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关键词： artificial intelligence   cytokines   IFN   IL-33   IL-4   machine learning   mast cells   omics   TGF beta   transcriptomics  

摘要： Mast cells (MCs) rapidly adapt to the microenvironment due to the plethora of cytokine receptors expressed. Understanding microenvironment-primed immune responses is essential to elucidate the phenotypic/functional changes MCs undergo, and thus understand their contribution to diseases and predict the most effective therapeutic strategies. We exposed primary human MCs to cytokines mimicking a T1/pro-inflammatory (IFN gamma), T2/allergic (IL-4 + IL-13), alarmin-rich (IL-33) and pro-fibrotic/pro-tolerogenic (TGF beta) microenvironment. We investigated MC surface receptor expression, activation, cytokine, histamine, and prostaglandin D2 release, and performed transcriptomics to define shared and unique genetic features. Using machine learning, we extracted minimal cytokine-activated signatures and performed gene set variation analysis (GSVA), single-cell clustering, and pseudotime analyses on tissue MCs from skin and respiratory diseases. MCs exposed in vitro to IFN gamma acquire an antigen-presenting phenotype (HLA-DR+), increase IgE-mediated responses and histamine release, while TGF beta inhibits activation and boosts integrin alpha v beta 3 expression. IL-33 primarily drives cytokine (GM-CSF, IL-5, IL-10, IL-13) and chemokine production (IL-8, MCP-1, MIP-1 alpha) and facilitates mixed IgG-IgE responses. Among uniquely expressed genes, 245 were highly informative to discriminate cytokine-primed MCs. GSVA revealed MC IL-4 + IL-13 signatures enriched in atopic dermatitis and psoriasis, IFN gamma in COVID-19 infection and cystic fibrosis, IL-33 in COVID-19 and chronic obstructive pulmonary disease (COPD) and TGF beta in pulmonary fibrosis (PF) and chronic rhinosinusitis. Furthermore, we detected positive IL-33/TGF beta priming in eosinophil-high COPD. Minimal cytokine-activated signatures identified disease-cytokine-specific MC clusters and pseudotime trajectories, suggesting involvement of MCs in fibrosis (COPD/PF), T1/alarmin-driven inflammation (COVID-19) and mixed

摘要： Psoriasis is a chronic skin disease that results in scaly patches and affects 2-3% of people worldwide. Therapeutic treatment targets the TNF-α/IL-17 axis to disrupt keratinocyte hyperproliferation and inflammation. While more is known about the role of dermal αß and γδ T cells in IL-17 production, less is understood about the role of resident epidermal T cells. Here, we examine how TNF-α modulates epidermal γδ T cell activation and function. We show that a subset of activated epidermal γδ T cells expresses TNFR2 with or without TNFR1. Stimulation with TNF-α induces epidermal γδ T cells to produce IL-17 family cytokines and chemokines. Epidermal γδ T cells do not require TNFR1 or 2 for development or homing to the skin. Instead, TNFR2 plays roles in epidermal γδ T cell function skewing them toward a Tγδ17 phenotype during psoriasis. Investigation of the mechanisms by which TNF-α associated inflammation impacts epidermal γδ T cell function may help identify new cellular targets for immunotherapy or mark them as early regulators of skin inflammation.

关键词： sepsis   interleukin-10   lymphocyte count   lactate   prognosis prediction   risk stratification  

