Frontiers in Immunology最新文献

Background: Metabolic reprogramming is a hallmark of hepatocellular carcinoma (HCC). Among various metabolic pathways, bile acids act not only as crucial metabolites but also as key signaling molecules that regulate diverse physiological and pathological processes in the liver. However, the biological functions and clinical implications of bile acid metabolism in HCC progression remain largely unclear.

Methods: Single-cell transcriptomic data from 67 patients with HCC were integrated to construct a bile acid metabolism scoring system. Pseudotime trajectory analysis was employed to characterize the differentiation patterns of cells exhibiting abnormal bile acid metabolism. Spatial transcriptomics was used to explore their spatial distribution features. Furthermore, machine learning algorithms were applied to analyze transcriptomic data from HCC cohorts to develop a prognostic prediction model. The findings were complemented by immune infiltration analysis, molecular characterization, and drug sensitivity prediction using CellMiner, followed by molecular docking validation.

Results: G6PD⁺ malignant tumor cells with high bile acid metabolism scores exhibited enhanced bile acid metabolic activity, accompanied by activation of macrophages and endothelial cells. These cells were predominantly localized at the tumor boundary region. A prognostic prediction model based on G6PD⁺ expression successfully identified a high-risk subgroup with significantly poorer outcomes. In vitro experiments demonstrated that knockdown or overexpression of G6PD markedly affected the proliferative, migratory, and invasive capacities of HCC cells.

Conclusion: This study reveals that bile acid metabolism promotes HCC progression by facilitating vascular network formation and establishing an immunosuppressive tumor microenvironment. The bile acid metabolism scoring system may serve as a novel prognostic biomarker and provide a theoretical foundation for developing precision therapeutic strategies in HCC.

In pediatric Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ B-ALL), the clinical value of highly sensitive minimal residual disease (MRD) detection by immunoglobulin next-generation sequencing (Ig-NGS), and its role for tracking clonal evolution, remains inadequately characterized. In this study, we evaluated MRD in a cohort of pediatric Ph+ B-ALL patients using Ig-NGS in parallel with conventional methods, including flow cytometry (FCM) and BCR-ABL reverse transcription polymerase chain reaction (RT-PCR). Malignant clonal burden at diagnosis, MRD kinetics, and immunoglobulin heavy chain (IGH) clonal evolution were analyzed for their prognostic relevance. We observed that a lower percentage of malignant clonal cells detected by Ig-NGS at diagnosis was associated with improved relapse-free survival (RFS) (p < 0.01). Ig-NGS-derived pre-treatment malignant clone burden showed stronger association with relapse risk compared with FCM or RT-PCR. Furthermore, Ig-NGS MRD negativity at the end of induction (EOI) was associated with superior two-yeas RFS (p = 0.01), and Ig-NGS detected molecular relapse earlier than FCM or RT-PCR in some patients. Specific IGHV and IGHJ gene usage patterns and the extent of V-replacement clonal evolution at diagnosis were also correlated with prognosis. In summary, these findings suggested that Ig-NGS based MRD assessment may provide enhanced prognostic stratification and enable dynamic monitoring of clonal evolution in pediatric Ph+ B-ALL. Its integration into routine clinical practice may enhance early relapse prediction and support more precise risk-adapted therapeutic decisions.

Background: Nasopharyngeal carcinoma (NPC) is an aggressive malignancy with endemic prevalence in southern China. Emerging evidence highlights the critical function of the N6-methyladenosine (m⁶A) methylation in NPC progression, where sustained cytokine activity contributes to immunosuppression and immune evasion.

Methods: Single-cell RNA sequencing (scRNA-seq) and bulk RNA sequencing datasets were obtained from the GEO database. High-dimensional downstream analyses, including hdWGCNA, cell-cell communication, and pseudotime analysis was performed to characterize cellular interactions and transcriptional programs. Machine learning algorithms and immune infiltration profiling were integrated with MeRIP-seq to identify the key m⁶A-regulated gene. The post-transcriptional regulatory role was further validated in NPC cells with overexpression or knockdown of METTL14, or in cells with YWHAH silenced.

