IgE responsiveness to Dermatophagoides farinae in West Highland white terrier dogs is associated with region on CFA35

Immunoglobulin E (IgE)-mediated hypersensitivity against environmental allergens, commonly including Dermatophagoides farinae, is associated with atopic diseases in both humans and dogs. We have recently identified a family of clinically healthy West Highland white terriers (WHWTs) with high-serum D. farinae-IgE levels. In this study, we investigated the genetic mechanism controlling IgE responsiveness in dogs by performing a genome-wide association study (GWAS) using the Affymetrix V2 Dog SNP array in 31 high-IgE and 24 low-IgE responder WHWTs. A gene-dropping simulation method, using SIB-PAIR software, showed significant allelic association between serum D. farinae-specific IgE levels and a 2.3-Mb area on CFA35 (best empirical P = 1 × 10(-5)). A nearby candidate gene, CD83, encodes a protein which has important immunological functions in antigen presentation and regulation of humoral immune responses. We sequenced this gene in 2 high-IgE responders and 2 low-IgE responders and identified an intronic polymorphic repeat sequence with a predicted functional effect, but the association was insufficient to explain the GWAS association signal in this population (P = 1 × 10(-3)). Further studies are necessary to investigate the significance of these findings for IgE responsiveness and atopic disease in the dog.     

Markers of atopic dermatitis,allergic rhinitis and bronchial asthma in pediatric patients: correlation with filaggrin,eosinophil major basic protein and immunoglobulin E

Background

Allergic reactions have been implicated as contributions in a number of atopic disorders, including atopic dermatitis (AD), allergic rhinitis (AR) and bronchial asthma (BA). However, the potential for filaggrin protein, eosinophil major basic protein (MBP) and immunoglobulin E (IgE) to elicit allergic response or to contribute to atopic disorders remains largely unexplored in pediatric patients. This study was undertaken to investigate the status and contribution of filaggrin protein, eosinophil MBP and total IgE in pediatric patients with AD, AR and BA.

Methods

Sera from 395 pediatric patients of AD, AR or BA with varying levels of disease activity according to the disease activity index and 410 age-matched non-atopic healthy controls were evaluated for serum levels of atopic markers, including filaggrin, eosinophil MBP and IgE.

Results

Serum analysis showed that filaggrin levels were remarkably high in pediatric patients with AD, followed by BA and AR, whereas its levels were low in non-atopic pediatric controls. Eosinophil MBP levels in sera of atopic patients were significantly high as compared with their respective controls, but its levels were highest in AR patients, followed by AD and BA. Total IgE in sera of AD patients was markedly high, followed by AR and BA patients, whereas its levels were low in non-atopic pediatric controls. Interestingly, not only was an increased number of subjects positive for filaggrin protein, eosinophil MBP or total IgE, but also their levels were statistically significantly higher among those atopic patients whose disease activity scores were higher as compared with atopic patients with lower disease activity scores.

Conclusions

These findings strongly support a role of filaggrin protein, eosinophil MBP and IgE in the onset of allergic reactions in pediatric patients with AD, AR and BA. The data suggest that filaggrin, eosinophil MBP or IgE might be useful in evaluating the progression of AD, AR or BA and in elucidating the mechanisms involved in the pathogenesis of these pediatric disorders.

     

Temperature preference and respiration of acaridid mites

The thermal preferences in a grain mass and respiration at various temperatures in mites (Acari: Acarididae) of medical and economical importance [Acarus siro (L. 1758), Dermatophagoides farinae Hughes 1961, Lepidoglyphus destructor (Schrank 1871), and Tyrophagus putrescentiae (Schrank 1781)] were studied under laboratory conditions. Based on the distribution of mites in wheat, Triticum aestivum L., grain along a thermal gradient from 10 to 40 degrees C, L. destructor, D. farinae, and A. siro were classified as eurythermic and T. putrescentiae as stenothermic. The lowest preferred temperature was found for D. farinae (28 degrees C), followed by A. siro (28.5 degrees C), L. destructor (29.5 degrees C), and T. putrescentiae (31.5 degrees C). The relationship between the respiration rate and the temperature was similar for all four mite species. The highest respiration was found in the range from 31 to 33 degrees C. This is approximately 2 degrees C higher than the preferred temperature of these species. The lower temperature threshold of respiration ranged from 1 to 5 degrees C and the upper threshold ranged from 45 to 48 degrees C. Acclimatization of A. siro to temperature regimes of 5, 15, and 35 degrees C resulted in thermal preferences between 9 and 12 degrees C, 9 and 20 degrees C, and 28 and 35 degrees C, respectively. The respiration rate of acclimatized specimens increased with the temperature, reaching a maximum at 29.0 degrees C for mites acclimatized at 5 and 15 degrees C and a maximum at 33.7 degrees C for those acclimatized at 30 degrees C.     

