课程文献中心 更多>>

摘要： Plasmacytoid dendritic cells (pDCs) are major producers of type I interferon (IFN-I), an important antiviral cytokine, and activity of these cells must be tightly controlled to prevent harmful inflammation and autoimmunity. Evidence exists that one regulatory mechanism is a fate-switching process from an IFN-I-secreting pDC to a professional antigen-presenting conventional dendritic cell (cDC) that lacks IFN-I-secreting capacity. However, this differentiation process is controversial owing to limitations in tracking the fate of individual cells over time. Here we use single-cell omics and functional experiments to show that activated human pDCs can lose their identity as IFN-I-secreting cells and acquire the transcriptional, epigenetic and functional features of cDCs. This pDC fate-switching process is promoted by tumor necrosis factor but blocked by IFN-I. Importantly, it occurs in vivo during human skin inflammatory diseases and injury, and physiologically in elderly people. This work identifies the pDC-to-cDC reprogramming trajectory and unveils a mechanistic framework for harnessing it therapeutically.

摘要： Type 1 diabetes is characterized by the destruction of pancreatic beta cells. Genetic factors account for ~50% of the total risk, with variants in the Human Leukocyte Antigen (HLA) region contributing to half of this genetic risk, with research historically focused on populations of European ancestry. We developed HLA-focused type 1 diabetes genetic risk scores (T1D GRS ) utilizing single nucleotide polymorphisms (SNPs) or HLA alleles from four ancestry groups (Admixed African (AFR; T1D GRS ), Admixed American (AMR; T1D GRS ), European (EUR; T1D GRS ), Finnish (FIN; T1D GRS ) and across ancestry (ALL; T1D GRS ). We assessed the performance of genetic risk scores in each population to determine transferability of constructed scores. A total of 41,689 samples and 13,695 SNPs in the HLA region were genotyped, with HLA alleles imputed using the HLA TAPAS multi-ethnic reference panel. Conditionally independent SNPs and HLA alleles associated with type 1 diabetes were identified in each population group to construct T1D GRS models. Generated T1D GRS models were used to predict HLA-focused type 1 diabetes genetic risk across four ancestry groups. Performance of each T1D GRS model was assessed using Receiver Operating Characteristic (ROC) Area Under the Curve (AUC) and compared statistically. Each T1D GRS model included a different number of conditionally independent HLA region SNPs (AFR, n = 5; AMR, n = 3; EUR, n = 38; FIN, n = 6; ALL, n = 36) and HLA alleles (AFR, n = 6; AMR, n = 5; EUR, n = 40; FIN, n = 8; ALL, n = 41). The ROC AUC values of T1D GRS from SNPs or HLA alleles were similar and ranged from 0.73 (T1D GRS applied to FIN) to 0.88 (T1D GRS to EUR). The ROC AUC using the combined set of conditionally independent SNPs (T1D GRS ) or HLA alleles (T1D GRS ) performed uniformly well across all ancestry groups, ranging from 0.82 to 0.88 for SNPs, and 0.80 to 0.87 for HLA alleles. T1D GRS models derived from SNPs performed equivalently to those derive

关键词： 右归丸   软骨细胞   丝裂原活化蛋白激酶/核因子-κB信号通路   凋亡   自噬  

摘要： 目的 研究右归丸通过丝裂原活化蛋白激酶p38-MAPK(p38-MAPK)/核因子-κB(NF-κB)信号通路调控肿瘤坏死因子-α(TNF-α)诱导软骨细胞自噬抑制凋亡的机制。方法 选择大鼠原代软骨细胞细胞分为空白组、模型组、右归丸含药血清组、对照组。采用CCK8检测软骨细胞增殖；TUNEL法检测软骨细胞凋亡情况；ELISA法检测各组软骨细胞上清液中IL-1β、IL-6水平；免疫荧光法测定软骨细胞Beclin1、微管相关蛋白轻链3B(LC3B)表达、凋亡相关蛋白B淋巴细胞瘤-2(Bcl-2)、Bcl-2相关X蛋白（Bax）表达水平；Western-blot法检测软骨细胞p-p38-MAPK,p-P65、Beclin1、LC3BⅡ/Ⅰ、Bcl-2、Bax、含半胱氨酸的天冬氨酸蛋白水解酶-3(Caspase-3)蛋白表达水平。结果 与模型组相比，右归丸组和对照组软骨细胞增殖抑制率均较低（P<0.05），软骨细胞凋亡率均较低（P<0.05），软骨细胞上清液中IL-1β、IL-6水平较低（P<0.05），软骨细胞Bax表达水平均较低，Bcl-2、Beclin1、LC3B表达水平较高（P<0.05），软骨细胞p-p38-MAPK、p-P65、Bax、Caspase-3表达水平均较低，LC3BⅡ/Ⅰ较高（P<0.05），右归丸组与对照组上述指标相比无差异（P>0.05）。结论 右归丸能够通过抑制p38-MAPK/NF-κB信号通路来调节软骨细胞自噬，抑制软骨细胞凋亡，减轻炎症反应，发挥软骨细胞保护作用。

