Frontiers in Immunology最新文献

Background: Under hyperglycemic conditions, impaired intestinal barrier integrity leads to heightened level of inflammation, playing important roles in driving diabetic complications. Emerging evidence supports the implications of neutrophil extracellular traps (NETs) in the pathogenesis of diabetes. However, whether NETs contribute to hyperglycemia-linked intestinal barrier impairment remains to be investigated. Moreover, baicalin, the major chemical component of Scutellaria baicalensis Georgi, is equipped with twofold intestinal protective and neutrophil suppressive activities. Yet, it is unclear if baicalin is effective at mitigating hyperglycemia-linked NETs-mediated intestinal barrier impairment.

Methods: To directly address the mechanistic implications of NETs in hyperglycemia-linked intestinal epithelial barrier impairment, the impact of DNase I treatment or Padi4 gene deficiency on intestinal epithelial integrity was first examined in the streptozotocin (STZ)-induced hyperglycemic mice in vivo. Next, the pharmacological impact of baicalin on NETs formation and intestinal epithelial barrier impairment was investigated in high glucose- and/or lipopolysaccharides (LPS)-stimulated neutrophils in vitro and in STZ-induced hyperglycemic mice in vivo, respectively.

Results: The in vitro experiments confirmed that high glucose and/or LPS induced NETs formation. NETs directly impaired the viability and tight junction of the intestinal epithelial cells. The histological and immunohistochemical examinations unveiled that along with impaired intestinal epithelial morphology, citrullinated histone H3 (H3Cit), a marker of NETs, and neutrophil specific Ly6G were readily detected in the intestinal epithelium in the hyperglycemic mice. Without affecting the presence of neutrophils, DNase I treatment or Padi4 gene deficiency markedly mitigated intestinal NETs formation and improved the intestinal morphology in the hyperglycemic mice. Notably, baicalin suppressed NETs formation and inhibited histone H3 citrullination stimulated by high glucose, LPS or both in vitro. Furthermore, baicalin blunted NETs formation and partially preserved the integrity of the intestinal epithelium in the hyperglycemic mice in vivo.

Conclusions: The current study sheds new light on the pathophysiological implications of NETs in intestinal epithelial barrier impairment under hyperglycemic conditions. Most importantly, the findings here demonstrate for the first time that baicalin directly inhibits NETs formation stimulated by high glucose and/or LPS, which may in part account for its pharmacological effects at protecting against hyperglycemia-linked intestinal epithelial barrier impairment.

Immune checkpoint inhibitors are increasingly being utilized for the treatment of advanced neoplastic disease, and Sintilimab as a selective anti-PD-1 antibody that inhibits interactions between PD-1 and its ligand, is a typical representative of them. Among all the adverse effects(AEs) of sintilimab, skin AEs had affected many people. Though exceedingly rare, eruptive keratoacanthomas-like lesion have been associated with the use of immune checkpoint inhibitors before. Here, we report a case of numerous eruptive keratoacanthoma-like lesions arising in a patient 2 weeks after initiation of sintilimab for rectal adenocarcinoma with liver metastasis. Although eruptive keratoacanthoma-like lesions secondary to sintilimab are exceptionally rarely reported, physicians should be aware of this cutaneous adverse effect as its use becomes more widespread.

Background: NUP62, a key component of the nuclear pore complex, is closely associated with cellular functions and cancer progression. However, its expression patterns, prognostic value, and relationship with tumour immunity and drug sensitivity across multiple cancers have not been systematically studied. This study used multi-omics analyses combined with experimental validation in gastric cancer to investigate the expression, functional characteristics, and clinical relevance of NUP62 in cancer.

Methods: Data from TCGA, GTEx, and CPTAC databases were used to analyse the expression, mutation characteristics, and clinical associations of NUP62. Tools such as SangerBox, TIMER 2.0, and GSEA were employed to evaluate the relationship between NUP62 and the tumour immune microenvironment, as well as its involvement in signalling pathways. Immunohistochemistry and RT-PCR were used to validate the expression of NUP62 in gastric cancer tissues. PRISM and CTRP databases were utilised to assess the correlation between NUP62 expression and drug sensitivity.

Results: NUP62 was significantly upregulated in multiple cancers and was associated with poor prognosis in cancers such as clear cell renal carcinoma (KIRC), lower-grade glioma (LGG), and adrenocortical carcinoma (ACC), while playing a protective role in others, such as bladder cancer (BLCA) and stomach cancer (STAD). Functional analyses showed that NUP62 is involved in cell cycle regulation, DNA damage repair, and tumour immunity. High NUP62 expression was significantly correlated with increased infiltration of immune cells, such as macrophages and T cells, and a higher response rate to immunotherapy. Drug sensitivity analysis identified NUP62 as a marker of sensitivity to various chemotherapeutic agents. Validation experiments demonstrated that NUP62 mRNA and protein levels were significantly higher in gastric cancer tissues than in adjacent normal tissues.

