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关键词： ACOT11   macrophage   fatty acid   IFNGR2   palmitoylation  

摘要： Fatty acid metabolism mediates macrophage function;however, the underlying mechanism by which fatty acid metabolism regulates macrophage interleukin (IL)-1 beta production remains to be uncovered. Here, we used genome-wide association studies (GWAS) to identify several porcine serum IL-1 beta-related genes, such as the fatty acid metabolizing enzyme acyl-CoA thioesterase 11 (ACOT11). We then demonstrated that inflammatory macrophages have low expression of ACOT11, and ACOT11 overexpression inhibits IL-1 beta maturation from inflammatory macrophages. Mechanistically, ACOT11 promotes intracellular fatty acids accumulation, including eicosatetraenoic acid (EA) and stearic acid (SA), which inhibit activation of the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) signaling through palmitoylation of interferon (IFN)-gamma receptor (IFNGR) 2 at C261site. Furthermore, we also found that EA attenuates lipopolysaccharide (LPS)-induced sepsis in mice. Collectively, our findings reveal a mechanism involving ACOT11-mediated post-translational modification that regulates macrophage function and provide a promising therapeutic target for the treatment of inflammatory diseases associated with macrophages.

关键词： 白血病   髓样   急性   嵌合抗原受体T细胞   分子靶向治疗  

摘要： 急性髓系白血病（AML）是成年人最常见的急性白血病，联合化疗序贯造血干细胞移植是其首选治疗方案。虽然嵌合抗原受体T细胞作为一种快速发展的细胞治疗方法，但目前暂无用于治疗AML的上市嵌合抗原受体T细胞产品。文章综述嵌合抗原受体T细胞治疗AML的研究进展。

摘要： OBJECTIVES:Rheumatoid arthritis (RA) is a complex, multifactorial autoimmune disease, whose aetiopathogenesis involves genetic and environmental factors. The aim of this case-control study is to confirm the impact of interaction of genetic and environmental factors in the pathogenesis of RA in Greek smoker and non-smoker patients. METHODS:We assessed the effects of shared epitope (SE) alleles and smoking on the presence of ACPA autoimmunity in three hundred Greek patients with longstanding RA (150 smokers and 150 non-smokers). Three hundred and forty-six Greek blood donors volunteers and hospital personnel served as controls. RESULTS:An increased frequency of HLA-DRB1 *01:01, *10:01, *04:04 and *04:05 alleles, as well as the protective role of *04:03 allele in Greek patients were confirmed during comparison with controls. The presence of any SE influenced the development of RA (OR: 4.37[3.13-6.11], p<0.001). A strong effect for ACPA production was observed in individuals carrying any SE allele (OR: 4.3[2.57-7.22], p<0.001). Single SE carriers in combination with smoking had an increased risk of developing ACPA-positive RA (OR: 6.53[1.47-28.91], p=0.013), which further increased in smokers with a double gene copy (OR: 15.27[1.39-167.52], p=0.026). The strongest interaction, with regard to ACPA-positive RA, was observed in individuals that possessed the HLA-DRB1 *01:01 (OR: 12.55[1.32-119.35], p=0.028) SE allele, whereas the combination of SE genes and smoking did not influence the risk of ACPA-negative RA (OR: 2.01[0.76-5.26], p=0.15). CONCLUSIONS:We identified that smoking and the presence of SE alleles increased the risk of developing ACPA-positive RA, indicating a strong genetic-environmental correlation that probably triggers the pathogenesis of RA in Greek patients.

关键词： Cyclosporin A   Influenza A virus   Lymphocytes   Chronic pulmonary inflammation   Interferon-gamma  

摘要： Influenza causes 3-5 million severe cases globally each year, with severe viral pneumonia often requiring hospitalization for over four weeks. While the inflammatory response to influenza infection helps control viral replication, excessive inflammation is a key driver of disease severity and mortality. Excessive pulmonary lymphocytes, particularly IFN-gamma-producing T lymphocytes, contribute significantly to pulmonary inflammation at the late-stage of H1N1 viral infection. Cyclosporin A, a potent T-cell inhibitor, mitigates influenza A virus-induced pulmonary inflammation in mice. However, the therapeutic role of lymphocyte suppression in cyclosporin A-mediated attenuation of H1N1 virus-induced chronic pulmonary inflammation remains unclear. Here, we demonstrated that the viral titer was 0 in all the homogenized lung tissues of mice on Day-21 post a sublethal H1N1 viral infection. H1N1 viral infection caused worsened general condition and pulmonary inflammation with the infiltration of lymphocytes and neutrophils on Day-21 post-infection. The bronchoalveolar lavage fluid of H1N1 virus-infected mice showed a 16-fold higher lymphocyte count compared to neutrophils. H1N1 viral infection significantly elevated both IFN-gamma-producing T lymphocyte populations and IFN-gamma levels in mouse lungs. H1N1 viral infection additionally expanded IFN-gamma-producing T lymphocyte populations in both spleen and peripheral blood. Cyclosporin A treatment significantly mitigated H1N1 viral infection-induced worsened general condition, pulmonary lymphocytic inflammation, increases of pulmonary IFN-gamma concentrations and IFN-gamma-producing T lymphocytes in the lung, spleen and blood of mice on Day-21 post-infection. Together, lymphocytes may contribute significantly to H1N1 virus-induced chronic pulmonary inflammation. Cyclosporin A may alleviate H1N1 virus-induced chronic pulmonary inflammation through decreasing IFN-gamma-producing T lymphocytes.

