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关键词： 多发伤   脓毒症   乳酸   降钙素原   白细胞计数   白细胞介素-6  

摘要： 目的 探讨联合检测严重多发伤患者乳酸（Lac）、降钙素原（PCT）、白细胞计数（WBC）、白细胞介素-6（IL-6）水平变化与继发脓毒症的关系。方法 选取120例严重多发伤患者为研究对象，均于创伤后6、12 、24、48、72 h检测Lac、PCT、WBC、IL-6水平。统计120例严重多发伤患者脓毒症发生情况，比较脓毒症组与非脓毒症组临床资料及、Lac、PCT、WBC、IL-6水平，采用受试者工作特征（ROC）曲线评价APACHEⅡ评分、ISS评分及Lac、PCT、WBC、IL-6水平对严重多发伤患者脓毒血症发生的预测价值。结果 120例严重多发伤患者脓毒症发生率为17.50%（21/120），创伤至感染发生的时间为44.9（29.12，73.84）h；脓毒症组与非脓毒症组性别、年龄、受伤至入院时间及体质量指数（BMI）比较差异均无统计学意义（P＞0.05），脓毒症组急性生理与慢性健康评分Ⅱ（APACHEⅡ）及创伤严重程度（ISS）评分均明显高于非脓毒症组，差异均有统计学意义（P＜0.05）；重复测量方差结果显示，脓毒症组与非脓毒症组创伤后6、12、24、48、72 h血清Lac、PCT、WBC、IL-6存在组间、时间及交互效应（P＜0.05）；多变量方差分析结果显示，创伤后6、12、24、48、72 h，脓毒症组Lac、PCT、WBC、IL-6水平均较非脓毒症组高，差异均有统计学意义（P＜0.05）。选取APACHEⅡ评分、ISS评分及创伤后24 h血清Lac、PCT、WBC、IL-6水平作为ROC曲线源数据，将脓毒症患者作为阳性，非脓毒症患者作为阴性，绘制ROC曲线，记过显示APACHEⅡ评分、ISS评分及创伤后24 h血清Lac、PCT、WBC、IL-6水平预测AUC值均在0.7以上；创伤后24 h血清Lac、PCT、WBC、IL-6水平联合预测严重多发伤患者脓毒症发生的AUC值最大，为0.949。结论 严重多发伤患者脓毒症发生率为17.50%，创伤早期血清Lac、PCT、WBC、IL-6水平明显升高，且创伤后24 h血清Lac、PCT、WBC、IL-6预测脓毒症效能较高，为脓毒症重要预测因子。

关键词： airway macrophages   cytokines   human   immunology   inflammation   lipopolysaccharide   metabolism   Mycobacterium tuberculosis   polarization  

摘要： Airway macrophages (AM) are the predominant immune cell in the lung and play a crucial role in preventing infection, making them a target for host directed therapy. Macrophage effector functions are associated with cellular metabolism. A knowledge gap remains in understanding metabolic reprogramming and functional plasticity of distinct human macrophage subpopulations, especially in lung resident AM. We examined tissue-resident AM and monocyte-derived macrophages (MDM;as a model of blood derived macrophages) in their resting state and after priming with IFN-γ or IL-4 to model the Th1/Th2 axis in the lung. Human macrophages, regardless of origin, had a strong induction of glycolysis in response to IFN-γ or upon stimulation. IFN-γ significantly enhanced cellular energetics in both AM and MDM by upregulating both glycolysis and oxidative phosphorylation. Upon stimulation, AM do not decrease oxidative phosphorylation unlike MDM which shift to 'Warburg'-like metabolism. IFN-γ priming promoted cytokine secretion in AM. Blocking glycolysis with 2-deoxyglucose significantly reduced IFN-γ driven cytokine production in AM, indicating that IFN-γ induces functional plasticity in human AM, which is mechanistically mediated by glycolysis. Directly comparing responses between macrophages, AM were more responsive to IFN-γ priming and dependent on glycolysis for cytokine secretion than MDM. Interestingly, TNF production was under the control of glycolysis in AM and not in MDM. MDM exhibited glycolysis-dependent upregulation of HLA-DR and CD40, whereas IFN-γ upregulated HLA-DR and CD40 on AM independently of glycolysis. These data indicate that human AM are functionally plastic and respond to IFN-γ in a manner distinct from MDM. These data provide evidence that human AM are a tractable target for inhalable immunomodulatory therapies for respiratory diseases. © 2024, Cox et al.;Inside the human body, immune cells known as macrophages are constantly looking for microbes, cell debris an