摘要： Background: Sepsis is a highly heterogeneous clinical syndrome, and the real-time prognosis prediction and risk stratification for it remain a big challenge in current clinical research. This study aimed to assess the performance of IL-10/lymphocyte ratio (ILR) and lactate (Lac) in the prognostic prediction and risk stratification of sepsis. Methods: This is a retrospective observational study that included 148 patients with sepsis admitted to the First Affiliated Hospital of Chongqing Medical University from January 2022 to February 2023. Data collection commenced on the first day of ICU admission, with clinical and laboratory parameters recorded within 24 h of diagnosis, including IL-10 levels, lymphocyte counts, Lac, SOFA score, and APACHE II score. The relationship between ILR and Lac and 28-day mortality were analyzed by multivariate logistic regression analysis and Cox proportional hazards regression, and their predictive efficacy were assessed by receiver operator characteristic curves (ROCs), and Kaplan-Meier survival curves were used to validate the effect of risk stratification. Results: Patients in the death group exhibited significantly higher ILR (302.33 vs. 16.37) and Lac levels (3.25 mmol/L vs. 1.90 mmol/L) compared to the survival group (both p < 0.001). Multivariate logistic regression analysis showed that ILR (OR = 1.005, 95% CI 1.001-1.009) was independent risk factor for death at 28 days. Analysis of ROCs showed that the predictive efficacy of ILR (AUC = 0.860) was superior to the APACHE II score (AUC = 0.797) and the SOFA score (AUC = 0.704). Based on stratification by ILR (cutoff value 97.4) and Lac (cutoff value 4.1 mmol/L), the four risk stratification levels (Levels I-IV) exhibited progressively decreasing 28-day mortality rates: Level I (78.95%), Level II (50.00%), Level III (15.38%), and Level IV (7.69%). Kaplan-Meier analysis confirmed significant survival differences (p < 0.001), with Level I demonstrating the worst prognosis. Conclusion

关键词： Chemical activation  

摘要： Regulatory Treg cells are essential for immune homeostasis. While CD4 Treg cells are well characterized, CD8 Treg cells remain less understood and are primarily observed in pathological or experimental contexts. Here, we identify a naturally occurring CD8 regulatory precursor Trp cell at the steady state, defined by a CD8+HLA-DR+CD27+ phenotype and a transcriptome resembling CD4 Treg cells. Multiomics analyses reveal activation of TCF7 and costimulatory and co-inhibitory molecules in CD8 Trp cells. CD8 Trp cells suppress T cell expansion in vitro and in vivo. In a humanized xenogeneic graft-versus-host disease (GVHD) model, they dampen T cell activation, alleviate GVHD pathology, and prolong survival without impairing antileukemia activity. Mechanistically, CD8 Trp cells promote immune regulation by inducing FOXP3 expression in both CD4 Treg cells and themselves. Their expansion also correlates with immune homeostasis restoration post-allogeneic stem cell transplantation. These findings establish CD8 Trp cells as a naturally occurring regulatory precursor population that promotes transplantation tolerance.

关键词： Adenoid hypertrophy   Interferon-gamma   CD-56   Otitis media with effusion   Tonsillar hyperplasia   Children   Immunohistochemistry  

摘要： This study aims to investigate the histopathological expression of Interferon-gamma (IFN-gamma) and CD-56 in pediatric patients who underwent surgery for adenoid hypertrophy, and to evaluate their association with coexisting otitis media with effusion (OME) and tonsillar hypertrophy. A total of 100 children who underwent adenoidectomy, adenotonsillectomy, adenoidectomy with ventilation tube insertion, or adenotonsillectomy with ventilation tube insertion were included and divided into four equal groups. Surgical specimens were stained with hematoxylin-eosin, CD-56, and IFN-gamma. Clinical data including age, sex, comorbidities, adenoid volume, tonsil grade, and presence of OME were analyzed. Immunohistochemical staining rates were compared among the groups. The rate of IFN-gamma staining was significantly higher in the group that underwent adenotonsillectomy with ventilation tube insertion compared to other groups (p < 0.05). A statistically significant increase in IFN-gamma staining was also observed in patients with OME (p < 0.05). CD-56 staining did not show significant differences among the groups (p > 0.05). The elevated IFN-gamma expression in patients with OME and tonsillar hypertrophy may indicate an active inflammatory response. These findings suggest that IFN-gamma may play a role in the pathogenesis of OME in children with adenoid hypertrophy and could be considered as a potential therapeutic target.