关键词： anti-TNF-alpha   diagnosis   hidradenitis suppurativa   scintigraphy  

摘要： Shedding light on Hidradenitis Suppurativa activity: a pilot study to evaluate the potential of [Tc]Tc-anti-TNF-alpha scintigraphy. : Hidradenitis suppurativa (HS), also known as acne inversa and Verneuil's disease, is a chronic and non-contagious auto-inflammatory disease of pilo-sebaceous units that can lead to severe complications and sequelae. The actual prevalence of HS is unknown due to diagnostic delay and/or misdiagnosis, but it is estimated to affect 0.00033-4.1% of the general population worldwide. Only severe cases are referred for imaging assessment, and the final diagnosis is mostly established on a clinical basis. Here, we present a pilot study aiming to evaluate clinically active inflammatory disease in patients with HS using [Tc]Tc-anti-TNF-alpha scintigraphy. : Four patients (2 male, 2 female) had their HS clinical features measured through the HS-PGA and Hurley Score and compared to [Tc]Tc-anti-TNF-alpha scintigraphy findings. : Scintigraphy with [Tc]Tc-anti-TNF-alpha showed abnormal uptake in clinically active lesions of HS and also detected some clinically unknown potential active lesions, later confirmed by clinical reassessment after the imaging. : Our results suggest that scintigraphy with [Tc]Tc-anti-TNF-alpha may be able to detect increased radiotracer uptake in most clinically identified active lesions in this pilot cohort. While promising, due to the inherent limitations of this pilot study, more studies need to be carried out to arrive at a definitive diagnostic assessment of active inflammatory disease using this method.

关键词： Immunotherapy   T cell therapy   Chimeric antigen receptor   TCR-mimic CAR   TCR-mimic bispecific antibody   KRAS neoepitopes  

摘要： Mutations in the KRAS proto-oncogene, particularly at codon 12, are among the most frequent genetic alterations in various cancers, and KRASG12V accounts for about 25% of all KRAS mutations observed in lung, pancreatic, and colorectal adenocarcinomas. Despite improved treatment regimes using targeted therapy and checkpoint inhibitors, cellular immunotherapy options for KRAS-mutated cancers remain elusive. We therefore developed two TCR-mimic (TCRm) anti-KRASG12V/HLA-A*02:01 chimeric antigen receptors (CARs) containing different hinge regions and, alternatively, a TCRm anti-KRASG12V/HLA-A*02:01 bispecific T cell engager (BiTE) to explore immunotherapy to the highly prevalent KRASG12V neoantigen. CAR-redirected or BiTE-exposed JNL-reporter cells demonstrated potent signaling capacity upon recognition of KRASG12V. Moreover, human CAR T and NK cells elicited IFN-gamma release and cellular cytotoxicity upon encountering target cells pulsed with KRASG12V peptide, and the anti-KRASG12V Strep-tagII hinge CAR showed superior reactivity compared to a human IgG1-Fc hinge CAR. Similarly, a novel TCRm BiTE induced strong T cell immunity to KRASG12V. In contrast, we observed only very low CAR or BITE-mediated responses to naturally presented KRASG12V/HLA-A*02:01 complexes. In summary, this study demonstrates that the mutation-derived KRASG12V5-14 peptide can be effectively targeted by TCRm CAR and BiTE-redirected T cells, suggesting that TCRm anti-KRASG12V CAR or BiTE represent promising formats to advance immunotherapy to mutated KRAS *** messagesSuccessful development of TCRm CAR and BiTE targeting mutated KRAS/HLA-A*02:***-KRASG12V TCRm CAR and BiTE induce potent immunity to KRASG12V ***-KRAS/HLA-I TCRm CARs and BiTEs are novel therapeutics for cancer immunotherapy.

