课程文献中心 更多>>

关键词： CD8+T cells   interferon-gamma   CD107a   cytotoxicity   subcellular localization   CRTAM  

摘要： CD8+ T lymphocytes (CTLs) act as serial killers of infected or malignant cells by releasing large amounts of interferon-gamma (IFN gamma) and granzymes. Although IFN gamma is a pleiotropic cytokine with diverse immunomodulatory functions, its precise spatiotemporal regulation and role in CTL-mediated cytotoxicity remain incompletely understood. Using wild-type and granzyme B-mTFP knock-in mice, we employed a combination of in vitro approaches, including T cell isolation and culture, plate-bound anti-CD3e stimulation, degranulation assays, flow cytometry, immunofluorescence, and structured illumination microscopy, to investigate IFN gamma dynamics in CTLs. IFN gamma expression in CTLs was rapid, transient, and strictly dependent on T cell receptor (TCR) activation. We identified two functionally distinct IFN gamma-producing subsets: IFN gamma high (IFN gamma hi) and IFN gamma low (IFN gamma lo) CTLs. IFN gamma hi CTLs exhibited an effector/effector memory phenotype, significantly elevated CD107a surface expression (a marker of lytic granule exocytosis), and higher colocalization with cis-Golgi and granzyme B compared to IFN gamma lo CTLs. Furthermore, CRTAM, an early activation marker, correlated with IFN gamma expression in naive CTLs. Our findings establish a link between elevated IFN gamma production and enhanced CTL cytotoxicity, implicating CRTAM as a potential regulator of early CTL activation and IFN gamma induction. These insights provide a foundation for optimizing T cell-based immunotherapies against infections and cancers.

关键词： Urticaria   treatment   cyclosporine   antihistamines   guidelines   omalizumab   updosing   triggering factors   special populations   pregnancy   elderly   children   chronic spontaneous urticaria   AERD/NERD   Aspirin/NSAIDs-exacerbated respiratory disease   ASST   autologous serum skin test   BAT   basophil activation test   BHRA   positive baseline basophil histamine release assay   COX   cyclooxygenase   CSU   chronic spontaneous urticaria   CU   chronic urticaria   IL   interleukin   NSAID   non-steroidal anti-inflammatory drugs   sgAH(s)   second-generation H1-antihistamine(s)   TNF   tumor necrosis factor-alpha  

摘要： Despite its significant impact on quality of life, optimal management of chronic spontaneous urticaria (CSU) remains challenging due to knowledge gaps regarding triggers, treatment response variability, and limited data for special populations. Second-generation H1-antihistamines (sgAHs) are the first-line treatment and effective in approximately 50% of patients. For those who remain symptomatic, up-dosing up to fourfold is safe and recommended. However, prolonged ineffective antihistamine therapy should be avoided to prevent delayed disease control. In such cases, timely escalation to biologics, particularly omalizumab, is essential. Omalizumab remains the cornerstone of biologic therapy, offering rapid and sustained efficacy with an excellent safety profile. Personalized approaches involving dose escalation or interval adjustments further optimize outcomes. Cyclosporine A serves as an effective third-line option, particularly for autoimmune CSU, but requires close monitoring due to dose-related adverse effects. Special considerations for children, pregnant individuals, and the elderly are discussed, reflecting the need for tailored approaches. Trigger avoidance—particularly NSAIDs—may aid management, though evidence is limited for many suspected exacerbating factors. Regular assessment of disease activity and control using validated tools such as the Urticaria Activity Score and Urticaria Control Test is essential for guiding treatment decisions and monitoring response. Updated international guidelines are anticipated to address emerging therapies and current knowledge gaps.

