Kazuyuki Meguro

Helios Enhances Treg Cell Function in Cooperation With FoxP3.

Helios+FoxP3+CD4+ (Helios+) Treg cells are believed to be involved in the regulation of various autoimmune diseases; however, the regulatory mechanisms underlying the development of Helios+ Treg cells remain uncertain. This study was undertaken to elucidate the regulatory mechanisms of Helios expression in CD4+ T cells and its roles in transforming growth factor β (TGFβ)–induced Treg cell function.

Pendant group orientation of poly(2-vinylnaphthalene) thin film surface studied by near-edge x-ray absorption fine structure spectroscopy (NEXAFS) and angle-resolved ultraviolet photoelectron spectroscopy (ARUPS)

Angle-resolved ultraviolet photoelectron spectroscopy (ARUPS) and near-edge x-ray absorption fine structure (NEXAFS) spectroscopy were applied to the investigation of the tilt angles of the naphthalene pendant groups at the surface of a poly(2-vinylnaphthalene) thin film. In contrast to NEXAFS, which provides only an average determination of the tilt angle, ARUPS combined with a sophisticated analysis of photoelectron angular dependence offers more detailed information. It was concluded that the naphthalene pendant groups are tilted randomly at the polymer surface, and that the tilt angle distribution is well described as a three-dimensional isotropic random orientation.

Roles of mast cells in the pathogenesis of inflammatory myopathy

IntroductionIn addition to the pivotal roles of mast cells in allergic diseases, recent data suggest that mast cells play crucial roles in a variety of autoimmune responses. However, their roles in the pathogenesis of autoimmune skeletal muscle diseases have not been clarified despite their distribution in skeletal muscle. Therefore, the objective of this study is to determine the roles of mast cells in the development of autoimmune skeletal muscle diseases.MethodsThe number of mast cells in the affected muscle was examined in patients with dermatomyositis (DM) or polymyositis (PM). The susceptibility of mast cell-deficient WBB6F1-KitW/KitWv mice (W/Wv mice) to a murine model of polymyositis, C protein-induced myositis (CIM), was compared with that of wild-type (WT) mice. The effect of mast cell reconstitution with bone marrow-derived mast cells (BMMCs) on the susceptibility of W/Wv mice to CIM was also evaluated.ResultsThe number of mast cells in the affected muscle increased in patients with PM as compared with patients with DM. W/Wv mice exhibited significantly reduced disease incidence and histological scores of CIM as compared with WT mice. The number of CD8+ T cells and macrophages in the skeletal muscles of CIM decreased in W/Wv mice compared with WT mice. Engraftment of BMMCs restored the incidence and histological scores of CIM in W/Wv mice. Vascular permeability in the skeletal muscle was elevated in WT mice but not in W/Wv mice upon CIM induction.ConclusionMast cells are involved in the pathogenesis of inflammatory myopathy.

Role of Bcl‐3 in the Development of Follicular Helper T Cells and in the Pathogenesis of Rheumatoid Arthritis

We have previously shown that expression of the Bcl‐3 gene, a member of the IκB family, is down‐regulated in CD4+ T cells from patients with rheumatoid arthritis (RA) following tocilizumab therapy. The objective of this study was to examine the role of Bcl‐3 in the pathogenesis of RA.

Surface States of Hydrogen-terminated Si(111)by Metastable Atom Electron Spectroscopy and Angle-resolved Ultraviolet Photoelectron Spectroscopy

The surface electronic states of hydrogen-terminated Si(111) [H–Si(111)-(1×1)] were studied by metastable atom electron spectroscopy (MAES) and angle-resolved ultraviolet photoelectron spectroscopy (ARUPS), coupled with an intensity analysis used for organic systems. The surface states of H–Si(111)-(1×1) originated from Si–H bonds were selectively observed by MAES which can excite electrons distributed at the outermost surface. Furthermore, the prominent ARUPS peak with very small dispersion at around 10 eV binding energy from the vacuum level was confirmed to originate from a nondispersive Si–H σ state by quantitative analysis of the photoelectron angular distribution using a simple computation model used for organic thin films.