关键词： HCV   HCV/HIV coinfection   HIV   HLA-G, Liver Disease   Hepatitis C  

摘要： INTRODUCTION AND OBJECTIVES:Hepatitis C-induced liver disease represents a significant threat to the survival of people living with HIV. HIV/HCV-coinfected individuals have a more rapid progression to cirrhosis and its complications than HCV monoinfected patients. Although the underlying mechanisms remain unclear, HLA-G, a non-classical class I HLA molecule, has a well-recognized property to down-regulate the immune response against viruses and may favor the progression of chronic hepatitis C. MATERIALS AND METHODS:We analyzed HLA-G expression in 59 liver specimens of patients harboring chronic HCV and HIV coinfection and stratified the findings according to clinical and histopathological features. RESULTS:Genotype 1 was the most prevalent (88%); the HLA-G expression was observed in 38 (64%) liver specimens, and it was more frequent in more severe stages than in milder stages of chronic hepatitis (94,1% x 55%; p<0.01). HLA-G expression in the liver was not correlated to antiviral response to hepatitis C therapy with pegylated-IFN-α plus ribavirin. CONCLUSIONS:HLA-G expression in the context of HCV/HIV coinfection is a complex process modulated by many factors. HLA-G expression may play a role in the mechanisms that facilitate disease progression and may contribute to the deterioration of the immune response against HCV in individuals living with HIV.

关键词： High-throughput virtual   screening   Rel-homology   region   MD simulation   GROMACS   MMPBSA   NF-kappa B   P38 and ERK1/2  

摘要： Chronic inflammation leads to many maladies in lung cancer. Tumor necrosis factor-alpha (T NF- alpha), a pleiotropic proinflammatory cytokine regulates the activation of the nuclear factor-kappa B (NF-kappa B) to drive many physiological and pathological signaling pathways in inflammation and cancer apoptosis. This study identified a novel natural product to inhibit T NF- alpha induced NF-kappa B activation. Virtual docking of ZINC natural product library and computational modeling analysis showed compounds that target crucial amino acid residues on p50 protein involved in DNA binding. Molecular dynamic simulation showed, compound SBS-3.1, as the best lead compound that binds efficiently and stably with p50 protein. MMP BSA analysis of the lead compound predicted a favorable binding free energy. The compound inhibited the proliferations of T NF- alpha induced A-549 with a GI50 value of 30.53 lM. SBS-3.1 decreased the percentage of T NF-alpha induced NF-kappa B-65, p38 and ERK1/2 positive lung cancer cells, while the apoptosis in these cells were elevated. In summary, SBS-3.1, a natural product, was identified as the lead compound targeting Rel-homology region of p50. Inhibition of NF-kappa B and inflammatory signals by SBS 3.1 promoted apoptosis in lung cancer. Further research can bring new therapeutic strategies for treating inflammation associated T ME of lung cancer cells.

关键词： Bispecific T cell engager - BiTE   Immunotherapy   T cell  

摘要： Background Glioblastoma multiforme (GBM) is known for its high antigenic heterogeneity, which undermines the effectiveness of monospecific immunotherapies. Multivalent immunotherapeutic strategies that target multiple tumor antigens simultaneously could enhance clinical outcomes by preventing antigen-driven tumor escape *** We describe novel trivalent antibodies, DNA-encoded tri-specific T-cell engagers (DTriTEs), targeting two GBM antigens, epidermal growth factor receptor variant III (EGFRvIII) and IL-13R alpha 2, and engaging T cells through CD3. We engineered three DTriTE constructs, each with a unique arrangement of the antigen-binding fragments within a single-chain sequence. We assessed the binding efficiency and cytotoxic activity of these DTriTEs in vitro on target cells expressing relevant antigens. In vivo efficacy was tested in immunocompromised mice, including a longitudinal expression study post-administration and a survival analysis in an NOD scid gamma (NSG)-K mouse model under a heterogeneous tumor burden. RNA sequencing of DTriTE-activated T cells was employed to identify the molecular pathways influenced by the treatment. The antitumor cytotoxicity of patient-derived immune cells was evaluated following stimulation by DTriTE to assess its potential effectiveness in a clinical *** All DTriTE constructs demonstrated strong binding to EGFRvIII and IL-13R alpha 2-expressing cells, induced significant T cell-mediated cytotoxicity, and enhanced cytokine production (interferon-gamma, tumor necrosis factor (TNF)-alpha, and interleukin(IL)-2). The lead construct, DT2035, sustained expression for over 105 days in vivo and exhibited elimination of tumor burden in a heterogeneous intracranial GBM model, outperforming monospecific antibody controls. In extended survival studies using the NSG-K model, DT2035 achieved a 67% survival rate over 120 days. RNA sequencing of DTriTE-activated T cells showed that DT2035 enhances genes linked