摘要： Objectives:Progressive supranuclear palsy (PSP) is a neurodegenerative 4R tauopathy clinically presenting with atypical parkinsonism or cognitive behavioral changes and a relatively uniform neuropathology. We recently identified rare HLA haplotypes in PSP and now examine whether HLA haplotypes are associated with different cytopathological and clinical phenotypes. Methods:Retrospective collection of clinical data and mapping of T and B cells, microglia, and phosphorylated-tau (p-Tau) cytopathologies in 32 PSP cases. Machine learning was used to analyze whether pathological variables and their ratios, or the sequence of clinical symptoms cluster or predict HLA haplotypes. Results:Four groups were defined based on HLA haplotypes: i) 12 cases with the haplotype associated with narcolepsy ( *15:01- *06:02); ii) 11 cases with other haplotypes; iii) 8 cases with various haplotypes frequent in the general population; and iv) one case with the haplotype frequent in IgLON5-disease ( *10:01- *05:01). Neuropathology revealed regional differences in the severity of microglia load, density of cytotoxic T cells, and p-Tau cytopathologies between groups. HLA haplotypes were most distinguishable using machine learned features of inflammatory markers and ratios of neuropathological variables (clustering accuracy: 86.96% and 91.30%, respectively). The sequence of clinical symptoms and the ratios of neuropathological variables were the strongest predictors of HLA haplotypes (prediction accuracy=80.00% and 71.43%, respectively). Interpretation:PSP pathology might be associated with various etiological-pathogenic events including targetable autoimmune mechanisms. The HLA-haplotype dependent diversity of neuroinflammatory markers should be evaluated in clinical and biomarker studies in, and beyond, PSP to understand its relevance for patient stratification in disease modifying therapy trials.

关键词： 牛肠病毒   重组腺病毒   结构蛋白VP1   细胞免疫  

摘要： 构建表达牛肠病毒（bovine enterovirus，BEV）结构蛋白VP1的重组腺病毒，并对其进行免疫原性和安全性的初步验证。首先，应用PCR扩增BEV VP1基因，并将其克隆至腺病毒载体pDC316-CMV-copGFP，获得的重组质粒pDC316-VP1-copGFP与pBHGlox-△E1，3cre共转染至293细胞后，进行病毒滴度测定及RT-PCR鉴定；其次，构建pET-32a-BEV-VP1原核表达质粒，优化诱导时间和温度后纯化BEV VP1蛋白；同时，将阴性对照腺病毒rAdv-copGFP、重组腺病毒rAdv-VP1及空白对照PBS分别肌注免疫BALB/c小鼠，观察小鼠临床症状；随后于免疫21 d后感染BEV，并于攻毒第0、5、10、15天采集小鼠肝、肺、脾、肾、小肠，分别提取组织RNA并制作病理切片，检测各组织中病毒载量并观察组织病理变化；最后，使用ELISA检测免疫血清中总IgG抗体、特异性抗体、细胞因子IFN-γ和IL-4水平。结果显示：成功构建腺病毒载体pDC316-VP1-copGFP；筛选出最优VP1原核表达条件为37 ℃诱导8 h，成功纯化出pET-32a-BEV-VP1蛋白；腺病毒免疫小鼠血清能够识别纯化后的VP1蛋白；重组腺病毒免疫能使小鼠产生特异性抗体，从而提高体液免疫与细胞免疫水平。本研究成功构建表达BEV VP1蛋白的重组腺病毒，在免疫小鼠后能够较好地诱导小鼠体内产生体液免疫应答和细胞免疫应答，从而对BEV感染起到了一定的保护作用，为进一步研发BEV新型疫苗奠定基础。

关键词： antisense oligonucleotide   chronic inflammation   enhancer RNA   rheumatoid arthritis   tumor necrosis factor alpha  

