Showing papers by "Kenji Matsumoto published in 2018"

Multiancestry association study identifies new asthma risk loci that colocalize with immune-cell enhancer marks

Abstract: We examined common variation in asthma risk by conducting a meta-analysis of worldwide asthma genome-wide association studies (23,948 asthma cases, 118,538 controls) of individuals from ethnically diverse populations. We identified five new asthma loci, found two new associations at two known asthma loci, established asthma associations at two loci previously implicated in the comorbidity of asthma plus hay fever, and confirmed nine known loci. Investigation of pleiotropy showed large overlaps in genetic variants with autoimmune and inflammatory diseases. The enrichment in enhancer marks at asthma risk loci, especially in immune cells, suggested a major role of these loci in the regulation of immunologically related mechanisms.

Type 2 innate lymphoid cells disrupt bronchial epithelial barrier integrity by targeting tight junctions through IL-13 in asthmatic patients.

Abstract: Background Bronchial epithelial barrier leakiness and type 2 innate lymphoid cells (ILC2s) have been separately linked to asthma pathogenesis; however, the influence of ILC2s on the bronchial epithelial barrier has not been investigated previously. Objective We investigated the role of ILC2s in the regulation of bronchial epithelial tight junctions (TJs) and barrier function both in bronchial epithelial cells of asthmatic patients and healthy subjects and general innate lymphoid cell– and ILC2-deficient mice. Methods Cocultures of human ILC2s and bronchial epithelial cells were used to determine transepithelial electrical resistance, paracellular flux, and TJ mRNA and protein expressions. The effect of ILC2s on TJs was examined by using a murine model of IL-33–induced airway inflammation in wild-type, recombination-activating gene 2 (Rag2)−/−, Rag2−/−Il2rg−/−, and Rorasg/sg mice undergoing bone marrow transplantation to analyze the in vivo relevance of barrier disruption by ILC2s. Results ILC2s significantly impaired the epithelial barrier, as demonstrated by reduced transepithelial electrical resistance and increased fluorescein isothiocyanate–dextran permeability in air-liquid interface cultures of human bronchial epithelial cells. This was in parallel to decreased mRNAs and disrupted protein expression of TJ proteins and was restored by neutralization of IL-13. Intranasal administration of recombinant IL-33 to wild-type and Rag2−/− mice lacking T and B cells triggered TJ disruption, whereas Rag2−/−Il2rg−/− and Rorasg/sg mice undergoing bone marrow transplantation that lack ILC2s did not show any barrier leakiness. Direct nasal administration of IL-13 was sufficient to induce deficiency in the TJ barrier in the bronchial epithelium of mice in vivo. Conclusion These data highlight an essential mechanism in asthma pathogenesis by demonstrating that ILC2s are responsible for bronchial epithelial TJ barrier leakiness through IL-13.

Defensive effect of microRNA-200b/c against amyloid-beta peptide-induced toxicity in Alzheimer's disease models.

Abstract: MiRNA molecules are important post-transcriptional regulators of gene expression in the brain function. Altered miRNA profiles could represent a defensive response against the pathogenesis of neurodegenerative disorders, such as Alzheimer's disease (AD). Endogenous miRNAs have lower toxic effects than other gene silencing methods, thus enhancing the expression of defensive miRNA could be an effective therapy. However, little is known about the potential of targeting miRNAs for the treatment of AD. Here, we examined the function of the miR-200 family (miR-200a, -141, -429, -200b, -200c), identified using miRNA microarray analysis of cortical tissue from Tg2576 transgenic mice. In murine primary neurons, we found that upregulation of miR-200b or -200c was induced by the addition of amyloid beta (Aβ). Neurons transfected with miR-200b or -200c reduced secretion of Aβ in conditioned medium. Moreover, mice infused with miR-200b/c into the brain were relieved of memory impairments induced by intracerebroventricular injection of oligomeric Aβ, and demonstrated proper spatial learning in the Barnes maze. To gain further understanding of the relationship between miR-200b/c and Aβ, we identified target mRNAs via an RNA-binding protein immunoprecipitation-microarray assay. Western blot analysis showed that expression of ribosomal protein S6 kinase B1 (S6K1), a candidate target, was inhibited by miR-200c. S6K1, a downstream effector of mammalian target of rapamycin (mTOR), serves as a negative feedback mediator that phosphorylates insulin receptor substrate 1 at serine residues (IRS-1pSer). S6K1-dependent IRS-1pSer suppresses insulin signaling leading to insulin resistance, which is frequently observed in AD brains. Notably, miR-200b/c transfection of SH-SY5Y cells reduced the levels of IRS-1pSer. This finding indicates that miR-200b/c has the potential to alleviate insulin resistance via modulation of S6K1. Taken together, miR-200b/c may contribute to reduce Aβ secretion and Aβ-induced cognitive impairment by promoting insulin signaling.