Conclusions: NUP62 plays a critical role in multiple cancers and shows potential as a biomarker for cancer diagnosis, prognosis, and therapeutic response prediction. Its role in tumour immunity and signalling pathways highlights its potential as a target for immunotherapy and precision medicine.

Introduction: Infants exposed to HIV and uninfected (HEUs) are at higher risk of infectious morbidity than HIV-unexposed uninfected infants (HUUs). Multiple immune defects of unknown origin were observed in HEUs. We hypothesized that HEUs have more regulatory and inhibitory checkpoint-expressing T cells (Treg, Tici) than HUUs, which may dampen their immune defenses against pathogens.

Method: We used flow cytometry to measure 25 Treg/Tici subsets in HEUs and HUUs at birth, 6, 28, and 62 weeks of life. We used maternal and infant gut microbiome data reported in a previous study to establish correlations with the Treg/Tici.

Results: At birth, 3 Treg subsets, including the prototypic CD4+FOXP3+ and CD4+FOXP3+CD25+, had higher frequencies in 123 HEUs than in 117 HUUs, and 3 subsets had higher frequencies in HUUs. At 28 and 62 weeks of age, 5 Treg/Tici subsets had higher proportions in HEUs than HUUs. The frequencies of the Treg/Tici subsets that diverged between HEUs and HUUs at birth correlated with differential relative abundances of bacterial taxa in the maternal gut microbiome. The Treg/Tici subsets with significantly different frequencies at subsequent visits correlated with the concurrent composition of the infant gut microbiome. In vitro, treatment of HUU peripheral blood mononuclear cells (PBMC) with bacterial taxa most abundant in HEUs expanded Treg/Tici subsets with higher frequencies in HEUs than HUUs, recapitulating the in vivo correlations. Conversely, in vitro treatment of HEU PBMC did not increase Treg/Tici frequencies. Other factors that correlated with increased Treg/Tici frequencies were low maternal CD4+ T cells in HEUs at birth and male sex in the HUUs at 28 weeks of life.

Discussion: This study shows that maternal and infant gut dysbiosis are central to the increase in Treg/Tici in HEUs and may be targeted by mitigating interventions.

Gastric cancer (GC) remains a significant global health concern due to its poor prognosis and limited therapeutic options, particularly in advanced stages. Tumor microenvironment (TME), particularly tumor-associated macrophages (TAMs), plays a key role in tumor progression, immune evasion, and therapy resistance. TAMs exhibit plasticity, shifting between pro-inflammatory M1 and immunosuppressive M2 phenotypes, with the latter predominating in GC and contributing to poor outcomes. Recent therapeutic advancements focus on targeting TAMs, including inhibiting M2 polarization, reprogramming TAMs to M1 phenotypes, and combining TAM-targeted approaches with immune checkpoint inhibitors. Innovations in nanotechnology, metabolic reprogramming, and targeting key pathways such as interleukin-6 and C-C motif ligand 2/C-C motif chemokine receptor 2 further enhance these strategies. However, challenges remain, including the spatial and functional heterogeneity of TAMs within the TME and the need for selective targeting to avoid disrupting immune homeostasis. Ongoing research on TAM origins, functions, and interactions within the TME is crucial for developing precise and effective therapies. These advances hold promise not only for improving outcomes in GC but also for addressing other cancers with similarly complex microenvironments.

Thymus-committed regulatory T cells (Tregs) are essential for immune homeostasis. Recent findings stress their heterogeneity, suggesting possible alternate routes for thymic Treg development with unique features in humans, namely the clear evidence of Treg commitment at the double-positive (DP) stage and the presence of a significant population of CD8 single-positive (SP) FOXP3^pos Tregs. Here, we present a dedicated analysis strategy to a spectral flow cytometry-based study of thymus from children and aged adults (≥ 74-years-old), to further elucidate Treg development and heterogeneity in the human thymus. We applied an unsupervised analysis pipeline to data generated from 6 high-dimensional panels, taking advantage of a common backbone of 11 markers, and we were able to map thymocytes along T cell maturation stages. Generating UMAP and FlowSOM cluster coordinates from the backbone, we projected all other markers onto these, characterizing clusters with the information of all markers. Focusing this analysis on events inside a putative total Treg gate, we could portray rarer subsets of human thymic Tregs and investigate their trajectories using pseudotime analysis. We uncover clusters within human DP thymocytes uniquely expressing FOXP3 or CD25, a DP-branching trajectory towards a CD103^posCD8SP Tregs endpoint, and define trajectories towards CD4SP Tregs, including towards a cluster of CXCR3^posCD4SP Tregs, that may consist of thymic resident or recirculating Tregs, and do not expand in the elderly. Our flow cytometry approach separates Treg populations with likely distinct functions and facilitates the design of future studies to unravel the complexity of human regulatory T cells.