关键词： TCR   MHC   peptide   HLA   conformational changes   T cell antigen specificity   structural biology  

摘要： Background T cells form one of the key pillars of adaptive immunity. Using their surface bound T cell antigen receptors (TCRs), these cells screen millions of antigens presented by major histocompatibility complex (MHC) or MHC-like molecules. In other protein families, the dynamics of protein-protein interactions have important implications for protein function. Case studies of TCR:class I peptide-MHCs (pMHC-Is) structures have reported mixed results on whether the binding interfaces undergo conformational change during engagement and no robust statistical quantification has been done to generalise these results. Thus, it remains an open question of whether movement occurs in the binding interface that enables the recognition and activation of T *** In this work, we quantify the conformational changes in the TCR:pMHC-I binding interface by creating a dataset of 391 structures, comprising 22 TCRs, 19 MHC alleles, and 79 peptide structures in both unbound (apo) and bound (holo) *** In support of some case studies, we demonstrate that all complementarity determining region (CDR) loops move to a certain extent but only CDR3 alpha and CDR3 beta loops modify their shape when binding pMHC-Is. We also map the contacts between TCRs and pMHC-Is, generating a novel fingerprint of TCRs on MHC molecules and show that the CDR3 alpha tends to bind the N-terminus of the peptide and the CDR3 beta tends to bind the C-terminus of the peptide. Finally, we show that the presented peptides can undergo conformational changes when engaged by TCRs, as has been reported in past literature, but novelly show these changes depend on how the peptides are anchored in the MHC binding *** Our work has implications in understanding the behaviour of TCR:pMHC-I interactions and providing insights that can be used for modelling Tcell antigen specificity, an ongoing grand challenge in immunology.

关键词： Autoimmunity   Cytokines   Dendritic cells   T cell development  

摘要： Type 1 diabetes (T1D) develops spontaneously despite functional antigen presentation machinery in the thymus and a perceptible central tolerance process. We found that intrathymic enrichment with IL-4 fine tunes signaling through the IL-4/ IL-13 heteroreceptor (HR) in early thymic progenitors (ETPs), augments negative selection of self-reactive T cells, sustains a diverse T cell repertoire devoid of clones expressing disease-associated T cell receptor (TCR) genes, and protects the nonobese diabetic (NOD) mouse from T1D. Indeed, optimal IL-4 activates STAT transcription factors to program ETP fate decision toward CD11c⁺CD8α⁺ dendritic cells (DCs) agile in negative T cell selection and clonal deletion of diabetogenic T cells. However, due to diminished invariant natural killer T (iNKT) 2 cell frequency in the NOD thymus, IL-4 is as suboptimal level, metering STAT activation to program ETP fate decision toward the T cell lineage leading to diminished negative selection, a clonally restricted TCR repertoire, and manifestation of spontaneous T1D. These insights uncover yet another interplay by which IL-4 affects T1D. © 2024, Cattin-Roy et al.

