Resident Macrophages in SS

Macrophages (MΦs) are critical regulators of immune response and serve as a link between innate and acquired immunity. The precise mechanism of involvement of tissue-resident MΦs in the pathogenesis of autoimmune diseases is not clear. Here, using a murine model for Sjögren’s syndrome (SS), we investigated the role of tissue-resident MΦs in the onset and development of autoimmunity. Two unique populations of CD11bhigh and CD11blow resident MΦs were observed in the target tissue of the SS model. Comprehensive gene expression analysis of chemokines revealed effective production of CCL22 by the CD11bhigh MΦs. CCL22 upregulated the migratory activity of CD4+ T cells by increasing CCR4, a receptor of CCL22, on T cells in the SS model. In addition, CCL22 enhanced IFN-γ production of T cells of the SS model, thereby suggesting that CCL22 may impair the local immune tolerance in the target organ of the SS model. Moreover, administration of anti-CCL22 antibody suppressed autoimmune lesions in the SS model. Finally, histopathological analysis revealed numerous CCL22-producing MΦs in the minor salivary gland tissue specimens of the SS patients. CCL22-producing tissue-resident MΦs may control autoimmune lesions by enhancing T cell response in the SS model. These results suggest that specific chemokines and their receptors may serve as novel therapeutic or diagnostic targets for SS

Heat-not-burn tobacco, electronic cigarettes, and combustible cigarette use among Japanese adolescents: a nationwide population survey 2017

Background: From among the global public health concerns, smoking remains one of the most crucial challenges. Especially for adolescents, the increase in the use of electronic cigarettes is controversial, as its use may lead to established smoking. In Japan, where a unique tobacco regulation system exists, the heat-not-burn tobacco market has been growing. However, the prevalence and association of combustible cigarettes and new tobacco-related products have not yet been closely investigated among Japanese adolescents. This study aimed to clarify the prevalence of smoking among adolescents, including new types of tobacco-related products, and to compare the characteristics of their users. Methods: The 2017 Lifestyle Survey of Adolescents is a nationally-representative survey collected in Japan. From the national school directory, 98 junior high schools and 86 high schools were randomly sampled throughout Japan. The students completed an anonymous questionnaire at school. We calculated the prevalence of use for each type of tobacco product. Then, the use of a combination of products and the characteristics of different types of products were examined. Results: In total, 64,152 students from 48 junior high schools and 55 high schools were included the analysis (school response rate = 56%, Mage = 15.7 years, 53.9% boys). The age-adjusted rate of ever (current) use of electronic cigarettes was 2.1% (0.7%) in junior high school and 3.5% (1.0%) in high school; that of combustible cigarettes was 2.6% (0.6%) in junior high school and 5.1% (1.5%) in high school. The rate of heat-not-burn tobacco use was lower relative to other products: 1.1% (0.5%) in junior high school and 2.2% (0.9%) in high school. An examination of the combined use of the three products identified a high number of dual users. Comparisons between different types of users indicated different backgrounds for combustible cigarette users and new product users. Conclusions: The prevalence of new tobacco-alternative products is growing in popularity among Japanese adolescents. Dual use is common, and many adolescents use new products only. Moreover, e-cigarettes might attract a broader range of groups to smoking. Continuous monitoring and research are needed to investigate their influence as a possible gateway to tobacco smoking

CD4+ T-cell-dependent differentiation of CD23+ follicular B cells contributes to the pulmonary pathology in a primary Sjögren’s syndrome mouse model