摘要： Chronic inflammatory diseases are driven by immune cell dysregulation and overproduction of pro-inflammatory molecules, such as tumor necrosis factor alpha (TNF alpha). Super-enhancers (SEs) and their enhancer RNAs (eRNAs) are critical gene expression regulators and offer therapeutic potential beyond protein-targeting approaches. This work hypothesizes that targeting eRNAs could reduce chronic inflammation by modulating TNF alpha expression. This work generates TNF-9 knockout (KO) mice by deleting a Tnf alpha-regulating enhancer region. These mice exhibit significantly reduced Tnf alpha levels, improved disease outcomes, and diminished immune cell activation in models of rheumatoid arthritis (RA), psoriasis, and lipopolysaccharide (LPS)-induced sepsis. Integrative epigenomic and transcriptomic analysis identify additional LPS-responsive, eRNA-producing enhancers as therapeutic targets. Antisense oligonucleotide (ASO)-mediated knockdown of TNF-9 eRNA in mouse macrophages demonstrate decreased Tnf alpha expression and alleviated RA symptoms. Furthermore, ASO-mediated inhibition of the eRNA of the human homolog of TNF-9 similarly reduce TNF alpha levels. These findings support eRNA-targeted interventions as potential treatment for chronic inflammatory diseases.

关键词： 非小细胞肺癌   表皮生长因子受体   基因突变   能谱CT   淋巴细胞与单核细胞比值   系统性炎症反应指数  

摘要： 目的 基于能谱CT参数、淋巴细胞与单核细胞比值(LMR)、系统性炎症反应指数(SIRI)构建非小细胞肺癌(NSCLC)患者表皮生长因子受体(EGFR)基因突变的预测模型.方法 比较EGFR突变型、野生型NSCLC患者的能谱CT参数、LMR、SIRI,分析EGFR基因突变的影响因素并构建风险预测模型.结果 EGFR突变型患者LMR、动脉期与静脉期70 keV CT值、标准化碘浓度(NIC)、能谱曲线斜率(λHU)和静脉期CT值变化值(ΔCT值)均高于EGFR野生型患者,SIRI、动脉期与静脉期标准化水浓度(NWC)低于EGFR野生型患者(P<0.05);女性、腺癌、无吸烟史、LMR和静脉期NIC、λHU、ΔCT值升高是EGFR基因突变的危险因素,SIRI升高是保护因素(P<0.05).决策曲线显示,风险阈值为0.2～0.6时模型具有较好的风险-收益比,Hosmer-Lemeshow拟合优度检验P=0.519,预测NSCLC患者EGFR基因突变的曲线下面积为0.911.结论 能谱CT参数、LMR、SIRI与NSCLC患者EGFR基因突变相关,基于上述指标构建的模型对EGFR基因突变具有较高的预测效能.

摘要： 患者 女,59岁.因绝经5年,发现子宫肌瘤4年,下腹胀1 d就诊.患者4年前于彩色多普勒超声发现子宫肌瘤,大小1.8 cm×1.4 cm,并1年后随诊变化不大.6 d前复查彩色多普勒超声:子宫体区低回声占位,大小7.2 cm×6.0 cm×7.7 cm,边界欠清,回声不均匀,前方见少许肌层样回声;彩色多普勒血流显像:肿块内部及周边可见血流信号(图1).

关键词： Heterogeneous catalysts   Photocatalysis   Built-in electric field   Conjugation   C–H trifluoromethylation  

