Serum periostin levels in adolescents.

BACKGROUND: The significance of periostin as a biomarker of Th2-induced airway inflammation has recently been highlighted in adult patients with allergic diseases. It may help identify drug-responsive inflammatory phenotypes, particularly in children. However, little is known about the usefulness of this parameter as a biomarker for allergic diseases in children. Furthermore, it is not known how much adolescent bone metabolism affects allergic inflammation. OBJECTIVE: To evaluate the relationship between serum periostin levels and allergic diseases in adolescents, we investigated periostin levels and the prevalence of allergic diseases. METHODS: We conducted a cross-sectional observational study of 100 males and females in two age groups: age 9-12 years (pre-early adolescence) and 13-15 years (post-early adolescence). Serum periostin levels were determined using Enzyme-Linked Immuno Sorbent Assay (ELISA). Presence of allergic diseases and allergy sensitization were obtained via a self-reported survey and the Multiple Antigen Simultaneous Test (MAST). The protocol was registered in a clinical trial registry as UMIN 000036051. RESULTS: There were no significant differences in serum periostin levels between pre-early and post-early adolescents. There were no differences by gender. Age and Body Mass Index were not significantly associated with serum periostin levels. Periostin levels were elevated in adolescents with allergic diseases overall compared to healthy adolescents [mean (95%CI): 41.6 (33.4, 49.7) vs. 28.6 (21.9, 35.3) ng/ml; P < 0.05]. CONCLUSIONS: The effects of bone metabolism on serum periostin levels may be limited at 9-15 years of age. Further studies are required to determine reference values in adolescents.

Assessment of heavy metal pollution in the coastal sediments of an urbanized atoll in the central Pacific: Majuro Atoll, the Marshall Islands.

Pacific atolls are extremely vulnerable to the effects of climate change. Coral reef ecosystems, which are responsible for the island formation and maintenance, can potentially keep pace with rising sea levels. Such ecosystems are sensitive to pollution; however, the sources and levels of atoll pollutants caused by urbanization have rarely been investigated. In this study, we assessed the heavy metal pollution (Cr, Mn, Ni, Cu, Zn, Cd, and Pb) of coastal sediments to evaluate the effects of urbanization on Majuro Atoll, the Marshall Islands. The densely populated area had the most significant pollution with high levels of Pb, Mn, Zn, and Cu due to road traffic activity. Domestic wastewater, a major pollution source in Pacific atolls, was not identified. Remarkably, the Zn and Pb levels in the lagoonal coasts of the remote island area were 697 - 1539 and 22 - 337 times higher, respectively, than in the natural area of Funafuti Atoll, Tuvalu. Thus, the remote island and sparsely populated areas were significantly polluted because of the maritime traffic activity in the lagoon and debris accumulation in/around the lagoon. This pollution resulted from improper municipal solid waste management of the main island. The contamination factor, pollution load index, and geo-accumulation index indicated high levels of heavy metal pollution in these areas. Urbanization of the atoll clearly resulted in a distinct heavy metal composition and high pollution levels compared with Funafuti Atoll. These findings emphasize the importance of pollution management in the conservation and rehabilitation of urbanized atolls threatened by future sea-level rises.

Effect of fexofenadine/pseudoephedrine combination tablet on nasal obstruction in patients with allergic rhinitis using rhinomanometry: A randomized controlled trial.