关键词： Cytokine   Immune Checkpoint Inhibitor   Immunotherapy   T cell   T regulatory cell - Treg  

摘要： BACKGROUND:Interleukin-2 (IL-2) immunotherapy can induce durable tumor remissions, but its clinical performance has been limited by significant drawbacks such as short serum half-life and high toxicity. Administration of IL-2 in complex with certain anti-IL-2 antibodies (IL-2cx) enhances circulation half-life while also selectivity directing the cytokine to particular immune cell subsets. In particular, IL-2cx has been developed that targets either cells expressing the CD25-containing high-affinity IL-2 receptor (ie, CD25-biased IL-2cx) or cells expressing the CD25-lacking intermediate-affinity IL-2 receptor (ie, CD25-blocking IL-2cx). Since regulatory T (Treg) cells primarily express the high-affinity IL-2 receptor whereas naïve effector T and natural killer cells mainly express the low-affinity IL-2 receptor, CD25-blocking IL-2cx have traditionally been considered as potential cancer therapeutics, particularly in combination with immune checkpoint inhibitors (ICIs). METHODS:Stimulation of antigen-primed T cells by IL-2cx in the absence or presence of ICIs was evaluated through adoptive transfer of primed ovalbumin-specific T cells and analysis of expansion. Effects of IL-2cx on Treg cell-mediated inhibition of CD8 T cells were assessed by flow cytometry and thymidine incorporation. Tumor-bearing mice received combination treatments comprizing IL-2cx and ICIs, where complexes were delivered either before or after ICIs. Tumor growth and mouse survival were monitored, and immune cell phenotyping was performed. Toxicity was determined by tracking body weight, temperature, and lung edema. Substitution of IL-2cx with single-agent cytokine/antibody fusion proteins (immunocytokines, ICs) was also explored. RESULTS:We showed that CD25-biased IL-2cx and ICs synergize with ICIs to completely eradicate large, established tumors despite robust Treg cell expansion. Importantly, we found that timing is crucial, as administration of IL-2cx after (but not before) ICIs led to profo

关键词： HBV   Lipid peroxidation   Ferroptosis   CD8   T-cell dysfunction   ACACA   acetyl-CoA carboxylase alpha   ACSL4   acyl-CoA synthetase long chain family member 4   AIFM2   apoptosis-inducing factor mitochondria-associated 2   BFA   brefeldin A   BSA   bovine serum albumin   CHB   chronic hepatitis B   DAMPs   damage-associated molecular patterns   DEGs   differentially expressed genes   ELISA   enzyme-linked immunosorbent assay   FASN   fatty acid synthase   FCM   flow cytometry   GPX4   glutathione peroxidase 4   GSH   glutathione   HBcAg   hepatitis B core antigen   HBsAg   hepatitis B surface antigen   HBV   hepatitis B virus   HC   healthy controls   HDs   healthy donors   H&E   hematoxylin and eosin   IFN-γ   interferon-gamma   IHC   immunohistochemistry   IT   immunotolerant patients   LAMP   lysosomal-associated membrane protein   LDLR   low-density lipoprotein receptor   Lip-1   liproxstatin-1   LSCM   laser scanning confocal microscopy   MDA   malondialdehyde   MFI   mean fluorescence intensity   MHC   major histocompatibility complex   MUFAs   monounsaturated fatty acids   OA   oleic acid   oxLDL   oxidized low-density lipoprotein   PA   palmitic acid   PBMC   peripheral blood mononuclear cells   PBS   phosphate-buffered saline   PEG-IFN   pegylated interferon   PI   propidium iodide   PMA   phorbol 12-myristate 13-acetate   PUFA   polyunsaturated fatty acids   rAAV   recombinant adeno-associated virus   ROS   reactive oxygen species   RT-qPCR   real-time quantitative reverse-transcription polymerase chain reaction   scRNA-seq   single-cell RNA sequencing   SCARB1   scavenger receptor class B member 1   SD   standard deviation   Se-Met   selenomethionine   SFAs   saturated fatty acids   SLC7A11   solute carrier family 7 member 11   SSO   sulfo-N-succinimidyl oleate   TEM   transmission electron microscopy   TGF-β1   transforming growth factor beta 1   TNF-α   tumor necrosis factor-alpha   UMAP   uniform manifold approximation and projection   WT   wild type  

摘要： Background & Aims CD8 + T cells play a crucial role in antiviral immunity; however, hepatitis B virus (HBV)-specific CD8 + T cells become dysfunctional during chronic HBV (CHB) infection. Blocking inhibitory pathways only partially restores efficient antiviral responses, suggesting that the mechanism underlying CD8 + T-cell dysfunction is complicated. This study aimed to investigate whether HBV-specific CD8 + T cells undergo ferroptosis, examine its correlation with T-cell dysfunction, and elucidate the underlying mechanism and potential intervention strategies. Methods Analysis of CD8+ T cells from CHB patients revealed ferroptosis markers via flow cytometry, electron microscopy, and scRNA-seq, and HBV-specific CD8 + T cells were identified using HBV-core antigen peptide-loaded MHC I tetramer. Flow cytometry, scRNA-seq and additional experimental approaches were employed to investigate the ferroptosis-associated mechanisms in CD8 + T-cell dysfunction. Results Ferroptosis was observed in CD8 + T cells from CHB patients, as indicated with increased lipid peroxidation, Fe 2+ accumulation and mitochondrial atrophy, particular in HBV-specific CD8 + T cells. Downregulation of GPX4 and upregulation of CD36 were found in CD8 + T cells with high level of lipid peroxidation. Furthermore, ferroptosis is accompanied by impaired antiviral ability. Mechanistically, palmitic acid (PA) upregulates CD36 expression, leading to lipid accumulation; while elevated serum TGF-β1 in CHB patients reduces GPX4 expression and impairs antioxidant capacity. These factors synergistically promote ferroptosis and dysfunction of CD8 + T cells. Treatment with selenium and liproxstain-1 enhanced cytotoxic cytokines production by CD8 + T cells, and subsequently improved antiviral efficacy in vivo . Conclusions Our study demonstrates that ferroptosis drives CD8 + T-cell dysfunction in chronic HBV infection. Targeting ferroptosis pathways may offer a novel therapeutic strategy to restore antiviral immu

