Selective IL-27 production by intestinal regulatory T cells permits gut-specific regulation of TH17 cell immunity.

Regulatory T cells (Treg cells) are instrumental in establishing immunological tolerance. However, the precise effector mechanisms by which Treg cells control a specific type of immune response in a given tissue remains unresolved. By simultaneously studying Treg cells from different tissue origins under systemic autoimmunity, in the present study we show that interleukin (IL)-27 is specifically produced by intestinal Treg cells to regulate helper T17 cell (TH17 cell) immunity. Selectively increased intestinal TH17 cell responses in mice with Treg cell-specific IL-27 ablation led to exacerbated intestinal inflammation and colitis-associated cancer, but also helped protect against enteric bacterial infection. Furthermore, single-cell transcriptomic analysis has identified a CD83+CD62Llo Treg cell subset that is distinct from previously characterized intestinal Treg cell populations as the main IL-27 producers. Collectively, our study uncovers a new Treg cell suppression mechanism crucial for controlling a specific type of immune response in a particular tissue and provides further mechanistic insights into tissue-specific Treg cell-mediated immune regulation.

CT findings of 144 in-hospital patients with influenza pneumonia: A retrospective analysis.

BACKGROUND/PURPOSE: Patients with influenza infection during their period of admission may have worse computed tomography (CT) manifestation according to the clinical status. This study aimed to evaluate the CT findings of in-hospital patients due to clinically significant influenza pneumonia with correlation of clinical presentations. METHODS: In this retrospective, single center case series, 144 patients were included. All in-hospital patients were confirmed influenza infection and underwent CT scan. These patients were divided into three groups according to the clinical status of the most significant management: (1) without endotracheal tube and mechanical ventilator (ETTMV) or extracorporeal membrane oxygenation (ECMO); (2) with ETTMV; (3) with ETTMV and ECMO. Pulmonary opacities were scored according to extent. Spearman rank correlation analysis was used to evaluate the correlation between clinical parameters and CT scores. RESULTS: The predominant CT manifestation of influenza infection was mixed ground-glass opacity (GGO) and consolidation with both lung involvement. The CT scores were all reach significant difference among all three groups (8.73 ± 6.29 vs 12.49 ± 6.69 vs 18.94 ± 4.57, p < 0.05). The chest CT score was correlated with age, mortality, and intensive care unit (ICU) days (all p values were less than 0.05). In addition, the CT score was correlated with peak lactate dehydrogenase (LDH) level and peak C-reactive protein (CRP) level (all p values were less than 0.05). Concomitant bacterial infection had higher CT score than primary influenza pneumonia (13.02 ± 7.27 vs 8.95 ± 5.99, p < 0.05). CONCLUSION: Thin-section chest CT scores correlated with clinical and laboratory parameters in in-hospital patients with influenza pneumonia.

Plastic ingestion by fish in the coastal waters of the Hengchun Peninsula, Taiwan: Associated with human activity but no evidence of biomagnification.

Plastic pollution has become a global threat to the marine environment. Many studies have indicated that marine creatures are at risk of plastic ingestion, but relevant studies are still lacking in Taiwan. In this study, we quantified plastic debris ingestion by marine fish in the coastal waters of the Hengchun Peninsula, including the Kenting National park, located in southern Taiwan. We also investigated possible biotic and abiotic factors associated with the quantity of ingested plastic by fish. In the 117 fish samples we examined, 94.87% of them had ingested plastic debris, and all of the observed debris was microplastics (<5 mm). The average number of ingested microplastics was 5.6 ± 5.1 pieces per fish (ranged 0-32 pieces per fish). The major type and color of microplastics were fiber (96%) and blue (43%), respectively. The quantity of ingested microplastics was not significantly different between the reef and pelagic fish. However, reef fish from the more populated west and south coast ingested more microplastics than that from the east coast, suggesting that microplastic ingestion by fish is related to human activity. Regarding biotic factors, the size, trophic level, and taxonomic family of the fish were not significantly associated with the number of ingested microplastics. Our results, the first investigation of microplastic ingestion in marine fish of Taiwan, show a high prevalence of microplastic ingestion but no biomagnification of microplastics in the fish. More research is much needed to better characterize the biological and ecological impacts of plastic debris on fish.