BACKGROUND: A fexofenadine/pseudoephedrine combination tablet (F/P) is an optimal product for nasal obstruction. It contains fexofenadine hydrochloride, a histamine H1-receptor antagonist for sneezing and rhinorrhea and pseudoephedrine hydrochloride, an α-adrenergic agonist. The effect of an antihistamine-decongestant on nasal obstruction has been demonstrated in previous studies, but onset of action and efficacy data on nasal obstruction are limited. OBJECTIVE: We estimated the efficacy of F/P on nasal obstruction in patients with house dust mite-induced allergic rhinitis (AR) versus fexofenadine (F) using objective methods. METHODS: In this single-center, single-dose, prospective, randomized, parallel-group study, 24 adult patients with a history of at least 2 years of AR and nasal obstruction were randomized to receive F/P or F. The effect on nasal obstruction was evaluated using nasal airflow and visual analog scale (VAS) score measured at 30-minute intervals before and for 8 hours after dosing. The primary end point was onset of action, based on a comparison of absolute change from baseline in nasal airflow between F/P and F. The protocol was registered in a clinical trial registry as UMIN 000041845. RESULTS: The onset of action for F/P was 30 minutes based on nasal airflow and 60 minutes based on VAS. F/P maintained a significant beneficial effect after onset of effect, while F showed no significant change during the test period. CONCLUSIONS: We found F/P had a clear effect on nasal obstruction associated with perennial AR when compared with F. There was a time lag in nasal airflow improvement and nasal obstruction relief.

Behavior of eukaryotic symbionts in large benthic foraminifers Calcarina gaudichaudii and Baculogypsina sphaerulata under exposure to wastewater.

Large benthic foraminifers (LBFs) are significant contributors to coral island formation in the Pacific Ocean. In recent years, the population of LBFs has decreased because of the increase in anthropogenic influences, such as wastewater (WW) discharge. To implement efficient mitigation measures, pollution tolerance in LBFs should be understood. However, the effects of WW on LBFs and their symbionts have not yet been demonstrated. This study examined the changes in the photosynthetic efficiency (Y[II]) of Calcarina gaudichaudii and Baculogypsina sphaerulata in response to WW by using a pulse-amplitude-modulation fluorometer. These LBFs were exposed to WW with different dilution levels for 22 days. The Y(II) values of the LBFs were found to deteriorate within 1-2 days. However, the Y(II) values both deteriorated and were enhanced in the experiments, thus indicating that WW contains both harmful and beneficial components. Baculogypsina sphaerulata showed an earlier response and greater sensitivity to WW and a higher epibiont infestation than C. gaudichaudii. This result can be attributed to the differences in the physiological and morphological responses of distinct LBFs. A sequencing analysis of 18S rDNA confirmed that the dominant eukaryotic symbionts in the two LBFs studied were Ochrophyta and Labyrinthulomycetes. These eukaryotic symbionts were released and attached as epibionts onto LBFs that were exposed to WW, thus leading to an increase in inactive LBFs. The Shannon-Weaver and Simpson diversity indices revealed that eukaryotic symbiont communities decreased in biodiversity after exposure to WW because of the abundance of algal symbionts. On the basis of these results, we conclude that WW, even with 10,000 × dilution, causes a decrease in active LBF populations owing to the release of eukaryotic symbionts, the decrease in biodiversity, and the infestation of epibionts even though Y(II) is temporarily enhanced. These responses are more significant in B. sphaerulata than in C. gaudichaudii.

Japanese guidelines for allergic rhinitis 2020.

Like asthma and atopic dermatitis, allergic rhinitis is an allergic disease, but of the three, it is the only type I allergic disease. Allergic rhinitis includes pollinosis, which is intractable and reduces quality of life (QOL) when it becomes severe. A guideline is needed to understand allergic rhinitis and to use this knowledge to develop a treatment plan. In Japan, the first guideline was prepared after a symposium held by the Japanese Society of Allergology in 1993. The current 8th edition was published in 2016, and is widely used today. To incorporate evidence based medicine (EBM) introduced from abroad, the most recent collection of evidence/literature was supplemented to the Practical Guideline for the Management of Allergic Rhinitis in Japan 2016. The revised guideline includes assessment of diagnosis/treatment and prescriptions for children and pregnant women, for broad clinical applications. An evidence-based step-by-step strategy for treatment is also described. In addition, the QOL concept and cost benefit analyses are also addressed. Along with Allergic Rhinitis and its Impact of Asthma (ARIA), this guideline is widely used for various clinical purposes, such as measures for patients with sinusitis, childhood allergic rhinitis, oral allergy syndrome, and anaphylaxis and for pregnant women. A Q&A section regarding allergic rhinitis in Japan was added to the end of this guideline.