关键词： HLA antigens   Ole e 7 allergen   Pru p 3 allergen   T-cell epitopes   non-specific lipid transfer proteins  

摘要： Concomitant sensitisation to non-specific lipid transfer proteins (nsLTPs) from olive pollen (Ole e 7) and peach (Pru p 3) has been observed in the south of Spain. In the search for reasons to explain this observation, we studied a potential causal relationship between Human Leukocyte Antigen (HLA) molecules and nsLTP sensitisation. For this purpose, eighteen Ole e 7-monosensitised (MONOLE) patients, 22 Pru p 3-monosensitised (MONPRU) patients, and 22 bisensitised (BI) patients were genotyped for HLA class II alleles. Complementarily, T-cell epitopes were predicted with the Immune Epitope Database analysis tool to test HLA epitope presentation. Our results showed a significant increase in DRB1*11 and DQB1*03 frequencies in MONPRU patients and DRB1*04 frequency in MONOLE patients. Additionally, T-cell epitope analysis revealed high binding affinity between the predicted Pru p 3 epitopes and DRB1*11 and between the predicted Ole e 7 epitopes and DRB1*04, suggesting that presentation of these epitopes may be favoured and predisposing individuals to sensitisation. Conversely, low DQB1*05 frequency and poor binding ability of predicted epitopes from both nsLTPs postulated this allele as a possible protective factor to sensitisation. Variations in the binding affinity between nsLTP epitopes and HLA molecules may underlie individual susceptibility to nsLTP allergy.

关键词： Children   Adolescents   Active tuberculosis   IFN-gamma   IL-2   Combined detection  

摘要： ObjectiveThis study aimed to conduct a combined detection of Mycobacteriumtuberculosis (MTB) infection using the tuberculosis (TB)-specific cytokine interferon-gamma (IFN-gamma) and interleukin-2 (IL-2) release assays in hospitalized children and adolescents with TB, evaluate the clinical value of this technique in the diagnosis of active TB in children and adolescents, and to analyze the related influencing factors. MethodA retrospective study was conducted to collect data from suspected pediatric and adolescent TB patients hospitalized at Chengdu Public Health Clinical Medical Center between April 2022 and December 2024. The combined detection of MTB infection using IFN-gamma and IL-2 release assays (referred to as "dual-factor detection of TB infection") was carried out. Microbiological or molecular biological test results of MTB were also obtained. A total of 904 patients diagnosed with TB and 176 non-TB patients were included in the analysis of the effectiveness of dual-factor TB infection testing and related influencing factors. ResultsThe combined detection of IFN-gamma and/or IL-2 demonstrated improved diagnostic performance for active tuberculosis (ATB), with a sensitivity of 91.04% and specificity of 65.34% (AUC = 0.782, 95% CI 0.745-0.818). While IFN-gamma and IL-2 levels showed no significant differences between MTB-positive and MTB-negative subgroups within the TB cohort (IFN-gamma: 365.52 vs. 382.11 pg/ml;IL-2: 241.56 vs. 213.12 pg/ml), both cytokines were markedly elevated in the TB group compared to non-TB controls (IFN-gamma: 68.1 pg/ml;IL-2: 41.68 pg/ml). Age-related variations were observed in IFN-gamma (P < 0.05) but not IL-2 concentrations. Untreated patients exhibited higher median levels of IFN-gamma (397.9 vs. 306.0 pg/ml) and IL-2 (239.2 vs. 173.3 pg/ml) than treated individuals. Among 904 ATB cases, 8.96% (81/904) were false-negative for both cytokines. Multivariate analysis identified advanced age, retreatment TB, pleural effusion, and TST

关键词： CCL11   CCL26   Ciliated epithelial cell   Goblet cell   IL-4R   IL-5   IL-5R