[Show abstract][Hide abstract] ABSTRACT: Experimental IgE-mediated food allergy depends on intestinal anaphylaxis driven by interleukin-9 (IL-9). However, the primary cellular source of IL-9 and the mechanisms underlying the susceptibility to food-induced intestinal anaphylaxis remain unclear. Herein, we have reported the identification of multifunctional IL-9-producing mucosal mast cells (MMC9s) that can secrete prodigious amounts of IL-9 and IL-13 in response to IL-33, and mast cell protease-1 (MCPt-1) in response to antigen and IgE complex crosslinking, respectively. Repeated intragastric antigen challenge induced MMC9 development that required T cells, IL-4, and STAT6 transcription factor, but not IL-9 signals. Mice ablated of MMC9 induction failed to develop intestinal mastocytosis, which resulted in decreased food allergy symptoms that could be restored by adoptively transferred MMC9s. Finally, atopic patients that developed food allergy displayed increased intestinal expression of Il9- and MC-specific transcripts. Thus, the induction of MMC9s is a pivotal step to acquire the susceptibility to IgE-mediated food allergy.
[Show abstract][Hide abstract] ABSTRACT: Rationale:
Serum chitinases may be novel biomarkers of airway inflammation and remodeling, yet less is known about factors regulating their levels.
To examine serum chitotriosidase activity and YKL-40 levels in patients with asthma and COPD, and to evaluate clinically relevant factors that may affect chitinase levels, including genetic variability, corticosteroid treatment, disease exacerbations and allergen exposure.
Serum chitotriosidase (CHIT1) activity and YKL-40 (CHI3L1) levels, and CHIT1 rs3831317 and CHI3L1 rs4950928 genotype, were examined in subsets of patients with mild-to-moderate asthma (n=76), severe asthma (n=93), and COPD (n=64), taking part in the European multicentre study BIOAIR. Blood was obtained at baseline, pre/post a 2-week oral steroid intervention, up to 6 times during one year and during exacerbations. Baseline chitinase levels were also measured in 72 healthy controls. The effect of allergen inhalation on blood and sputum YKL-40 was measured in two separate groups of mild atopic asthmatics (n=15-16).
Serum chitotriosidase and YKL-40 were significantly elevated in patients with asthma and COPD, compared to controls. Genotype and age strongly affected both YKL-40 and chitotriosidase activity, yet associations with disease remained following adjustment for these factors. Correlations were observed with lung function, but not other biomarkers including exhaled NO, blood eosinophils, periostin or IgE. Generally, acute exacerbations, allergen-induced airway obstruction, and corticosteroid treatment did not affect circulating chitinase levels.
YKL-40 and chitotriosidase are increased in asthma, and more so in COPD. The data support these substances as being relatively steroid-insensitive, non-Th2-type biomarkers distinctly related to chronic inflammatory disease processes.
American Journal of Respiratory and Critical Care Medicine 09/2015; DOI:10.1164/rccm.201504-0760OC · 13.00 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background
Assessment of inflammation is becoming a common practice in the clinical work-up of children with persistent asthma. Biomarkers of Th2-mediated inflammation include blood eosinophils (B-Eos) exhaled nitric oxide (FeNO), total serum IgE (S-IgE) and serum periostin. The aim was to investigate the associations between asthma morbidity and increased levels of these biomarkers in pediatric asthma.Methods
School-age children (n=96) with various manifestations of persistent asthma were included in this nationwide Swedish study. The protocol included the Asthma control test, Juniper′s Quality of life questionnaire (QoL), assessment of pulmonary function, bronchial hyperresponsiveness, height adjusted FeNO, blood sampling for S-IgE, B-Eos and periostin and high resolution computed tomography (HRCT) of the lungs.ResultsChildren with both high levels of height adjusted FeNO and B-Eos were younger (p=0.001), had more often severe asthma (p=0.015), were more allergic (p<0.001), had a reduced asthma control (p=0.035), reduced QoL (p=0.035), more exacerbations (p=0.004), reduced FEV1/FVC (p=0.001) and increased bronchial hyperresponsiveness (p<0.001) as well as greater bronchial wall thickening on HRCT (p=0.022) compared to those with low levels of both biomarkers. Grouping children according to high and low serum periostin level did not relate to differences in clinical characteristics and biomarkers.Conclusions
Assessment of both local and systemic Th2-mediated inflammation by analysis of easily attainable biomarkers such as exhaled NO and blood eosinophils has a high predictive value for the identification of children with the highest asthma morbidity. Adjusting FeNO values according to the individual child′s height increases the clinical usefulness of this biomarker.This article is protected by copyright. All rights reserved.