A Novel miR-24-TCF1 Axis in Modulating Effector T Cell Responses.

miR-23∼27∼24 was recently implicated in restricting Th2 immunity, as well as the differentiation and function of other effector T cell lineages. Interestingly, miR-24, unlike other family members, actually promotes Th1 and Th17 responses. In this article, we show that miR-24 drives the production of IFN-γ and IL-17 in T cells at least in part through targeting TCF1, a transcription factor known for its role in limiting Th1 and Th17 immunity. Surprisingly, whereas TCF1 was previously shown to promote Th2 responses through inducing GATA3, enforced TCF1 expression in miR-24-overexpressing T cells led to further downregulation of IL-4 and GATA3 expression, suggesting miR-24-mediated inhibition of Th2 immunity cannot be attributed to TCF1 repression by miR-24. Together, our data demonstrate a novel miR-24-TCF1 pathway in controlling effector cytokine production by T cells and further suggest miR-24 could function as a key upstream molecule regulating TCF1-mediated immune responses.

Selective IL-27 production by intestinal regulatory T cells permits gut-specific regulation of Th17 immunity.

Regulatory T (Treg) cells are instrumental in establishing immunological tolerance. However, the precise effector mechanisms by which Treg cells control a specific type of immune response in a given tissue remains unresolved. By simultaneously studying Treg cells from different tissue origins under systemic autoimmunity, here we show that IL-27 is specifically produced by intestinal Treg cells to regulate Th17 immunity. Selectively increased intestinal Th17 responses in mice with Treg cell-specific IL-27 ablation led to exacerbated intestinal inflammation and colitis-associated cancer, but also helped protect against enteric bacterial infection. Furthermore, single-cell transcriptomic analysis has identified a CD83+TCF1+ Treg cell subset that is distinct from previously characterized intestinal Treg cell populations as the main IL-27 producers. Collectively, our study uncovers a novel Treg cell suppression mechanism crucial for controlling a specific type of immune response in a particular tissue, and provides further mechanistic insights into tissue-specific Treg cell-mediated immune regulation.

Induction of Airway Hypersensitivity to Ovalbumin and Dust Mite Allergens as Mouse Models of Allergic Asthma.

Mouse models of allergic asthma have been utilized to establish the role of T helper type 2 (Th2) cells in driving lung inflammation, airway hyperresponsiveness, and obstruction. Here, we present the allergic asthma models, in which mice are hypersensitized to ovalbumin (OVA) and house dust mite (HDM). These models mimic the major characteristics of human asthma including the eosinophilic inflammation and hyperactivity of the airway, overproduction of Th2 cytokines in the lung, and elevated total and allergen-specific immunoglobulin E (IgE) in serum.

Gut epithelial IL-27 confers intestinal immunity through the induction of intraepithelial lymphocytes.

IL-27 controls a diverse range of immune responses in many disease settings. Here, we identify intestinal epithelial cells (IECs) as one of the major IL-27 cellular sources in the gut-associated tissue. Unlike IL-27 secreted by innate immune cells, gut epithelial IL-27 is dispensable for T-bet+ regulatory T cell (T reg cell) differentiation or IL-10 induction. Rather, IEC-derived IL-27 specifically promotes a distinct CD8αα+CD4+ intraepithelial lymphocyte (IEL) population that acquires their functional differentiation at the intestinal epithelium. Loss of IL-27 in IECs leads to a selective defect in CD8αα+CD4+ IELs over time. Consequently, mice with IEC-specific IL-27 ablation exhibited elevated pathogen burden during parasitic infection, and this could be rescued by transfer of exogenous CD8αα+CD4+ IELs. Collectively, our data reveal that in addition to its known regulatory properties in preventing immune hyperactivity, gut epithelial IL-27 confers barrier immunity by inducing a specific IEL subset and further suggest that IL-27 produced by different cell types plays distinct roles in maintaining intestinal homeostasis.

miR-155 promotes T reg cell development by safeguarding medullary thymic epithelial cell maturation.

During thymocyte development, medullary thymic epithelial cells (mTECs) provide appropriate instructive cues in the thymic microenvironment for not only negative selection but also the generation of regulatory T (T reg) cells. Here, we identify that miR-155, a microRNA whose expression in T reg cells has previously been shown to be crucial for their development and homeostasis, also contributes to thymic T reg (tT reg) cell differentiation by promoting mTEC maturation. Mechanistically, we show that RANKL stimulation induces expression of miR-155 to safeguard the thymic medulla through targeting multiple known and previously uncharacterized molecules within the TGFß signaling pathway, which is recognized for its role in restricting the maturation and expansion of mTECs. Our work uncovers a miR-155-TGFß axis in the thymic medulla to determine mTEC maturity and, consequently, the quantity of tT reg cells and suggests that miR-155 ensures proper tT reg cell development in both cell-intrinsic and -extrinsic manners.

Spatial and seasonal distribution of microplastics on sandy beaches along the coast of the Hengchun Peninsula, Taiwan.

