American journal of clinical and experimental immunology最新文献

Granzyme B (GrB)-producing B cells have dual roles in tumor immunity, either killing tumor cells or suppressing antitumor responses by eliminating effector T cells. In this study, we aimed to investigate how breast cancer cells influence GrB-producing B cells from tumor-draining lymph nodes and whether B cell activation enhances their cytotoxic potential. Mononuclear cells were isolated from 14 fresh axillary lymph node samples by density gradient centrifugation using Ficoll-Hypaque. Lymphocytes were co-cultured with breast tumor cell lines (MCF-7 and MDA-231) in the presence of recombinant interleukin-21 (rIL-21) and anti-B cell receptor (BCR). B cell granzyme B production was measured by flow cytometry, while tumor cell (MCF-7) apoptosis was assessed using calcein AM release assays. Direct co-culture of lymphocytes with MCF-7 or MDA-MB-231 significantly reduced the frequency of GrB-producing B cells (P=0.001 and P=0.031, respectively), while tumor supernatants alone had no effect. When B cells were pre-stimulated with IL-21 and anti-BCR for 24 hours before direct co-culture, GrB expression was maintained at baseline levels (no significant difference vs. control). Additionally, B cells activated with IL-21 and anti-BCR caused significant apoptosis in MCF-7 cells (38±8.9%, P=0.023). In conclusion, breast cancer cells suppress GrB⁺ B cell responses via direct contact, but this suppression is reversible through B cell activation. Importantly, pre-activated B cells exhibit direct cytotoxic activity against tumor cells, highlighting their potential as an effector population for breast cancer immunotherapy.

Despite advances in screening and therapy, colorectal cancer (CRC) remains a leading cause of cancer-related mortality worldwide, underscoring the need for early detection and for predicting treatment efficacy. This review highlights circulating cell-free DNA (cfDNA) fragmentomics as a promising non-invasive approach for tumor detection and disease monitoring. We focus on fragmentomic features - such as fragment size distributions, fragment-end motifs, and epigenetic signals - which, when integrated into machine-learning models, have shown strong performance in distinguishing patients with CRC from healthy controls. Emerging evidence indicates that, these signatures may support early-stage detection, track disease progression, and predict pathologic complete response (pCR), thereby enabling more personalized treatment strategies. We also discuss the potential role of fragmentomics in non-operative management, including "watch-and-wait" approaches. However, important gaps remain in clinical translation; prospective trials and standardized assays/analysis pipelines are required to validate these findings and define their real-world utility.

This study was carried out to analyze the time-dependent changes of Wnt3a/β-catenin signaling during lupus nephritis (LN). At the age of 5 weeks, 30 female MRL/lpr mice and C57BL/6 (C57) mice were randomly grouped. Moreover, 12 females MRL/lpr mice were split into two groups, cyclophosphamide treatment (LN-CTX) and one was untreated. Mice in the LN-CTX group were injected intraperitoneally with cyclophosphamide (CTX) from the age of 16 wk. Urinary protein, serum antinuclear antibodies (ANA), and anti-double-stranded DNA (dsDNA) antibody levels were measured. The detection of renal injury was later confirmed through histopathology, and immunofluorescence analysis. Compared with C57 mice, LN mice had much higher levels of 24-hour urinary protein, ANA and dsDNA antibodies (P<0.05). Histological examination exhibited the proliferation of mesangial cells with the invasion of inflammatory cells, while deposition of immune complex was shown to reach the peak at 28 weeks. The production of Wnt3a and β-catenin proteins and mRNA was significantly increased in the kidneys of LN mice. In contrast, 24-hour urinary protein, ANA and dsDNA antibodies levels decreased significantly and CTX treatment caused a drop in the aforementioned immune response (P<0.05). Renal histopathological changes and immune complex deposition were ameliorated by CTX treatment. the renal levels. Notably, the renal levels of Wnt3a/β-catenin at LN-CTX were found to be lower than that in the untreated LN group. The abnormal activation of the Wnt/β-catenin signaling pathway may play a role in LN formation and thus important molecular target for CTX drug. This research shows that CTX inhibits renal Wnt3a/β-catenin activation in LN mice for the first time, offering a potential molecular mechanism for its renoprotective effects.