Pediatric Allergy and Immunology 08/2015; DOI:10.1111/pai.12457 · 3.40 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Tissue injury promotes metastasis of several human cancers, although factors associated with wound healing that attract circulating tumor cells have remained unknown. Here, we examined the primary and metastatic lesions that appeared 1 month after trauma in a patient with acral lentiginous melanoma. The levels of mRNA for periostin (POSTN), type 1 collagen, and fibronectin were significantly increased in the metastatic lesion relative to the primary lesion. The increase of these extracellular matrix proteins at the wound site was reproduced in a mouse model of wound healing, with the upregulation of Postn mRNA persisting the longest. POSTN was expressed in the region surrounding melanoma cell nests in metastatic lesions of both wounded mice and the patient. POSTN attenuated the cell adhesion and promoted the migration of melanoma cells without affecting their proliferation in vitro. In the mouse model, the wound site as well as subcutaneously injected osteoblasts that secrete large amounts of POSTN invited the metastasis of remotely-transplanted melanoma cells on the sites. Osteoblasts with suppression of POSTN by shRNA showed a greatly reduced ability to promote such metastasis. Our results suggest that POSTN is a key factor in promoting melanoma cell metastasis to wound sites by providing a premetastatic niche.
PLoS ONE 06/2015; 10(6):e0129704. DOI:10.1371/journal.pone.0129704 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Although it is currently recognized that bronchial asthma is not a single disease but a syndrome, we have not yet made use of our new understanding of this heterogeneity as we treat asthma patients. To increase the efficacy of anti-asthma drugs and to decrease costs, it is important to stratify asthma patients into subgroups and to develop therapeutic strategies for each subgroup. Periostin has recently emerged as a biomarker for bronchial asthma, unique in that it is useful not in diagnosis but in categorizing asthma patients. We first found that periostin is a novel component of subepithelial fibrosis in bronchial asthma downstream of IL-13 signals. Thereafter, it was shown that periostin can be a surrogate biomarker of type 2 immune responses, the basis of the notion that a detection system of serum periostin is potentially a companion diagnostic for type 2 antagonists. Furthermore, we have recently shown that serum periostin can predict resistance or hyporesponsiveness to inhaled corticosteroids, based on its contribution to tissue remodeling or fibrosis in bronchial asthma. Thus, serum periostin has two characteristics as a biomarker for bronchial asthma: it is both a surrogate biomarker of type 2 immune responses and a biomarker reflecting tissue remodeling or fibrosis. We can take advantage of these characteristics to develop stratified medicine in bronchial asthma.
Allergology International 06/2015; 18. DOI:10.1016/j.alit.2015.04.012 · 2.46 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background:
Epidermal hyperplasia is a histological hallmark observed in both atopic dermatitis (AD) and psoriasis, although the clinical features and the underlying immunological disorders of these diseases are different. We previously showed that periostin, a matricellular protein, plays a critical role in epidermal hyperplasia in AD, using a mouse model and a 3-dimensional organotypic coculture system. In this study, we explore the hypothesis that periostin is involved in epidermal hyperplasia in psoriasis.
To examine expression of periostin in psoriasis patients, we performed immunohistochemical analysis on skin biopsies from six such patients. To investigate periostin's role in the pathogenesis of psoriasis, we evaluated periostin-deficient mice in a psoriasis mouse model induced by topical treatment with imiquimod (IMQ).
Periostin was substantially expressed in the dermis of all investigated psoriasis patients. Epidermal hyperplasia induced by IMQ treatment was impaired in periostin-deficient mice, along with decreased skin swelling. However, upon treatment with IMQ, periostin deficiency did not alter infiltration of inflammatory cells such as neutrophils; production of IL-17, -22, or -23; or induction/expansion of IL-17- and IL-22-producing group 3 innate lymphoid cells.
Periostin plays an important role during epidermal hyperplasia in IMQ-induced skin inflammation, independently of the IL-23-IL-17/IL-22 axis. Periostin appears to be a mediator for epidermal hyperplasia that is common to AD and psoriasis.
Allergology International 01/2015; 64(1):41-48. DOI:10.1016/j.alit.2014.06.001 · 2.46 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background
Recent studies recommend periostin as a systemic biomarker of eosinophilic airway inflammation to predict responses to novel treatments that targets eosinophilic TH2-driven inflammation in asthmatic patients.
To investigate the clinical implications of serum periostin levels in patients with aspirin-exacerbated respiratory disease (AERD) based on its overlapping TH2-mediated pathogenesis with the eosinophilic asthma.
Serum periostin levels were measured by human periostin enzyme-linked immunosorbent assay (ELISA) in serum samples from 277 adults with asthma. Serum periostin levels were compared between patients with AERD and aspirin tolerant asthma (ATA) with other asthma phenotypes, such as severe or nonsevere asthma and eosinophilic or noneosinophilic asthma. The association of serum periostin levels with clinical parameters (including disease severity and comorbid condition) was analyzed.
Serum periostin levels were significantly higher in patients with AERD vs ATA, patients with severe asthma vs nonsevere asthma, and patients with eosinophilic asthma vs noneosinophilic asthma (P=.005, P=.02, and P=.001, respectively). Multivariate regression analysis revealed serum periostin levels as a significant parameter to predict AERD phenotype (P=.006) together with severe asthma phenotype (P=.04). In addition, serum periostin levels correlated with blood eosinophil counts (Spearman ñ = 0.244, P<.001) and sputum eosinophil counts (Spearman ñ = 0.261, P < 0.001). Higher serum periostin levels were noted in comorbid AERD patients with more severe chronic rhinosinusitis (Lund-Mackay stages 3 and 4) than those with less severe chronic rhinosinusitis (Lund-Mackay stages 1 and 2) (P = .03).