Results: B cells were identified as the primary senders to the TNF pathway, with epithelial and myeloid cells acting as influencers and receivers. YWHAH emerged as a key TNF-associated, m⁶A-regulated gene, with elevated expression in naive/GC B cells, interleukin (IL)-1β+ tumor-associated macrophages, and differentiated epithelial cells. METTL14-deficient increased YWHAH transcript abundance and RNA stability, whereas TNF-α stimulation further enhanced YWHAH expression. Conversely, YWHAH knockdown impaired NPC cell migration and upregulated IL-6/IL-8 expression, effects that were partially rescued by TNF-α treatment.

Conclusion: Integration of multi-omics data facilitated the identification of YWHAH as a METTL14-regulated gene, which plays a pivotal role in the NPC immune microenvironment. The elevated expression of YWHAH indicates its role in regulating immune balance. Together these findings suggest a potential regulatory link between TNF-α, YWHAH and METTL14 in the context of NPC.

Objective: To evaluate the clinical relevance of the C-reactive protein/albumin ratio (CAR) in patients with autoimmune encephalitis (AE), with an emphasis on its predictive utility for disease severity, intensive care unit (ICU) admission, and functional outcomes.

Methods: A retrospective cohort of 114 patients with AE was analyzed. Serum C-reactive protein (CRP) and albumin (ALB) levels were measured within 24 hours of admission, and CAR was subsequently calculated. Disease severity was assessed using the Clinical Assessment Scale for Autoimmune Encephalitis (CASE) and the modified Rankin Scale (mRS) at discharge. Statistical analyses included the Mann-Whitney U test, Spearman correlation, logistic regression, and receiver operating characteristic (ROC) curve analysis to evaluate associations with ICU admission, respiratory failure, and disability.

Results: Patients requiring ICU admission exhibited significantly elevated CRP levels (11.00 vs. 2.40 mg/L, p < 0.001), reduced ALB levels (36.00 vs. 38.00 g/L, p = 0.029), and higher CAR values (0.282 vs. 0.064, p < 0.001). Comparable patterns were observed in patients with respiratory failure and severe disability (mRS ≥ 3). CAR demonstrated stronger correlations with both CASE score at admission (r = 0.448, p < 0.001) and mRS at discharge (r = 0.222, p = 0.018) than either CRP or ALB alone. Multivariate logistic regression analysis, adjusted for age, sex, CASE score, and other potential confounders, identified CAR (OR = 2.100; 95% CI: 1.151-3.831; p = 0.016), CRP (OR = 1.023; 95% CI: 1.004-1.042; p = 0.015), and ALB (OR = 0.875; 95% CI: 0.787-0.973; p = 0.013) as independent predictors of ICU admission. ROC curve analysis indicated high predictive accuracy for CAR (AUC = 0.835; cutoff = 0.125; sensitivity = 91.3%) and CRP (AUC = 0.820; cutoff = 4.35; sensitivity = 82.6%).

Conclusion: CAR represents a novel and readily accessible biomarker that outperforms CRP or ALB alone in predicting disease severity and the need for ICU care in patients with AE. Its incorporation into early clinical assessment protocols may enhance risk stratification and inform decisions regarding intensive care resource allocation.

Introduction: The immunological drivers of portal hypertension regression after hepatitis C virus (HCV) cure are poorly understood, particularly in the context of human immunodeficiency virus (HIV) coinfection We aimed to identify baseline immune signatures predicting the evolution of the hepatic venous pressure gradient (HVPG) in people with and without HIV (PWH/PWoH).

Methods: We prospectively followed 41 individuals with advanced cirrhosis (18 PWoH, 23 PWH) who were cured of HCV with direct-acting antivirals (DAA). Baseline plasma and cellular immune markers were extensively profiled using multiplex assays and flow cytometry. We used mixed-effects modeling to test for associations between these baseline immune features and the change in HVPG over a 48-week follow-up period, with q-values controlling for false discoveries.