Background: This study investigated whether the combined treatment of melatonin and tofacitinib offers enhanced protection against dextran sulfate sodium-induced acute colitis (AC) in rats. Using CCD-18Co fibroblasts and a rat colitis model, we assessed the anti-inflammatory, anti-apoptotic, and immunomodulatory effects of the combination therapy.

Methods: CCD-18Co cells were grouped as A1 (CCD-18Co), A2 (CCD-18Co + lipopolysaccharide (LPS)), A3 (CCD-18Co + LPS + Melatonin), A4 (CCD-18Co + LPS + Tofacitinib), or A5 (CCD-18Co + LPS + melatonin + tofacitinib). Sprague-Dawley rats were categorized into groups 1 (normal control), 2 (AC), 3 (AC + melatonin), 4 (AC + tofacitinib), and 5 (AC + melatonin + tofacitinib), and the colons were harvested 14 days after AC induction.

Key findings: Cell viability at time points of 24, 48, and 72 h was the highest in A1, lowest in A2, and progressively increased from A3 to A5 (all P < 0.0001). The protein expression levels of inflammatory, DNA-damaged, and autophagic (ratio of LC3-BII to LC3-BI) biomarkers displayed identical patterns of apoptosis among the groups (all P < 0.0001). Additionally, the blood stool, colon leakage, and colon injury scores were the lowest in group 1, highest in group 2, and significantly progressively reduced from groups 3 to 5 (all P < 0.0001). The protein expression of the Janus kinase family-signal transducer and activator of transcriptions/cell-stress signaling, inflammation, oxidative stress, DNA-damaged, apoptotic biomarkers, and cellular expression of immune and inflammatory factors exhibited an identical pattern of colon injury scores among the groups.

Conclusions: Combined melatonin-tofacitinib treatment effectively protected the colon against dextran sulfate sodium-induced damage, mainly through the suppression of Janus kinase family-signal transducer and activator of transcriptions/cell-stress signaling, inflammation, and oxidative stress.

Successful implantation and pregnancy rely on complex interactions between the embryo and the maternal reproductive tract. Seminal plasma components, including proteins, cytokines, and growth factors, are pivotal in enhancing endometrial receptivity and inducing maternal immune tolerance to the developing conceptus. Exposure to seminal plasma facilitates pathogen clearance, supports embryo development, and modulates immune responses by altering the endometrial transcriptome and promoting regulatory T cell (Treg) expansion. Proteomic studies have identified seminal plasma factors involved in these processes. Changes in the immunomodulatory components of seminal plasma can diminish its positive effects on the endometrium, potentially resulting in reduced fertility and increased risk of adverse pregnancy outcomes. This review explores how seminal plasma influences maternal immune responses and highlights the clinical implications, particularly its potential to improve outcomes in assisted reproductive technologies (ART) like in vitro fertilization (IVF). Understanding the molecular dialogue between seminal plasma and the endometrium may lead to new strategies for enhancing fertility and promoting healthy pregnancy.

Background: Prostate cancer (PRAD) poses a significant threat to male health. The tumor microenvironment (TME) plays a crucial role in its development process, yet the regulatory significance of specific extracellular matrix proteins such as Dermatopontin (DPT) in PRAD remains poorly understood.

Methods: A total of 534 PRAD transcriptome profiles were retrieved from The Cancer Genome Atlas (TCGA) database. CIBERSORT and ESTIMATE computational methods were used to quantify the presence of immune and stromal components. Differentially expressed genes (DEGs) were identified based on ImmuneScore and StromalScore, followed by Gene Ontology (GO) and Kyoto Encyclopedia of Genomes (KEGG) pathway enrichment analyses. DPT expression was analyzed in relation to overall survival, TNM staging, immune-related pathways using Gene Set Enrichment Analysis (GSEA), and tumor-infiltrating immune cells (TICs).

