Vitamin D constrains inflammation by modulating the expression of key genes on Chr17q12-21.1.

Vitamin D possesses immunomodulatory functions and vitamin D deficiency has been associated with the rise in chronic inflammatory diseases, including asthma (Litonjua and Weiss, 2007). Vitamin D supplementation studies do not provide insight into the molecular genetic mechanisms of vitamin D-mediated immunoregulation. Here, we provide evidence for vitamin D regulation of two human chromosomal loci, Chr17q12-21.1 and Chr17q21.2, reliably associated with autoimmune and chronic inflammatory diseases. We demonstrate increased vitamin D receptor (Vdr) expression in mouse lung CD4+ Th2 cells, differential expression of Chr17q12-21.1 and Chr17q21.2 genes in Th2 cells based on vitamin D status and identify the IL-2/Stat5 pathway as a target of vitamin D signaling. Vitamin D deficiency caused severe lung inflammation after allergen challenge in mice that was prevented by long-term prenatal vitamin D supplementation. Mechanistically, vitamin D induced the expression of the Ikzf3-encoded protein Aiolos to suppress IL-2 signaling and ameliorate cytokine production in Th2 cells. These translational findings demonstrate mechanisms for the immune protective effect of vitamin D in allergic lung inflammation with a strong molecular genetic link to the regulation of both Chr17q12-21.1 and Chr17q21.2 genes and suggest further functional studies and interventional strategies for long-term prevention of asthma and other autoimmune disorders.

Factors contributing to the diagnosis and onset prediction of perennial allergic rhinitis in high-risk children: A sub-analysis of the CHIBA study.

BACKGROUND: This study aimed to clarify the diagnostic and predictive factors for perennial allergic rhinitis (PAR) onset in children by analyzing the results of the Chiba High-risk Birth Cohort for Allergy study, which examined newborns with a family history of allergies. METHODS: Overall, 306 pregnant women were recruited. Their newborns were examined by otolaryngologists and pediatric allergists at 1, 2, and 5 years of age. Participants with clinical and laboratory data available at all consultation points were considered eligible. RESULTS: Among 187 eligible participants, the prevalence rates of PAR were 2.1%, 4.3%, and 24.1% at 1, 2, and 5 years of age, respectively. AR-specific nasal local findings and eosinophils in nasal smear were observed in a substantial number of patients with PAR at 1 and 2 years of age. Factors present up to 2 years of age that were associated with PAR onset at 5 years of age, in descending order, were as follows: sensitization to house dust mites (HDM), nasal eosinophilia, and sensitization to cat dander. In 44 cases with HDM sensitization, nasal eosinophilia up to 2 years of age achieved a sensitivity of 76.0% and a specificity of 73.7% for predicting PAR onset at 5 years. CONCLUSIONS: Rhinitis findings and nasal eosinophilia are useful auxiliary diagnostic items for pediatric PAR. Sensitization to HDM and nasal eosinophilia were the most influential factors associated with future PAR onset. A combination of these factors may facilitate the prediction of PAR onset.

The propionate-GPR41 axis in infancy protects from subsequent bronchial asthma onset.

Evidence has accumulated that gut microbiota and its metabolites, in particular the short-chain fatty acid propionate, are significant contributors to the pathogenesis of a variety of diseases. However, little is known regarding its impact on pediatric bronchial asthma, one of the most common allergic diseases in childhood. This study aimed to elucidate whether, and if so how, intestinal propionate during lactation is involved in the development of bronchial asthma. We found that propionate intake through breast milk during the lactation period resulted in a significant reduction of airway inflammation in the offspring in a murine house dust mite-induced asthma model. Moreover, GPR41 was the propionate receptor involved in suppressing this asthmatic phenotype, likely through the upregulation of Toll-like receptors. In translational studies in a human birth cohort, we found that fecal propionate was decreased one month after birth in the group that later developed bronchial asthma. These findings indicate an important role for propionate in regulating immune function to prevent the pathogenesis of bronchial asthma in childhood.

Comparison of 30 Cytokines in Human Breast Milk between 1989 and 2013 in Japan.

