Asthma is the most prevalent allergic disease of the airway, which is characterized by eosinophilic inflammation, mucus hyperproduction, and airway hyper-responsiveness. Although these pathognomonic features are mainly mediated by antigen-specific Th2 cells and their cytokines, such as IL-4, IL-5, and IL-13, recent studies have revealed that other inflammatory cells, including Th17 cells and innate lymphoid cells (ILCs), also play a critical role in the pathogenesis of asthma. IL-22, one of the cytokines produced by Th17 cells and type 3 ILCs, has distinct functional properties, as IL-22 exclusively acts on non-hematopoietic cells including epithelial cells of mucosal surface and exhibits a broad range of action in regeneration and host protection. In accordance with the fact that lung epithelial cells play a critical role in the pathogenesis of asthma, we and other groups have shown that IL-22 is involved in the regulation of allergic airway inflammation. In this review, we discuss recent advances in the biology of IL-22 and its involvement in the pathogenesis of allergic airway inflammation.

The recent discovery of innate lymphoid cells has revolutionized our understanding of the pathogenesis of immune diseases including allergy and asthma. Innate lymphoid cells (ILCs) are a heterogeneous collection of lymphocytes that lack antigen-specificity (non-T, non-B cells) and potently produce characteristic cytokines of T cell subsets (Th1, Th2, Th17). ILCs are divided into group 1 (ILC1s), group 2 (ILC2s), or group 3 (ILC3s). Similar to Th2 cells, ILC2s produce IL-4, IL-5, and IL-13, among others, and are present in increased numbers in samples from patients with many allergic disorders including asthma and chronic rhinosinusitis (CRS). Animal models have identified that ILC2s contribute to eosinophilic tissue infiltration, airway hyperresponsiveness, mucus production, as well as coordinate adaptive immune responses. Finally, recent studies support regulation of ILC2s by neuro-immune mechanisms as well as demonstrate a significant degree of plasticity between ILC subsets that may impact the immune responses in asthma and allergic airway diseases. Here, we review the current literature on ILC2s in human asthma and allergic airway diseases, as well as highlight some recent mechanistic insights into ILC2 function from in vitro studies and in vivo animal models.

Despite its direct exposure to huge amounts of microorganisms and foreign and dietary antigens, the gut mucosa maintains intestinal homeostasis by utilizing the mucosal immune system. The gut mucosal immune system protects the host from the invasion of infectious pathogens and eliminates harmful non-self antigens, but it allows the cohabitation of commensal bacteria in the gut and the entry of dietary non-self antigens into the body via the mucosal surface. These physiological and immunological activities are regulated by the ingenious gut mucosal immune network, comprising such features as gut-associated lymphoid tissue, mucosal immune cells, cytokines, chemokines, antimicrobial peptides, secretory IgA, and commensal bacteria. The gut mucosal immune network keeps a fine tuned balance between active immunity (against pathogens and harmful non-self antigens) and immune tolerance (to commensal microbiota and dietary antigens), thus maintaining intestinal healthy homeostasis. Disruption of gut homeostasis results in persistent or severe gastrointestinal infection, inflammatory bowel disease, or allergic inflammation. In this review, we comprehensively introduce current knowledge of the gut mucosal immune system, focusing on its interaction with allergic inflammation.

Background: Atopic dermatitis (AD) and exercise-induced asthma (EIA) are common in asthmatic children, and exercise is the most common trigger other than infection for acute onset asthma attack in children. We examined whether AD is related to exercise-induced wheezing (EIW), some proxy for EIA.

Methods: Japanese version of the International Study of Asthma and Allergies in Childhood questionnaires were used. For 12,405 asthmatic school children, AD was defined as itchy rash coming and going for at least 6 months at any time in the last 12 months with affecting places of flexural parts of body, and severity of AD was rated according to frequency of being kept awake at night with the itch as follows: never in the past 12 months, less than one night per week and one or more nights per week.