Roles of alternatively activated M2 macrophages in allergic contact dermatitis

Alternatively activated macrophages (M2 macrophages) play key roles in the suppression of Th1 cell responses and the orchestration of tissue repair. However, recent studies have shown that M2 macrophages have potentials to produce high levels of proinflammatory cytokines such as IL-1β, IL-6, and TNF-α, suggesting that M2 macrophages may exacerbate inflammation in some settings. In this regard, we have recently shown that large numbers of M2 macrophages accumulate in the sites of hapten-induced contact hypersensitivity (CHS), an animal model of allergic contact dermatitis, and that M2 macrophages exacerbate hapten-induced CHS by producing matrix metalloproteinase 12 (MMP12). We have also shown that suppressor of cytokine signaling-3 (SOCS3), a member of SOCS family proteins that are cytokine-inducible negative regulators of the JAK/STAT signaling pathways, is highly and preferentially expressed in M2 macrophages in hapten-induced CHS and that SOCS3 expressed in M2 macrophages is involved in the attenuation of CHS by suppressing MMP12 production. These findings underscore the importance of M2 macrophage-derived MMP12 in the development of CHS, and suggest that inhibition of M2 macrophages or MMP12 could be a potential therapeutic strategy for the treatment of allergic contact dermatitis.

Reaction at the Outermost Surface Selectively Induced by Metastable-Atom Beams

This paper reports the first spectroscopic observation of changes in surface electronic states that originate from a chemical reaction at the outermost surface which is selectively induced by the impact of slow metastable atoms. Using metastable-atom electron spectroscopy, structural changes of titanyl phthalocyanine (OTiPc) molecules as a result of the impact of slow He*(23S) were observed for an oriented OTiPc monolayer on a graphite substrate where the molecule is oriented flat with the oxygen atom protruding outside the surface. Unlike photons and electrons, metastable atoms do not penetrate into the bulk of solids. Therefore, they interact only with electrons distributed at the outermost surface of the film, and excite these electrons selectively. The observed spectral change in metastable-atom electron spectrum indicates that the surface reaction can be realized by the selective ionization of the outermost surface with the impact of slow metastable atoms.

Matrix metalloproteinase 12 is produced by M2 macrophages and plays important roles in the development of contact hypersensitivity.

possible that toddlers who wheeze and cough a lot because of increased exposure to infectious agents (nursery care, crowding) have a better prognosis than do peers who have these symptoms in the absence of exposure. This might explain the trend toward a poorer prognosis in children who were not in nursery care and did not live in crowded households, which was seen in some of the models with reduced penalization. Our findings contrast with those reported by Balemans et al, who found that maternal smoking while children were toddlers predicted asthma in young adults in their cohort. Balemans et al included only a few symptoms as potential predictors and used stepwise logistic regression to derive the finalmodel, whichmight explain why maternal smoking was a better predictor in their model than in ours. In our cohort, maternal smoking was one of the first predictors joining the PARC tool score when we lowered the penalization, but it did not improve the predictive performance of the PARC tool. The strength of our study lies in its large sample size and clinically relevant population. We used an objective approach for variable selection that minimized overfitting the data. A limitation common to other tools is that symptoms and exposures are parentreported. This reflects the situation in clinical practice, in which many decisions are based on medical history taken from parents. Future research should evaluate whether such tools can be improved by including results from clinical tests, such as allergy tests, lung function, and exhaled nitric oxide. In summary, the asthma risk assessment tool PARC, which uses detailed clinical data, performs moderately well. Adding information on environmental and socioeconomic exposures did not improve the PARC tool’s predictive performance.

Serum periostin levels serve as a biomarker for both eosinophilic airway inflammation and fixed airflow limitation in well-controlled asthmatics

ABSTRACT Objective: Periostin, a matricellular protein, is produced from airway epithelial cells and lung fibroblasts by IL-13. It has been suggested that periostin is involved in allergic inflammation and fibrosis. However, the usefulness of serum periostin measurement in the assessment of airway inflammation and remodeling and management of asthmatic patients is still debated. We aimed to determine whether serum periostin levels reflect eosinophilic airway inflammation and airway remodeling in asthma. Methods: We examined the relationship of serum periostin levels with clinical features, biomarkers for eosinophilic airway inflammation, fraction of exhaled nitric oxide (FeNO) levels and blood eosinophil counts, and pulmonary functions in 235 well-controlled asthmatic patients on inhaled corticosteroids (ICS) treatment. Results: Serum periostin levels were positively correlated with blood eosinophil counts (%) and age (r = 0.36 and 0.23, respectively), and were negatively correlated with body weight and FEV1/FVC (%) (r = −0.24 and − 0.23, respectively) in well-controlled asthmatic patients on ICS treatment (daily dose of 453 µg equivalent to fluticasone propionate). Blood eosinophil counts and serum periostin levels were similarly associated with increased FeNO levels (≥40 ppb) in the asthmatics. Serum periostin levels were better associated with fixed airflow limitation (FEV1/FVC ratio <70%) than FeNO levels, blood eosinophil counts or total IgE levels in the asthmatics. Multivariate analysis showed that fixed airflow limitation was significantly associated with high serum periostin levels (≥97 ng/ml) (Odds ratio 3.2). Conclusions: Serum periostin levels serve as a biomarker for both eosinophilic airway inflammation and fixed airflow limitation in well-controlled asthmatics on ICS treatment.