Results: Two distinct immunological profiles of impaired HVPG regression emerged. In PWoH, impaired regression was linked to a broad proinflammatory profile [TNF-α (AMR = 1.13; q=0.012), IL17A (AMR = 1.28; q=0.012), and IL10 (AMR = 1.2; q=0.028)], a widespread total CD4+ T-cell activation [HLA-DR+ (AMR = 1.44; q<0.001) and CD38+HLA-DR+ (AMR = 1.3; q=0.007)], and robust activation across central memory (CM) and effector memory (EM) subsets. Conversely, in PWH, impaired HVPG regression was associated with sVCAM-1 (AMR = 1.58; q=0.096), and a more focused activation within EM (HLA-DR+, AMR = 1.08; q=0.030) and TemRA (CD38+HLA-DR+, AMR = 1.12; q=0.030) CD4+ T-cells.

Discussion: HIV coinfection fundamentally reshapes the immunological landscape of post-cure portal hypertension recovery. The shift from systemic inflammation in PWoH to endothelial dysfunction and T-cell exhaustion in PWH reveals distinct pathological pathways. Understanding these signatures is a crucial step toward developing targeted therapies to promote complete hepatic recovery.

Arrhythmia is a prevalent complication associated with various cardiovascular diseases. The onset of cardiac disease or injury can impair the normal function of cardiomyocytes, thereby precipitating arrhythmic events. Moreover, non-cardiomyocytes, including immune cells, may also play a contributory role in arrhythmogenesis. For instance, processes such as the infiltration of inflammatory cells that secrete pro-inflammatory mediators, fibroblast-to-myofibroblast transformation, and endothelial-to-mesenchymal transition have all been implicated in this process. Recent investigations have identified a distinct subset of resident macrophages within cardiac tissue that exhibit functional properties differing from those of bone marrow-derived macrophages. Cardiac tissue-resident macrophages (CRMs) are distinguished from bone marrow-derived macrophages by their developmental origin, transcriptomic profile, and functional traits. Beyond their canonical immune functions shared with bone marrow-derived macrophages, CRMs uniquely contribute to cardiac homeostasis by exerting direct electrophysiological modulation via ion channels and gap junctions. This constitutes a distinct mechanism underlying their role in arrhythmogenesis. Advanced methodologies, such as patch-clamp electrophysiology, high-throughput sequencing, and proteomic analyses in mammalian models, have revealed the complex electrophysiological interactions between CRMs and cardiomyocytes. While both CRMs and bone marrow-derived macrophages play roles in arrhythmia initiation and progression, existing reviews have primarily focused on bone marrow-derived macrophages. This review seeks to clarify the electrophysiological properties of CRMs and to delineate the specific mechanisms through which these cells contribute to arrhythmogenesis, thereby providing novel perspectives for the development of anti-arrhythmic therapeutic strategies.

Introduction: Systemic lupus erythematosus (SLE) is a chronic autoimmune disease affecting multiple organs. Some patients still develop severe refractory SLE despite conventional treatments. Belimumab, a biologic targeting B lymphocyte stimulator (BLyS), shows therapeutic promise in SLE, but its effects on pediatric patients remain unclear.

Methods: This study used CyTOF to analyze immunophenotypic changes before and after belimumab treatment and investigate immune features in refractory SLE.

Results: Results showed that belimumab treatment primarily reduced transitional and naïve B cells, and also decreased age-associated B cells (ABCs), a subset implicated in autoimmunity or chronic inflammation. Plasma cells and plasmablasts persisted in refractory cases. CD38 expression on B cells was elevated in severe disease and correlated with disease activity, while CD73 expression increased during recovery and inversely correlated with activity.

Discussion: These findings indicate that combining belimumab with conventional therapy induces significant immune modulation, particularly within B cells. Persistent plasma cells and plasmablasts may contribute to disease refractoriness. CD38 and the CD73-mediated adenosine pathway may provide insights for future research strategies in SLE.