Results: Adjusted for frequency of asthma attack, odds ratios (OR) of children with current AD as compared to those without AD for having EIW were 1.32 (95% confidence interval = 1.15-1.52), 1.35 (1.14-1.68) and 1.10 (0.92-1.31) for primary school, junior high school and high school children, respectively. EIW was more likely observed in accordance with increasing severity of AD in the primary school children with ORs of 1.12, 1.59 and 1.54 (p for trend < 0.01), and in the junior high school ones with ORs of 1.18, 1.31, 2.03 (<0.01), respectively.

Conclusions: AD may be possibly related to EIW. Further studies investigating effect of AD treatment on EIW may be required.

Background: Cough variant asthma (CVA) is characterized by a chronic cough and bronchial hyperresponsiveness without confirmation of wheezing. Using a breath sound analyzer, we evaluate the characteristics of breath sound in children with CVA.

Methods: Nine children with CVA (median age, 7.0 years) participated. The existence of breath sounds was confirmed by sound spectrogram. Breath sound parameters, the frequency limiting 50% and 99% of the power spectrum (F₅₀ and F₉₉), the roll-off from 600 to 1200 Hz (Slope) and spectrum curve indices, the ratio of the third and fourth area to the total area of the power spectrum (P₃/P_T and P₄/P_T) and the ratio of power and frequency at 50% and 75% of the highest frequency of the power spectrum (RPF₇₅ and RPF₅₀) were calculated before and after β₂ agonist inhalation. A spirogram and/or forced oscillation technique were performed in all subjects.

Results: On a sound spectrogram, wheezing was confirmed in seven of nine patients. All wheezing on the image was polyphonic, and they almost disappeared after β₂ agonist inhalation. An analysis of the breath sound spectrum showed that P_T, P₃/P_T, P₄/P_T, RPF₅₀ and RPF₇₅ were significantly increased after β₂ agonist inhalation.

Conclusions: Children with CVA showed a high rate of inaudible wheezing that disappeared after β₂ agonist inhalation. Changes in the spectrum curve indices also indicated the bronchial reversibility. These results may suggest the characteristics of CVA in children.

Background: Genetic and environmental factors are proposed to be involved in cedar pollen allergy sensitization and onset. The impact of these factors will provide key information for the prevention of cedar pollen sensitization and allergy onset, which we investigated in this cross-sectional study.

Methods: Subjects were 382 young adult volunteers who completed a self-administered questionnaire on self-reported subjective symptoms of pollinosis, physician-diagnosed pollinosis, and background factors. We also measured their serum IgE antibody titers specific for cedar, cypress, and mites. Factors associated with subjective symptoms, physician diagnosis, and the three specific antigens were determined using both univariate and multivariate analyses.

Results: Sensitization to cedar, cypress, and mites, defined as specific IgE levels of class 1 or above, was found in 78.8%, 64.4%, and 56.0% of subjects, respectively. The prevalence of cedar pollinosis was 41.2% based on subjective symptoms and 22.2% based on physician diagnosis. Factors associated with increased cedar pollen sensitization were mite sensitization, comorbid allergic rhinitis, and family history of cedar pollinosis. Risk-reducing factors for cedar pollen sensitization were keeping a cat, number of common colds, and hours of sleep. Risk-increasing factors for both subjective pollinosis symptoms and physician-diagnosed pollinosis were comorbid allergic rhinitis and family history of cedar pollinosis.

Conclusions: Sensitization to cedar pollen in this population was extremely high. Both common and distinct factors were associated with sensitization to pollen and with the development of pollinosis. The distinct factors were associated with sensitization to cedar and cypress antigens.

Background: The Japan Asthma Control Survey (JACS) questionnaire, developed as a tool for measuring asthma control levels in Japanese asthma patients, was previously tested for its reliability and validity. However, many of the patients enrolled in the original validation study had mild asthma; thus a re-evaluation including severe cases was required to calculate more reliable cut-off values.

Methods: Pooled analysis of data from the original validation study and the subsequent medication guidance study including adult patients with severe asthma was conducted to calculate the JACS questionnaire cut-off values and to assess their sensitivity and specificity for identifying “well-controlled”, “not well-controlled”, and “poorly controlled” asthma as described in the Asthma Prevention and Management Guideline 2015 (JGL2015). The data were from 353 patients with mild to severe persistent asthma classified according to JGL2015.