IL-31 is crucial for induction of pruritus, but not inflammation, in contact hypersensitivity.

Abstract: IL-31, which is a member of the IL-6 family of cytokines, is produced mainly by activated CD4+ T cells, in particular activated Th2 cells, suggesting a contribution to development of type-2 immune responses. IL-31 was reported to be increased in specimens from patients with atopic dermatitis, and IL-31-transgenic mice develop atopic dermatitis-like skin inflammation, which is involved in the pathogenesis of atopic dermatitis. However, the role of IL-31 in development of contact dermatitis/contact hypersensitivity (CHS), which is mediated by hapten-specific T cells, including Th2 cells, is not fully understood. Therefore, we investigated this using IL-31-deficient (Il31−/−) mice, which we newly generated. We demonstrated that the mice showed normal migration and maturation of skin dendritic cells and induction of hapten-specific T cells in the sensitization phase of FITC-induced CHS, and normal induction of local inflammation in the elicitation phase of FITC- and DNFB-induced CHS. On the other hand, those mice showed reduced scratching frequency and duration during FITC- and/or DNFB-induced CHS. Our findings suggest that IL-31 is responsible for pruritus, but not induction of local skin inflammation, during CHS induced by FITC and DNFB.

Distinct gene expression profiles and regulation networks of nasal polyps in eosinophilic and non-eosinophilic chronic rhinosinusitis

Abstract: Background Chronic rhinosinusitis with nasal polyps (CRSwNP) is known to have 2 phenotypes in East Asia. Eosinophilic CRSwNP (ECRSwNP), defined as tissue eosinophilia and easily recurrent, is distinguished from other non-eosinophilic CRSwNP (NECRSwNP) types. However, the pathogenesis of each remains unclear. Methods Nasal polyp tissues from ECRS (ECRSwNP) and NECRS (NECRSwNP) patients were obtained, and their comprehensive gene expression profiles were investigated by microarray analysis. Bioinformatics approaches (eg, Ingenuity Pathway Analysis [IPA]) were used to interrogate the data sets. Results Hierarchical clustering and principal component analysis (PCA) collectively showed that ECRSwNP and NECRSwNP had distinct gene expression patterns. Of note, these genes could be divided into 8 distinctive clusters having different expression patterns and functions. Upstream Regulator Analysis revealed that not only T-helper 2 (Th2) and the eosinophilia-related molecules (interleukin 4 [IL4], IL5, and colony stimulating factor 2 [CSF2]) reported so far, but also cell cycle regulators (cyclin dependent kinase inhibitor 1A [CDKNA1] and cyclin D1 [CCND1]) and a tissue fibrosis-related molecule (transforming growth factor β [TGFβ]) were identified in ECRSwNP. On the other hand, mainly interferons (IFNs) and acute inflammatory cytokines (IL1 and IL6) were predicted as upstream regulators in NECRSwNP. Conclusion These results are useful for understanding the molecular basis of the mechanisms of CRSwNP and point to new targets for developing specific biomarkers and personalized therapeutic strategies for CRSwNP.

IL-25 enhances TH17 cell-mediated contact dermatitis by promoting IL-1β production by dermal dendritic cells.