关键词： Ovarian cancer   FCGBP   IL-6   Cell proliferation   Therapeutic target  

摘要： BackgroundOvarian cancer is among the deadliest gynecological malignancies, primarily due to late-stage diagnosis and poor prognosis. Novel biomarkers and therapeutic targets are urgently needed to enhance early detection and treatment efficacy. Fc fragment of IgG-binding protein (FCGBP), a mucin-like glycoprotein, has been associated with various cancers, but its specific role in ovarian cancer progression has not been well-defined. This study aimed to investigate the clinical relevance, functional role, and underlying mechanisms of FCGBP in ovarian cancer *** expression profiles from multiple public datasets were analyzed to identify differentially expressed genes. Weighted gene co-expression network analysis was performed to correlate FCGBP expression with clinical traits. Single-cell RNA sequencing and pseudotime trajectory analyses were used to examine FCGBP expression dynamics. FCGBP expression was validated in ovarian cancer tissues using quantitative PCR, western blotting, and immunohistochemistry. Functional assays, including proliferation, migration, invasion, and colony formation, were conducted in SKOV3 and ES-2 ovarian cancer cell lines with FCGBP knockdown. The molecular mechanism was explored using dual-luciferase reporter assays and co-immunoprecipitation. Enzyme-linked immunosorbent assays and western blotting assessed cytokine levels and pathway activation. An in vivo xenograft mouse model was used to evaluate tumorigenic *** expression was significantly elevated in ovarian cancer tissues and correlated with advanced tumor stage and poor prognosis. Single-cell analysis showed FCGBP expression peaked in terminally differentiated epithelial cancer cells. Silencing FCGBP significantly reduced proliferation, migration, invasion, and colony formation in vitro, and suppressed tumor growth and improved survival in vivo. Mechanistically, FCGBP enhanced interleukin-6 expression by interacting with NF-kappaB subunit p65,

关键词： 猪繁殖与呼吸综合征病毒   N蛋白   单克隆抗体   抗原表位  

摘要： 旨在制备猪繁殖与呼吸综合征病毒（PRRSV）N蛋白单克隆抗体（mAb）及解析其抗原表位。本研究以原核表达的重组蛋白His-GFP-N为抗原免疫BALB/c鼠，利用间接ELISA筛选获得一株分泌N蛋白抗体的杂交瘤细胞（1F8）。MAb 1F8的亚类为IgG1，轻链是κ链，腹水ELISA效价为1:109。IFA显示mAb 1F8能特异性识别PRRSV，Western blot试验表明该mAb能与I型和II型PRRSV N蛋白发生反应。通过对逐步截短表达的N蛋白进行Western blot鉴定，最终确定mAb 1F8识别的核心抗原表位为52KPH54，是一个超短且高度保守抗原表位。本研究为后续研究提供了必要的抗体试剂，也证明了B细胞抗原表位可以短至3个氨基酸。

关键词： Inborn Error of Immunity   Immune dysregulation   T cell dysregulation   primary immune dysregulatory disease   PIRD   Inflammatory disease   MAP4K1   HPK1   IFN-γ–mediated inflammation in IEI   TNF–mediated inflammation in IEI   SLP-76 phosphorylation   regulation of TCR-signaling   B-ALL   B cell acute lymphoblastic leukemia   EBV   Epstein–Barr virus   ERK   Extracellular-signal-regulated kinase   GO   Gene Ontology   HLH   hemophagocytic lymphohistiocytosis   HPK1   Hematopoietic progenitor kinase 1   IEI   Inborn Error of Immunity   IFN-γ   interferon gamma   IL   interleukin   KEGG   Kyoto Encyclopedia of Genes and Genomes   KO   knockout   LAT   Linker for activation of T cells   LDH   lactate dehydrogenase   LOD   logarithm of odds   LOF   loss-of-function   MFI   mean fluorescence intensity   NF-κB   Nuclear factor kappa-light-chain-enhancer of activated B cells   PBMC   peripheral blood mononuclear cell   PLC-γ1   Phospholipase C-gamma-1   SLP-76   Src Homology 2 domain-containing leukocyte protein of 76 kDa   TCR   T cell receptor   Th1   T helper 1   TNF   tumor necrosis factor   WES   whole exome sequencing   ZAP70   Zeta chain of T cell receptor associated protein kinase 70  