Milk cytokines play a vital role in mucosal immunity during infancy by supporting immune development and functions. Although the maternal background characteristics influence milk cytokines, changes in cytokine levels across generations remain unclear. Colostrum (C, n = 48) and mature milk (MM, n = 49) samples were collected from lactating Japanese women in 1989 (2727 samples) and 2013 (1408 samples). Milk cytokines were comprehensively measured using a suspension array and immunosorbent assays. The positive rates and cytokine concentrations were compared between the two generations using logistic and multiple regression analyses. Twenty-eight cytokines tested positive in all sample groups (1989-C, 1989-MM, 2013-C, and 2013-MM). The median osteopontin (OPN) level was significantly higher in the 1989-C group than in the 2013-C group (318.1 vs. 137.5 µg/mL; p = 0.0016) but did not differ between the MM groups. The median TGF-ß1 level was significantly lower in the 1989-MM group than in the 2013-MM group (1056.2 vs. 1330.8 pg/mL; p = 0.008) but did not differ between the C groups. Most cytokines were comparable between generations, except for potential variation in the C-OPN and TGF-ß1 levels. Milk cytokine secretion may reflect temporal changes in maternal background characteristics; however, the results from the analysis of 30-year-old samples may have influenced the milk cytokine levels. Further studies are needed with a larger number of milk samples collected from the same individuals at multiple time points over a wide lactation period, with detailed data on the maternal and infant background characteristics and diets.

Association of umbilical cord serum TARC/CCL17 with childhood allergies: A birth cohort study.

BACKGROUND: Early identification of infants at high risk of allergies can improve the efficacy of preventive interventions. However, an established quantifiable risk assessment method in the early postnatal period does not exist. TARC (or CCL17) is a Th2 chemokine used as an activity marker for atopic dermatitis (AD). Therefore, we evaluated the association between cord blood TARC (cTARC) and the development of allergic diseases in childhood. METHODS: This is a high-risk birth cohort for allergy, consisting of children with a family history of allergy. We collected 263 pairs of maternal and child cord blood samples perinatally and child blood samples at ages 1, 2, and 5 years. TARC and allergen-specific immunoglobulin E levels were measured, and the relationship between allergic diseases was analyzed. RESULTS: The median cTARC was 989 pg/mL (interquartile range [IQR]: 667-1430 pg/mL). The cTARC levels in children who developed AD were higher than those in children who did not develop AD, and the association strengthened with younger age (median [IQR] at 1 year: 1285 [816-1965] vs. 933 [662-1330] pg/mL, p < 0.01; at 2 years: 1114 [787-1753] vs. 950 [660-1373] pg/mL, p = 0.02). In the multivariate analysis, cTARC was associated with AD, egg white sensitization, food allergy, allergic rhinitis, and Japanese cedar pollen sensitization. CONCLUSIONS: cTARC was associated with the development of allergic diseases and allergen sensitization in early childhood. These results suggest that, infantile AD-mediated atopic march starts during fetal life, and this immune status is reflected in the cTARC at birth.

Increase in eosinophil-derived neurotoxin level in school children with allergic disease.

Background: Eosinophils are major effector cells of allergic disease and excellent markers of eosinophilic inflammation. Accurate and reliable biomarkers are helpful in the diagnosis, treatment, and control of allergic disease. Objective: This study aimed to investigate an alternate marker of eosinophilic inflammation, eosinophil-derived neurotoxin (EDN), in a number of allergic diseases. Methods: Three hundred ninety-six elementary school-age children with various allergic conditions were recruited for this study. Subgroups included food allergies (FAs), atopic dermatitis (AD), bronchial asthma (BA), and allergic rhinitis (AR). EDN levels in these groups were compared to those in 93 healthy controls (HC). Results: All subjects with allergic disease had elevated levels of serum EDN (median [interquartile range]: FA, 124.2 ng/mL [59.13-160.5 ng/mL]; AD, 110.8 ng/mL [57.52-167.9 ng/mL]; BA, 131.5 ng/mL [60.60-171.0 ng/mL]; AR, 91.32 ng/mL [46.16-145.0 ng/mL]) compared to HC (38.38 ng/mL [32.40-55.62 ng/mL]) (p < 0.0001). These elevated levels were consistent throughout the age range (6-12 years) of the healthy study subjects (p = 0.0679). EDN levels also correlated well with total immunoglobulin E (Rs = 0.5599, p < 0.0001). Looking at all individuals with an allergic disease, the area under the curve was 0.790. Conclusions: Direct measures of eosinophilic inflammation are needed for accurate diagnosis, treatment, and monitoring of allergic diseases. EDN may be a worthy biomarker of eosinophil activity and a useful screening tool for allergic diseases including FA, AD, BA, and AR.