A genetic study of immunoglobulin E and atopic disease based on families ascertained through asthmatic children

In order to investigate the modes of inheritance of serum immunoglobulin E (IgE) levels and atopic disease, serum IgE levels and data on allergic disease were obtained from 42 families ascertained through asthmatic children visiting an allergy clinic. Although the mean IgE levels were elevated (mean 637 U/ml), the prevalence of atopic disease in this population was surprisingly low. When the data were analyzed using complex segregation analysis, no major locus could be detected. Moreover, the polygenic heritability was unexpectedly small even though the correlation between serum IgE levels and the liability to atopic disease was around 0.4. Given this unusual set of findings, it is postulated that parasitic infections in this population have (in accordance with well-established results of parasitic disease) caused both elevated levels of serum IgE and a decreased prevalence of allergic disease with the possible masking of the various genetic components of serum IgE levels and atopic disease.     

Oral administration of a hop water extract ameliorates the development of dermatitis induced by the periodical topical application of a mite antigen in atopic dermatitis model NC/Nga mice

We investigated the inhibitory effect of an oral administration of a hop water extract (HWE) on the development of dermatitis by using NC/Nga atopic dermatitis model mice. The induction of allergic dermatitis was conducted by tape-stripping and topical application of a mite antigen (Dermatophagoides farinae) on to the ear once a week for 10 weeks. HWE was orally administered at a dose of 100 or 500 mg/kg. The total immunoglobulin E (IgE) concentration in serum and the ear thickness were periodically examined. Finally, the antigen-specific IgE level in the serum and the production of interleukin (IL)-4, IL-12 and interferon (IFN)-gamma from splenocytes and cervical lymph node cells were measured. The oral administration of HWE significantly inhibited the increase of total IgE production and ear swelling throughout the experimental period. The production of IL-12 was significantly lower in the HWE administered group than in the control group. The results suggest that the intake of HWE may be effective in preventing and alleviating the development of atopic dermatitis-like skin disease.     

Delayed hypersensitivity to house dust-storage mites Thyrophagus putrescentiae in experimental allergic dermatoses]

House dust mites and storage mites proved to be one of the main allergens causing hypersensitivity in atopic dermatitis in allergic patients. The authors reproduced experimental allergic dermatosis on the model of delayed type hypersensitivity in guinea pigs, caused by sensitization to the allergen from the mite's bodies Tyrophagus putrescentiae--species having wide distribution in the country. The results characteristic for T-cell type hypersensitivity have been obtained: delayed positive skin tests after 24 hours, typical histomorphological picture (strong allergic alteration, epidermis desquamation, vasculitis, dermis T-cell infiltration and spongiosis--Waksman's syndrome). It is concluded that side by side with humoral IgE-mediated reaction there is strong delayed T-cell hypersensitivity to the storage mites Tyrophagus putrescentiae.     

Genetic variants of the receptors for thromboxane A2 and IL-4 in atopic dermatitis

Thromboxane A2 (TXA2) is an arachidonate metabolite which is considered to relate to chronic inflammation in atopic diseases characterized by elevated immunoglobulin E productivity. The elevation of immunoglobulin E levels involves many molecules including interleukin-4 (IL-4) and interleukin-4 receptor alpha chain (IL-4R alpha). To assess whether genetic variants of TXA2 receptor, IL-4 and IL-4R alpha genes relate to the elevation of serum immunoglobulin E levels in patients with atopic dermatitis (AD), we conducted an association study of genetic polymorphisms of TXA2 receptor (795C/T), IL-4 (-589C/T), and IL-4R alpha (Ile50Val) in a Japanese population (n = 789). The TXA2 receptor 795TT genotype strongly related to AD with high serum immunoglobulin E concentrations. AD patients with both TXA2 receptor 795TT genotype and the IL-4R alpha Ile50/Ile50 genotype showed the greatest immunoglobulin E concentrations. These results suggest TXA2 receptor polymorphism strongly interacts with IL-4R alpha polymorphism as a major determinant of high serum immunoglobulin E levels in AD.     