[LONG-TERM RESULTS OF AIRBORNE POLLEN SURVEYS IN THE JAPANESE ARCHIPELAGO FROM THE PERSPECTIVE OF POLLEN ANTIGEN].

BACKGROUND: In 1986, the Ministry of Health and Welfare started an airborne pollen survey as part of measures against JC pollinosis. We reported the important tree pollen antigens in 2016. We have now estimated the longitudinal investigated results for successful prevention and treatment for allergic symptoms related to grass and weed pollen in Japan. METHOD: Since July 1986 we have monitored airborne pollen, year- round, using a gravitational pollen sampler (Durham's sampler), at more than 20 locations across Japan. Specimens were mailed to our facility, where they were stained with Calberla solution, counted under an optical microscope, and converted to the number of pollen per square centimeter. For convenience the number of collected pollen were compiled every six months, with the January to June samples classified as spring pollen and the July to December as autumn pollen even same family. RESULT: Total pollen counts at each location were extremely small compared to tree-pollen, averaging 73~650 pollen grains per year. The Sagamihara location had the greatest count. Unlike cedar and cypress there were no significant annual fluctuations, but grass and Ambrosia pollen counts are increasing in some regions. Spring grass pollen gave the largest count, at 30% of the total collected. CONCLUSION: This indicated we need to examine the rinoconjuctivitis and oral allergy syndrome related to herbaceous pollen carefully.The importance of airborne pollen surveys for the treatment of the patients with pollen allergies was suggested.

LONGITUDINAL MONITORING OF TREE AIRBORNE POLLEN IN JAPAN.

RATIONAL: In Japan patients with Japanese Cedar (JC) pollinosis have increased nation widely since the latter of 1970's. The Ministry of Health and Welfare of Japanese Governments has begun to take preventive measures against JC pollinosis and airborne pollen monitoring has begun to investigate as a causative agent since 1986. We have estimated the longitudinal investigation result for successful prevention and treatment against pollinosis in Japan. METHOD: We have monitored airborne pollen all year around since July 1986 by gravitational pollen sampler, Durham's sampler, at more than 20 locations in the Japanese Islands. Pollen samples were sent to our hospital and counted pollen number per cm2 after stained by Calberla solution and then classified main pollen grains as a causative agent of pollinosis. RESULT AND DISCUSSION: JC pollen number was the most of all, more than 40%, next cypress family, about 20%. They were occupied of more than 60% of all and they increased with the remarkable annual fluctuation as the allergen of JC pollinosis. Beech family pollen counting were also increasing and occupied about 10% of all pollen counts. In Hokkaido the prevalence of birch family pollen count was larger than that in other districts. There is cross-reactivity between beech and birch family which related with oral allergic syndrome.Perspective and Conclusion: In future new occurrences of oral allergy syndrome due to increasing allergic tree pollen grains would be appeared. The contentious pollen research should be important for patients with pollinosis in Japan.

Japanese guidelines for allergic rhinitis 2017.

Like asthma and atopic dermatitis, allergic rhinitis is an allergic disease, but of the three, it is the only type I allergic disease. Allergic rhinitis includes pollinosis, which is intractable and reduces quality of life (QOL) when it becomes severe. A guideline is needed to understand allergic rhinitis and to use this knowledge to develop a treatment plan. In Japan, the first guideline was prepared after a symposium held by the Japanese Society of Allergology in 1993. The current 8th edition was published in 2016, and is widely used today. To incorporate evidence based medicine (EBM) introduced from abroad, the most recent collection of evidence/literature was supplemented to the Practical Guideline for the Management of Allergic Rhinitis in Japan 2016. The revised guideline includes assessment of diagnosis/treatment and prescriptions for children and pregnant women, for broad clinical applications. An evidence-based step-by-step strategy for treatment is also described. In addition, the QOL concept and cost benefit analyses are also addressed. Along with Allergic Rhinitis and its Impact of Asthma (ARIA), this guideline is widely used for various clinical purposes, such as measures for patients with sinusitis, childhood allergic rhinitis, oral allergy syndrome, and anaphylaxis and for pregnant women. A Q&A section regarding allergic rhinitis in Japan was added to the end of this guideline.