关键词： Exosomes   Juvenile idiopathic arthritis   Human umbilical cord mesenchymal stem cells   MiR-29-3p/AhR   Interleukin-22  

摘要： BackgroundJuvenile idiopathic arthritis (JIA) is one of the most common chronic inflammatory rheumatic diseases in children. Human umbilical cord mesenchymal stem cells (HUCMSCs)-derived exosomes (HUCMSCs-Exos) are involved in autoimmune diseases. This study investigates the mechanism of HUCMSC-Exos in improving JIA by targeting AhR through delivery of miR-29-3p to inhibit IL-22 expression in CD4+ T *** induced arthritis (CIA) mouse model was established, and mice were treated with HUCMSCs-Exos and miR-29-3p antagomir, respectively. CD4+ T cells from JIA patients were used for cell experiments. The mechanism was elucidated by histopathological staining, transmission electron microscopy (TEM), immunohistochemistry, CCK-8 assay, flow cytometry, Western blotting, real-time PCR, and enzyme-linked immunosorbent assay (ELISA), laser confocal microscopy, and luciferase ***-CD4+ T cells showed higher expression of IL-22 and lower the levels of miR-29-3p, while HUCMSCs-Exos significantly inhibited the expression of IL-22 and increased the levels of miR-29a-3p, miR-29b-3p, and miR-29c-3p in CD4+ T cells from JIA patients. The expression of miR-29a-3p, miR-29b-3p, miR-29c-3p, AhR, and IL-22 in CD4+ T cells was significantly reversed when co-cultured with HUCMSCs transfected with miR-29-3p mimic or miR-29-3p inhibitor. In vivo experiment, HUCMSCs-Exos ameliorated CIA mice by delivering miR-29-3p to inhibit AhR, IL-22, IL-22R1, MMP3, and MMP13 expression. Furthermore, HUCMSCs-Exos also deliver miR-29-3p targeting AhR expression to inhibit IL-22 in JIA-CD4 + T cells through alleviating arthritic synovial fibroblast ***-Exos loaded miR-29-3p targets AhR to improve JIA via inhibiting the expression of IL-22 in CD4+ T cell, which provides a scientific basis for the treatment of JIA.

关键词： Cancer immunotherapy   Dendritic cells   Immunology   Oncology   Radiation therapy  

摘要： The RNA N⁶-methyladenosine (m⁶A) reader YTHDF1 is implicated in cancer etiology and progression. We discovered that radiotherapy (RT) increased YTHDF1 expression in dendritic cells (DCs) of PBMCs from patients with cancer, but not in other immune cells tested. Elevated YTHDF1 expression in DCs was associated with poor outcomes for patients receiving RT. We found that loss of Ythdf1 in DCs enhanced the antitumor effects of ionizing radiation (IR) by increasing the cross-priming capacity of DCs across multiple murine cancer models. Mechanistically, IR upregulated YTHDF1 expression in DCs through stimulator of IFN genes/type I IFN (STING/IFN-I) signaling. YTHDF1 in turn triggered STING degradation by increasing lysosomal cathepsins, thereby reducing IFN-I production. We created a YTHDF1 deletion/inhibition prototype DC vaccine that significantly improved the therapeutic effect of RT and radioimmunotherapy in a murine melanoma model. Our findings reveal a layer of regulation between YTHDF1/m⁶A and STING in response to IR, which opens new paths for the development of YTHDF1-targeting therapies. Copyright: © 2024, Wen et al.

关键词： CD47   cervical cancer   IL-37   immunotherapy   macrophage phagocytosis   STAT3  

摘要： As a promising therapeutic approach, immunotherapy is being extensively investigated in cervical cancer. Although immunotherapy has been validated to improve progression-free survival and overall survival in clinical trials, the overall response rate for cervical cancer remains inadequate, necessitating further improvement. Interleukin (IL)-37, an emerging immunomodulator, exhibits antitumour potentials by inhibiting tumour progression and regulating tumour-associated macrophage recognition. We found a significant downregulation of IL-37 expression in cervical cancer, correlated with a poor prognosis. Moreover, the upregulation of IL-37 expression exhibited a suppressive effect on various tumorigenic processes, suppressing the proliferation, invasion, migration, apoptosis and angiogenesis of tumour cells. We also found that the upregulation of IL-37 suppressed cluster of differentiation 47 (CD47) expression in tumour cells via suppression of the signal transducer and activator of transcription 3 (STAT3) expression and phosphorylation, thereby enhancing macrophage recognition and phagocytosis to tumour cells, ultimately reducing immune evasion. Overall, our study highlighted the crucial role of IL-37 in antitumour efficacy and downregulating the expression of CD47 in tumour cells to reduce immune evasion, suggesting the potential of IL-37 as a prognostic biomarker in cervical cancer and offering innovative therapeutic strategies to improve cancer treatment outcomes.