to the JCP and HDM non-sensitized group. This seems to indicate that HDM sensitization was very strongly associated with JCP sensitization.
Conclusions: Elevated serum IgE is a consequence of specific sensitization to HDM and HDM sensitization appeared to develop prior to the start of primary school which distinguishes HDM sensitization from JCP sensitization.

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Background: The clinical usefulness of fixed-dose maintenance therapy with salmeterol/fluticasone (SFC) and budesonide/formoterol combination inhaler (BUD/FM) has been established, though evidence of the long-term anti-inflammatory effects of these 2 inhalers are limited.
Methods: Patients with moderate persistent adult asthma who had received SFC 50/250μg bid with well-control status were recruited. After switching to 8-week therapy with fixed-dose BUD/FM 4 puffs (640/18μg) (phase-1), patients chose either SFC or BUD/FM. FeNO and ACT score were evaluated every 8 weeks until the end of the 52-week treatment period for both treatment groups (phase-2).
Results: In total, 103 patients were examined: BUD/FM was chosen by 34 patients (BUD/FM group), while SFC was chosen by 23 (SFC group). Thirty-six received SFC consistently from the beginning of the study (control). Patients in the BUD/FM and SFC groups showed significant improvements in ACT scores and FeNO levels in phase-1; these beneficial effects persisted for 52 weeks in the BUD/FM group. On the other hand, in the SFC group, although the FeNO level decreased from 54.3 ± 26.4 ppb to 41.9 ± 18.3 ppb in phase-1, it increased to 54.5 ± 26.2 ppb, a level similar to the baseline prior to the beginning of BUD/FM therapy, at 8 weeks in phase-2, and remained at 50-odd ppb thereafter.
Conclusions: These results suggest that maintenance therapy with fixed-dose BUD/FM is a useful treatment option exerting an airway anti-inflammatory effect for a period as long as 1 year, even for asthmatics who could not accomplish total control with SFC.

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Background: The forced oscillation technique (FOT) is useful for studying pulmonary function in children, as well as in school children with asthma. However, the standard values for respiratory resistance (Rrs) in Asian school children remain unknown. We evaluated the standard Rrs using a type of FOT, impulse oscillometry (IOS), in healthy Japanese children at elementary and junior high schools.
Methods: A total of 795 children (age range: 6-15 years; mean age ± SD: 11.1 ± 2.4 years; 404 boys, 391 girls) at elementary and junior high schools participated in the study. Of the 795 children, we evaluated the Rrs of 537 children aged 6-15 years (mean ± SD: 10.8 ± 2.4 years) using IOS.
Results: Regression analyses with three IOS parameters, Rrs at 5Hz (R5), Rrs at 20Hz (R20), and Rrs difference between 5Hz and 20Hz (R5-R20), for age, height, weight, and degree of obesity as independent variables demonstrated the strongest correlation between each parameter and children's height. All parameters decreased with increasing height. Using the lambda-mu-sigma (LMS) method, we created standard curves for the Rrs values based on height.
Conclusions: Our standard curves could be useful for diagnosis and control evaluation of childhood asthma.

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