摘要： Background MAP4K1 encodes Hematopoietic Progenitor Kinase 1 (HPK1), a serine/threonine kinase that negatively regulates T cell receptor (TCR) signaling via phosphorylation of the adaptor proteins SLP-76 and Gads. While common MAP4K1 variants have been implicated in polygenic immune-mediated diseases, the impact of rare germline variants on human immunity remains undefined. Objective To investigate the immunological and functional consequences of HPK1 deficiency in individuals with suspected Inborn Errors of Immunity (IEI). Methods We performed genomic linkage analysis and exome sequencing to identify disease-associated variants in IEI patients. Immunophenotyping, RNA-sequencing and functional assays were conducted on patient-derived lymphocytes, complemented by CRISPR-Cas9-mediated MAP4K1 disruption and correction in primary T cells. Results Heterozygous MAP4K1 loss-of-function variants were identified in two kindreds presenting with diverse immune dysregulatory symptoms, including recurrent fevers, inflammatory arthritis, EBV-related complications, and nephritis. These variants led to reduced HPK1 protein levels and SLP-76 Ser376 phosphorylation. While lymphocyte development was largely preserved, T cells from HPK1-deficient individuals displayed hyperresponsiveness to TCR stimulation, characterized by elevated secretion of proinflammatory cytokines, particularly interferon-γ (IFN-γ) and tumor necrosis factor (TNF). CRISPR-mediated knockout recapitulated, and variant-correction partially reversed this phenotype. Transcriptomic profiling of stimulated CD4 + T cells further revealed upregulation of immune signaling pathways—including NF-κB, JAK/STAT, and AP-1—as well as increased expression of multiple T cell cytokines, consistent with enhanced TCR signaling and T cell responses in HPK1-deficient individuals. Conclusion HPK1 deficiency, caused by heterozygous loss of MAP4K1 , is a novel monogenic cause of immune dysregulation. Increased T cell activation and pro-infl

关键词： HMGB-1   S100A8   acute lymphoblastic leukemia   fever   inflammatory cytokines   systemic inflammatory response syndrome  

摘要： In acute lymphoblastic leukemia (ALL), neutropenia and fever of unknown origin may occur, indicating the use of antimicrobials to control a probable infection. However, in 60-70% of cases there is no obvious infectious focus so treatment is empirical, increasing the risk of developing systemic inflammatory response syndrome (SIRS). The construction of a prognostic model of fever and development of SIRS based on the identification of endogenous molecules, called alarmins or damage-associated molecular patterns (DAMPs) and inflammatory cytokines, can help identify children with ALL and fever or SIRS and who do not have an infection. A cohort of 30 children with recently diagnosed ALL and absence of infectious microorganisms before starting the remission induction phase was studied. Two groups were identified: (1) a group with SIRS (fever, tachycardia, tachypnea, and leukopenia, without focus of infection) and (2) a group without SIRS. The DAMPs, namely HMGB1 and S100A8 proteins, were quantified by ELISA and inflammatory mediators were determined by multiple protein analysis. The medians of DAMPs and inflammatory mediators in children with SIRS were higher than in children who did not have SIRS, and the delta values of the biomarkers studied in patients with and without SIRS showed important differences, with statistically higher medians in patients with SIRS compared to those without SIRS. HMGB1 together with IL-1β, IL-8, IL-10, and MCP-1 can serve as biomarkers to identify children with ALL and fever or SIRS who should not receive antimicrobial treatment because the origin of their fever is not due to an infectious agent.

关键词： Chaihu-Shugan-San   Breast cancer   Depression   Microglia   IL-17/ NF-kappa B pathway  

摘要： Background: Breast cancer-related depression (BCRD) is one of the severest comorbidities, affecting the quality of life and the treatment efficacy in BC patients. Chaihu-Shugan-San (CSS), a traditional Chinese medicine presents a potential therapeutic method in BCRD. Purpose: The main purpose of the research was to investigate the effects of CSS on BCRD in a mouse model and to elucidate its mechanisms, particularly its impact on microglial polarization through the IL-17/ NF-kappa B pathway. Methods: A mouse BCRD model was constructed and treated with CSS. Behavioral testing, biochemical parameters, H&E staining, and small animal imaging were used to assess the depressive-like behaviors and tumor growth in mice. RNA sequencing analysis was performed, and the data were authenticated by Western blot as well as quantitative qRT-PCR to explore the mechanisms of CSS treatment in BCRD. The BV2 microglia were stimulated with LPS in vitro and intervened by IL-17 protein, IL-17 antagonist, IMD-0354, and CSS. In addition, western blot was utilized to confirm the expression of IL-17/ NF-kappa B pathway-related factors. Molecular docking technique and UPLC-Q-TOF/MS were used to find out the key active components of CSS. Results: CSS treatment significantly improved depression-like behaviors and retarded tumor growth in mice. Through RNA sequencing analysis, it was indicated that the improvement of BCRD by CSS was highly associated with the regulation of the IL-17/ NF-kappa B pathway. Western blot and qRT-PCR outcomes suggested that CSS inhibited the IL-17/ NF-kappa B pathway, facilitating the transformation from pro-inflammatory M1 microglial phenotype to anti-inflammatory M2 phenotype, contributing to the reduction of neuroinflammation. In vitro experiments demonstrated that CSS modulated the immune reaction through the induction of phenotypic transformation of microglia from M1 toward M2 phenotype, hence reducing neuroinflammation. Notably, this therapeutic effect of CSS was h