Urinary tract infections (UTIs) cause a high economic burden with frequent medical visits, and in severe cases can lead to hospitalization due to complications like bacteremia or sepsis. UTIs are treated with antibiotics; however, this contributes to the emergence of antimicrobial resistant (AMR) bacterial strains because of misuse and overuse of antibiotics. Uropathogenic E. coli (UPEC) is the most common cause of UTIs and is commonly associated with antibiotic resistance. Several host defense mechanisms including the urothelial barrier, antimicrobial peptides, and complement protect the urinary tract from infection. If UPEC is encountered, a pro-inflammatory immune response starts to combat the infection, with antimicrobial peptides and protein as a first line of defense followed by the activation of the innate and adaptive immune responses. These innate and adaptive immune responses are sometimes inadequate during established UTI, and recurrence of UTI is common. In addition, an overactivation of the immune response to UPEC causes immunopathologic damage to tissues and cells. Anti-E. coli vaccines have been proposed as an ideal approach both to improve the immune response to infection and to limit the emergence and spread of AMR strains. Currently, a few UTI vaccines have been licensed in a couple of countries but are not broadly approved and novel vaccines are being explored. In this review, we focus on the pro-inflammatory response to UPEC infections and the immunopathologic effects of an overactive pro-inflammatory response during UTIs in humans. We highlight the components of the immune response during UTI that can be utilized for the development of a preventative UPEC vaccine.

Objective: To assess platelet-to-lymphocyte ratio (PLR) prognostic utility for overall (OS) and progression-free survival (PFS) in immune checkpoint inhibitor-treated cancer patients, and examine impacts of geography, cancer type, cutoff, ICI class, treatment line and stage.

Methods: A systematic literature search identified studies investigating PLR and prognosis in ICI treated patients. Hazard ratios (HRs) with 95% confidence intervals (CIs) were pooled using random-effects models. Subgroup analyses examined key covariates; publication bias was assessed.

Results: Analysis of 98 publications (86 OS, 72 PFS) demonstrated that elevated PLR was a robust predictor of shorter OS (HR 1.79, 95% CI: 1.60-2.00) and PFS (HR 1.60, 95% CI: 1.44-1.78). Subgroup analyses revealed: (1) Geographic region: Asian populations exhibited the most consistent correlation with OS and the highest PFS risk (69%). (2) Cancer type: For OS, prognostic value was maintained across all cancers; the most pronounced impacts were observed in hepatocellular carcinoma (HR 2.10), esophageal carcinoma (HR 2.08), and head and neck squamous cell carcinoma (HR 2.61). For PFS, a notable link to poor outcomes was observed in NSCLC and hepatocellular carcinoma, whereas renal cell carcinoma showed no such correlation. (3) PLR cutoff: both PLR ≥180 (OS: HR 1.87; PFS: HR 1.68) and PLR <180 (OS: HR 1.73; PFS: HR 1.53) subgroups consistently yielded unfavorable outcomes. (4) ICI category: for OS, camrelizumab showed the strongest prognostic relevance (HR 4.68), whereas for PFS, all ICIs yielded consistent results. (5) Treatment line: both first-line (OS: HR 1.98; PFS: HR 1.93) and second-line or beyond (OS: HR 1.87; PFS: HR 1.79) demonstrated clear prognostic utility without inter-subgroup differences. (6) Tumor stage: Advanced stages (III-IV, IIIB-IV, IV) confirmed the predictive value of PLR for both OS and PFS. (7) Cancer Subtypes: PLR remained prognostic in nivolumab-treated, stage IV genitourinary cancers; correlated with survival in pembrolizumab-treated but not nivolumab-treated NSCLC; and remained predictive in camrelizumab-treated/advanced gastrointestinal tumors. Notably, elevated PLR was uniquely associated with worsened OS and PFS in nivolumab-treated renal cell carcinoma.

Conclusions: Elevated PLR is consistently associated with shortened OS across the cancer types receiving ICIs, while its prognostic value for PFS fluctuates depending on cancer type and ICI class. The prognostic impact of PLR is particularly robust in the nivolumab-treated RCC, pembrolizumab-treated NSCLC, camrelizumab-treated gastrointestinal tumors, and various advanced-stage malignancies.

Systematic review registration: https://www.crd.york.ac.uk/prospero/.