Oral Administration of a Hop Water Extract Ameliorates the Development of Dermatitis Induced by the Periodical Topical Application of a Mite Antigen in Atopic Dermatitis Model NC/Nga Mice

We investigated the inhibitory effect of an oral administration of a hop water extract (HWE) on the development of dermatitis by using NC/Nga atopic dermatitis model mice. The induction of allergic dermatitis was conducted by tape-stripping and topical application of a mite antigen (Dermatophagoides farinae) on to the ear once a week for 10 weeks. HWE was orally administered at a dose of 100 or 500 mg/kg. The total immunoglobulin E (IgE) concentration in serum and the ear thickness were periodically examined. Finally, the antigen-specific IgE level in the serum and the production of interleukin (IL)-4, IL-12 and interferon (IFN)-γ from splenocytes and cervical lymph node cells were measured. The oral administration of HWE significantly inhibited the increase of total IgE production and ear swelling throughout the experimental period. The production of IL-12 was significantly lower in the HWE administered group than in the control group. The results suggest that the intake of HWE may be effective in preventing and alleviating the development of atopic dermatitis-like skin disease.     

Absence of association between a variant of the mast cell chymase gene and atopic dermatitis in an Italian population

Atopic dermatitis (AD) is a chronic dermatitis which belongs to the group of atopy-related diseases together with asthma and rhinitis. IgE and mast cell chymase (MCC) play a key role in atopic or allergic inflammation of the skin. An association between AD and a genetic variant of the MCC has been reported in a Japanese population, but failure of confirmation has rendered this association questionable. We have tested for genetic association to an MCC variant in relation to AD in an Italian population. No significant association was found between AD and MCC genotypes. These data suggest that BstXI MCC polymorphism may not be involved in AD.     

Genome-wide scan on total serum IgE levels identifies FCER1A as novel susceptibility locus

High levels of serum IgE are considered markers of parasite and helminth exposure. In addition, they are associated with allergic disorders, play a key role in anti-tumoral defence, and are crucial mediators of autoimmune diseases. Total IgE is a strongly heritable trait. In a genome-wide association study (GWAS), we tested 353,569 SNPs for association with serum IgE levels in 1,530 individuals from the population-based KORA S3/F3 study. Replication was performed in four independent population-based study samples (total n = 9,769 individuals). Functional variants in the gene encoding the alpha chain of the high affinity receptor for IgE (FCER1A) on chromosome 1q23 (rs2251746 and rs2427837) were strongly associated with total IgE levels in all cohorts with P values of 1.85 x 10(-20) and 7.08 x 10(-19) in a combined analysis, and in a post-hoc analysis showed additional associations with allergic sensitization (P = 7.78 x 10(-4) and P = 1.95 x 10(-3)). The "top" SNP significantly influenced the cell surface expression of FCER1A on basophils, and genome-wide expression profiles indicated an interesting novel regulatory mechanism of FCER1A expression via GATA-2. Polymorphisms within the RAD50 gene on chromosome 5q31 were consistently associated with IgE levels (P values 6.28 x 10(-7)-4.46 x 10(-8)) and increased the risk for atopic eczema and asthma. Furthermore, STAT6 was confirmed as susceptibility locus modulating IgE levels. In this first GWAS on total IgE FCER1A was identified and replicated as new susceptibility locus at which common genetic variation influences serum IgE levels. In addition, variants within the RAD50 gene might represent additional factors within cytokine gene cluster on chromosome 5q31, emphasizing the need for further investigations in this intriguing region. Our data furthermore confirm association of STAT6 variation with serum IgE levels.     

Genome-wide scan on total serum IgE levels identifies no common variants in a healthy Chinese male population

Immunoglobulin E (IgE) provides important information on the humoral immune status, and the IgE level is routinely detected in clinical practice. There are many diseases associated with IgE, such as atopic disease, autoimmune diseases, and so on. IgE is a genetically complex trait, but comprehensive genetic assessment of the variability in serum IgE levels is lacking. Previous genome-wide association studies (GWAS) on total serum IgE levels have identified FCER1A as the susceptibility locus; however, the candidate gene association study in southern Chinese patients reported no association. Given the genetic difference in different populations, we firstly conducted this two-stage GWAS in a Chinese population of 3,495 men, including 1,999 unrelated subjects in the first stage and 1,496 independent individuals replicated in the second stage. In the first stage, we totally identified three single nucleotide polymorphisms (SNPs) which reached a P value of 1.0?×?10^?5. Rs17090302 on chromosome 3 and Rs28708846 on chromosome 13 are intergenic. Rs432085 from chromosome 3p28 is located in the gene CCDC50. When the two-stage data was combined, none of the SNPs reached the genome-wide significant level. Collectively, we did not identify novel loci associated with the serum IgE level in Chinese males, but we hypothesized that CCDC50 was a candidate gene in regulation on IgE level.     

