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关键词： CAR-NK cells   Membrane-bound IL-2 or IL-15   Anti-apoptosis   Autonomous proliferation   Tumor cytotoxicity  

摘要： Chimeric antigen receptor (CAR)-engineered natural killer (NK) cells hold promise for off-the-shelf cancer immunotherapy, yet their clinical application is hindered by poor persistence due to cytokine dependency and systemic toxicity from exogenous cytokine support. Here, we developed membrane-bound cytokine (mbCytokine) modules to enable autonomous survival signaling in CAR-NK cells. By fusing IL-2, IL-15, or the potent mimic Neo-2/15 to their cognate receptor alpha-chains (IL-2R alpha or IL-15R alpha), we generated self-sustaining CAR-NK92 cells that bypass reliance on external cytokines. Among these constructs, membrane-bound IL-2 (mbIL2) demonstrated superior efficacy, driving robust proliferation and resistance to apoptosis under serum-free conditions. Notably, mbIL2-armored CAR-NK cells exhibited enhanced cytotoxicity against MICA/B-expressing tumor cells. Mechanistically, mbIL2 mitigated activation-induced apoptosis and suppressed exhaustion during tumor engagement, thereby sustaining NK cell viability. These findings establish mbIL2 as a critical enhancer of CAR-NK cell persistence and antitumor function, offering a clinically translatable strategy to overcome the limitations of cytokine-dependent therapies.

摘要： Excess TNF causes systemic inflammatory response syndrome and mortality. RIPK1 coordinates TNF signaling through kinase-dependent and -independent mechanisms. S161 autophosphorylation is a primary function of RIPK1 kinase activity in vitro, and here we show that it is sufficient to mediate RIPK1 kinase-dependent function in vivo. S161 phospho-mimic mutation (S161E) effectively overcomes chemical or genetic inhibition of RIPK1 kinase activity in TNF-treated cells and mice. Mechanistically, S161 autophosphorylation is necessary for further autophosphorylation in RIPK1, including at S166. Ripk1S161E/S161E mice are hypersensitive to TNF, enabling us to observe low-dose TNF-induced necroptosis in cecal intestinal epithelial cells (IECs) and endothelial cells (ECs) and uncover a reciprocal enhancement between IEC and EC necroptosis and a selective increase of IL-6 in the circulation by necroptosis. IL-6 promotes cecal edema and synergizes with IEC and EC necroptosis, causing cecal damage and mouse death. Our data elucidate a mechanism of RIPK1 kinase-dependent function in TNF signaling and its role in cecal pathology and mouse mortality.

摘要： Identifying the causes of a red eye remains a significant clinical challenge, as it is crucial not to overlook an ophthalmological emergency. The causes are varied, ranging from benign conditions to serious diseases that may threaten vision. Based on current evidence, this article aims to provide primary care physicians with clear and relevant clinical guidelines to help them identify situations requiring urgent ophthalmological care. Taking a focused medical history, identifying red flags and performing a standardized clinical examination are essential. The article also offers tailored treatment strategies for each common cause of a red eye. Rapid referral to an ophthalmologist is essential in cases of uncertainty or severity.;Identifier les causes d’un œil rouge demeure un enjeu clinique important pour ne pas passer à côté d’une urgence ophtalmologique. Les causes sont variées, allant de pathologies bénignes à des affections graves menaçant le pronostic visuel. Basé sur les données actuelles, cet article vise à fournir aux médecins de premier recours des éléments cliniques clairs et pertinents permettant d’identifier les situations nécessitant une prise en charge ophtalmologique urgente. Une anamnèse ciblée, l’identification de signes d’alarme (drapeaux rouges) et un examen clinique standardisé sont essentiels. L’article propose également une stratégie thérapeutique adaptée à chaque étiologie courante. Une orientation rapide vers un ophtalmologue est essentielle en cas de doute ou de gravité.

关键词： 炎症性肠病   白细胞介素-17   免疫调节   靶向治疗   溃疡性结肠炎   动物模型  

摘要： 炎症性肠病（IBD)是一种累及回肠、结肠和直肠的特发性肠道炎性疾病，IBD的发病机制涉及多种因素，主要是环境因素、遗传因素、肠道微生态和免疫失衡。白细胞介素-17(IL-17)家族是辅助性T细胞17(Th17)细胞免疫应答的核心效应细胞因子，在宿主防御和炎症病理中发挥至关重要的作用，参与多种免疫介导的炎症性疾病，近年来的研究发现IL-17家族在IBD中发挥更为复杂的重要作用。本文就IL-17家族对IBD发生发展及作为治疗靶点的研究进展进行综述，为临床决策提供依据。

