Double-negative T cells ameliorate psoriasis by selectively inhibiting IL-17A-producing γδlow T cells.

BACKGROUND: Psoriasis is a chronic immune-mediated skin condition. Although biologic treatments are effective in controlling psoriasis, some patients do not respond or lose response to these therapies. Thus, new strategies for psoriasis treatment are still urgently needed. Double-negative T cells (DNT) play a significant immunoregulatory role in autoimmune diseases. In this study, we aimed to evaluate the protective effect of DNT in psoriasis and explore the underlying mechanism. METHODS: We conducted a single adoptive transfer of DNT into an imiquimod (IMQ)-induced psoriasis mouse model through tail vein injection. The skin inflammation and IL-17A producing γδ T cells were evaluated. RESULTS: DNT administration significantly reduced the inflammatory response in mouse skin, characterized by decreased skin folds, scales, and red patches. After DNT treatment, the secretion of IL-17A by RORc+ γδlow T cells in the skin was selectively suppressed, resulting in an amelioration of skin inflammation. Transcriptomic data suggested heightened expression of NKG2D ligands in γδlow T cells within the mouse model of psoriasis induced by IMQ. When blocking the NKG2D ligand and NKG2D (expressed by DNT) interaction, the cytotoxic efficacy of DNT against RORc+IL17A+ γδlow T cells was attenuated. Using Ccr5-/- DNT for treatment yielded evidence that DNT migrates into inflamed skin tissue and fails to protect IMQ-induced skin lesions. CONCLUSIONS: DNT could migrate to inflamed skin tissue through CCR5, selectively inhibit IL-17-producing γδlow T cells and finally ameliorate mouse psoriasis. Our study provides feasibility for using immune cell therapy for the prevention and treatment of psoriasis in the clinic.

Upregulation of RACGAP1 is correlated with poor prognosis and immune infiltration in hepatocellular carcinoma.

Background: Hepatocellular carcinoma (HCC) is a primary liver cancer with high mortality worldwide. Even though the patients with HCC received standard therapies, patients with HCC continue to experience unsatisfactory therapy outcomes. Presently, immune therapy acts as a novel therapeutic management for HCC. The aim of this study was to determine overexpressed genes in HCC and evaluate the association between overexpressed genes with the prognosis and immune infiltration. Methods: Gene expression profiles of HCC were analyzed using multiple online databases, and then confirmed by qualitative real time-polymerase chain reaction (RT-qPCR) and immunohistochemical analysis. The correlations of gene overexpression with the prognosis and immune infiltration were determined. Results: Top 11 common differentially expressed genes were identified in HCC, and RACGAP1 was selected for further analysis. RACGAP1 expression was significantly higher in HCC tissues than that in normal tissues. Upregulation of RACGAP1 was correlated with clinical stage and poor prognosis. Additionally, RACGAP1 overexpression was positively related to the infiltration of suppressive immune cells. Moreover, we speculate RACGAP1 may promote tumorigenesis of HCC through immunosuppression mediated by YAP activation. Conclusions: Overexpression of RACGAP1 was associated with unfavorable prognosis and immune infiltration in HCC, which indicated that RACGAP1 could be a molecular target for HCC.

The transcription factor T-bet promotes the pathogenesis of nonalcoholic fatty liver disease by upregulating intrahepatic inflammation.