Results: The JACS questionnaire cut-off values were 8.0 (sensitivity, 67.9%; specificity, 81.9%) for “well-controlled” and “not well-controlled” and 4.8 (sensitivity, 85.3%; specificity, 53.3%) for “not well-controlled” and “poorly controlled”.

Conclusions: JACS cut-off values can be expected to be more useful for evaluating asthma control status in clinical practice and clinical research, thus improving asthma treatment, in Japan. This analysis was the original validation study (UMIN000016589) and the subsequent medication guidance study (UMIN000024353).

Background: Previous epidemiologic studies of the natural course of urticaria mainly focused on chronic spontaneous urticaria and were conducted at hospitals. The natural course of new-onset urticaria in the general population is unknown.

Methods: Patients with new-onset urticaria were identified from the National Health Insurance Service-National Sample Cohort data. Patients who had at least one visit for urticaria in 2002 and 2003 were excluded and the study cohort consisted of 1,027,620 subjects with no history of urticaria. We analyzed cumulative incidences of urticaria, chronic urticaria, and chronic urticaria remission using the life table estimation method from 2004 to 2013. Their association with related factors was analyzed using the Cox proportional hazards analysis.

Results: From 2004 to 2013, a total of 49,129 patients with new-onset urticaria were identified. The 10-year cumulative incidence rate of urticaria for the general population was 4.9% and that of chronic urticaria among patients with new-onset urticaria was 7.8%. Remission rates of chronic urticaria were 52.6% at 1 year and 88.9% at 5 years. Age, sex, residential area, and autoimmune thyroid disease were significantly associated with urticaria or chronic urticaria, but not with chronic urticaria remission, after adjusting for covariates. Female individuals were more likely to have new-onset urticaria but less likely to develop chronic urticaria compared with male individuals.

Conclusions: During the 10-year follow-up period, only a small proportion of patients with new-onset urticaria developed chronic urticaria. Remission was achieved in the majority of patients with chronic urticaria regardless of demographic characteristics or accompanying thyroid disease.

Background: Rupatadine, a novel nonsedating second-generation H1-antihistamine with antiplatelet-activating factor activity, has been used in the treatment of allergic rhinitis and urticaria in European countries since 2003. However, its efficacy and safety in Japanese patients with chronic spontaneous urticaria (CSU) are unknown.

Methods: We conducted a prospective, multicenter, randomized, placebo-controlled, double-blind study in adolescent and adult CSU outpatients aged 12 to < 65 years (JAPIC-CTI No. 152786). Overall, 94, 91, and 92 eligible patients orally received placebo, rupatadine 10 mg, and 20 mg once daily for 2 weeks, respectively. The primary endpoint was change from baseline to the second week of treatment in total pruritus score (TPS, sum of daytime and nighttime pruritus scores).

Results: The results yielded a least squares mean TPS difference of -1.956 between rupatadine 10 mg versus placebo, and -2.121 between rupatadine 20 mg versus placebo (analysis of covariance, both P < 0.001). The incidence of adverse events was 8.5% for placebo, 20.9% for rupatadine 10 mg, and 17.4% for rupatadine 20 mg. Somnolence was the only adverse drug reaction to rupatadine reported in 2 or more subjects. No serious or clinically significant adverse events were observed.

Conclusions: The primary and secondary efficacy endpoints consistently favored rupatadine 10 and 20 mg doses over the placebo. No noteworthy dose-related increase in the incidence of adverse drug reactions was observed. Rupatadine is safe and effective at a dose of 10 mg once daily, and can be safely increased to 20 mg once daily, as necessary.

Background: To diagnose and treat respiratory allergic diseases, it is important to identify the specific allergens involved. Many differences exist between common inhalant allergens depending on the residential environment and demographic factors. This study aimed to compare common inhalant allergens between Koreans and non-Koreans according to their residential region, age, and sex.

