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关键词： MHC class II   antigen presentation   ubiquitination  

摘要： MHC class II glycoproteins (MHC-II) bind peptides derived from exogenous antigens and dendritic cells (DCs) present these peptide MHC-II (pMHC-II) complexes to antigen-specific CD4 T cells during immune responses. The turnover of surface pMHC-II on antigen-presenting cells (APCs) is controlled by ubiquitin-mediated degradation of pMHC-II by the E3 ubiquitin ligase March-I. To study March-I protein expression, we have generated a mouse in which a V5 epitope-tag was knocked-in to the endogenous March-I gene, thereby allowing us to follow the fate of March-I using high-affinity anti-V5 antibodies. Quantitative analysis revealed that resting spleen DCs and B cells express only similar to 500 and 125 March-I molecules/cell, respectively. Endogenous March-I protein has a very short half-life in DCs and March-I mRNA, March-I protein, and MHC-II ubiquitination are rapidly terminated upon activation of both DCs and B cells. Like March-I, CD83 is a known regulator of MHC-II expression in APCs and we also show that CD83 suppresses endogenous March-I-dependent MHC-II ubiquitination, endocytosis, and degradation in mouse spleen DCs. Thus, our study reveals molecular mechanisms for both March-I- and CD83-dependent regulation of MHC-II expression in APCs.

关键词： 类风湿关节炎   白介素-35   骨代谢指标   早期应用  

摘要： 目的 探讨白介素-35(IL-35)与骨代谢四项指标在类风湿关节炎(RA)早期的应用前景,以期为RA的早期诊断和治疗提供新的生物标志物。方法 选择100例类风湿关节炎患者(观察组)和100例健康体检者(对照组)的临床数据,记录所有研究对象的血清白介素-35(IL-35)水平及骨代谢标志物水平,包括血清骨钙素N端中分子(N-MID)、总I型胶原氨基端延长肽(TPINP)、β-胶原降解产物(β-CTX)及25-羟基维生素D(25-OHVD),并比较两组之间的差异。结果 观察组的IL-35、NMID、TPINP、25-OHVD水平均低于健康对照组,β-CTX水平高于健康对照组,差异均具有统计学意义(P<0.05);根据DAS28(28关节疾病活动)评分对患者进行分组后,发现对照组、缓解组、活动组的IL-35、N-MID、TPINP、25-OHVD水平依次降低,β-CTX水平依次升高(P<0.05);IL-35水平与骨代谢标志物之间存在相关性(P<0.05),且IL-35水平的降低与RA早期骨质流失密切相关。结论IL-35在RA早期病程监测中具有潜在的应用价值,其与骨代谢指标的联合检测可为RA的早期诊断提供重要的参考依据。

关键词： Multiple myeloma   Visfatin   Apoptosis   Interleukin-6   Nuclear factor kappa-B  

摘要： BackgroundMultiple myeloma (MM) is the second most prevalent hematological malignancy that results in the proliferation of malignant plasma cells and the overproduction of monoclonal immunoglobulin. Visfatin plays an important role in the regulation of apoptosis, oxidative stress, and inflammation;however, to this date, the role of visfatin in multiple myeloma is *** explore the role of visfatin in multiple myeloma and find new targets for MM *** this study, expression of visfatin in bone marrow was detected by ELISA. The diagnostic value of visfatin was determined by receiver operating characteristic (ROC) curve analysis. After the quality control by performing western blot to confirm the knockdown of visfatin in two MM cell lines, the phenotype (proliferation and apoptosis) of visfatin in MM was determined by carrying out in vitro experiments, including CCK8, flow cytometry, and western blot. Several cytokines were determined by real-time PCR, followed by in vivo experiments and immunohistochemical assays. I kappa B, NF-kappa bp65, and phosphorylation were determined by western *** found that visfatin level increased in the bone marrow of MM patients compared to controls. ROC curve analysis result showed that bone marrow visfatin was able to distinguish MM patients from controls. In vitro and in vivo, visfatin promotes MM cell proliferation. The production of IL-6 was attenuated by visfatin knockdown. Furthermore, we showed that visfatin could activate IL-6 production via the NF-kappa B signaling *** MM, visfatin promotes tumor progression by upregulating IL-6 production, which may be a novel therapeutic target for the treatment of MM patients.