Effects of antihistamine on up-regulation of histamine H1 receptor mRNA in the nasal mucosa of patients with pollinosis induced by controlled cedar pollen challenge in an environmental exposure unit.

In the present study, we examined the effects of antihistamine on the up-regulation of H1R mRNA in the nasal mucosa of patients with pollinosis induced by controlled exposure to pollen using an environmental exposure unit. Out of 20 patients, we designated 14 responders, whose levels of H1R mRNA in the nasal mucosa were increased after the first pollen exposure and excluded 6 non-responders. Accordingly, the first exposure to pollen without treatment significantly induced both nasal symptoms and the up-regulation of H1R mRNA in the nasal mucosa of the responders. Subsequently, prophylactic administration of antihistamine prior to the second pollen exposure significantly inhibited both of the above effects in the responders. Moreover, the nasal expression of H1R mRNA before the second pollen exposure in the responders pretreated with antihistamine was significantly decreased, as compared with that before the first pollen exposure without treatment. These findings suggest that antihistamines suppressed histamine-induced transcriptional activation of H1R gene in the nasal mucosa, in addition to their blocking effect against histamine on H1R, resulting in a decrease of nasal symptoms. These findings further suggest that by their inverse agonistic activity, antihistamines suppress the basal transcription of nasal H1R in the absence of histamine in responders.

Effects of bifidobacterial supplementation to pregnant women and infants in the prevention of allergy development in infants and on fecal microbiota.

BACKGROUND: Probiotic administration may be a useful method for preventing allergies in infants; however, there have been controversial results about the efficacy. We investigated the effects of bifidobacterial supplementation on the risk of developing allergic diseases in the Japanese population. METHODS: In an open trial, we gave Bifidobacterium breve M-16V and Bifidobacterium longum BB536 prenatally to 130 mothers beginning 1 month prior to delivery and postnatally to their infants for 6 months. Another 36 mother-infant pairs served as controls and did not receive the bifidobacterial supplementation. Development of allergic symptoms in the infants was assessed at 4, 10 and 18 months of age. Fecal samples were collected from the mothers and infants. RESULTS: The risk of developing eczema/atopic dermatitis (AD) during the first 18 months of life was significantly reduced in infants in the probiotic group (OR: 0.231 [95% CI: 0.084-0.628] and 0.304 [0.105-0.892] at 10 and 18 months of age, respectively). Pyrosequencing analyses indicated an altered composition of the fecal microbiota at 4 months for infants who developed eczema/AD at 4 and 10 months of age. The proportion of Proteobacteria was significantly lower (P = 0.007) in mothers at the time of delivery who received the supplementation when compared with the control group and was positively correlated (r = 0.283, P = 0.024) with that of infants at 4 months of age. No adverse effects were related to the use of probiotics. CONCLUSIONS: These data suggest that the prenatal and postnatal supplementation of bifidobacteria is effective in primary preventing allergic diseases. Some limited changes in the composition of fecal microbiota by the bifidobacterial supplementation were observed.

[Anti-allergic effects of the probiotic preparations of enterococcus on experimental allergic rhinitis in mice].