Detection and identification of species-specific bacteria associated with synanthropic mites

Internal bacterial communities of synanthropic mites Acarus siro, Dermatophagoides farinae, Lepidoglyphus destructor, and Tyrophagus putrescentiae (Acari: Astigmata) were analyzed by culturing and culture-independent approaches from specimens obtained from laboratory colonies. Homogenates of surface-sterilized mites were used for cultivation on non-selective agar and DNA extraction. Isolated bacteria were identified by sequencing of the 16S rRNA gene. PCR amplified 16S rRNA genes were analyzed by terminal restriction fragment length polymorphism analysis (T-RFLP) and cloning sequencing. Fluorescence in situ hybridization using universal bacterial probes was used for direct bacterial localization. T-RFLP analysis of 16S rRNA gene revealed distinct species-specific bacterial communities. The results were further confirmed by cloning and sequencing (284 clones). L. destructor and D. farinae showed more diverse communities then A. siro and T. putrescentiae. In the cultivated part of the community, the mean CFUs from four mite species ranged from 5.2?×?10(2) to 1.4?×?10(3) per mite. D. farinae had significantly higher CFUs than the other species. Bacteria were located in the digestive and reproductive tract, parenchymatical tissue, and in bacteriocytes. Among the clones, Bartonella-like bacteria occurring in A. siro and T. putresecentiae represented a distinct group related to Bartonellaceae and to Bartonella-like symbionts of ants. The clones of high similarity to Xenorhabdus cabanillasii were found in L. destructor and D. farinae, and one clone related to Photorhabdus temperata in A. siro. Members of Sphingobacteriales cloned from D. farinae and A. siro clustered with the sequences of "Candidatus Cardinium hertigii" and as a separate novel cluster.     

Suppressive potential of bean (Phaseolus vulgaris) flour against five species of stored-product mites (Acari: Acarididae)

Previous research has demonstrated that legume proteins have insecticidal activity against stored-product pests, but activity against stored-product mites has not been tested. A study was therefore conducted to explore the potential of bean, Phaseolus vulgaris L., flour as novel botanical acaricide against five species of storage and dust mites: Acarus siro L., Aleuroglyphus ovatus (Troupeau), Caloglyphus redickorzevi (Zachvatkin), Lepidoglyphus destructor (Schrank), and Tyrophagus putrescentiae (Schrank). The effect of wheat, Triticum aestivum L., grain enriched with bean flour to eight concentrations (0, 0.01, 0.1, 0.5, 1, 2.5, 5, and 10%) on population growth initiating from the density of 50 mites per 100 g of wheat was recorded for 21 d under laboratory conditions (grain moisture 14.6% moisture content and 25 degree C in darkness). The enrichment of grain with bean flour suppressed the population growth of all tested species: 0.01% concentration reduced population growth of all tested species to >50% in comparison with the control population. The most sensitive species were A. siro and L. destructor, followed by T. putrescentiae and C. redickorzevi. The least sensitive species was A. ovatus. The terminal (i.e., after 21 d) density of mites positively correlated with bean flour concentration. The suppressive effect of bean flour was not linear but rather asymptotic. The results of this study are discussed in the context of the application of bean flour in integrated control of stored-product mites and the elimination of stored-product mite allergens.     