Abstract: Background In addition to thymic stromal lymphopoietin and IL-33, IL-25 is known to induce T H 2 cytokine production by various cell types, including T H 2 cells, T H 9 cells, invariant natural killer T cells, and group 2 innate lymphoid cells, involved in T H 2-type immune responses. Because both T H 2-type and T H 17-type cells/cytokines are crucial for contact hypersensitivity (CHS), IL-25 can contribute to this by enhancing T H 2-type immune responses. However, the precise role of IL-25 in the pathogenesis of fluorescein isothiocyanate–induced CHS is poorly understood. Objective We investigated the contribution of IL-25 to CHS using Il25 −/− mice. Methods CHS was evaluated by means of measurement of ear skin thickness in mice after fluorescein isothiocyanate painting. Skin dendritic cell (DC) migration, hapten-specific T H cell differentiation, and detection of IL-1β–producing cells were determined by using flow cytometry, ELISA, and immunohistochemistry, respectively. Results In contrast to thymic stromal lymphopoietin, we found that IL-25 was not essential for skin DC migration or hapten-specific T H cell differentiation in the sensitization phase of CHS. Unexpectedly, mast cell– and non–immune cell–derived IL-25 was important for hapten-specific T H 17 cell–mediated rather than T H 2 cell–mediated inflammation in the elicitation phase of CHS by enhancing T H 17-related, but not T H 2-related, cytokines in the skin. In particular, IL-1β produced by dermal DCs in response to IL-25 was crucial for hapten-specific T H 17 cell activation, contributing to induction of local inflammation in the elicitation phase of CHS. Conclusion Our results identify a novel IL-25 inflammatory pathway involved in induction of T H 17 cell–mediated, but not T H 2 cell–mediated, CHS. IL-25 neutralization can be a potential approach for treatment of CHS.

IL-33, IL-25 and TSLP contribute to development of fungal-associated protease-induced innate-type airway inflammation.

Abstract: Certain proteases derived from house dust mites and plants are considered to trigger initiation of allergic airway inflammation by disrupting tight junctions between epithelial cells. It is known that inhalation of proteases such as house dust mite-derived Der p1 and/or papaya-derived papain caused airway eosinophilia in naive mice and even in Rag-deficient mice that lack acquired immune cells such as T, B and NKT cells. In contrast, little is known regarding the possible involvement of proteases derived from Aspergillus species (fungal-associated proteases; FAP), which are ubiquitous saprophytic fungi in the environment, in the development of allergic airway eosinophilia. Here, we found that inhalation of FAP by naive mice led to airway eosinophilia that was dependent on protease-activated receptor-2 (PAR2), but not TLR2 and TLR4. Those findings suggest that the protease activity of FAP, but not endotoxins in FAP, are important in the setting. In addition, development of that eosinophilia was mediated by innate immune cells (ILCs) such as innate lymphoid cells, but not by acquired immune cells such as T, B and NKT cells. Whereas IL-33, IL-25 and thymic stromal lymphopoietin (TSLP) are involved in induction of FAP-induced ILC-mediated airway eosinophilia, IL-33—rather than IL-25 and/or TSLP—was critical for the eosinophilia in our model. Our findings improve our understanding of the molecular mechanisms involved in induction of airway inflammation by FAP.

Chitin promotes antigen-specific Th2 cell-mediated murine asthma through induction of IL-33-mediated IL-1β production by DCs

Abstract: Chitin, which is a major component of house dust mites (HDM), fungi, crustaceans, etc., can activate immune cells, suggesting that it contributes to development of allergic disorders such as asthma. Although the pathophysiological sensitization route of asthmatic patients to allergens is considered via the respiratory tract, the roles of intranasally-administered chitin in development of asthma remain unclear. After ovalbumin (OVA) challenge, development of airway inflammation was profoundly exacerbated in mice sensitized with OVA in the presence of chitin. The exacerbation was dependent on IL-33, but not IL-25, thymic stromal lymphopoietin or IL-17A. Chitin enhanced IL-33-dependent IL-1β production by dendritic cells (DCs). Furthermore, chitin- and IL-33-stimulated DC-derived IL-1β promoted OVA-specific Th2 cell activation, resulting in aggravation of OVA-induced airway inflammation. These findings indicate the adjuvant activity of chitin via a new mechanism and provide important clues for development of therapeutics for allergic disorders caused by HDM, fungi and crustaceans.

