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关键词： cytokines   DRESS   drug hypersensitivity   HLA   T-lymphocytes   vancomycin  

摘要： Vancomycin, a glycopeptide antibiotic used to treat severe Gram-positive bacterial infections, is associated with the development of drug reaction with eosinophilia and systemic symptoms (DRESS) in individuals expressing HLA-A*32:01. Previous studies have identified the potential role of T-cells using HLA-A*32:01-positive healthy donor models. However, DRESS pathogenesis remains poorly defined, and a deeper mechanistic understanding is required to aid the diagnosis and prediction of vancomycin-induced DRESS. The present study aims to elucidate CD4+ and CD8+ T-cell involvement within the pathogenesis of vancomycin-induced DRESS following the isolation and functional study of cloned T-cells from hypersensitive patients. CD4+ and CD8+ vancomycin-responsive T-cell clones (TCCs) were generated by serial dilution from peripheral blood mononuclear cells collected from suspected vancomycin-DRESS patients. Functionality of drug-responsive TCCs was assessed using T-cell proliferation ([3H]-thymidine). Cytokine analysis was performed using intracellular cytokine staining, enzyme-linked immunospot assay, and LEGENDplex immunoassays. Vancomycin-responsive TCCs expressing CD4+ and CD8+ phenotypes were successfully generated from suspected vancomycin-DRESS patients (n = 3). CD45RO+ memory T-cells were the primary activated population, with both CD4+ and CD8+ T-cells associated with the release of IFN-gamma, IL-5, IL-13, granzyme B, and perforin. Vancomycin-responsive CD4+ and CD8+ T-cells are activated by direct, pharmacological interactions, with antigen presentation possible through HLA class I and HLA class II molecules. This study provides in vitro evidence for the dual role of antigen-specific CD4+ and CD8+ T-cells within the pathogenesis of vancomycin-induced DRESS. This has been demonstrated following the generation of cloned T-cells with strong vancomycin specificity from patients presenting with vancomycin-DRESS and positive for expression of HLA-A*32:01.

摘要： Glioblastoma (GBM) frequently expresses cytomegalovirus (CMV) antigens, making CMV-specific CD8＋T cells attractive candidates for adoptive immunotherapy due to their longevity and inherent tumor reactivity. However, these T cells encounter significant immunosuppressive challenges within the GBM microenvironment, including cytokine scarcity and checkpointmediated inhibition, which limit their proliferation and function. Here, we assessed strategies to overcome these limitations by modulating immune checkpoint pathways. Antigen stimulation combined with IL-2 robustly expanded high-avidity (tetramer-high) CMV-specific T cells with significant enrichment of CD62L＋ central memory (TCM) cells. In contrast, antigen stimulation alone modestly expanded tetramer-high cells with limited TCM enrichment. PD-L1 blockade in the absence of IL-2 favored expansion of tetramer-high CMV-specific CD8＋T cells, preserved CD62L expression, and enhanced CD226 expression. Furthermore, combining anti-PD-L1 blockade with an anti-CD226 agonist markedly enhanced proliferation, IFN-γ production, and TCM enrichment in both tetramer-high and tetramer-low populations, reaching levels comparable to IL-2-supported conditions. Together, these findings highlight that simultaneous modulation of PD-L1 and CD226 pathways can restore CMV-specific T cell function, offering a promising strategy to boost TCR-T efficacy in cytokine-deprived environments.

关键词： Airway   Allergy   Fibroblast   IL-4   Th2  

摘要： • Airway fibroblasts in allergic asthma (AA) mice demonstrated a 2.3-fold increase in IL-4+ cell proportion (p < 0.01), indicating their dominant role in driving Th2 inflammation compared to CD4+ T cells (24.7 % contribution, p < 0.001). • Fibroblasts upregulated activation markers CD80/CD83/CD86 (p < 0.0001), which correlated with enhanced IL-4-dependent Th2 polarization (30.01 % Teffs vs. 8.89 % with naive fibroblasts, p < 0.0001), suggesting their capacity to amplify allergic responses. • Targeted FbNP therapy reduced pathological fibroblast frequency by 24.6 % and systemic IL-4 levels by 48.83 %, accompanied by significant suppression of Th2 cytokines (IL-5: 46.88 %; IL-13: 50.84 %, all p < 0.001), demonstrating dual anti-inflammatory and immunoregulatory effects. • Clinically, FbNP alleviated asthma symptoms (52–65 % reduction in airway resistance) and improved airway hyperresponsiveness (AHR, 41 % correction, p < 0.01), with sustained therapeutic efficacy for 14 days and no detectable toxicity.