Successful management of a case of intestinal Behçet's disease with a splenic abscess by intensified immunosuppressive therapy without splenectomy.

Behçet's disease (BD) is often associated with neutrophilic dermatosis. However, BD is rarely associated with aseptic abscesses in the spleen or liver. A 2-year-old girl presented to our hospital with a 2-week history of fever, abdominal pain, and a skin ulcer on her leg. Each time her skin was punctured with a needle for a blood test or spinal fluid test, she developed intractable aseptic abscesses on her skin. She was diagnosed with intestinal BD based on gastrointestinal endoscopy findings and was treated with prednisolone, mesalazine, and elemental diet therapy. Although these were effective for her colon ulcers, low-grade fever and mild abdominal pain persisted. Abdominal computed tomography revealed a low-density area in the spleen. Although it is recommended to check the contents with puncture drainage, it was difficult due to the risk of bleeding and pathergy. The abscess expanded despite antimicrobial therapy. We discontinued antimicrobial therapy and switched to intensified immunosuppressive therapy for BD [intravenous infliximab (IFX)]. After administration of IFX, the splenic abscess gradually disappeared, and all her symptoms improved. In cases of BD with splenic abscesses resistant to antimicrobial therapy, intensifying immunosuppressive therapy can be expected to shrink the abscesses and avoid splenectomy.

A three-generation Muckle-Wells syndrome family: Detailed family history, physical examination, and inter-departmental collaboration.

Cryopyrin-associated periodic syndrome (CAPS) is a rare inherited autoinflammatory disease caused by gain-of-function mutations in the NLRP3 gene, with a genotype-phenotype correlation. The clinical presentation of each mutation has been previously studied. However, very few studies have reported on the clinical characteristics and treatment effectiveness across different generations within a family with the same mutation. A detailed investigation of family members of patients with CAPS may help in the appropriate diagnosis and treatment of undiagnosed CAPS. Herein, we report a 2-year-old boy (proband), his father, and his grandmother who presented with several symptoms of CAPS, such as persistently positive inflammatory reactions and hearing impairment. All three patients had the same pathogenic mutation in the NLRP3 gene (c.1049C > T (p.Thr350Met) heterozygous mutation) and were diagnosed with CAPS. With canakinumab treatment, the laboratory data of all three patients improved, the proband and father's skin rash disappeared, and his grandmother's arthropathy improved. The proband's hearing also showed slight improvement but not in his father or grandmother. Among the various non-specific symptoms associated with CAPS, chronic ocular hyperaemia is a finding that can be easily identified by non-ophthalmologists. Diagnosis of CAPS should be considered when eye symptoms are present in a combination of hyperinflammatory response, arthropathy, or skin symptoms. Thorough family history records, physical examinations, and close collaboration between paediatricians and adult rheumatologists are important for prompt diagnosis and appropriate treatment of inherited autoinflammatory diseases.

Association of the Maternal Gut Microbiota/Metabolome with Cord Blood CCL17.