关键词： tumor necrosis factors   cancer   infections   antagonists   inflammatory disorders   janus kinases   tumor necrosis factor inhibitors   venous thromboembolism   comparative effectiveness research   janus kinase inhibitors   adverse event   cardiovascular event  

摘要： Importance Janus kinase (JAK) inhibitors are highly effective medications for several immune-mediated inflammatory diseases (IMIDs). However, safety concerns have led to regulatory restrictions. Objective To compare the risk of adverse events with JAK inhibitors vs tumor necrosis factor (TNF) antagonists in patients with IMIDs in head-to-head comparative effectiveness studies. Data Sources For this systematic review and meta-analysis, the Ovid Medline, Ovid EMBASE, and Web of Science databases were searched from inception to June 25, 2025. Study Selection Head-to-head comparative effectiveness studies of adults (aged >= 18 years) with IMIDs (including rheumatoid arthritis, inflammatory bowel disease, psoriasis or psoriatic arthritis, or spondyloarthropathy) treated with either JAK inhibitors or TNF antagonists were included. Randomized clinical trials, noncomparative observational studies, studies not reporting outcomes of interest or focused solely on specific safety events, and studies with a sample size of less than 500 were excluded. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guideline was followed. Data Extraction and Synthesis Four investigators independently, and in pairs, abstracted data from included studies. A random-effects meta-analysis was conducted to obtain incidence rates (IRs) and hazard ratios (HRs) for JAK inhibitors vs TNF antagonists for each safety outcome (serious infections, malignant neoplasms, major cardiovascular events [MACEs], or venous thromboembolism [VTE]), adjusting for key confounding variables. Heterogeneity was quantified using the I2 statistic. Risk of bias was assessed by 2 investigators independently using the Newcastle-Ottawa Scale. Main Outcomes and Measures The primary outcome was risk of serious infections, malignant neoplasms, MACEs, or VTE. Results This meta-analysis of 42 studies with low to moderate risk of bias included 813 881 patients (median age, 55.7 years [IQR, 53.0-5

关键词： 胞内劳森菌   单克隆抗体   阻断ELISA   重组MltA蛋白  

摘要： 本研究旨在建立一种检测胞内劳森菌（Lawsonia intracellularis）抗体的阻断ELISA方法。采用原核表达的胞内劳森菌重组MltA蛋白免疫小鼠，制备获得单克隆抗体，通过Western blot和间接免疫荧光（IFA）鉴定了单克隆抗体的特异性。以重组蛋白MltA为包被抗原，待检血清为一抗，建立了检测胞内劳森菌抗体的阻断ELISA方法。确定了阻断ELISA方法最佳反应条件，并对方法的灵敏度、特异性、重复性及符合率进行分析。结果显示: 所建立方法的灵敏度和特异性分析显示在胞内劳森菌阳性血清稀释度为1:4时仍可稳定检出阳性，且与猪流行性腹泻病毒、伪狂犬病病毒及大肠杆菌阳性血清无交叉反应；重复性试验结果显示，批内重复试验的变异系数为1.4％～9.3％，批间重复试验的变异系数为1.0％～9.6％；与IFA结果对比，本研究所建立方法的敏感性为95.91%，特异性为80.65%，总符合率为85.92%。本研究对胞内劳森菌外膜蛋白MltA进行原核表达和纯化，制备了针对MltA的单克隆抗体，建立了一种检测胞内劳森菌抗体的阻断ELISA方法，可用于猪增生性肠病的临床诊断。

关键词： Fibrosis   Immunology   Nephrology   Therapeutics  

摘要： Low-intensity pulsed ultrasound stimulation (LIPUS) has become increasingly appreciated for its therapeutic effect on kidney diseases. However, its role and biological mechanism in treating chronic kidney disease remain poorly defined. Here, we revealed that LIPUS was applied in a safe range with an intensity of 25-315 mW/cm2. Daily LIPUS at an intensity of 315 mW/ cm2 ameliorated ischemia/reperfusion-induced (IR-induced) tubular injury and renal fibrosis, accompanied by the remarkable downregulation of IL-1R. Transcriptome sequencing showed that LIPUS significantly downregulated IL-1R and its downstream genes in IL-1(3-stimulated IRinjured mice. LIPUS effectively reversed IL-1(3-induced tubular injury and reduced the production of pro-fibrotic cytokines by downregulating IL-1R in vivo and in vitro. Renal proximal tubule-specific Il1r1-knockout mice exhibited milder renal tubular injury and fibrosis after IR injury. However, LIPUS did not ameliorate IR injury in proximal tubule-specific Il1r1-knockout mice. Collectively, daily LIPUS at an intensity of 315 mW/cm2 relieves IR-induced tubular injury and fibrosis, potentially by downregulating tubular IL-1R.