Atopic dermatitis in West Highland white terriers is associated with a 1.3-Mb region on CFA 17

Canine atopic dermatitis (AD) is an allergic inflammatory skin disease that shares similarities with AD in humans. Canine AD is likely to be an inherited disease in dogs and is common in West Highland white terriers (WHWTs). We performed a genome-wide association study using the Affymetrix Canine SNP V2 array consisting of over 42,800 single nucleotide polymorphisms, on 35 atopic and 25 non-atopic WHWTs. A gene-dropping simulation method, using SIB-PAIR, identified a projected 1.3 Mb area of association (genome-wide P = 6 × 10⁻⁵ to P = 7 × 10⁻⁴) on CFA 17. Nineteen genes on CFA 17, including 1 potential candidate gene (PTPN22), were located less than 0.5 Mb from the interval of association identified on the genome-wide association analysis. Four haplotypes within this locus were differently distributed between cases and controls in this population of dogs. These findings suggest that a major locus for canine AD in WHWTs may be located on, or in close proximity to an area on CFA 17.     

Blood Lead Levels and Increased Bronchial Responsiveness

The immune system is one of the targets most sensitive to lead toxicity, and the association between lead exposure and serum immunoglobulin E (IgE) has been published. Recent studies also reported that lead caused the development of IgE-mediated allergy. To investigate whether blood lead levels contribute to other allergic conditions, we examined the effect of blood lead on bronchial responsiveness (BR) in the general population. We performed a cross-sectional study with adults aged 19 to 58 years in a Korean community. Blood lead level and the methacholine provocation test were performed. The overall mean blood lead level was 2.9 microg/dl, and the mean BR index was 1.14. The percent of subjects with clinically diagnosed asthma was 21 (4%) and there was no difference in blood lead level with and without asthma. In the multiple regression model, the elevation of blood lead level was related to the increase of BR after adjusting for age, sex, height, smoking status, and the presence of asthma. Blood lead level was significantly associated with increased BR that came from the elevation of the IgE level with lead exposure. Lead may contribute to the increase of asthma and other allergic conditions.     

SNPs in the FCER1A gene region show no association with allergic rhinitis in a Han Chinese population

Background

Immunoglobulin E (IgE) is a central player in the allergic response, and raised total IgE levels are considered as an indicator of atopy or potential development of atopy. A recent genome-wide scan in a German population-based cohort of adults identified the gene encoding the alpha chain of the high affinity receptor for IgE (FCER1A) as a susceptibility locus influencing total serum IgE levels. The aim of this study was to investigate whether the polymorphisms in the FCER1A gene are associated with allergic rhinitis (AR) in a Han Chinese population.

Methodology/Principal Findings

A population of 378 patients with AR and 288 healthy controls was studied. Precise phenotyping of patients was accomplished by means of a questionnaire and clinical examination. Blood was drawn for DNA extraction and total serum immunoglobulin E (IgE) measurement. A total of 16 single nucleotide polymorphisms (SNPs) in FCER1A were selected and individually genotyped. None of the SNPs in the FCER1A showed an association with AR. Similarly, the lack of association was also evident in subgroup analysis for the presence of different allergen sensitivities. None of the selected SNPs in FCER1A was associated with total IgE level.

Conclusions

Although FCER1A presents itself as a good candidate for contributing to total serum IgE, this study failed to find an association between SNPs in the FCER1A gene region and IgE level or AR susceptibility.     

Significant evidence for linkage of mite-sensitive childhood asthma to chromosome 5q31-q33 near the interleukin 12 B locus by a genome-wide search in Japanese families

Childhood-onset asthma is frequently found in association with atopy. Although asthmatic children may develop IgE antibodies against variety of allergens, asthma is associated primarily with allergy to house-dust mites, molds, or other allergens. In this study, we conducted a genome-wide linkage search in 47 Japanese families (197 members) with more than two mite-sensitive atopic asthmatics (65 affected sib-pairs) using 398 markers. Multipoint linkage analysis was carried out for atopic asthma as a qualitative trait using the MAPMAKER/SIB program. We observed significant evidence for linkage with maximum lod scores (MLS) of 4.8 near the interleukin 12 B gene locus on chromosome 5q31-q33. In addition, suggestive evidence on 4q35 with MLS = 2.7 and on 13q11 with MLS = 2.4 was obtained. The other possible linkage regions included 6p22-p21.3 (MLS = 2.1), 12q21-q23 (MLS = 1.9), and 13q14.1-q14.3 (MLS = 2.0). Many of the linkage loci suggested in this study were at or close to those suggested by genome-wide studies for asthma in Caucasian populations. The present study suggests the contribution of the interleukin 12 B gene or nearby gene(s) to mite-sensitive atopic asthma and a considerable number of genetic variants common across Caucasians and Japanese populations contributing to asthma, although the relative importance of various variants may differ between the groups.     