The roles of IL-17C in T cell-dependent and -independent inflammatory diseases

Abstract: IL-17C, which is a member of the IL-17 family of cytokines, is preferentially produced by epithelial cells in the lung, skin and colon, suggesting that IL-17C may be involved in not only host defense but also inflammatory diseases in those tissues. In support of that, IL-17C was demonstrated to contribute to development of T cell-dependent imiquimod-induced psoriatic dermatitis and T cell-independent dextran sodium sulfate-induced acute colitis using mice deficient in IL-17C and/or IL-17RE, which is a component of the receptor for IL-17C. However, the roles of IL-17C in other inflammatory diseases remain poorly understood. Therefore, we investigated the contributions of IL-17C to development of certain disease models using Il17c−/− mice, which we newly generated. Those mice showed normal development of T cell-dependent inflammatory diseases such as FITC- and DNFB-induced contact dermatitis/contact hypersensitivity (CHS) and concanavalin A-induced hepatitis, and T cell-independent inflammatory diseases such as bleomycin-induced pulmonary fibrosis, papain-induced airway eosinophilia and LPS-induced airway neutrophilia. On the other hand, those mice were highly resistant to LPS-induced endotoxin shock, indicating that IL-17C is crucial for protection against that immunological reaction. Therefore, IL-17C neutralization may represent a novel therapeutic approach for sepsis, in addition to psoriasis and acute colitis.

Are both early egg introduction and eczema treatment necessary for primary prevention of egg allergy

Abstract: The Learning Early About Peanut Allergy (LEAP) study proved that early introduction of peanut significantly prevented the development of peanut allergy. However, in regard to similar attempts to prevent egg allergy through early egg introduction, the Prevention of Egg Allergy in High-risk Infants with Eczema (PETIT) study is the only randomized intervention trial to show a statistically significant effect. Meta-analysis of those studies indicated that neither the total amount nor pretreatment of egg showed any effect on egg allergy at the age of 12 months. However, raw egg powder resulted in a significantly higher prevalence of allergic reactions at initial introduction, whereas use of boiled egg was much safer. The prevalence of atopic dermatitis/eczema at introduction of egg correlated significantly with the subsequent prevalence of allergic reactions at initial introduction. In addition, the prevalence of egg allergy in the late introduction group correlated significantly with the prevalence of atopic dermatitis at introduction, even when the atopic dermatitis was proactively treated with a topical corticosteroid ointment. It is definitely true that the number of trials and number of participants in each trial are insufficient for drawing firm conclusions, especially regarding the optimal dose, raw versus boiled, when to start, and for whom to intervene. Therefore we propose various studies that should be performed to generate stronger data and conclusions. However, on the basis of the most recent results, we postulate that simultaneous intervention by both early boiled egg introduction and eczema treatment is probably indispensable for primary prevention of egg allergy.

Having small-for-gestational-age infants was associated with maternal allergic features in the JECS birth cohort.

Abstract: S. W. Lee E. K. Ha K. S. Lee Y.-H. Jung H. M. Jee M. A. Kim J.-C. Ahn Y. H. Sheen M. Y. Han Department of Pediatrics, CHA Bundang Medical Center, CHA University School of Medicine, Seongnam, Korea Department of Internal Medicine, CHA Bundang Medical Center, CHA University School of Medicine, Seongnam, Korea Department of Otorhinolaryngology–Head and Neck Surgery, CHA Bundang Medical Center, CHA University School of Medicine, Seongnam, Korea Department of Pediatrics, CHA Gangnam Medical Center, CHA University School of Medicine, Seoul, Korea Email: drmesh@gmail.com

Gastrin-Releasing Peptide Is Involved in the Establishment of Allergic Rhinitis in Mice

