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摘要： Macrophages, as key sentinel cells of the innate immune system, can retain memory of prior stimulus exposure. Interferon gamma (IFNγ) plays a central role in maintaining trained immunity and can induce potent memory in macrophages. Such memory is associated with the formation of enhancers that alter gene expression responses to subsequent stimuli. However, how such enhancers are maintained after cytokine exposure remains unclear. We report that durable IFNγ-induced enhancers can last for days after cytokine washout, yet the underlying persistence mechanism is not cell-intrinsic. IFNγ-treated macrophages continue to exhibit JAK/STAT signaling days after cytokine removal. Blocking IFNγ signaling with a JAK inhibitor or anti-IFNγ neutralizing antibodies after cytokine removal is sufficient to reverse IFNγ-induced enhancers and erase the potentiated state of the treated macrophages. Our findings suggest that epigenetic changes in macrophages do not inherently encode innate immune memory or a "potentiated" macrophage state, but in fact are themselves dependent on ongoing cytokine signaling. These findings suggest new possibilities for pharmacologic interventions to reverse aberrantly trained immune states associated with pathology.

关键词： 白细胞介素-35   富含丝氨酸-精氨酸剪接因子6   结核性胸膜炎   胸膜厚度   胸膜结核瘤  

摘要： 目的 分析白细胞介素-35(IL-35)、富含丝氨酸-精氨酸剪接因子6(SRSF6)水平与结核性胸膜炎胸膜厚度的关系及联合评估患者胸膜结核瘤发生风险的价值。方法 选取2022年1月—2024年7月于浙江大学医学院附属第二医院临平院区收治的100例结核性胸膜炎。检测患者的胸腔积液IL-35、SRSF6水平及胸膜厚度。分析IL-35、SRSF6水平与结核性胸膜炎患者胸膜厚度的关系。随访1年,结核组患者根据是否发生胸膜结核瘤分为发生组与未发生组,分析结核性胸膜炎患者发生胸膜结核瘤的危险因素,分析IL-35和SRSF6评估结核性胸膜炎患者胸膜结核瘤发生风险的价值。结果 结核性胸膜炎患者的胸腔积液IL-35水平为(529.78±146.85) ng/L、胸腔积液SRSF6水平(1.44±0.43) ng/ml,胸膜厚度为(4.07±0.53) mm。结核性胸膜炎患者胸腔积液IL-35、SRSF6水平与胸膜厚度呈正相关(P<0.05)。logistic分析显示,结核性胸膜炎患者出现胸水分隔包裹、胸膜厚度异常及胸腔积液IL-35、SRSF6水平上升时,其发生胸膜结核瘤的风险显著增加(P<0.05)。绘制受试者工作特征(ROC)曲线分析显示,胸腔积液IL-35和SRSF6水平联合预测结核性胸膜炎患者发生胸膜结核瘤的曲线下面积(AUC)、特异度、灵敏度均高于两者单独检测值(P<0.05)。结论 IL-35和SRSF6水平与结核性胸膜炎胸膜厚度呈正相关,两者联合检测可有效评估结核性胸膜炎患者胸膜结核瘤发生风险。

关键词： Resveratrol glycoside   Peritoneal fibrosis   NLRP3   Inflammation   Epithelial-mesenchymal transition  

摘要： ObjectiveResveratrol glycoside (also known as polydatin, PLD), known for its anti-inflammatory and anti-fibrotic properties, has shown potential in mitigating fibrosis in various organs. This study aimed to investigate the effects of PLD on high glucose-induced peritoneal fibrosis and its underlying mechanisms, focusing on the NOD-like receptor protein 3 (NLRP3)/interleukin-1 beta (IL-1 beta)/nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappa B) *** Sprague-Dawley rats were divided into three groups: control, peritoneal fibrosis, and resveratrol glycoside treatment. Histological and immunohistochemical analyses were performed to assess peritoneal fibrosis. Human peritoneal mesothelial cells (HMrSV5) were treated with high glucose and PLD to evaluate cell morphology, viability, and the expression of fibrosis and inflammatory markers via Western Blot and *** significantly reduced peritoneal fibrosis in rats, as evidenced by histological analyses showing decreased tissue thickness and collagen deposition. It also downregulated the expression of transforming growth factor beta 1 (TGF-beta 1), collagen type I (Col I), alpha-smooth muscle actin (alpha-SMA), vascular endothelial growth factor (VEGF), NLRP3, phosphorylated p65 subunit of NF-kappa B (p-p65), IL-1 beta, interleukin-18 (IL-18), cleaved caspase-1 p20 subunit (caspase-1p20) and ROS level, while upregulating E-cadherin. In HMrSV5 cells, PLD mitigated high glucose-induced epithelial-mesenchymal transition, angiogenesis, reactive oxygen species (ROS) production and inflammation, which was reversed by overexpression of NLRP3, suggesting the involvement of the NLRP3/IL-1 beta/NF-kappa B *** alleviates high glucose-induced peritoneal fibrosis, angiogenesis, ROS production and inflammation by inhibiting the NLRP3/IL-1 beta/NF-kappa B signaling pathway, highlighting its potential as a therapeutic agent for peritoneal fibrosis.