Results: A total of 454 DEGs overlapping between high ImmuneScore and StromalScore groups were enriched in immune-related processes and pathways. DPT expression was positively correlated with the survival of PRAD patients, especially the N Stage of PRAD. GSEA revealed that high DPT expression correlated with immune-related activities such as allograft rejection, apical junction, complement, and epithelial mesenchymal transition while low DPT expression was correlated with metabolic pathways such as E2f targets, G2m checkpoint, mitotic spindle, and mitorc1 signaling. Analysis of TICs showed that DPT expression was positively correlated with resting mast cells and neutrophils. Conversely, regulatory T cells, M1 macrophages, M2 macrophages, and resting dendritic cells exhibited negative correlations with DPT expression.

Conclusions: DPT may serve as a novel prognostic biomarker in PRAD, potentially affecting the survival of PRAD patients by regulating the immune environment of TME. These findings provide new insights into the immunomodulatory role of DPT and its potential as a therapeutic target for PRAD.

This study aimed to investigate the relationship between immunosenescence and osteoarthritis (OA) and analyze its potential clinical implications. Thus, we conducted transcriptome sequencing by collecting clinical meniscus (Aging_meniscus:Control_meniscus = 3:7) and cartilage tissues (Aging_cartilage:Control_cartilage = 2:6). Meanwhile, immune-related genes (IRGs) and aging-related genes (ARGs) were included in this research. The differentially expressed genes (DEGs) between Aging_meniscus and Control_meniscus as well as Aging_cartilage and Control_cartilage were analyzed by differential analysis, respectively. Then, differentially expressed IRGs (DEIRGs) were generated by crossing DEG with IRGs. Similarly, differentially expressed ARGs (DEARGs) were achieved by intersecting DEG and ARGs. To obtain genes simultaneously associated with immune and aging in both meniscus and cartilage samples, biomarkers were screened out by crossing share.IRGs and share.ARGs overlapped by DEIRGs1 and DEIRGs2 as well as DEARGs1 and DEARGs2, respectively. In addition, the biomarkers' functions were analyzed by gene set enrichment analysis (GSEA). To detect the regulatory mechanism, a miRNA-mRNA-transcription factors (TFs) regulatory network and a X2K network were constructed. Moreover, disease association analysis and potential small molecule drugs for biomarkers were also performed to further reveal the possible role of biomarkers for OA. Then, 3 biomarkers, namely Insulin-like Growth Factor 1 Receptor (IGF1R), Interleukin 7 receptor (IL7R) and Leptin receptor (LEPR), were selected out through the intersection of 14 share.IRGs and 4 share.ARGs. And they were all enriched in 'ribosome' from both meniscus and cartilage samples, and had complex regulatory networks. In all, the expression of IGF1R was markedly up-regulated in OA (P < 0.05). Eventually, mecasermin could stably bind to IGF1R and simvastatin could stably bind to LEPR. It suggested that mecasermin and simvastatin may exhibit significant clinical potential in treating immunosenescence-related OA.

Cell-free DNA (cfDNA) fragmentomics has emerged as a powerful and noninvasive approach for cancer detection, characterization, and monitoring. By analyzing genome-wide fragmentation patterns - including fragment length distributions, end motifs, nucleosome footprints, and copy number variations - cfDNA fragmentomics provides high-resolution insights into tumor-specific biological signals even at low tumor burden. This technology offers advantages over conventional mutation-based assays by capturing aggregate structural and epigenomic alterations without requiring prior knowledge of driver mutations. In non-small cell lung cancer (NSCLC), cfDNA fragmentomics enables early detection, discrimination of malignant pulmonary nodules, and post-surgical monitoring of minimal residual disease. Recent studies have demonstrated that fragmentomic risk scores can accurately stratify recurrence risk and improve prognostic sensitivity beyond traditional genomic assays. In hepatocellular carcinoma (HCC), integration of fragment size selection, CNV profiling, and end-motif analysis has led to high-performing models for early diagnosis, particularly in high-risk populations. Moreover, cfDNA fragmentomics has proven effective in detecting malignant transformation in patients with neurofibromatosis-associated peripheral nerve sheath tumors, distinguishing benign from premalignant or malignant lesions with high precision. Expanding beyond these major cancers, fragmentomic approaches have demonstrated diagnostic potential in gastric, urological, hematologic, and pediatric malignancies. Notably, the DELFI-TF (DNA Evaluation of Fragments for early Interception-Tumor Fraction) framework has shown prognostic relevance by correlating pre-treatment cfDNA features with survival outcomes in colorectal and lung cancer patients, outperforming conventional imaging. All of these results highlight the translational importance of cfDNA fragmentomics as a cutting-edge precision oncology tool. Its continued integration into clinical workflows may redefine early cancer detection, facilitate subtype-specific interventions, and enable real-time, individualized treatment monitoring.