关键词： CD8+T cells   T cell receptors   COVID-19   severe disease   HLA-B*15:01  

摘要： Understanding host factors driving asymptomatic versus severe disease outcomes is of key importance if we are to control emerging and re-emerging viral infections. HLA-B*15:01 has been associated with asymptomatic SARS-CoV-2 infection in nonhospitalized individuals of European ancestry, with protective immunity attributed to preexisting cross-reactive CD8(+) T-cells directed against HLA-B*15:01-restricted Spike-derived S919-927 peptide (B15/S(919)(+)CD8(+) T-cells). However, fundamental questions remained on the abundance and clonotypic nature of CD8(+) T-cell responses in HLA-B*15:01-positive patients who succumbed to life-threatening COVID-19. Here, we analyzed B15/S(919)(+)CD8(+) T-cell responses in COVID-19 patients from independent HLA-typed COVID-19 patient cohorts across three continents, Australia, Asia and Europe. We assessed B15/S(919)(+)CD8(+) T-cells in COVID-19 patients across disease outcomes ranging from asymptomatic to hospitalized critical illness. We found that severe/critical COVID-19 patients mounted B15/S(919)(+)CD8(+) T-cell responses lacking a highly expanded key public B15/S(919)(+)CD8(+) T-cell receptor (TCR;TRAV9-2/TRBV7-2) which recurred across multiple individuals in COVID-19 patients with a mild disease. Instead, B15/S(919)(+)CD8(+) T-cell responses in life-threatening disease had a prevalence of an alternate TCR clonotypic motif (TRAV38-2/DV8/TRBV20-1), potentially contributing, at least in part, to why B15/S(919)(+)CD8(+) T-cells in severe COVID-19 patients were less protective. Interestingly, the frequency, memory phenotype, and activation profiles of circulating B15/S(919)(+)CD8(+) T-cells did not differ across disease severity. Moreover, B15/S(919)(+)CD8(+) T-cells were better maintained into convalescence compared to other SARS-CoV-2-specificities. Our study thus provides evidence on the differential nature of the TCR clonal repertoire in 22.37% of HLA-B*15:01-positive COVID-19 patients who developed severe or critical disease in o

关键词： italic>hnRNP-FTNF alpha-NF kappa B signaling pathway  

摘要： Background Diabetic kidney disease (DKD), with its complex pathogenesis, is the most important cause of end-stage renal disease and has become an urgent public health problem worldwide. Heterogeneous nuclear ribonucleoprotein F (hnRNP-F) is a member of a subfamily of widely expressed nuclear heterogeneous ribonucleoproteins with biological roles in regulating gene expression and variable splicing. Some studies have investigated hnRNP-F in DKD. However, its potential mechanism in renal intrinsic cells has rarely been reported. Therefore, it is necessary to further investigate its potential mechanism in DKD in the search for novel ideas for new therapeutic targets for *** In this study, hnRNP-F was overexpressed in human renal proximal tubular epithelial (HK-2) cells cultured in high-glucose conditions, while an empty vector was transfected into HK-2 cells as a control group (NC). Meanwhile, to avoid any osmotic stress that might be caused by the use of high sugar, we also added mannose as a non-osmotic control. RNA-seq was utilized to generate transcriptome data following hnRNP-F overexpression, allowing for the analysis of differential gene expression and alternative splicing events influenced by hnRNP-F overexpression. Similarly, we overexpressed hnRNP-F in mouse podocyte clone 5 (MPC5) cells and verified the relevant indicators using Western blotting (WB) under high-glucose and high-mannitol conditions, respectively. We also downloaded the CLIP-seq data of hnRNP-F in human 293T cells from the Gene Expression Omnibus (GEO) database. Through integrative analysis of RNA-seq and CLIP-seq, we tried to identify a set of potential direct targets of hnRNP-F in *** In this study, RNA sequencing (RNA-seq) was utilized to demonstrate that the upregulation of hnRNP-F in HK-2 cells cultured under high-glucose conditions resulted in a substantial decrease in the expression of genes associated with the inflammatory response and suppression of the TNF alpha-NF k