关键词： 腹膜透析相关性腹膜炎   扶肾颗粒   驻留巨噬细胞   细胞因子   中药复方   随机对照试验  

摘要： 目的观察扶肾颗粒干预Vsig4驻留巨噬细胞治疗腹膜透析相关性腹膜炎（PDAP）的临床疗效和作用机制。方法本研究通过随机对照试验评估扶肾颗粒联合抗生素治疗PDAP的有效性。纳入天津中医药大学第一附属医院2023年7月—2024年2月就诊的40例PDAP患者，随机分为扶肾颗粒组20例，对照组20例。对照组控制患者血压、血糖，予患者腹腔注射敏感抗生素治疗14天。扶肾颗粒组在对照组的基础上，加用口服扶肾颗粒治疗，每次2袋，每天2次，共治疗14天。记录患者PDAP转阴时间及腹膜透析总超滤量变化；收集PDAP治疗前后的腹膜透析液样本，检测腹腔Vsig4驻留巨噬细胞、T细胞和细胞因子IL-6、IL-10、TNF-α的变化。结果扶肾颗粒组患者平均转阴时间[（2.50±0.26）天]短于对照组[（3.30±0.25）天，t=-2.223,P=0.032]。与对照组比较，第3天时扶肾颗粒组超滤量更多（P<0.05）。与本组治疗前比较，两组IL-6、IL-10、TNF-α浓度降低（P<0.01）；扶肾颗粒组CD3+T细胞、CD14+巨噬细胞、Vsig4+巨噬细胞、Vsig4+巨噬细胞/CD14+巨噬细胞水平升高（P<0.05,P<0.01），对照组CD3+T细胞、Vsig4+巨噬细胞、Vsig4+巨噬细胞/CD14+巨噬细胞水平亦升高（P<0.05,P<0.01）。与对照组比较，扶肾颗粒组Vsig4+巨噬细胞的比例及IL-10浓度更高（P<0.05）,IL-6浓度更低（P<0.01）。结论PDAP患者早期应用扶肾颗粒能够缩短腹透液常规转阴时间，其作用机制可能与其调节Vsig4驻留巨噬细胞比例和细胞因子浓度减轻腹腔炎症反应有关。

关键词： X射线   辐照   淋巴细胞   血常规   剂量  

摘要： 考察了X射线辐照抑制血液中淋巴细胞增殖的效果,以确定预防输血相关性移植物抗宿主病(TA-GVHD)的最佳辐照剂量。实验在150 kV管电压、8 mA束流下进行,通过调整辐照距离和时间控制剂量。结果显示,40 Gy剂量下,淋巴细胞增殖抑制率达92.62%±1.32%,且对血常规参数无显著不良影响。当剂量提高到70 Gy时,尽管淋巴细胞增殖抑制率没有显著提升,却导致红细胞内钾离子浓度急剧升高,引发溶血。这表明高剂量辐照会损害红细胞完整性。因此,40Gy被认为是全血X射线辐照的最佳剂量,能在有效抑制淋巴细胞增殖的同时保持血液成分稳定性。此剂量下,能够有效降低TA-GVHD风险,且不会对血液质量造成显著影响。该研究为临床输血安全提供了重要的实验数据和指导,有助于优化辐照参数,提高输血安全性及有效性,减少不良反应的发生。

关键词： computational protein design   HLA   human leukocyte antigen   peptide antigen   T cell receptor  

摘要： Recognition of epitopic peptide antigens presented on class I major histocompatibility complex (MHC-I) proteins by T cell receptors (TCRs) forms the cornerstone of immune surveillance, leading to a plethora of adaptive immune responses. Characterization of TCR:peptide/MHC-I interactions is critical for understanding immune recognition, and developing immunotherapies, but the large variation in docking orientations of TCRs on their peptide/MHC-I targets challenges structural modeling. NMR spectroscopy could potentially resolve this ambiguity, but the large size of the TCR:peptide/MHC-I complex limits data quality. Here, we demonstrate that a designed MHC-I protein, SMART A*02:01, enables facile solution mapping of MHC-I:TCR interactions at scale. Our approach can be combined with computational modeling and structure-guided engineering to aid the development of TCR-based therapeutics. Copyright © 2025 the Author(s).

关键词： Asthma   Immunology   Inflammation   Pulmonology  

摘要： The mechanism of neutrophilic and mixed neutrophilic-eosinophilic asthma is poorly understood. We found that extracellular DNA and nucleosomes (Nuc) were elevated in the airways from neutrophilic-eosinophilic asthma patients and correlated with bronchoalveolar lavage neutrophils. Bronchial tissue from neutrophilic-eosinophilic asthma expressed increased DNA sensor-positive cells. Intranasally administered DNA did not induce airway hyperreactivity (AHR) or any pathology but induced AHR and neutrophilic-eosinophilic inflammation when co- administered with the allergen Alternaria (Alt). Nuc alone induced anti-inflammatory/defensive genes whereas the Nuc-Alt combo increased TNF and innate cytokines. The Alt-Nuc phenotype was abolished in Cgas-/-, ALR-/-, Sting-/-, LysMCre:Stingf/f, IL7RCre:Rorαf/f and Tnfr2-/- mice. Alt, unexpectedly, played an essential role in the Nuc-induced phenotype. It abrogated Nuc-induction of anti-inflammatory genes, facilitated Nuc uptake, induced ILC2s, which, in presence of Nuc, produced high levels of TNFα and promoted neutrophilic infiltration. We established a paradigm where allergens inhibit the anti-inflammatory effects of DNA/Nuc and facilitate STING-TNFα-driven neutrophilic-eosinophilic inflammation in asthma.