OBJECTIVE: To investigate the effect of the transcription factor T-bet on the pathogenesis of nonalcoholic fatty liver disease (NAFLD) and the regulation of the intrahepatic immune microenvironment. METHODS: Wild-type and T-bet knockout NASH mouse models were constructed. The effect of T-bet knockout on the pathogenesis of NAFLD was observed by histochemical staining. The expression of T-bet in immune cells in the liver and the effect of T-bet knockout on the proportion and function of immune cell subsets in the liver were determined by flow analysis. RESULTS: Flow cytometry results indicated that T-bet expression was increased in immune cells, especially NKT cells, in the livers of NAFLD mice. Knocking out the transcription factor T-bet reduced intrahepatic inflammation, reduced lipid accumulation, and ameliorated the pathogenesis of NAFLD. Based on the analysis of immune cell subsets, knocking out the transcription factor T-bet decreased the proportion, survival, and degree of activation of NK, NKT, and CD8 T cells in NAFLD liver; additionally, it decreased the secretion of IFN-γ by T cells and NKT cells but had no effect on the proportion of Th17 cells and Treg cells. Knocking out the transcription factor T-bet also reduced the proportion of proinflammatory myeloid-derived macrophages (MoMFs) in NAFLD liver, mainly the proportion of proinflammatory Ly6Chigh MoMFs. Furthermore, knocking out the transcription factor T-bet had no significant effect on the secretion of TNF-α from MoMFs but significantly reduced the expression of MHC class II molecules. Further analysis showed that the transcription factor T-bet may directly affect the expression of MHC class II molecules H2-AB1 and H2-Dmb1 through transcriptional regulation. CONCLUSIONS: Knocking out the transcription factor T-bet reduced the proinflammatory effect of innate immune cells (MoMFs, NK cells, and NKT cells) and T lymphocytes in NAFLD liver, thereby reducing intrahepatic inflammation and delaying the pathogenesis of NAFLD.

Diagnosis and Endoscopic Treatment of Gastrointestinal Stromal Tumors Arising from Esophagus.

Aim: The primary purpose of this study was to investigate the diagnosis and endoscopic treatment of gastrointestinal stromal tumors (GISTs) arising from esophagus. Materials and Methods: From January 2013 to December 2017, 16 cases of GISTs of esophagus were retrospectively identified from a total of >3000 GISTs treated in our center. Demographic characteristics, clinical data, endoscopic therapy outcomes, histopathology, and follow-up were analyzed. Results: The mean age of the patients was 53 years (range 35-71 years), mostly female (56.3%). Seven tumors were in the lower esophagus, five in the middle esophagus, and one in the upper esophagus. The most common symptom was abdominal discomfort (8/16; 50.0%), followed by acid reflux (6/16; 37.5%). All of the patients underwent CT scan, gastroscopy, and/or endoscopic ultrasound. Two patients were diagnosed with esophageal GISTs with a preoperative endoscopic biopsy. Tumors were resected completely in all patients by endoscopic surgery. The median operating time was 85 minutes (range 28-153 minutes), and the average tumor size was 11.6 mm (range 6-21 mm). Postoperative histopathology demonstrated esophageal GISTs were positive for CD117 and CD34. The mean length of postoperative hospital stay was 4.7 days (range 2-7 days). The median postoperative follow-up duration was 28 months (range 1-59 months). Conclusion: Endoscopic treatment seems to be safe and effective for tumors size <20 mm in diameter. However, long-term prospective randomized controlled trials are further needed.

Endoscopic submucosal dissection for gastric ectopic pancreas: a single-center experience.

BACKGROUND AND OBJECTIVE: Endoscopic submucosal dissection (ESD) is a minimal invasive technology and could allow "en bloc" resection for superficial gastric tumors. The aim of this study is to evaluate the safety and feasibility of ESD for gastric ectopic pancreas (EP). METHODS: A total of 93 patients diagnosed with ectopic pancreas who underwent ESD between January 2011 and June 2017 were enrolled. The demographic, clinical, and endoscopic data were collected and analyzed. RESULTS: The average maximal diameter of lesions was 1.01 (range 0.4-3.0) cm with mean age of patients which was 39.75 (range 15-66) years. Overall, all of procedures en bloc was successful. The median operative time was 76.87 (range 30-160) min. A total of 12 patients experienced complications. In seven patients, bleeding occurred during the operation and was treated using hot biopsy forceps or metal clip. Five cases suffered from pneumoperitoneum which was managed well. The mean length of postoperative hospital stay was 5.7 (range 2-17) days. There was no relapse in any cases during the follow-up. CONCLUSION: ESD appears to be a safe and feasible approach for curative treatment in gastric ectopic pancreas. Larger studies are needed to identify the role and the outcomes of ESD in another center.