Introduction: Primary Sjögren’s syndrome (pSS) is a systemic autoimmune disease that affects the function of exocrine glands, such as the lacrimal and the salivary glands. Extraglandular lesions and malignant lymphoma also occur during the progressive stage of pSS. We have, herein, focused on the pulmonary lesions of pSS and have aimed clarifying their pathophysiological mechanism by comparing the glandular with the extraglandular lesions observed in a mouse model of pSS. Results: The histopathological analysis of lung tissues obtained from NFS/sld mice that have undergone neonatal thymectomy was performed. Moreover, in vivo and in vitro experiments were conducted along with immunological analyses in order to characterize the unique phenotypes of the pulmonary lesions identified in these pSS model mice. Inflammatory lesions with a bronchus-associated lymphoid tissue-like structure were identified in the lungs of pSS model mice. In addition, relative to salivary gland lesions, pulmonary lesions showed increased CD23+ follicular B (FB) cells. In vitro and pulmonary B cells were more readily driven to CD23+ FB cell phenotype than salivary gland B cells in pSS model mice. Furthermore, the CD23+ FB cell differentiation was found to be enhanced in a CD4+ T-cell-dependent manner under a Th2-type condition in the lungs of herein examined pSS model mice. Discussion: A Th2-type response in the pSS lung may promote the progression of autoimmune lesions through an enhanced abnormal differentiation of B cells

Effect of CNT exposure on alveolar macrophages

Background Nanomaterials are widely used in various fields. Although the toxicity of carbon nanotubes (CNTs) in pulmonary tissues has been demonstrated, the toxicological effect of CNTs on the immune system in the lung remains unclear. Methods and finding In this study, exposure to Taquann-treated multi-walled CNTs (T-CNTs) was performed using aerosols generated in an inhalation chamber. At 12 months after T-CNT exposure, alveolar inflammation with macrophage accumulation and hypertrophy of the alveolar walls were observed. In addition, fibrotic lesions were enhanced by T-CNT exposure. The macrophages in the bronchoalveolar lavage fluid of T-CNT-exposed mice were not largely shifted to any particular population, and were a mixed phenotype with M1 and M2 polarization. Moreover, the alveolar macrophages of T-CNT-exposed mice produced matrix metalloprotinase-12. Conclusions These results suggest that T-CNT exposure promoted chronic inflammation and fibrotic lesion formation in profibrotic macrophages for prolonged periods

原発性シェーグレン症候群モデルマウスにおいて唾液腺Natural killer細胞の恒常性の破綻がIFN-γを介して自己免疫病変を増強する

Objective: Innate lymphoid cells (ILCs), including natural killer (NK) cells, ILC1, ILC2, lymphoid tissue-inducer (LTi) cells, and ILC3 cell, play a key role in various immune responses. Primary Sjögren’s syndrome (pSS) is an autoimmune disease characterized by chronic inflammation of exocrine glands, such as the lacrimal and salivary glands (SGs). The role of NK cells among ILCs in the pathogenesis of pSS is still unclear. In this study, the characteristics and subsets of NK cells in the salivary gland (SG) tissue were analyzed using a murine model of pSS. Methods: Multiple phenotypes and cytotoxic signature of the SG NK cells in control and pSS model mice were evaluated by flow cytometric analysis. Intracellular expression of interferon-γ (IFN-γ) among T cells and NK cells from the SG tissues was compared by in vitro experiments. In addition, pathological analysis was performed using anti-asialo-GM1 (ASGM1) antibody (Ab)-injected pSS model mice. Results: The number of conventional NK (cNK) cells in the SG of pSS model mice significantly increased compared with that in control mice at 6 weeks of age. The production level of IFN-γ was significantly higher in SG NK cells than in SG T cells. The depletion of NK cells by ASGM1 Ab altered the ratio of tissue resident NK (rNK) cells to cNK cells, which inhibited the injury to SG cells with the recovery of saliva secretion in pSS model mice. Conclusion: The results indicate that SG cNK cells may enhance the autoreactive response in the target organ by upregulating of IFN-γ, whereas SG rNK cells protect target cells against T cell cytotoxicity. Therefore, the activation process and multiple functions of NK cells in the target organ could be helpful to develop potential markers for determining autoimmune disease activity and target molecules for incurable immune disorders