关键词： Cytokines   Genetics   Immunology   Innate immunity   Molecular genetics  

摘要： Loss-of-function (LOF) variants in IL6ST, encoding GP130, can cause hyper-IgE syndrome (HIES). Monoallelic LOF variants in IL6ST lead to HIES when located in the intracellular domain downstream of box 1/2 and upstream of the STAT3 phosphorylation sites and the recycling motif, due to their dominant negative (DN) activity. In this region, two previously unreported IL6ST variants, p.K702Sfs7* and p.Y759Wfs26*, were identified in two families with autosomal dominant (AD) HIES. Both variants were LOF, exhibited DN effects, leading to the accumulation of mutant GP130 on the cell surface. The p.K702Sfs7* mutation was the most upstream N-terminal mutation linked to HIES caused by heterozygous IL6ST variants. Comprehensive screening of IL6ST mutants revealed that most premature terminations downstream of amino acid F641, at the end of the transmembrane domain, resulted in LOF and DN effects via GP130 accumulation on the cell surface. The absence of the recycling motif (positions 782-787) in surface-expressed LOF GP130 led to its accumulation, contributing to the DN effect. The importance of intracellular truncating IL6ST variants can possibly be predicted based on the location of the premature stop codon. GP130 accumulation on the cell surface is a characteristic and potentially diagnostic finding in HIES patients with heterozygous IL6ST variants.

关键词： 非洲猪瘟病毒   单克隆抗体   M1249L蛋白  

摘要： 本研究旨在制备非洲猪瘟病毒（ASFV）M1249L蛋白的单克隆抗体并分析其亚型、灵敏性及反应性。首先对M1249L（673 aa～1249 aa）序列进行密码子优化，并将该片段插入pET-28a载体中，构建原核表达质粒；经过转化、挑取单克隆、诱导表达及蛋白纯化，用纯化后的M1249L截短蛋白免疫小鼠；经细胞融合、有限稀释法筛选分泌抗体的杂交瘤细胞株，进行亚型鉴定和腹水制备。采用蛋白质免疫印迹（Western-blot）和间接免疫荧光试验（IFA）检测该单抗的反应性。结果显示，该单抗1D6重链属于IgG1型，轻链为Kappa型，腹水抗体效价可达1∶1 024 000。Western-blot结果显示，该单克隆抗体能够特异性识别ASFV感染后不同时间点猪肺泡巨噬细胞（PAMs）表达的M1249L蛋白以及HEK 293T细胞转染不同质粒量后表达的M1249L蛋白。IFA结果显示，在ASFV感染的PAMs细胞中出现绿色荧光，表明有良好的反应性。综上所述，本研究成功制备出M1249L单克隆抗体，为后续研究M1249L蛋白的生物学功能和ASFV诊断检测奠定了基础。

关键词： Positive ions  

摘要： Hybrid solid-state electrolytes, which combine ionic liquids with metal-organic frameworks, offer a promising approach to enhancing the safety and energy density of next-generation batteries. A thorough understanding of the interplay between the solid and liquid phases in hybrid solid-state electrolytes is crucial for optimizing their performance as battery electrolytes. This study investigates how interactions between different ionic liquid-based electrolytes and the metal-organic framework ZIF-8 influence the coordination and dynamics of Li+ in confinement. To this end, we examine five different ionic liquids, varying the chemical nature of the cation. Raman spectroscopy, supported by 2D solid-state NMR and simulations, are used to elucidate Li+ coordination and ion-wall interactions. The impact of these interactions on local Li+ dynamics and charge transport in the ionic liquid-ZIF-8 hybrid system is investigated using 7Li spin relaxation, impedance spectroscopy, and simulations. The results reveal a competitive interaction between Li+ and the ionic liquid cation with the ZIF-8 framework, which can be fine-tuned by modifying the molecular structure of the ionic liquid cation. As a consequence, local Li+ dynamics is enhanced, depending on the ionic liquid cation. The beneficial interactions in the confined system can even make Li+ the fastest diffusing species, in contrast to bulk electrolyte, where Li+ transport is limited by strong Li-anion clusters. Thus, blocking Li+-framework interactions through other competitive interactions might be an effective strategy to enhance Li+ dynamics and increase Li conductivity in a hybrid solid-state electrolyte. Although confinement within the ZIF-8 model system leads to an overall decrease in conductivity, this study provides valuable insights into the design of hybrid electrolytes for next-generation battery applications.