Here we present the first report on microplastic pollution on the beaches along the coast of the Hengchun Peninsula, which is one of the major tourist attractions in Taiwan. By using a standard operating procedure, sand samples were collected from eight beaches in June and November in 2017, and the microplastics in the sand samples were quantified and characterized in the laboratory. The average density of microplastics ranged from 80 to 480 particles/kg dry weight sand. There was no apparent seasonal difference but there were significant spatial differences among sampling sites. No significant difference in microplastic levels was observed among the west, south, and east coasts, but microplastic density was higher on beaches with higher tourism activity levels. The most abundant type of microplastics was fiber (>97%) and the most common color was white/transparent (57%). In addition, using a Fourier Transform Infrared (FTIR) spectrophotometer we identified microplastics as polyethylene (PE) and polypropylene (PP). Our results show that microplastics are ubiquitous along the coast of the Hengchun Peninsula, and the major factor associated with the abundance of microplastics is tourism activity.

Clinic image surveillance reduces mortality in patients with primary hepato-gastrointestinal cancer who develop second primary lung cancer: A STROBE-compliant retrospective study.

Second primary cancer is prevalent in patients with gastrointestinal (GI) cancer, for which lung cancer is the most common and associated with high lethality. Image screening for lung cancer was proved to be effective in early diagnosis and lower mortality. However, trials of screen for lung cancer generally excluded patients with a previous diagnosis of malignancy. The study aimed to investigate the outcome of second primary lung cancer and the factor that improve survival in patients with hepato-GI cancer.A total of 276 patients with secondary lung cancer were found among 3723 newly-diagnosed lung cancer patients diagnosed in Chang Gung Memorial Hospital, between 2010 and 2014. Patients' clinical characteristics, stages and survival were recorded and analyzed. The patients were separated into 2 groups: Group I was defined as lung cancer detected in original primary cancer clinic and group II patients defined as lung cancer detected in other medical places.Sixty-nine cases with primary GI-hepatic and secondary lung cancer were diagnosed (42 (60.8%) in Group I and 27 (39.1%) in Group II). Although both groups had comparable primary cancer stages and treatment, more patients in Group I than Group II were diagnosed as early stage lung cancer (stage I-II: 40.5% vs 11.1%; P = .023). Group II had larger lung tumor sizes than Group I (4.7 vs 3.5 cm; P = .025). Group I showed better 5-year overall survival than Group II (P = .014, median survival: 27 vs 10 months). Among Group II, only 37% had received image follow up in clinic compared with 67% of Group I cases (P = .025). Patients with chest image follow up in clinics also had better 5-year overall survival (P = .043).GI-hepatic cancer was the most common primary malignancy in the lung cancer cohort. Patients had better survival outcome when secondary lung cancer was diagnosed in original primary cancer clinic. Chest image screening strategy may contribute better survival in secondary lung cancer due to detection at an earlier stage.

Safety and efficacy of computed tomography-guided dye localization using patent blue V for single lung nodule for video-assisted thoracoscopic surgery: a retrospective study.

BACKGROUND: For invisible or impalpable lung nodules, video-assisted thoracoscopic surgery (VATS) has some limitations; some preoperative localization has been developed to overcome this limitation. This study aimed to assess the safety and efficacy of preoperative computed tomography (CT)-guided localization with patent blue V dye. METHODS: In this retrospective study, we examined patients with solitary pulmonary nodule undergoing preoperative CT-guided patent blue V dye localization from 2013 to 2015. We analyzed patients' demographic data, nodular features, and procedures undergone. RESULTS: We enrolled 282 patients (282 lung nodules; mean age: 56.6±11.6 years, with female preponderance) in this study. The mean size of nodules was 0.9±0.5 cm, and mean time of localization was 24 min. The leading complications after localization were asymptomatic pneumothorax (48 patients, 17%) and localized pulmonary hemorrhage (51 patients, 18%). Other rare complications included subcutaneous emphysema and hematoma. We noted two cases with intraoperative poor or fail dye localization. Most patients underwent wedge resection (221 patients, 78.4%) and segmentectomy (36 patients, 12.8%), whereas 25 patients underwent lobectomy (8.9%) after the intraoperative frozen histopathological study confirmed malignancy. Furthermore, postoperative hospital stay was 4.8±2.0 days. Few patients experienced postoperative complications such as empyema (n=1), air leakage (n=3), and chylothorax (n=1). CONCLUSIONS: This study establishes that CT-guided dye localization is a safe and efficient method with rare severe complications and high success rate.

MiR-23~27~24-mediated control of humoral immunity reveals a TOX-driven regulatory circuit in follicular helper T cell differentiation.