Chemokine (C-C motif) ligand 17 (CCL17) is a pro-allergic factor: high CCL17 levels in cord blood (CB) precede later allergic predisposition. Short-chain fatty acid (SCFA) treatment during pregnancy has been shown to protect mouse pups against allergic diseases. The maternal microbial metabolome during pregnancy may affect fetal allergic immune responses. We therefore examined the associations between CB CCL17 and gut SCFA levels in healthy pregnant Japanese women. CB CCL17 serum levels at birth, and maternal non-specific IgE levels in maternal sera at 32 weeks of gestation were measured. Maternal stool samples were collected at 12 (n = 59) and 32 (n = 58) weeks of gestation for gut microbiota analysis, based on barcoded 16S rRNA sequencing and metabolite levels. The CB CCL17 levels correlated negatively with butyrate concentrations and positively with isobutyrate at 12 weeks; CB CCL17 correlated positively with valerate and lactate at 32 weeks. Similarly, butyrate levels correlated negatively with maternal non-specific IgE levels, whereas the lactate concentration correlated positively with IgE levels. At 32 weeks, the Shannon diversity index (SDI) of Firmicutes and Proteobacteria correlated negatively with CB CCL17 levels, while those of the total microbiota correlated positively with the CB CCL17 levels. These metabolites may alter fetal immune responses. This study provides the first link between maternal metabolites during pregnancy and the risk of allergic diseases in human offspring.

Long-chain saturated fatty acids in breast milk are associated with the pathogenesis of atopic dermatitis via induction of inflammatory ILC3s.

Breastfeeding influences the immune system development in infants and may even affect various immunological responses later in life. Breast milk provides a rich source of early nutrition for infant growth and development. However, the presence of certain compounds in breast milk, related to an unhealthy lifestyle or the diet of lactating mothers, may negatively impact infants. Based on a cohort study of atopic dermatitis (AD), we find the presence of damage-associated molecular patterns (DAMPs) activity in the mother's milk. By non-targeted metabolomic analysis, we identify the long-chain saturated fatty acids (LCSFA) as a biomarker DAMPs (+) breast milk samples. Similarly, a mouse model in which breastfed offspring are fed milk high in LCSFA show AD onset later in life. We prove that LCSFA are a type of damage-associated molecular patterns, which initiate a series of inflammatory events in the gut involving type 3 innate lymphoid cells (ILC3s). A remarkable increase in inflammatory ILC3s is observed in the gut, and the migration of these ILC3s to the skin may be potential triggers of AD. Gene expression analysis of ILC3s isolated from the gut reveal upregulation of genes that increase ILC3s and chemokines/chemokine receptors, which may play a role in ILC migration to the skin. Even in the absence of adaptive immunity, Rag1 knockout mice fed a high-LCSFA milk diet develop eczema, accompanied by increased gut ILC3s. We also present that gut microbiota of AD-prone PA milk-fed mice is different from non-AD OA/ND milk-fed mice. Here, we propose that early exposure to LCSFAs in infants may affect the balance of intestinal innate immunity, inducing a highly inflammatory environment with the proliferation of ILC3s and production of interleukin-17 and interleukin-22, these factors may be potential triggers or worsening factors of AD.

Precision medicine reaching out to the patients in allergology - a German-Japanese workshop report.

An expert workshop in collaboration of the German Society of Allergy and Clinical Immunology (DGAKI) and the Japanese Society of Allergy (JSA) provided a platform for key opinion leaders of both countries aimed to join expertise and to highlight current developments and achievements in allergy research. Key domains of the meeting included the following seven main sections and related subchapters: 1) basic immunology, 2) bronchial asthma, 3) prevention of allergic diseases, 4) food allergy and anaphylaxis, 5) atopic dermatitis, 6) venom allergy, and 7) upper airway diseases. This report provides a summary of panel discussions of all seven domains and highlights unmet needs and project possibilities of enhanced collaborations of scientific projects.

Evaluation of torque moment in esthetic brackets from bendable alloy wires.