OBJECTIVE: The aim of this study was to investigate the anti-allergic effects of lysozyme/heat-treated Enterococcus faecalis FK-23 (LFK) and heat-treated Enterococcus faecium sp. TN-3 (TN) on experimental allergic rhinitis (AR). METHODS: A total of twenty-four BALB/c mice were divided into four groups randomly: (1) positive control group, (2) LFK-fed group, (3) TN-fed group, and (4) negative control group. To establish the murine AR model, intraperitoneal injection and nasal drip with ovalbumin (OVA) were performed. Saline was used instead of OVA for negative control. Probiotic preparations of LFK and TN were orally administrated for 42 days [60 mg (0.5 ml)/d] in LFK-fed and TN-fed mice, respectively. The positive and negative control mice received saline orally for 42 days. Nasal rubbing and sneezing were monitored on d 21, d 27, and d 35. After the final challenge, mice were sacrificed on d 42, and eosinophilic infiltration into the nasal mucosa was quantified (H&E stain). IFN-gamma, IL4 and OVA-specific IgE levels in the sera and splenocyte culture supernatants were determined by ELISA kits. RESULTS: Nasal rubbing of LFK-fed mice was significantly reduced compared to the positive control group on day 27 (t = 2.95, P = 0.028). Both in the LFK-fed and TN-fed mice, nasal rubbing (t value was 3.75 and 3.06, P value was 0.005 and 0.011, respectively) and sneezing (t value was 2.56 and 3.35, P value was 0.038 and 0. 01, respectively) were significantly decreased compared to the positive control group on d 35. The H&E strain section of nasal tissue showed that eosinophil influx into the nasal mucosa decreased significantly both in the LFK-fed and TN-fed mice compared to the positive control group on day 42 (t value was 3.44 and 2.97, P value was 0.014 and 0.025, respectively); however, the LFK-fed mice and TN-fed mice had significant eosinophil influx into the nasal mucosa than that in the negative control group (t value was 2.54 and 3.39, P value was 0.044 and 0.015, respectively). There were no significant differences in the serum levels of IL-4 and OVA-specific IgE, as well as the levels of IFN-gamma and IL-4 in splenocyte culture supernatants between the LFK-fed group and positive control group on d 42 (all P > 0.05). Interestingly, the TN-fed mice had significantly higher serum levels of IFN-gamma compared to the LFK-fed mice [TN-fed mice: (27.07 +/- 3.83) pg/ml, LFK-fed mice: (14.83 +/- 0.99) pg/ml; Z = 2.49, P = 0.016], but not the negative control group [negative control group: (37.12 +/- 1.65) pg/ml; Z = 1.18, P = 0.343] on day 42. The serum levels of IL-4 were significantly lower in the TN-fed mice than those in the positive control group [TN-fed mice: (34.48 +/- 7.53) pg/ml, positive control group: (58.68 +/- 6.59) pg/ml; Z = 2.11, P = 0.035]; however, the levels were significantly higher in the TN-fed mice than those in the negative control group [negative control group: (20.22 +/- 1.75) pg/ml; Z = 2. 31, P = 0.021]. The TN-fed mice had significantly higher levels of IFN-gamma in splenocyte culture supernatants compared to the LFK-fed mice (Z = 2.72, P = 0.03) and the positive control group (Z = 2.30, P = 0.029), whilst the splenocyte culture supernatant levels of IL-4 (Z = 2.12, P = 0.034) and the serum levels of OVA-specific IgE (Z = 2.31, P = 0.021) were significantly lower in the TN-fed mice compared to the positive control mice. CONCLUSIONS: It is suggested that oral administration of probiotic LFK or TN may alleviate nasal symptoms and reduce nasal eosinophilia in the murine AR model. TN supplementation has obviously regulatory effects on the cytokine levels of IFN-gamma and IL-4, and significantly inhibitory effects on antigen-specific IgE levels.

Genome-wide association study identifies eight new susceptibility loci for atopic dermatitis in the Japanese population.