Methods: This study evaluated 15,334 individuals who underwent serum tests for multiple allergen-specific immunoglobulin E at a tertiary academic medical center between January 2010 and December 2016. The individuals included 14,786 Koreans and 548 non-Koreans. The AdvanSure^™ Allostation assay (LG Life Science, Korea) was used to test for 33 inhalant allergens.

Results: The house dust mite (HDM) was the most common allergen in both Koreans and non-Koreans, although the proportion of individuals with HDM sensitization was greater among Koreans. High sensitization rates for various pollen types were detected among Koreans in Gangwon region, whereas Japanese cedar pollen was unique among Koreans in Jeju region. Grass pollen and animal dander were relatively common among individuals from the Americas, whereas weed and grass pollen accounted for the 10 most common allergens for individuals from Central Asia. The total sensitization rate, sensitization to HDM, and sensitization to animal dander peaked among adolescents and young adults, then subsequently decreased with age.

Conclusions: This large-scale study demonstrates that various regional and age-related differences exist in the allergen sensitization rates of Koreans and non-Koreans. These data could be useful for development of avoidance measures, immunotherapy for causative allergens, and policymaking regarding allergic diseases.

Background: TYRO3 is a member of the TAM (TYRO3, AXL, MERTK) receptor tyrosine kinase family and functions to limit type 2 immune responses implicated in allergic sensitization. Recent studies have shown that multiple intronic variants of TYRO3 were associated with asthma, implying that genetic variation could contribute to errant immune activation. We therefore hypothesized that expression quantitative trait loci (eQTLs) of the TYRO3 gene influence the development of allergic diseases (including asthma and allergic rhinitis) in Japanese populations.

Methods: We performed a candidate gene case-control association study of 8 eQTLs of TYRO3 on atopy, asthma, and allergic rhinitis using 1168 unrelated Japanese adults who had GWAS genotyping. We then examined the genetic impact of rs2297377 (TYRO3) on atopy and allergic rhinitis in 2 other independent Japanese populations.

Results: A meta-analysis of 3 Japanese populations (a total of 2403 Japanese adults) revealed that rs2297377 was associated with atopy and allergic rhinitis (OR = 1.29 and 1.31; P = 0.00041 and 0.0010, respectively). The risk allele at rs2297377 correlated with decreased expression of TYRO3 mRNA. The gene-gene interaction between HLA-DPB1 and TYRO3 was not significant with regard to sensitization. The estimated proportion of atopy and allergic rhinitis cases attributable to the risk genotype was 14% and 16%, respectively.

Conclusions: Our study identified TYRO3 as an important susceptibility gene to atopy and allergic rhinitis in Japanese.

Background: The development of methods to predict the clinical effectiveness of sublingual immunotherapy (SLIT) for allergic diseases is a crucial matter. We sought to determine whether whole saliva, which is the first body component that contacts allergen extracts during SLIT, is associated with the clinical effectiveness of SLIT in Japanese cedar pollinosis.

Methods: Blood monocytes or monocytic THP-1 cells were cultured in the presence or absence of either whole saliva or pure saliva with or without treatments including filtration and blockade of TLR2 and/or TLR4 signaling. IL-10 levels in the supernatants were then measured. Whole saliva-induced IL-10 production by THP-1 cells was compared between asymptomatic and disease-onset patients during peak pollen dispersal after SLIT.

Results: Both monocytes and THP-1 cells produced substantial amounts of IL-10 in response to whole saliva. IL-10 production was significantly reduced in response to pure saliva and 0.2 μm-filtered saliva. Simultaneous treatment with polymyxin B and TL2.1, a neutralizing antibody against TLR2, also reduced IL-10 production. IL-10 levels produced by THP-1 cells in response to whole saliva collected prior to SLIT were significantly higher in asymptomatic patients determined by symptom-medication scores than disease-onset patients following SLIT. Such differences were not seen in saliva collected 3 months after the initiation of SLIT or saliva collected during peak pollen dispersal.

Conclusions: Our results provide a basis for why the sublingual route is effective and preferable in allergen immunotherapy. Saliva-induced IL-10 levels produced by THP-1 cells may be a predictive marker for clinical remission after SLIT.