Lymph nodes are essential for immune function as they contain immune cells that activate responses and filter pathogens from lymph. This study investigates how diabetes-related metabolic challenges affect immune function, focusing on the impact of Lactobacillus probiotics on lymph node responses to meningococcal vaccines in thirty male Albino rats with Streptozotocin-induced diabetes, established two weeks before vaccination. The diabetic rats were divided equally and randomly into three groups: one untreated (UD group), one receiving two shots of the meningococcal vaccine (DM group), and one receiving the same vaccination regimen alongside oral doses of Lactobacillus rhamnosus probiotics (DML group). We monitored the rats' weights and measured the expression levels of inflammatory cytokines (IL-1β, TNF-α, and IL-2) in their lymph nodes as markers of immune activation after vaccination. Diabetic rats vaccinated against meningococcal disease showed increased levels of IL-1β and TNF-α, which showed a significant reduction by Lactobacillus supplementation after three weeks. However, following the second vaccination, Lactobacillus significantly increased IL-1β and TNF-α levels. Also, Lactobacillus appeared to modulate the initial spike in IL-2, with a notable increase observed five weeks after the second vaccine dose. Notably, the vaccination protocol did not affect the body weight of the diabetic rats. These findings suggest that while the vaccine elevates inflammatory cytokine levels in the lymph nodes of diabetic rats, Lactobacillus may help mitigate these responses and regulate IL-2 levels, indicating its potential value in enhancing diabetes management, optimizing vaccine effectiveness, and addressing autoimmune issues in diabetic individuals.

Background: The tumor microenvironment (TME) of breast cancer (BRCA) influences disease progression through dynamic interactions between immunity and stroma, but its key regulatory molecules and prognostic value remain to be elucidated. The aim of this study was to explore the prognostic potential of immunoglobulin λ-like polypeptide 5 (IGLL5) in BRCA and its association with immune infiltration in TME.

Methods: 1178 BRCA cases were obtained from The Cancer Genome Atlas (TCGA) database. CIBERSORT and ESTIMATE computational methods were used to quantify the composition of tumor-infiltrating immune cells (TICs) and the presence of immune and stromal components. Prognostic indicator closely associated with BRCA was identified by Cox regression analysis and protein-protein interaction (PPI) network construction. Through Gene Set Enrichment Analysis (GSEA) and other means, the correlations between IGLL5 expression and patient survival, immune activities, metabolic pathways, and immune cell types were studied.

Results: Overall survival was significantly prolonged in patients with high IGLL5 expression (HR=0.62, 95% CI 0.45-0.86, P=0.013) and positively correlated with immune-activating pathways (complement signaling, interferon response) and anti-tumor TICs (CD8⁺ T cells, M1 macrophages) (r>0.3, P<0.001) and negatively correlated with tumor-promoting TICs (M2 macrophages, resting NK cells). The low IGLL5 group was enriched in metabolic pathways (estrogen response, oxidative phosphorylation), suggesting that it may promote immune escape through metabolic reprogramming.

Conclusion: IGLL5 is a novel prognostic marker for BRCA, and its expression level affects patient survival by modulating TME immune infiltration and metabolic reprogramming. This study provides a theoretical basis for IGLL5-directed immunotherapeutic strategies (e.g., combining PD-1 inhibitors), and its mechanism needs to be verified by multicenter clinical cohorts and functional experiments in the future.