OBJECTIVES: To examine the torque moment that occurs between esthetic brackets and bendable alloy (stainless steel [SS], titanium-molybdenum [Ti-Mo], and titanium-niobium [Ti-Nb]) wires. MATERIALS AND METHODS: This study examined ceramic (CR), zirconium oxide (ZC), polycarbonate (PC), and conventional metallic brackets (MT) (upper, 0.018-inch and 0.022-inch slots) combined with SS, Ti-Mo, and Ti-Nb wires using elastic module ligation. The torque moments delivered by various wire and bracket combinations were measured using a torque gauge apparatus. The wire torque angles at 5-40° were examined. RESULTS: The torque value increased in the order of CR, ZC, MT, and PC brackets for both 0.018-inch and 0.022-inch slots. The fracture points of the CR and ZC brackets combined with SS and Ti-Mo wires were approximately more than 30° and 35°, respectively. No fracture points were detected in the combination of ZC brackets and Ti-Nb wires. CONCLUSIONS: The current study identified the material characteristics of CR, ZR, and PC brackets during torque tooth movements. The present results demonstrate a characteristic combined effect between different esthetic brackets and bendable alloy wires.

Corrigendum to "Association of the maternal microbiome in Japanese pregnant women with the cumulative prevalence of dermatitis in early infancy: A pilot study from the Chiba study of Mother and Child Health birth cohort" [World Allergy Organ J 12/10 (2019) 100065].

[This corrects the article DOI: 10.1016/j.waojou.2019.100065.].

Staphylococcus Agr virulence is critical for epidermal colonization and associates with atopic dermatitis development.

Atopic dermatitis (AD) is commonly associated with colonization by Staphylococcus aureus in the affected skin. To understand the role of S. aureus in the development of AD, we performed whole-genome sequencing of S. aureus strains isolated from the cheek skin of 268 Japanese infants 1 and 6 months after birth. About 45% of infants were colonized with S. aureus at 1 month regardless of AD outcome. In contrast, skin colonization by S. aureus at 6 months of age increased the risk of developing AD. Acquisition of dysfunctional mutations in the S. aureus Agr quorum-sensing (QS) system was primarily observed in strains from 6-month-old infants who did not develop AD. Expression of a functional Agr system in S. aureus was required for epidermal colonization and the induction of AD-like inflammation in mice. Thus, retention of functional S. aureus agr virulence during infancy is associated with pathogen skin colonization and the development of AD.

Association of the maternal microbiome in Japanese pregnant women with the cumulative prevalence of dermatitis in early infancy: A pilot study from the Chiba study of Mother and Child Health birth cohort.

BACKGROUND: The prenatal maternal microbiome, including the gut microbiota, has been suggested to influence the incidence of allergies in offspring. Moreover, epidermal barrier dysfunction in early infancy has been attributed to the development of subsequent allergies. We hypothesized that the prenatal microbiome may affect the gut microbiota, acting as an initial trigger to alter immune development in the foetus. The maternal microbial composition may be linked to the prevalence of dermatitis in early infancy (DEI) of the offspring, leading to subsequent allergic symptoms. METHODS: This study was conducted as part of the Chiba Study of Mother and Child Health (C-MACH) birth cohort that was initiated in 2013; 434 healthy pregnant women at < 13 weeks of gestation were recruited. DEI was assessed for up to 4 months after birth, and allergic symptoms were determined in 10-month-old infants using questionnaires. Other information related to the maternal microbiome was obtained from questionnaires filled out during pregnancy. Stool samples were collected from pregnant women at 12 (n = 59) and 32 weeks (n = 58) of gestation, which were used for gut microbiota analysis using barcoded 16S rRNA gene sequencing. RESULTS: Symptoms of allergy, especially of inherited allergies, show a higher prevalence at 10 months after birth in the DEI group. DEI occurrence was negatively correlated with family size and cat ownership. The diversity of Proteobacteria at 12 weeks of gestation and the relative abundance of Actinobacteria at 32 weeks of gestation in maternal feces were lower at both time points of gestation in the DEI group. In addition, the diversity of Proteobacteria in prenatal feces was negatively correlated with family size at 12 weeks, and with dog ownership at both gestational time points. CONCLUSIONS: The composition of the maternal microbiome may influence the risk of allergies in offspring, even before birth. Furthermore, the diversity of Proteobacteria and the relative abundance of Actinobacteria in maternal feces were negatively associated with DEI, which may be associated with the risk of allergy development in infancy. This early trigger may be a good predictor of allergy development during infancy and childhood.