摘要： Advancements in vaccination and sanitation have significantly reduced the prevalence and burden of infectious diseases; however, these benefits have coincided with a marked rise in autoimmune and allergic disorders. Recent studies have investigated these linked trends through the lens of host–microbiome alterations, proposing these shifts as a potential explanatory mechanism. Previously, we demonstrated that vancomycin -induced depletion of short-chain fatty acid (SCFA)-producing bacteria results in hyperactivation of ILC2s and exacerbated allergic responses. Here we investigate the effects of low-dose streptomycin on innate and adaptive immune cell populations and their activation states. Although streptomycin-treated mice exhibit normal allergic responses, they display heightened susceptibility to Th1/Th17-mediated disease, specifically hypersensitivity pneumonitis (HP). This is characterized by a two-fold increase in ILC3s and Th17 cells in the lungs, alongside activation of antigen-presenting cells (APCs) at steady state—an effect that is further amplified upon exposure to HP-inducing agents. Shotgun metagenomic analysis revealed that streptomycin-induced dysbiosis reduces microbial diversity, depletes bile acid–metabolizing bacteria, and enriches for metabolic pathways involved in branched-chain amino acid biosynthesis, including leucine—a known activator of mTORC1. Strikingly, administration of the secondary bile acid metabolite isolithocholic acid (an inverse agonist of RORγt), or an IL-23 neutralizing antibody, reverses the enhanced susceptibility to HP. Inhibition of mTORC1 significantly reduced Th17/ILC3 responses and histopathology. Our findings underscore microbial equilibrium as a key determinant of susceptibility to HP and uncover a positive feedback loop between IL and 23–producing APCs and ILC3/Th17 cells that mechanistically links dysbiosis to sustained type 3 inflammation, and we identify a simple, actionable means of intervention

摘要： Growing evidence suggests that the proapoptotic TNF-related apoptosis-inducing ligand receptor 2 (TRAIL-R2/DR5) signaling pathway can also trigger the production of inflammatory cytokines, thereby promoting tumor progression. We recently reported that glutamine depletion impacts the survival of glutamine-dependent tumor cells by activating the TRAIL-R2/DR5-mediated apoptotic machinery. However, it remains unclear whether glutamine limitation activates a TRAIL-R2/DR5-regulated inflammatory response. In this study, we demonstrate that glutamine starvation activates two parallel signaling pathways, leading to the gene expression and secretion of the pro-angiogenic and pro-inflammatory interleukin-8 (IL-8/CXCL8) in tumor cells. Our findings reveal that the amino acid-sensing general control nonderepressible-2 kinase (GCN2)/activating transcription factor 4 (ATF4) signaling axis contributes to the upregulation of IL-8 gene expression in glutamine-deprived tumor cells. Furthermore, our results indicate that the loss of the long isoform of cellular FLICE-inhibitory protein (cFLIPL), which occurs as result of the metabolic stress induced by glutamine limitation, promotes TRAIL-independent activation of the NF-kB pathway via TRAIL-R2/DR5, a key mechanism driving the observed IL-8 upregulation under starvation conditions. Given the severe depletion of glutamine observed in growing tumors, our data suggest that IL-8 secretion, induced by this metabolic stress, may play a significant role in activating inflammatory and angiogenic responses, thereby counteracting apoptosis and ultimately promoting tumor progression.

摘要： Acute graft-versus-host disease (GVHD) remains a life-threatening complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT), with limited treatment options for steroid-refractory cases. Current therapies broadly suppress immune responses, increasing infection risk and impairing graft function. We hypothesized that selective depletion of donor immune cells through HLA allele-specific targeting could offer a safer and more precise alternative. To test this, we developed a monoclonal antibody (AN7) against HLA-A2 by immunizing HLA-A24 transgenic mice with recombinant HLA-A2 tetramers, followed by hybridoma screening. AN7 specifically recognized HLA-A2 and HLA-A68, and was reformatted into murine IgG2a and human chimeric IgG1 recombinant antibodies. These retained binding specificity and mediated robust complement-dependent cytotoxicity (CDC), antibody-dependent cellular cytotoxicity (ADCC), and antibody-dependent cellular phagocytosis (ADCP) against HLA-A2+ target cells. To evaluate therapeutic potential, we established a fully MHC-mismatched allo-HSCT model using HLA-A2 transgenic donor bone marrow in lethally irradiated BALB/c recipients. A single ultra-low dose of AN7 (1-100 ng) administered post-transplant significantly improved survival and reduced GVHD while preserving donor hematopoiesis. These findings highlight the potential of allele-specific antibody-mediated clearance as a mechanistically distinct approach to donor immune modulation in GVHD.