Inhibition of immunoglobulin E production in allergic model mice by supplementation with vitamin E and beta-carotene

A diet containing different amounts of vitamin E (alpha-tocopherol; 0.5 mg, 5 mg, 10 mg or 50 mg per 100 g diet) was supplemented to BALB/c mice for 6 weeks. These mice were subcutaneously immunized twice with ovalbumin (OVA). A passive cutaneous anaphylaxis (PCA) analysis demonstrated that the mice fed on the diet containing 5 mg of vitamin E produced the highest level of the OVA-specific immunoglobulin E (IgE) antibody. A lower level of serum IgE was found in the mice supplemented with 0.5 mg, 10 mg and 50 mg of vitamin E. A sandwich ELISA analysis showed that the pattern of the total IgE antibody level among these four groups was the same as that of the allergen-specific IgE. In a separate experiment, 5 mg of vitamin E and/or 50 mg of beta-carotene was supplemented to the basal diet containing vitamin E as alpha-tocopherol acetate (5 mg) in order to evaluate the effect of their combination on OVA-specific and total IgE production in the mice. The supplementation with beta-carotene alone had no effect on OVA-specific or total IgE production. In contrast, supplementation with vitamin E plus beta-carotene effectively suppressed both the antigen-specific and total IgE antibodies. The serum vitamin E and beta-carotene levels were increased by supplementation with the respective compounds. These results strongly suggest that the combination of dietary vitamin E and beta-carotene suppressed IgE production and would therefore help to prevent the type-I allergic reaction.     

Molecular cloning and the allergenic characterization of tropomyosin from Tyrophagus putrescentiae

Storage mites have been recognized as a cause of asthma and rhinitis. Studies from several countries have shown that the IgE-mediated allergy to storage mites is of considerable importance, especially in rural populations. This study aimed to identify and characterize new allergens from Tyrophagus putrescentiae. A partial cDNA sequence encoding tropomyosin was isolated from the cDNA library by immunoscreening using anti-mouse IgG1 sera raised against T. putrescentiae whole body extract. The deduced amino acid sequence shares 64-94% identity with previously known allergenic tropomyosins. Its recombinant protein was produced by using a pET 28b expression system and purified by affinity chromatography using Ni-NTA agarose. The IgE reactivities of tropomyosins from T. putrescentiae and Dermatophagoides farinae were compared by enzyme linked immunosorbent assay (ELISA). Recombinant Tyr p 10 showed 12.5% (5/40) IgE-binding reactivity, whereas recombinant Der f 10 showed 25% (10/40) IgE-binding reactivity against the same sera from storage mite-sensitized and house dust mite-sensitized subjects. Both recombinant Tyr p 10 and Der f 10 showed little inhibition of IgE binding to T. putrescentiae crude extract by ELISA. Tropomyosin seems to contribute only a small portion of the cross-reactivity with house dust mites.     

Treatment with phosphodiester CpG-ODN ameliorates atopic dermatitis by enhancing TGF-β signaling

Synthetic oligodeoxynucleotides (ODNs) containing unmethylated CpG phosphorothioate (PS CpG-ODN) are known to decrease IgE synthesis in Th2 allergy responses. Nonetheless, the therapeutic role of PS CpG-ODN is limited due to cytotoxicity. Therefore, we developed a phosphodiester (PO) form of CpG-ODN (46O) with reduced toxicity but effective against allergies. In this study, we first compared the toxicity of 46O with CpG-ODNs containing a PS backbone (1826S). We also investigated the therapeutic efficacy and mechanism of 46O injected intravenously in a mouse model of ovalbumin (OVA)-induced atopic dermatitis (AD). To elucidate the mechanism of 46O underlying the inhibition of IgE production, IgE- and TGF-β-associated molecules were evaluated in CD40/IL-4- or LPS/IL-4-stimulated B cells. Our data showed that the treatment with 46O was associated with a lower hematological toxicity compared with 1826S. In addition, injection with 46O reduced erythema, epidermal thickness, and suppressed IgE and IL-4 synthesis in mice with OVA-induced AD. Additionally, 46O induced TGF-β production in LPS/IL-4-stimulated B cells via inhibition of Smad7, which suppressed IgE synthesis via interaction between Id2 and E2A. These findings suggest that enhanced TGF-β signaling is an effective treatment for IgE-mediated allergic conditions, and 46O may be safe and effective for treating allergic diseases such as AD and asthma.