Atopic dermatitis is a common inflammatory skin disease caused by interaction of genetic and environmental factors. On the basis of data from a genome-wide association study (GWAS) and a validation study comprising a total of 3,328 subjects with atopic dermatitis and 14,992 controls in the Japanese population, we report here 8 new susceptibility loci: IL1RL1-IL18R1-IL18RAP (P(combined) = 8.36 × 10(-18)), the major histocompatibility complex (MHC) region (P = 8.38 × 10(-20)), OR10A3-NLRP10 (P = 1.54 × 10(-22)), GLB1 (P = 2.77 × 10(-16)), CCDC80 (P = 1.56 × 10(-19)), CARD11 (P = 7.83 × 10(-9)), ZNF365 (P = 5.85 × 10(-20)) and CYP24A1-PFDN4 (P = 1.65 × 10(-8)). We also replicated the associations of the FLG, C11orf30, TMEM232-SLC25A46, TNFRSF6B-ZGPAT, OVOL1, ACTL9 and KIF3A-IL13 loci that were previously reported in GWAS of European and Chinese individuals and a meta-analysis of GWAS for atopic dermatitis. These findings advance the understanding of the genetic basis of atopic dermatitis.

Examination, diagnosis and classification for Japanese allergic rhinitis: Japanese guideline.

Many countries throughout the world have experienced an increase in the prevalence of allergic rhinitis (AR), which has come to be a major cause of morbidity in developed countries. The pathology underlying AR is regarded as IgE-mediated type I allergy characterized by mucosal inflammation that occurs in response to allergen exposure. In Japan, AR caused by Japanese cedar pollen, the most common allergic disease, has become a salient public health challenge. Almost all primary care physicians and otorhinolaryngologists have been consulted by AR patients between February and April. Although most such patients have received treatment, numerous patients with AR have not received proper examinations for AR. Clinical guidelines are systematically developed statements that are designed to help practitioners make decisions about appropriate and effective health care. Guidelines in many countries including Japan have been published for AR. Unfortunately, those guidelines have remained untested. Moreover, they might be difficult for non-specialists to use. In this review, we specifically examine the present standard examination for diagnosis of AR and optimal classification for AR in Japan. We hope that this review would be used not only for the support of daily practice but also for selection of AR patients for clinical trials.

ORAI1 genetic polymorphisms associated with the susceptibility of atopic dermatitis in Japanese and Taiwanese populations.

Atopic dermatitis is a chronic inflammatory skin disease. Multiple genetic and environmental factors are thought to be responsible for susceptibility to AD. In this study, we collected 2,478 DNA samples including 209 AD patients and 729 control subjects from Taiwanese population and 513 AD patients and 1027 control subject from Japanese population for sequencing and genotyping ORAI1. A total of 14 genetic variants including 3 novel single-nucleotide polymorphisms (SNPs) in the ORAI1 gene were identified. Our results indicated that a non-synonymous SNP (rs3741596, Ser218Gly) associated with the susceptibility of AD in the Japanese population but not in the Taiwanese population. However, there is another SNP of ORAI1 (rs3741595) associated with the risk of AD in the Taiwanese population but not in the Japanese population. Taken together, our results indicated that genetic polymorphisms of ORAI1 are very likely to be involved in the susceptibility of AD.

Effects of lysed Enterococcus faecalis FK-23 on experimental allergic rhinitis in a murine model.

In the current study, we sought to investigate whether lysed Enterococcus faecalis FK-23 (LFK), a heat-killed probiotic preparation, attenuated eosinophil influx into the upper airway and had immunomodulatory activity in a murine allergic rhinitis model. Eighteen BALB/c mice were divided into three groups; the ovalbumin (OVA)-sensitized/challenged group, which received saline orally for 6 weeks (OVA group), the OVA-sensitized/challenged group, which received LFK orally for 6 weeks (LFK-fed group), and the non-sensitized group, which received saline for 6 weeks (saline control group). Nasal rubbing and sneezing were monitored during the study. After the final challenge, interleukin (IL)-4, interferon (IFN)-γ, and OVA-specific IgE levels in the sera and splenocyte culture supernatants were determined, eosinophilic infiltrate into the upper airway was quantified, and splenic CD4+CD25+ regulatory T cells (Tregs) were examined by flow cytometry. We found that nasal rubbing was significantly reduced in LFK-fed mice compared to the OVA group on d 27 and 35, and sneezing was significantly inhibited by LFK administration for 35 d. LFK-fed mice had significantly less eosinophil influx into the nasal mucosa than the OVA group. There were no significant differences between the LFK-fed group and OVA group in the serum and splenocyte culture supernatant levels of IL-4, IFN-γ, and OVA-specific IgE. Interestingly, the LFK-fed mice had a significantly greater percentage of splenic CD4+CD25+ Tregs than OVA group. Our results indicate that oral administration of LFK may alleviate nasal symptoms, reduce nasal eosinophilia, and increase the percentage of CD4+CD25+ Tregs in experimental allergic rhinitis.