关键词： 前列腺癌   多溴蛋白1   CD8   T淋巴细胞   CD4   T淋巴细胞   免疫逃逸   预后   靶向治疗   病理特征  

摘要： 目的 探讨前列腺癌组织中多溴蛋白1（PBRM1）的表达情况及其与CD8+T淋巴细胞浸润的相关性。方法 选取124例前列腺癌患者纳入观察组,另选取同期80例前列腺良性肿瘤患者纳入对照组。分别采用免疫组织化学染色法（免疫组化法）、实时荧光定量聚合酶链反应（qRT-PCR）及蛋白质印迹法（Western blot）检测2组患者肿瘤组织及观察组肿瘤邻近正常组织中PBRM1表达情况,并采用流式细胞术检测组织中CD8+和CD4+T淋巴细胞浸润情况。结果 观察组肿瘤组织中PBRM1阳性表达率为59.68%,低于对照组的85.00%和观察组肿瘤邻近正常组织的81.45%,差异有统计学意义（P<0.001）;观察组肿瘤组织中PBRM1 mRNA和PBRM1蛋白相对表达量以及CD8+T淋巴细胞浸润百分比均低于对照组肿瘤组织、观察组肿瘤邻近正常组织,差异有统计学意义（P<0.05）。Pearson相关分析结果显示,肿瘤组织中PBRM1蛋白相对表达量与CD8+T淋巴细胞浸润百分比呈正相关（r=0.856,P<0.001）。观察组中,肿瘤最大径≥3cm、低分化、临床分期Ⅲ～Ⅳ期、Gleason评分≥8分、前列腺特异性抗原（PSA）≥20ng/mL患者的PBRM1蛋白相对表达量分别低于最大径<3cm、中高分化、临床分期Ⅰ～Ⅱ期、Gleason评分<8分、PSA<20ng/mL患者,差异有统计学意义（P<0.05）。结论 前列腺癌组织中PBRM1表达下调可能与肿瘤恶性程度增加及CD8+T淋巴细胞浸润减少相关,进而增强了肿瘤的免疫逃逸能力。

关键词： 骨骼肌   骨骼肌再生   卫星细胞   细胞因子   运动   修复   炎症   综述  

摘要： 背景：卫星细胞和骨骼肌再生密切相关，当骨骼肌受到损伤或刺激时，卫星细胞能够迅速被激活并参与骨骼肌的修复过程。卫星细胞受到细胞因子的调控，而且研究表明运动能够促进卫星细胞的增殖和分化，但目前尚不清楚运动是否能够与细胞因子共同作用于卫星细胞促进骨骼肌修复。目的：综述细胞因子和运动对卫星细胞的调控作用，为肌肉疾病的治疗和康复提供新的思路和潜在的干预目标。方法：第一作者和通讯作者于2023-12-01/2024-02-01检索Web of Science、PubMed、中国知网、万方、维普等数据库，检索文献时限为各数据库建库至2024年2月。英文检索词为“skeletal muscle regeneration,satellite cells,cytokines in muscle repair,exercise,muscle stem cells,inflammation and repair”，中文检索词为“骨骼肌，卫星细胞，细胞因子，运动，肌肉再生，肌肉干细胞，炎症和修复”。最终严格按照纳入和排除标准筛选，共纳入76篇文献。结果与结论：(1)细胞因子在卫星细胞激活中的作用：在骨骼肌损伤后迅速激活卫星细胞，白细胞介素6促进卫星细胞增殖和迁移，从而加速肌肉的修复。肿瘤坏死因子α通过调控细胞凋亡和增殖通路，参与卫星细胞的分化和功能调节。干扰素γ则在炎症反应中发挥重要作用，调控卫星细胞参与肌肉损伤修复的免疫反应。(2)运动对细胞因子表达的调控作用：耐力运动和抗阻训练能够显著增加血液循环中白细胞介素6和肿瘤坏死因子α水平，进而可能促进卫星细胞的活化，参与骨骼肌再生过程。此外，运动还能增加骨骼肌分泌肌肉特异性蛋白(如肌肉生长抑制素、鸢尾素和胰岛素样生长因子1)，这些因子对卫星细胞的增殖和肌肉再生具有重要调控作用。(3)未来研究的方向与展望：尽管已有研究揭示了多种细胞因子在卫星细胞调控中的关键作用，但相关机制仍需进一步深入探索，未来的研究可以通过整合多组学和生物信息学方法，深入解析不同细胞因子在运动促进骨骼肌损伤修复中的交互作用网络，以优化运动介入策略并提高骨骼肌再生的效率和质量。

关键词： 浣熊眼   免疫球蛋白轻链淀粉样变性   眶周紫癜  

摘要： 目的　报告1例以“浣熊眼”为特征的免疫球蛋白轻链（AL）淀粉样变性患者的临床资料并文献复习，探讨其典型的病情特征、诊断与治疗，以提高临床医师对该病的认识及诊治水平。方法　报告了1名63岁男性AL淀粉样变性患者的浣熊眼征，并分析该患者临床表现。检索PubMed数据库相关病例报道并进行文献复习，重点总结AL淀粉样变性伴罕见的眶周紫癜的患者的临床表现和治疗预后。结果　从PubMed数据库共检索到15例以“浣熊眼”为特征的AL淀粉样变性患者，结合我们报道的1例，共16例患者纳入分析。其中，男8例，女8例，男性平均年龄为63.7±7.2岁，女性平均年龄为67.8±8.2岁。在16例患者中，有9例出现肾脏受累，8例出现心脏受累。肾脏受累表现为蛋白尿和/或出现肾功能受损。心脏受累主要表现为左心室肥厚及早期N端脑钠肽前体的升高。此外，有些患者还有肝脏、肺脏、神经系统受累和巨舌表现。AL淀粉样变性还可能会出现非特异症状，主要表现为乏力和无意识的体重减轻。有5例患者在出现浣熊眼征之后几个月内死亡。结论　当患者出现“浣熊眼”这一典型症状，临床医师要警惕AL型淀粉样变性的可能，尽快明确诊断和治疗。