Serum periostin levels are significantly elevated in AERD patients and associated with AERD phenotype and disease severity.
Annals of allergy, asthma & immunology: official publication of the American College of Allergy, Asthma, & Immunology 09/2014; 113(3). DOI:10.1016/j.anai.2014.06.014 · 2.60 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: In steroid-naive patients with asthma, several gene variants are associated with a short-term response to inhaled corticosteroid (ICS) treatment; this has mostly been observed in Caucasians. However, not many studies have been conducted for other ethnicities. Here, we aimed to determine the relationship between the annual decline in forced expiratory flow volume in one second (FEV1 ) and the variant of the glucocorticoid-induced transcript 1 gene (GLCCI1) in Japanese patients with asthma receiving long-term ICS treatment, taking into account the effect of high serum periostin levels, a known association factor of pulmonary function decline and a marker of refractory eosinophilic/Th2 inflammation.
In this study, 224 patients with asthma receiving ICS treatment for at least 4 years were enrolled. The effects of single-nucleotide polymorphisms (SNPs) in GLCCI1, stress-induced phosphoprotein 1 (STIP1), and T gene on the decline in FEV1 of 30 ml/year or greater were determined.
Besides the known contributing factors, that is, the most intensive treatment step, ex-smoking, and high serum periostin levels (≥95 ng/ml), the GG genotype of GLCCI1 rs37973, and not other SNPs, was independently associated with a decline in FEV1 of 30 ml/year or greater. When patients were stratified according to their serum periostin levels, the GG genotype of rs37973 was significantly associated with blood eosinophilia (≥250/μl) in the high serum periostin group.
A GLCCI1 variant is a risk factor of pulmonary function decline in Japanese patients with asthma receiving long-term ICS treatment. Thus, GLCCI1 may be associated with response to ICS across ethnicities.
[Show abstract][Hide abstract] ABSTRACT: Periostin, an extracellular matrix protein belonging to the fasciclin family, has been shown to play a critical role in the process of remodeling during tissue/organ development or repair. Periostin functions as a matricellular protein in cell activation by binding to their receptors on cell surface, thereby exerting its biological activities. After we found that periostin is a downstream molecule of interleukin (IL)-4 and IL-13, signature cytokines of type 2 immune responses, we showed that periostin is a component of subepithelial fibrosis in bronchial asthma, the first formal proof that periostin is involved in allergic inflammation. Subsequently, a great deal of evidence has accumulated demonstrating the significance of periostin in allergic inflammation. It is of note that in skin tissues, periostin is critical for amplification and persistence of allergic inflammation by communicating between fibroblasts and keratinocytes. Furthermore, periostin has been applied to development of novel diagnostics or therapeutic agents for allergic diseases. Serum periostin can reflect local production of periostin in inflamed lesions induced by Th2-type immune responses and also can predict the efficacy of Th2 antagonists against bronchial asthma. Blocking the interaction between periostin and its receptor, αv integrin, or down-regulating the periostin expression shows improvement of periostin-induced inflammation in mouse models or in in vitro systems. It is hoped that diagnostics or therapeutic agents targeting periostin will be of practical use in the near future.
Allergology International 03/2014; 63(2). DOI:10.2332/allergolint.13-RAI-0663 · 2.46 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background Recent findings indicate that periostin, an extracellular matrix protein induced by T helper 2 cytokines, plays a critical role in the pathogenesis of atopic dermatitis (AD). Objectives To determine whether serum periostin level is associated with clinical phenotype in adult patients with AD. Methods An enzyme-linked immunosorbent assay was performed to determine serum periostin levels in 257 adult patients with AD, 66 patients with psoriasis vulgaris (PV) as a disease control and 25 healthy controls. Serum periostin levels were analysed together with clinical characteristics and laboratory parameters, including thymus and activation-regulated chemokine (TARC), lactate dehydrogenase (LDH), blood eosinophil count and total IgE. Immunohistochemical analysis evaluated the expression of periostin in association with various clinical phenotypes of AD. The effect of treatment on serum periostin level was also assessed. Results Serum periostin was significantly higher in patients with AD than in patients with PV and healthy controls. Periostin level was found to be positively correlated with disease severity, TARC level, LDH level and eosinophil count, but not with IgE level. Higher serum periostin level was observed in patients with extrinsic AD compared with patients with intrinsic AD; the positive correlation of disease severity disappeared in patients with intrinsic AD. Robust expression of periostin was detected in the dermis of patients with AD with erythroderma, lichenification and, to a lesser extent, scaly erythema. Serial measurement of serum periostin revealed decreased levels of periostin after treatment for AD. Conclusions Periostin may play a critical role in disease severity and chronicity in the pathogenesis of AD.
British Journal of Dermatology 03/2014; 171(2). DOI:10.1111/bjd.12943 · 4.28 Impact Factor