OP0120 Roles of B Cell Leukemia/Lymphoma 3 in The Development of T Follicular Helper Cells and the Pathogenesis of Rheumatoid Arthritis

Background Rheumatoid arthritis (RA) is a chronic inflammatory disease and proinflammatory cytokines such as TNFα and IL-6 play critical roles in the pathogenesis of RA. The blockade of IL-6 signaling by Tocilizumab (TCZ) has shown the clinical efficacy for patients with RA. To clarify the roles of IL-6 signaling in CD4+ T cells in the pathogenesis of RA, we previously compared gene expression profiles of CD4+ T cells by DNA microarray analysis before and after the treatment with TCZ in RA patients who exhibited good clinical responses to the treatment (1, 2), and identified that B cell leukemia/lymphoma 3 (Bcl3), an IκB family member, was down-regulated by TCZ therapy (1). However, the role of Bcl3 expressed in CD4+ T cells in the pathogenesis of RA remains unclear. Objectives The objective of this study is to examine the role of Bcl3 expressed in CD4+ T cells in the pathogenesis of RA. Methods We compared signal intensity of Bcl3 in CD4+ T cells between untreated RA patients and healthy controls by DNA microarray analysis. We examined the roles of IL-6-STAT3 signaling in Bcl3 induction. We also analyzed gene expression profiles of Bcl3-transduced CD4+ T cells by RNA-sequencing analysis. We examined the effect of enforced expression as well as gene silencing of Bcl3 on the development of T follicular helper (Tfh) cells. Finally, we examined a correlation between signal intensities of Bcl3 and Tfh cell-related genes in CD4+ T cells in untreated RA patients. Results Bcl3 levels were significantly higher in RA patients than those in healthy controls. IL-6 induced Bcl3 expression in CD4+ T cells in a STAT3-dependent manner. Transcriptome analysis revealed that the expression of Bcl6, a master regulator of Tfh cell differentiation, was significantly upregulated by the enforced Bcl3 expression (Figure1). The enforced Bcl3 expression increased but the Bcl3 silencing decreased IL-21-producing Tfh-like cells. Bcl3 levels were positively correlated with those of Tfh cell-related genes such as CXCR5, ICOS, and ASCL2 in CD4+ T cells in RA patients. Conclusions Bcl3 is involved in the development of Tfh cells and the pathogenesis of RA presumably by inducing IL-21 production. References Saito Y, Kagami SI, Sanayama Y, Ikeda K, Suto A, Kashiwakuma D, et al. AT-rich interactive domain-containing protein 5a functions as a negative regulator of RORγt-induced Th17 cell differentiation. Arthritis Rheum. 2014;66(5):1185-94. Sanayama Y, Ikeda K, Saito Y, Kagami S, Yamagata M, Furuta S, et al. Prediction of therapeutic responses to tocilizumab in patients with rheumatoid arthritis: biomarkers identified by analysis of gene expression in peripheral blood mononuclear cells using genome-wide DNA microarray. Arthritis Rheum. 2014;66(6):1241-31. Disclosure of Interest K. Meguro: None declared, K. Suzuki: None declared, J. Hosokawa: None declared, Y. Sanayama: None declared, S. Tanaka: None declared, S. Furuta: None declared, K. Ikeda: None declared, H. Takatori: None declared, A. Suto: None declared, O. Ohara: None declared, H. Nakajima Grant/research support from: Chugai Pharmaceutical Co., Ltd, Bristol-Myers Squibb, and Mitsubishi Tanabe Pharma Co.