[Nonspecific IgE potential in nasal discharge for diagnosing allergic rhinitis].

Given that the nasal discharge of subjects with allergic rhinitis contains IgE, we studied nonspecific IgE potential in nasal discharge as a diagnostic marker for allergic rhinitis. We divided 38 adults into 2 groups, one with 22 with Japanese cedar pollinosis and one with 16 with watery rhinorrhea negative to MAST33. The pollinosis group was exposed to Japanese cedar pollen in an environmental exposure unit, and eosinophils in nasal discharge, serum total IgE, pollen-specific IgE, and local IgE in nasal discharge were examined for the 2 groups to determine IgE levels in nasal discharge using the Allerwatch rapid test. In the pollinosis group, nasal discharge IgE correlated significantly with the number of eosinophils. The nasal discharge IgE had higher specificity than the eosinophil examination, whereas nasal discharge eosinophils had higher sensitivity than the IgE examination. We thus found that measuring IgE and eosinophils in nasal discharge is useful for clinically diagnosing allergic rhinitis.

Variants of C-C motif chemokine 22 (CCL22) are associated with susceptibility to atopic dermatitis: case-control studies.

Atopic dermatitis (AD) is a common inflammatory skin disease caused by multiple genetic and environmental factors. AD is characterized by the local infiltration of T helper type 2 (Th2) cells. Recent clinical studies have shown important roles of the Th2 chemokines, CCL22 and CCL17 in the pathogenesis of AD. To investigate whether polymorphisms of the CCL22 gene affect the susceptibility to AD, we conducted association studies and functional studies of the related variants. We first resequenced the CCL22 gene and found a total of 39 SNPs. We selected seven tag SNPs in the CCL22 gene, and conducted association studies using two independent Japanese populations (1(st) population, 916 cases and 1,032 controls; 2(nd) population 1,034 cases and 1,004 controls). After the association results were combined by inverse variance method, we observed a significant association at rs4359426 (meta-analysis, combined P = 9.6×10⁻6; OR, 0.74; 95% CI, 0.65-0.85). Functional analysis revealed that the risk allele of rs4359426 contributed to higher expression levels of CCL22 mRNA. We further examined the allelic differences in the binding of nuclear proteins by electrophoretic mobility shift assay. The signal intensity of the DNA-protein complex derived from the G allele of rs223821, which was in absolute LD with rs4359426, was higher than that from the A allele. Although further functional analyses are needed, it is likely that related variants play a role in susceptibility to AD in a gain-of-function manner. Our findings provide a new insight into the etiology and pathogenesis of AD.

Genome-wide association study identifies three new susceptibility loci for adult asthma in the Japanese population.

Bronchial asthma is a common inflammatory disease caused by the interaction of genetic and environmental factors. Through a genome-wide association study and a replication study consisting of a total of 7,171 individuals with adult asthma (cases) and 27,912 controls in the Japanese population, we identified five loci associated with susceptibility to adult asthma. In addition to the major histocompatibility complex and TSLP-WDR36 loci previously reported, we identified three additional loci: a USP38-GAB1 locus on chromosome 4q31 (combined P = 1.87 × 10(-12)), a locus on chromosome 10p14 (P = 1.79 × 10(-15)) and a gene-rich region on chromosome 12q13 (P = 2.33 × 10(-13)). We observed the most significant association with adult asthma at rs404860 in the major histocompatiblity complex region (P = 4.07 × 10(-23)), which is close to rs2070600, a SNP previously reported for association with FEV(1)/FVC in genome-wide association studies for lung function. Our findings offer a better understanding of the genetic contribution to asthma susceptibility.