关键词： 少弱畸形精子症   温针灸   左卡尼汀   针药结合   肾阳不足   白细胞介素-6(IL-6)   白细胞介素-10(IL-10)   随机对照试验  

摘要： 目的：观察温针灸联合西药治疗肾阳不足型少弱畸形精子症的临床疗效及对精浆白细胞介素-6（IL-6）、白细胞介素-10（IL-10）含量的影响。方法：将60例肾阳不足型少弱畸形精子症患者随机分为针药组和西药组，每组30例。西药组予口服左卡尼汀口服溶液治疗，每次10 mL，每日3次；针药组在西药组基础上联合温针灸治疗，穴取百会、关元、命门，隔日1次，每周3次。两组均治疗12周。分别于治疗前后观察两组患者中医证候积分，检测精液常规指标[精子浓度、前向运动（PR）精子活力、PR+非前向运动（NP）精子活力、精子畸形率]、血清性激素指标[卵泡刺激素（FSH）、促黄体生成素（LH）、睾酮（T）、雌二醇(E2)]及精浆白细胞介素-6（IL-6）、白细胞介素-10（IL-10）含量，并于治疗后评定临床疗效。结果：治疗后，除西药组性欲减退积分外，两组患者各项中医证候积分及总分较治疗前降低（P＜0.01，P＜0.05），精子畸形率、血清FSH和LH含量、精浆IL-6含量较治疗前降低（P＜0.01，P＜0.05），PR精子活力和PR+NP精子活力、血清T含量、精浆IL-10含量较治疗前升高（P<0.01，P<0.05）；针药组患者精子浓度较治疗前升高（P<0.01）。治疗后，除性欲减退和夜尿频数积分外，针药组患者各项中医证候积分及总分低于西药组（P＜0.01，P＜0.05）；精子浓度、PR精子活力和PR+NP精子活力、血清T含量、精浆IL-10含量高于西药组（P<0.01，P＜0.05）；精子畸形率、血清FSH和LH含量、精浆IL-6含量低于西药组（P<0.01，P＜0.05）。针药组总有效率为83.3%（25/30），高于西药组60.0%（18/30，P<0.05）。结论：温针灸联合西药可有效治疗肾阳不足型少弱畸形精子症，平衡性激素水平，其机制可能与降低精浆IL-6含量、提高精浆IL-10含量有关。

关键词： Triple-negative breast cancer   MHC-II   Anthracycline exemption   Immunotherapy   KAT2B  

摘要： BackgroundAnthracycline-based chemotherapy, while foundational in breast cancer treatment, confers substantial cardiotoxicity. Identifying biomarkers to guide anthracycline exemption without compromising efficacy has remained an unresolved clinical challenge for *** conducted multi-cohort spatial-omics and clinical validation integrating 345 early-stage triple-negative breast cancer (eTNBC) and 167 HER2 + breast cancer patients from Fudan University Shanghai Cancer Center (FUSCC) cohorts, alongside 150 eTNBC patients from a validation cohort. Tumor-specific MHC-II (tsMHC-II) expression was quantified via multiplex immunohistochemistry (mIHC). Mechanistic insights were derived from the NeoTRIP immunotherapy spatial cohort, I-SPY2 trial data, TCGA database, ATAC-seq chromatin profiling, ChIP, and patient-derived organoid (PDO)-immune cell co-culture *** eTNBC, high tsMHC-II expression predicted improved disease-free survival (DFS) and comparable overall survival (OS) with paclitaxel-carboplatin (PCb) versus anthracycline-sequential paclitaxel (EC-P), identifying tsMHC-II as a predictive marker for anthracycline exemption. High tsMHC-II correlated with prolonged DFS and OS in both TNBC and HER2 + subtypes. Multi-omics including spatial and transcriptional cohorts revealed tsMHC-II-high tumors harbor immune-rich microenvironments with elevated cytotoxic T cells, B cells, and antigen-presenting cells. Validation in NeoTRIP and I-SPY2 cohorts demonstrated superior immunotherapy response in tsMHC-II-high patients. Mechanistically, ATAC-seq, ChIP and PDO co-culture models confirmed that KAT2B upregulated tsMHC-II via CIITA promoter acetylation, sustaining immunotherapeutic ***-II serves as a dual biomarker for adjuvant anthracycline chemotherapy exemption and neoadjuvant immunotherapy stratification in TNBC, driven by KAT2B-mediated epigenetic remodeling. These findings advance precision strategies to reduce anthracyclin