关键词： 羊痘病毒   122蛋白   多克隆抗体   胶体金试纸条  

摘要： 旨在建立一种快速、简便、特异、灵敏的羊痘病毒抗体的通用型胶体金检测方法。通过原核表达、纯化获得羊痘病毒122重组蛋白，并制备122蛋白多克隆抗体。将122蛋白与胶体金偶联，作为金标抗原，再将122蛋白及兔多克隆抗体包被在硝酸纤维素膜（NC）上，分别作为检测线（T线）和质控线（C线），经条件优化，研制成检测羊痘病毒抗体的胶体金免疫层析试纸条。结果表明，成功获得122重组蛋白，大小约为32 ku，胶体金试纸条可在12 min特异性检测到羊痘病毒抗体；与其他常见家畜疫病病原阳性血清无交叉反应；检测SPPV、LSDV和GTPV阳性血清的灵敏度分别为1:64、1:128和1:128，与市售羊痘抗体间接ELISA诊断试剂盒（效价1:128、1:256和1:256）的敏感性相当；对130份临床血清样品的检测与商品化试剂盒检测结果进行比较，两者的kappa值为0.93，为高度一致。本研究成功研制了羊痘病毒抗体通用型胶体金免疫层析试纸条，具有较高的敏感性和特异性，且具有成本低、检测快速、操作简便、结果容易判断等特点，对羊痘现场检测具有实际应用价值。

关键词： CAST/EiJ mice   IFN-α/β   monkeypox virus   rhesus macaques   splenomegaly   STING  

摘要： The recent mpox outbreak underscores the urgent need for more accessible vaccines and treatments. However, the mpox virus (MPXV) clade IIb exhibits milder virulence and fails to develop typical pathological characteristics in mouse models. Herein, we found that CAST/EiJ mice infected intraperitoneally with MPXV clade IIb exhibited more efficient viral replication and experienced splenomegaly. Additionally, MPXV infection triggers the phosphorylation of stimulator of interferon genes (STING), TANK-binding kinase 1 (TBK1), and interferon regulatory factor 3 (IRF3) in ex vivo bone marrow-derived macrophages from mice and promotes the transcription of interferon (IFN)-β via the cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS)-STING pathway. Notably, IFN-β treatment significantly reduced viral replication and alleviated splenomegaly in MPXV-infected CAST/EiJ mice. In rhesus macaques, the clinically approved pegylated IFN alpha-2b treatment markedly reduced the severity of MPXV infection by alleviating skin lesions and lowering plasma viremia. These findings demonstrate that MPXV clade IIb activates the cGAS-STING pathway and highlight the potential of type I interferon (IFN-I) treatment in CAST/EiJ mice and rhesus macaques for mpox. © 2025 The Author(s)

关键词： 大剂量甲氨蝶呤   急性淋巴细胞白血病   碱性磷酸酶   骨代谢   排泄延迟  

摘要： 目的：探讨大剂量甲氨蝶呤（MTX）对碱性磷酸酶（ALP）的影响、ALP的变化对骨骼代谢、骨髓粒系功能、肝功能及排泄的影响。方法：对某儿童医院血液肿瘤科2022年1月至2024年3月收治的急性淋巴细胞白血病（acute lymphoblastic leukemia，ALL）患儿巩固化疗前后生化、电解质、血常规指标及甲氨蝶呤C48h血液浓度进行回顾性分析，以天门冬氨酸转氨酶（AST）、丙氨酸转氨酶（ALT）、白蛋白（ALB）为肝功指标，血清钙（Ca）、磷（P）为骨代谢指标，中性粒细胞（ANC）、白细胞计数（WBC）为骨髓粒系功能观测指标，以甲氨蝶呤C48h浓度≥1 μmol/L为排泄延迟；对首次化疗、再次化疗前后ALP水平进行单因素方差分析，按ALP水平将再次化疗患儿分成正常组及低下组，对化疗前后7项指标进行定量及定性分析，并对再次化疗患儿甲氨蝶呤C48h浓度与上述指标进行单因素及多因素Logistic回归分析。结果：首次化疗、再次化疗后，ALP明显降低（204.0±83.6 vs. 172.8±67.3，179.4±59.3 vs. 169.6±57.1，P均<0.05），ALP低下患儿再次化疗后，血清Ca、P、ANC、WBC、ALB均明显降低（P<0.05），AST、ALT升高（P<0.05）；ALT是排泄延迟独立危险因素（OR=1.049，95%CI 1.023-1.077，P<0.001），ALB为排泄延迟独立保护因素（OR=0.551，95%CI 0.460-0.660，P<0.001），ALP不是MTX排泄延迟的显著影响因素。结论：大剂量MTX导致ALP显著下降，伴随整个巩固化疗过程，ALP不是一个良好的肝功及骨髓粒系功能的预测指标，ALP连同血清钙磷水平可以构成骨代谢障碍的一个预警指标，ALL患儿接受MTX巩固化疗期间，可适量补充钙剂。