Abstract: Objective Gastrin-releasing peptide (GRP) is a neuropeptide that targets transmembrane-type receptors Its role in allergic rhinitis (AR) has yet to be investigated The present study utilized the nasal mucosa of AR model mice to examine GRP and GRP receptor (GRPR) expression levels, localization, and other factors to evaluate their role in AR pathology Study design In vivo study in an animal model Methods GRP and GRPR expression levels were examined in three different AR models established in BALB/c mice In addition, a GRPR antagonist (RC-3095) was administered to AR mice to investigate its effect The distribution of GRPR expression on mast cells in the nasal mucosa with AR was examined Finally, we investigated the inhibitory effect of RC-3095 on allergy symptoms induced by histamine Results GRP and GRPR were highly expressed in the nasal mucosal epithelium and interstitial tissues surrounding the nasal glands in AR groups according to immunostaining GRP and GRPR expression as determined by western blotting increased in the nasal mucosa as the degree of nasal sensitization increased In addition, the average counts of sneezing and nasal rubbing after treatment in the AR + RC-3095 group were significantly lower than those in the AR + nasal saline group Mast cells often colocalized with GRPR around nasal glands Moreover, RC-3095 was effective in reducing sneezing induced by histamine Conclusion The GRP-GRPR system is likely to be involved in allergic inflammation This system may represent a novel therapeutic target for refractory AR Level of evidence NA Laryngoscope, E377-E384, 2018

[estimated number of patients with food allergy in japan: the present status and issues regarding epidemiological investigation].

Abstract: Background The number of patients with food allergy in Japan is increasing year by year, although the precise prevalence of them is not clear. We aimed to determine the estimated number of people with food allergies in Japan and produce new methods of the investigation of them. Methods We determined the number of people with food allergies using government data and statistics such as demographic statistic and the number of students. Results In infants, the number of patients with a food allergy was 800000 as per the self-reported prevalence; however, as per the physician's diagnoses, 300000-500000 of them had a food allergy. In students, the selfreported number was 600000, while 350000 cases were diagnosed by physicians. In adults, the consumer agency investigated the patients who visited the hospital with the immediate hypersensitivity. In this study, the participants were limited to patients who visited the hospital. This made the estimation of the overall prevalence of food allergy in Japan. Conclusion For children, if we add the questionnaire to the existing study, which questions them regarding the symptoms of food allergy, the diagnosis by the physician, and the blood test, we can better investigate the prevalence of food allergies and changing pattern by the year. In adults, we propose that future investigations consisting of the National Health and Nutrition Survey and a comprehensive survey of living conditions should be conducted, because few studies have reported on food allergies.

Acute lymphoblastic leukemia with hypereosinophilia in a 3-year-old boy.

Abstract: study (10 mg/day). This indicates that the present, high, cord blood EO concentration of 20 ng/mL was probably due to the concomitant use of EL. This may be explained by the competitive metabolizing of EL and EO. EL is extensively metabolized by the metabolic enzyme CYP3A4, while EO is partially metabolized by the same enzyme. The competition between EL and EO for this isoenzyme could explain the elevated EO concentration. It is possible that the elevated EO concentration played a causative role in this transient respiratory weakness. The baby’s symptom developed immediately after birth and the condition quickly resolved within 24 h, therefore the symptom seemed to be due to neonatal maladaptive syndrome rather than to withdrawal. The combination of EL and EO should have been avoided in the present case. This is the first report on concomitant maternal EL and EO use in relation to neonatal morbidity immediately after birth. It is important to note that in the case of maternal SSRI and BZP treatment, the baby should be closely monitored at birth, regardless of the doses prescribed.

Examination method and examination kit for eosinophilic gastrointestinal disease or food-protein induced enteropathy

Abstract: Provided is a new method for examining eosinophilic gastrointestinal diseases or food-protein induced enteropathies. In other words, the present invention relates to a method for examining eosinophilic gastrointestinal diseases or food-protein induced enteropathies, the method including a measuring step for measuring the expression level of at least one of TSLP gene, IL-33 gene, CCL7 gene, and CCL21 gene in a sample collected from a living human subject or measuring the amount of at least one of TSLP protein, IL-33 protein, CCL7 protein, and CCL21 protein in said sample.