Background: Sepsis-induced coagulopathy (SIC) is a complex condition characterized by systemic inflammation and coagulopathy. This study aimed to develop and validate a machine learning (ML) model to predict SIC risk in patients with sepsis.

Methods: Patients with sepsis admitted to the intensive care unit (ICU) between March 1, 2021, and March 1, 2024, at Hebei General Hospital and Handan Central Hospital (East District) were retrospectively included. Patients were categorized into SIC and non-SIC groups. Data were split into training (70%) and testing (30%) sets. Additionally, for temporal validation, patients with sepsis admitted between March 1, 2024, and October 31, 2024, at Hebei General Hospital were included. Feature selection was performed using least absolute shrinkage and selection operator (LASSO) regression and multivariate logistic regression. Nine ML algorithms were tested, and model performance was assessed using receiver operating characteristic curve (ROC) analysis, including area under the curve (AUC), calibration curves, and decision curve analysis (DCA). The SHaply Additive Explanations (SHAP) algorithm was used to interpret the best-performing model and visualize key predictors.

Results: Among 847 patients with sepsis, 480 (56.7%) developed SIC. The random forest (RF) model with eight variables performed best, achieving AUCs of 0.782 [95% confidence interval (CI): 0.745, 0.818] in the training set, 0.750 (95% CI: 0.690, 0.809) in the testing set, and 0.784 (95% CI: 0.711, 0.857) in the validation set. Key predictors included activated partial thromboplastin time, lactate, oxygenation index, and total protein.

Conclusions: This ML model reliably predicts SIC risk. SHAP enhances interpretability, supporting early, individualized interventions to improve outcomes in patients with sepsis.

Background: Wilms tumor (WT) is the most common childhood renal malignancy, with recurrence linked to poor prognosis. Identifying the molecular features of tumor phenotypes that drive recurrence and discovering novel targets are crucial for improving treatment strategies and enhancing patient outcomes.

Methods: Single-nuclei RNA sequencing (snRNA-seq), spatial transcriptomics (ST), bulk RNA-seq, and mutation/copy number data were curated from public databases. The Seurat package was used to process snRNA-seq and ST data. Scissor analysis was applied to identify tumor subpopulations associated with poor relapse-free survival (RFS). Univariate Cox and LASSO analyses were utilized to reduce features. A prognostic ensemble machine learning model was developed. Immunohistochemistry was used to validate the expression of key features in tumor tissues. The CellChat and Commot package was utilized to infer cellular interactions. The PERCEPTION computational pipeline was used to predict the response of tumor cells to chemotherapy and targeted therapies.

Results: By integrating snRNA-seq and bulk RNA-seq data, we identified a subtype of Scissor+ tumor cells associated with poor RFS, predominantly derived from cap mesenchyme-like blastemal and fibroblast-like tumor subgroups. These cells displayed nephron progenitor signatures and cancer stem cell markers. A prognostic ensemble machine learning model was constructed based on the Scissor+ tumor signature to accurately predict patient RFS. TGFA was identified as the most significant feature in this model and validated by immunohistochemistry. Cellular communication analysis revealed strong associations between Scissor+ tumor cells and cancer-associated fibroblasts (CAFs) through IGF, SLIT, FGF, and PDGF pathways. ST data revealed that Scissor+ tumor cells were primarily located in immune-desert niche surrounded by CAFs. Despite reduced responsiveness to conventional chemotherapy, Scissor+ tumor cells were sensitive to EGFR inhibitors, providing insights into clinical intervention strategies for WT patients at high risk of recurrence.

Conclusion: This study identified a relapse-associated tumor subtype resembling nephron progenitor cells, residing in immune-desert niches through interactions with CAFs. The proposed prognostic model could accurately identify patients at high risk of relapse, offering a promising method for clinical risk stratification. Targeting these cells with EGFR inhibitors, in combination with conventional chemotherapy, may provide a potential therapeutic strategy for WT patients.

We report on a rare case of adult pro-B acute lymphoblastic leukemia (pro-B ALL) accompanied with severe refractory plaque psoriasis treated using autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy. An 18-year-old man with a known history of mild plaque psoriasis for 1 year was diagnosed with pro-B ALL. After induction chemotherapy, his psoriasis began to worsen. Extensive erythema and desquamation developed on the whole body, with severe plaque psoriasis on the knees and elbows, which did not respond to topical therapy. The application of CAR T-cell therapy not only enabled the patient to achieve deep complete remission (CR) but also allowed his skin lesions to completely subside. This successful treatment supports a potential pathogenic link between B cells and psoriasis, which could provide a new option for overcoming refractory psoriasis.