关键词： 金黄色葡萄球菌   奶牛骨髓源巨噬细胞   PGE   脂蛋白   细胞因子  

摘要： 金黄色葡萄球菌（Staphylococcus aureus，S aureus）在侵入哺乳动物体内时会引起宿主炎症反应，但金葡菌脂蛋白对细胞因子的释放以及PGE2的合成是否具有影响目前尚不明确。本研究使用金黄色葡萄球菌SA113及其脂蛋白缺失菌株和回复菌株感染奶牛骨髓源巨噬细胞后，探究金黄色葡萄球菌脂蛋白在诱导免疫细胞炎症介质及PGE2的分泌合成中的作用机制。试验结果表明，与SA113感染组相比，金葡菌敲除株Δlgt感染奶牛骨髓源巨噬细胞后PGE2分泌水平发生显著下降，同时促炎性细胞因子（TNF-α和IL-1β）和抗炎因子（IL-10）的分泌水平均发生显著下降。Western blot结果表明，金黄色葡萄球菌脂蛋白对巨噬细胞NF-κB/MAPK通路激活以及PGE2合成酶COX-2和mPGES-1的表达具有影响。此外，金黄色葡萄球菌脂蛋白缺失后巨噬细胞中TLR2、TLR4和NLRP3基因表达水平发生显著降低。综上所述，在金葡菌感染过程中，金葡菌脂蛋白对巨噬细胞炎症信号通路的激活，所介导的炎症介质的分泌具有重要作用，且与PGE2的合成与分泌存在紧密联系。该研究可为兽医临床应用前列腺素合成酶抑制剂和非甾体抗炎药防治金葡菌感染性疾病提供理一定的理论依据。

关键词： Centipeda minima (CMX)   brevilin A   tumor necrosis factor-alpha (TNF-alpha)   oxidative stress   extracellular matrix (ECM)   skin aging   inflammation  

摘要： Skin aging and inflammatory skin lesions are exacerbated by reactive oxygen species (ROS) generated in the mitochondria of human dermal fibroblasts (HDFs). These oxidative stressors degrade the extracellular matrix (ECM), promote inflammation, and accelerate skin aging. Antioxidants that suppress reactive oxygen species (ROS) production play a crucial role in mitigating these effects. This study investigated the protective effects of Centipeda minima (CMX) and its active constituent, brevilin A, against tumor necrosis factor-alpha (TNF-alpha)-induced oxidative stress and ECM degradation in normal human dermal fibroblasts (NHDFs). Both CMX and brevilin A significantly inhibited TNF-alpha-induced elevations in ROS, nitric oxide (NO), and prostaglandin E2 (PGE2) levels, thereby reducing oxidative stress and inflammatory responses. Additionally, they effectively suppressed matrix metalloproteinase-1 (MMP-1) expression and restored the procollagen I alpha 1 (COLIA1) levels, indicating their potential to preserve ECM integrity. Mechanistically, brevilin A selectively inhibited ERK phosphorylation in the mitogen-activated protein kinase (MAPK) pathway, suggesting its role in regulating collagen degradation and inflammation. These findings highlight that CMX and brevilin A are promising natural agents for protection against skin aging and inflammation. However, further in vivo studies are necessary to validate their efficacy and explore their potential applications in dermatological formulations.

关键词： cGAS   STING   inflammasome   NLRP3   IFN  

摘要： Over the past decade, inflammasome and cGAS-STING have received significant attention as immune components that coordinate host immune homeostasis. Although the inflammasome and cGAS-STING are relatively independent immune signaling pathways, some studies have pointed out that there is an important association between cGAS-STING and the inflammasome. As the downstream of cGAS-STING, inflammasome plays an important role in many diseases. In this mini-review, we review the association between CGAS-STING and NLRP3 inflammasome, the progression of the cGAS/STING/NLRP3 signaling pathway in the pathogenesis of disease, the therapeutic strategies that targeted cGAS/STING/NLRP3 signaling pathway. We believe that targeting the cGAS/STING/NLRP3 signaling pathway in the future has broad prospects and significance for the treatment of disease.

关键词： Autoimmune diseases   Autoimmunity   Cellular immune response   Immunology   T cells  

摘要： Dysregulation of T follicular helper (Tfh) and T follicular regulatory (Tfr) cell homeostasis in germinal centers (GCs) can lead to antibody-mediated autoimmunity. While interleukin-1β (IL-1β) modulates the GC response via IL-1R1 and IL-1R2 receptors on follicular T cells in animal models, its role in humans remains unclear. We analyzed Tfh and Tfr phenotypes in human secondary lymphoid organs (tonsils, spleen, and mesenteric lymph nodes) using flow cytometry, single-cell transcriptomics, and in vitro culture, comparing findings with samples from autoimmune patients. We observed organ-specific Tfh/Tfr phenotypes according to activation status and IL-1 receptor expression. An excess of IL-1R1 over IL-1R2 expression promoted a unique activated Tfr subset with Treg and GC-Tfh features. IL-1β signaling via IL-1R1 enhanced follicular T-cell activation and Tfh-to-Tfr differentiation, while IL-1β inhibition upregulated IL-1R1, indicating a tightly regulated process. In autoimmune patients, high IL-1β and circulating Tfr levels correlated with increased autoantibody production, linking inflammation, IL-1β signaling, and Tfr/Tfh balance. Our findings highlight the critical role of IL-1β in follicular T-cell activation and suggest that targeting IL-1β signaling in Tfh and Tfr cells could be a promising strategy for treating antibody-mediated autoimmune diseases.