关键词： 阿卡斑病毒   多克隆抗体   间接免疫荧光   检测方法   N蛋白  

摘要： 为建立阿卡斑病毒（Akabane virus， AKAV）的间接免疫荧光检测方法（indirect immunofluorescence assay， IFA），本试验利用大肠杆菌原核表达系统将AKAV的N蛋白进行表达，蛋白纯化后免疫小鼠制备多克隆抗体，以AKAV感染后的BHK-21细胞作为抗原，小鼠抗N多克隆抗体为一抗，FITC标记的山羊抗小鼠IgG为二抗，建立AKAV的IFA检测方法，优化筛选抗体的最佳孵育浓度和孵育时间，评估所建立方法的特异性、敏感性和重复性。最后，利用该方法对临床样品进行检测，并与荧光定量PCR方法进行符合性验证。结果发现，N蛋白可在大肠杆菌中高效表达，4次免疫小鼠后多克隆抗体效价可达1∶51 200；经优化筛选，在一抗稀释浓度1∶200、孵育2 h，二抗稀释浓度1∶500、孵育1.5 h条件下，IFA检测效果最佳；敏感性试验显示所建方法对25 TCID50的AKAV可有效检出，特异性试验显示与其他病原无交叉反应，且重复性良好。该方法对24份临床羊血液样本进行检测，共检出8份阳性、16份阴性样本，与荧光定量PCR方法检测结果相比，二者的符合率为95.8%。本试验为AKAV实验室诊断技术及产品的开发提供了技术支持，同时为深入研究AKAV感染机制奠定基础。

关键词： Jiawei Zicao Plaster   atopic dermatitis   network analysis   inflammation   skin microbiota  

摘要： Background Atopic dermatitis (AD) is a prevalent and difficult-to-cure chronic inflammatory skin condition. The mechanism of Jiawei Zicao Plaster (JZP), a clinically used Traditional Chinese Medicine (TCM) for AD, remains incompletely *** Following successful model induction, JZP was topically applied to the dorsal skin of mice. Therapeutic efficacy was evaluated through histopathological examination of skin sections and quantification of inflammatory biomarkers using ELISA. To investigate the underlying mechanisms, we performed qRT-PCR to analyze gene expression in related signal pathway, along with 16S rRNA sequencing to characterize skin microbiota *** Network pharmacological analysis revealed that JZP may exert therapeutic effects by targeting antibacterial and anti-inflammatory pathways. Subsequent in vivo experiments demonstrated that JZP effectively ameliorates biochemical markers of AD by activating the IL-17 pathway. Analysis of skin microbiota indicated that JZP treatment led to an increase in Chryseobacterium abundance and a decrease in Staphylococcus *** This study seeks to validate the efficacy of JPZ as a treatment for AD. Initial findings suggest that JPZ attains its therapeutic efficacy through the synergistic actions of IL-17 and antibacterial properties, providing a theoretical basis for the future development and application of this traditional Chinese medicine formula.

关键词： islets of Langerhans   diabetes   immune tolerance   islet organoids   HLA  

摘要： The immune protection of pancreatic beta cells has three layers: anatomical, with their distribution in 1 million islets;central, with the thymic deletion of beta cell-specific T cells;and peripheral, with inhibitory cellular networks. The failure of the latter leads to most spontaneous type 1 diabetes and all diabetes induced by checkpoint inhibitor therapy. Because CD4 T cells initiate disease, major histocompatibility complex (MHC) class II-expressing cells are central to the onset. In non-diabetic mouse and human islets, two such cells were detected outside of the islet boundaries near the efferent post-capillary venules: one related to the vasculature and a fibroblast referred to as a "vascular-associated fibroblast"(VAF). Functionally, primary VAFs spontaneously presented islet antigens to CD4 T cells and expressed high levels of inhibitory B7 receptors and no costimulatory receptors. VAFs induced anergy in primary pre-activated anti-islet CD4 T cells. VAFs are likely important to protect the endocrine pancreas from autoimmunity.

关键词： Cholangiocarcinoma   Chemo-immunotherapy   Necroptosis   T cell activation   Immune checkpoint inhibitors   IL-6 signaling  

摘要： BackgroundCholangiocarcinoma (CCA) is an aggressive malignancy with limited treatment options. Despite the approval of chemotherapy and immune checkpoint inhibitors (ICIs) in clinical practice, treatment outcomes remain poor, largely due to the poorly immunogenic tumor microenvironment associated with this type of carcinoma. Necroptosis, an inflammatory form of programmed cell death, has emerged as a promising therapeutic target for stimulating antitumor immunity. Our previous study linked necroptosis to increased CD8 + T cell infiltration and T cell-induced PD-L1 expression in CCA cells, suggesting its role in enhancing ICI efficacy. However, the underlying mechanisms by which necroptosis-activated T cells induce PD-L1 expression remain unclear. Here, we investigate how necroptosis in CCA cells influences T cell response, which subsequently promotes PD-L1 expression, thus providing insights for optimizing necroptosis-based therapies in combination with *** medium from gemcitabine-induced necroptotic CCA cells triggers PBMC-derived T cell activation by upregulating the surface activation marker CD69 and promoting cytokine release, primarily IL-6 and IL-1 beta. This cytokine release subsequently induces PD-L1 expression in CCA cells via IL-6, as confirmed by IL-6 neutralizing antibodies. Furthermore, T cell killing assays demonstrated that pembrolizumab, an anti-PD-1 inhibitor, enhances T cell cytotoxicity against PD-L1-upregulated CCA cells. Additionally, bioinformatics analysis identified an IL-6 signaling-related gene signature associated with ICI responsiveness, suggesting potential biomarkers for personalized treatment *** study highlights that necroptosis shapes the tumor immune microenvironment by promoting T cell activation and IL-6-mediated PD-L1 upregulation in CCA cells. These findings support the integration of necroptosis-based therapies with ICIs as a sequential chemo-immunotherapy strategy. Additionally, the id