Thymic stromal lymphopoietin gene promoter polymorphisms are associated with susceptibility to bronchial asthma.

Thymic stromal lymphopoietin (TSLP) triggers dendritic cell--mediated T helper (Th) 2 inflammatory responses. A single-nucleotide polymorphism (SNP), rs3806933, in the promoter region of the TSLP gene creates a binding site for the transcription factor activating protein (AP)-1. The variant enhances AP-1 binding to the regulatory element, and increases the promoter--reporter activity of TSLP in response to polyinosinic-polycytidylic acid (poly[I:C]) stimulation in normal human bronchial epithelium (NHBE). We investigated whether polymorphisms including the SNP rs3806933 could affect the susceptibility to and clinical phenotypes of bronchial asthma. We selected three representative (i.e., Tag) SNPs and conducted association studies of the TSLP gene, using two independent populations (639 patients with childhood atopic asthma and 838 control subjects, and 641 patients with adult asthma and 376 control subjects, respectively). We further examined the effects of corticosteroids and a long-acting ß(2)-agonist (salmeterol) on the expression levels of the TSLP gene in response to poly(I:C) in NHBE. We found that the promoter polymorphisms rs3806933 and rs2289276 were significantly associated with disease susceptibility in both childhood atopic and adult asthma. The functional SNP rs3806933 was associated with asthma (meta-analysis, P = 0.000056; odds ratio, 1.29; 95% confidence interval, 1.14-1.47). A genotype of rs2289278 was correlated with pulmonary function. Moreover, the induction of TSLP mRNA and protein expression induced by poly(I:C) in NHBE was synergistically impaired by a corticosteroid and salmeterol. TSLP variants are significantly associated with bronchial asthma and pulmonary function. Thus, TSLP may serve as a therapeutic target molecule for combination therapy.

Enhancement of anti-allergic effects mediated by the Kampo medicine Shoseiryuto (Xiao-Qing-Long-Tang in Chinese) with lysed Enterococcus faecalis FK-23 in mice.

Kampo is a traditional Japanese medicine originating from ancient Chinese medicine which included the administration of herbal prescription, lifestyle advice and acupuncture. Orally administered Kampo prescriptions are believed to be influenced by diet and intestinal microbiota. However, reports on the Kampo administration effects are still limited. Shoseiryuto (TJ-19), which has anti-allergic and anti-inflammatory properties, is a Kampo prescription used clinically for the treatment of allergic bronchial asthma. We examined whether Shoseiryuto administration is affected by a probiotic product, lysed Enterococcus faecalis FK-23 (LFK). BALB/c mice were sensitized with cedar pollen allergen, and the peritoneal accumulation of eosinophils was induced. During a sensitization period of 21 days, varying amounts of Shoseiryuto (and saline as a control) were administered to the mice. The accumulation of eosinophils was significantly reduced by 30 mg/day doses of Shoseiryuto but not by 3 or 9 mg/day doses. Similarly, 3 mg/day Shoseiryuto, 30 mg/day LFK, 3 mg/day of Shoseiryuto co-administered with 30 mg/day of LFK, and saline control were compared. A significant reduction in the accumulation of eosinophils was observed at 3 mg/day Shoseiryuto co-administered with 30 mg/day of LFK. These results suggest that Shoseiryuto-mediated anti-allergic effects are enhanced by the probiotic (LFK). Although not significant statistically, serum allergen-specific and total IgE levels in the treatment group exposed to the mixed agent (ie. Shoseiryuto and LFK) were generally lower than those receiving either one alone. The results indicate a synergistic effect of a Kampo medicine (Shoseiryuto, Xiao-Qing-Long-Tang in Chinese) and lysed Enterococcus faecalis FK-23 on allergic responses in mice.