Follicular helper T (TFH) cells are essential for generating protective humoral immunity. To date, microRNAs (miRNAs) have emerged as important players in regulating TFH cell biology. Here, we show that loss of miR-23~27~24 clusters in T cells resulted in elevated TFH cell frequencies upon different immune challenges, whereas overexpression of this miRNA family led to reduced TFH cell responses. Mechanistically, miR-23~27~24 clusters coordinately control TFH cells through targeting a network of genes that are crucial for TFH cell biology. Among them, thymocyte selection-associated HMG-box protein (TOX) was identified as a central transcription regulator in TFH cell development. TOX is highly up-regulated in both mouse and human TFH cells in a BCL6-dependent manner. In turn, TOX promotes the expression of multiple molecules that play critical roles in TFH cell differentiation and function. Collectively, our results establish a key miRNA regulon that maintains optimal TFH cell responses for resultant humoral immunity.

Differential cell-intrinsic regulations of germinal center B and T cells by miR-146a and miR-146b.

Reciprocal interactions between B and follicular T helper (Tfh) cells orchestrate the germinal center (GC) reaction, a hallmark of humoral immunity. Abnormal GC responses could lead to the production of pathogenic autoantibodies and the development of autoimmunity. Here we show that miR-146a controls GC responses by targeting multiple CD40 signaling pathway components in B cells; by contrast, loss of miR-146a in T cells does not alter humoral responses. However, specific deletion of both miR-146a and its paralog, miR-146b, in T cells increases Tfh cell numbers and enhanced GC reactions. Thus, our data reveal differential cell-intrinsic regulations of GC B and Tfh cells by miR-146a and miR-146b. Together, members of the miR-146 family serve as crucial molecular brakes to coordinately control GC reactions to generate protective humoral responses without eliciting unwanted autoimmunity.

Autophagy-Regulated ROS from Xanthine Oxidase Acts as an Early Effector for Triggering Late Mitochondria-Dependent Apoptosis in Cathepsin S-Targeted Tumor Cells.

Cathepsin S (CTSS), which is highly expressed in various malignant tumor cells, has been proposed to promote tumor progression, migration, and invasion. CTSS inhibition not only blocks tumor cell invasion and endothelial tube formation but also induces cellular cytotoxicity. In our previous studies, we have observed that CTSS inhibition induces autophagy, which is responsible for up-regulating xanthine oxidase for early ROS generation and consequent cell death. However, whether the autophagy-regulated early ROS triggers apoptosis remains unclear. We conducted a long-term follow-up study to investigate the relationship between early autophagy and late mitochondria-dependent apoptosis. We demonstrated that early ROS generation is critical for mitochondria damage and the activation of intrinsic apoptotic pathway. Attenuating the early ROS level diminished later mitochondrial damage and downstream apoptotic signaling. Collectively, mitochondria-dependent apoptosis is regulated by autophagy-regulated early ROS, which serves as an early effector that triggers mitochondrial signaling for late apoptosis. The data emphasize the essential role of autophagy-regulated early ROS in triggering late apoptotic signaling.

Solution structure of the ligand binding domain of the fibroblast growth factor receptor: role of heparin in the activation of the receptor.

The three-dimensional solution structure of the ligand binding D2 domain of the fibroblast growth factor receptor (FGFR) is determined using multidimensional NMR techniques. The atomic root-mean-square distribution for the backbone atoms in the structured region is 0.64 A. Secondary structural elements in the D2 domain include 11 beta-strands arranged antiparallely into two layers of beta-sheets. The structure of the D2 domain is characterized by the presence of a short flexible helix that protrudes out of the layers of beta-sheets. Results of size exclusion chromatography and sedimentation velocity experiments show that the D2 domain exists in a monomeric state both in the presence and in the absence of bound sucrose octasulfate (SOS), a structural analogue of heparin. Comparison of the solution structure of the D2 domain with the crystal structure of the protein (D2 domain) in the FGF signaling complex reveals significant differences, suggesting that ligand (FGF) binding may induce significant conformational changes in the receptor. SOS binding sites in the D2 domain have been mapped on the basis of the 1H-15N chemical shift perturbation data. SOS binds to the positively charged residues located in beta-strand III and the flexible helix. Isothermal titration calorimetry data indicate that the ligand (hFGF-1) binds strongly (Kd approximately 10(-9) M) to the D2 domain even in the absence of SOS. Binding of SOS to either the D2 domain or hFGF-1 does not seem to be the driving force for the formation of the D2-hFGF-1 binary complex. The function of SOS binding appears to stabilize the preformed D2-FGF binary complex.