Trends in sleep problems and patterns among Japanese adolescents: 2004 to 2017

Background Sleep problems in adolescence, such as insomnia and short sleep duration, are associated with physical and mental health problems. However, little is known about the recent trends in sleep problems among adolescents. Therefore, this study examined trends in sleep problems among Japanese adolescents. Methods Using data from the Lifestyle Survey of Adolescents collected in 2004 (n = 102,451), 2008 (n = 95,680), 2010 (n = 98,867), 2012 (n = 101,134), 2014 (n = 85,931), and 2017 (n = 64,417), we calculated the trends of insomnia, shorter sleep duration, late bedtimes, and poor sleep quality. Multivariable logistic regression analysis models were used to examine the association of each sleep problem and survey years. Findings We analyzed data from 545,285 Japanese adolescents. Results indicated that, since 2004, the odds ratio for insomnia have decreased (Adjusted odds ratio [AOR] 0•85, 95% CI 0•82–0•87), as have the odds ratio for poor sleep quality (AOR 0•92, 95% CI 0•88–0•95). However, the odds ratio for shorter sleep duration (AOR 1•13, 95% CI 1•10–1•17) and late bedtimes tended to increase (AOR 1•06, 95% CI 1•03–1•08) during this period. Interpretation The prevalence of insomnia symptoms and poor sleep quality among adolescents decreased from 2004 to 2017. However, there were increasing trends toward shorter sleep duration and late bedtimes. These changes are both relieving and concerning. Teachers, parents, and health professionals should consider educating adolescents regarding sleep hygiene, adjusting schedules of extracurricular activities, and enhancing time management to improve their sleep quantity

Effectiveness of Screening and Brief Alcohol Intervention at the Workplace: A Study Protocol for a Randomized Controlled Trial at Five Japan-Based Companies

Background: Despite evidence regarding the effectiveness of screening and brief interventions for excessive alcohol use in primary care, these tools are not a part of routine practice. It has been suggested that using these tools at the workplace may be critical to alcohol-associated harm; however, evidence for this claim is unclear. The aim of this article is to develop a study protocol which evaluates the effect of brief alcohol intervention at the workplace to reduce harmful alcohol drinking. Methods: A randomized controlled trial involving employees (aged 20–74 years) of five Japan-based companies who were screened “positive” by Alcohol Use Disorder Identification Test (AUDIT) is on-going. Participants were randomized into “Patient Information Leaflet” (control group), “Brief Advice and Counselling,” and “Five-minute Brief Advice” groups. A self-administered questionnaire was used to assess alcohol consumption, lifestyle behavior, health status, work performance, and consequences of alcohol use. Data of laboratory markers were collected from routine health checkups.Results: A total of 351 participants were randomized into Patient Information Leaflet (n = 111), Brief Advice and Counselling (n = 128), and Five-minute Brief Advice (n = 112) groups. Participants were mostly men with a median age of 49 years. Median AUDIT score and weekly alcohol consumption were 11 points and 238 g/week, respectively. Two-thirds of the participants were manufacturing workers. Conclusion: This study protocol developed the first trial in Japan to investigate the effect of brief alcohol intervention combined with a recommended screening tool at the workplace. Our findings can provide evidence on the effectiveness and relevance of these tools to occupational health

ピエゾ型機械受容チャネル1による歯の発生過程におけるWNTシグナルと一次繊毛発現の調整

Signal transmission from the mechanical forces to the various intracellular activities is a fundamental process during tissue development. Despite their critical role, the mechanism of mechanical forces in the biological process is poorly understood. In this study, we demonstrated that in the response to hydrostatic pressure (HP), the piezo type mechanosensitive ion channel component 1 (PIEZO1) is a primary mechanosensing receptor for odontoblast differentiation through coordination of the WNT expression and ciliogenesis. In stem cells from human exfoliated deciduous teeth (SHED), HP significantly promoted calcium deposition as well as the expression of odontogenic marker genes, PANX3 and DSPP, and WNT related-genes including WNT5b and WNT16, whereas HP inhibited cell proliferation and enhanced primary cilia expression. WNT signaling inhibitor XAV939 and primary cilia inhibitor chloral hydrate blocked the HP-induced calcium deposition. The PIEZO1 activator Yoda1 inhibited cell proliferation but induced ciliogenesis and WNT16 expression. Interestingly, HP and Yoda1 promoted nuclear translocation of RUNX2, whereas siRNA-mediated silencing of PIEZO1 decreased HP-induced nuclear translocation of RUNX2. Taken together, these results suggest that PIEZO1 functions as a mechanotransducer that connects HP signal to the intracellular signalings during odontoblast differentiation