Background: Breath sound parameters have been suggested as biomarkers of the airway narrowing in children. Using a commercially available breath sound analyzer, the characteristics of the airway condition were investigated in infants with the risk factors for asthma development.

Methods: A total of 443 infants (mean age, 9.9 months; range, 3-24 months) were included in the present study. The breath sound parameters of the frequency limiting 99% of the power spectrum (F₉₉), the roll-off from 600 to 1200 Hz (Slope) and spectrum curve indices, the total area under the curve of the dBm data (A₃/A_T) and the ratio of power and frequency at 50% and 75% of the highest frequency of the power spectrum (RPF₇₅ and RPF₅₀), were evaluated. Using an ATS-DLD based original Japanese questionnaire, we examined the characteristics of airway condition of infants.

Results: Finally, 283 infants in good health were included in the present study. The RPF₇₅, RPF₅₀, Slope and F₉₉ in infants with positive results of allergy and atopic dermatitis were significantly increased more than those in the infants with negative result.

Conclusions: Our data highlight the characteristics of breath sounds in infants with risk factors for asthma. The breath sound analysis may be useful for assessing the airways of infants for asthma development.

Background: Pteridines are metabolites of tetrahydrobiopterin, which serves as co-enzyme of nitric oxide synthase. We sought to investigate the usefulness of pteridines as biomarkers for childhood asthma control.

Methods: We conducted a single-center prospective cohort study involving 168 asthmatic children aged 4-17 years who visited the periodical asthma checkup program. Serum neopterin and biopterin levels were measured as pteridines at each visit along with measurement of FeNO, respiratory function tests, nasal eosinophil test, blood eosinophil count, and IgE level. We calculated coefficients for relation between pteridines and asthma control, which was assessed by questionnaires (JPAC: Japanese Pediatric Asthma Control Program).

Results: A total of 168 participants aged 10.3 ± 3.39 years (mean ± SD) with asthma were recruited. The participants in this study contained 58 patients (34.5%) of complete-controlled based on JPAC, 132 patients (76.0%) of well-controlled group based on GINA. FeNO and serum neopterin level did not correlate with following period's JPAC scores. In contrast, serum biopterin level significantly correlated with following period's JPAC total score (Coefficients 0.398; 95% CI 0.164 to 0.632; p value 0.001) and frequency of wheezing during exercise (Coefficients 0.272; 95% CI 0.217 to 0.328; p value < 0.001).

Conclusions: We found serum biopterin effected the following period's control status of asthmatic children, thus monitoring biopterin level will be a useful for management of asthma to adjust treatment.

Background: Bronchial asthma is a chronic airway disease characterized by eosinophilic airway inflammation. Lung fibroblasts activated by IL-13 serve as important sources of chemokines, such as eotaxins, contributing to persistent eosinophilic inflammation. Src-homology 2-containing protein (CISH), belonging to the suppressor of cytokine signaling (SOCS) family, acts as a negative regulator of cytokine induction. The aim of this study was to elucidate the role of CISH in the production of eosinophil chemotactic chemokines in human lung fibroblasts.

Methods: Normal human lung fibroblasts were stimulated by IL-13, and global gene expression profile was assessed by cDNA microarray. Expression changes and downstream of IL-13 signaling were evaluated by quantitative RT-PCR, ELISA or western blotting. Loss- and gain-of-function analyses of CISH were performed by small interfering RNA and vector overexpression, respectively.

Results: Ingenuity pathway analysis revealed that IL-13 induced chemokine signaling, including the eotaxin family, while significantly suppressing IFN-α/β signaling. Among eight SOCS family members, CISH was most strongly induced by IL-13 via phosphorylation of signal transducer and activator of transcription 6 (STAT6). Loss- and gain-of-function studies demonstrated that CISH negatively regulated the expression of CCL26.

Conclusions: These findings suggest that CISH plays a key role in the eosinophilic inflammation associated with bronchial asthma by regulating IL-13-induced CCL26 production. Augmentation of CISH function could be a novel approach for treating eosinophilic inflammation in severe asthma.