Frontiers in Immunology最新文献

Sepsis-induced acute lung injury (S-ALI) represents a life-threatening condition with complex molecular pathophysiology and limited therapeutic options. Emerging evidence highlights the critical role of competing endogenous RNA (ceRNA) networks, particularly long non-coding RNA (lncRNA)-microRNA (miRNA)-mRNA axes, in orchestrating cell type-specific responses during S-ALI. This review synthesizes recent advances illustrating how these regulatory circuits modulate alveolar epithelial apoptosis, endothelial permeability, macrophage polarization, and neutrophil infiltration, thereby driving inflammation, barrier dysfunction, and immune dysregulation. Furthermore, we explore the promising therapeutic potential of engineered extracellular vesicles for targeted delivery of ceRNA components-such as miRNA mimics or lncRNA inhibitors-to precisely manipulate these networks. Despite progress, significant challenges remain, including model translatability, functional redundancy, and delivery efficiency. Overcoming these hurdles may unlock novel strategies for treating S-ALI, moving toward personalized and context-specific interventions.

[This corrects the article DOI: 10.3389/fimmu.2025.1644885.].

Introduction: Non-small cell lung cancer is the leading cause of cancer-related mortality worldwide, with lung adenocarcinoma (LUAD) as the most common subtype. Although early-stage disease is often treated surgically, advanced LUAD typically requires chemotherapy, radiation, and/or immunotherapy, largely focused on T cell-mediated responses. Therapeutic efficacy, however, is also shaped by tumor-infiltrating (TI) B cells, whose roles in LUAD remain incompletely understood.

Methods: We performed cytometry by time of flight (CyTOF) using 44 markers on matched tumor, adjacent lung, and peripheral blood samples from 48 LUAD patients to define TI immune landscapes. 66 immune cell subsets were identified, and patients were stratified into four groups based on TI cell composition. Adaptive immune receptor repertoire sequencing (AIRR-seq) of IgM and IgG was conducted on matched samples from 29 patients to assess clonal expansion and affinity maturation. Subisotype-resolved AIRR-seq was additionally performed on tumor samples from 18 patients.

Results: CyTOF analysis revealed four patient groups with distinct TI immune profiles. AIRR-seq demonstrated increased clonal expansion and affinity maturation in tumors compared to adjacent lung and blood. Tumor-specific IGHV enrichment patterns were observed but were not associated with patient group assignment. Instead, clonal expansion was greatest in tumors with higher lymphocyte proportions. Subisotype-resolved analysis showed enrichment of IGHG2 and IGHG3 in tumors from patients with low TI B cell abundance, whereas IGHG4 was enriched in patients with high TI B cell infiltration and correlated with four CyTOF-defined immune subsets.

Discussion: These findings reveal substantial inter-individual variation in TI immune landscapes and highlight distinct B cell repertoire and subisotype features within LUAD tumors. Together, these data suggest that B cell composition and antibody subisotype usage may contribute to immune contexture and could inform the development of more tailored immunotherapeutic strategies in LUAD.

Background: Esophageal squamous cell carcinoma (ESCC) carries a high risk of recurrence after neoadjuvant immunochemotherapy and surgery. Both host inflammatory-nutritional status and circulating tumor markers may jointly influence clinical outcomes. We evaluated the prognostic value of the Advanced Lung Cancer Inflammation Index (ALI) and a composite Tumor Load Index (TL) to refine risk stratification in this setting.

Methods: We retrospectively analyzed 460 consecutive ESCC patients who received 2-3 cycles of PD-1 inhibitor plus platinum/taxane-based chemotherapy followed by esophagectomy. ALI was calculated as BMI × albumin/NLR. TL was derived via LASSO Cox regression from pre-treatment SCC-Ag, CEA, and CA19-9. Optimal cutoffs were identified using maximally selected rank statistics (ALI: 31.22; TL: 0.224). Patients were categorized as low-risk (high ALI/low TL), intermediate-risk (high ALI/high TL or low ALI/low TL), and high-risk (low ALI/high TL). Endpoints included overall survival (OS), disease-free survival (DFS), pathologic complete response (pCR), and major pathologic response (MPR).

Results: With a median follow-up of 42 months, 3-year OS rates were 84.7%, 66.0%, and 34.6% for the low-, intermediate-, and high-risk groups, respectively (log-rank P < 0.001). Corresponding 3-year DFS rates were 75.4%, 61.6%, and 29.0%. In multivariable Cox models, intermediate- and high-risk groups had progressively worse OS (adjusted HR = 2.11 and 3.43) and DFS (adjusted HR = 1.64 and 2.62) compared with the low-risk reference (all P < 0.01). High-risk status independently predicted lower odds of achieving MPR (adjusted OR = 0.34, P = 0.002) and pCR (OR = 0.07, P = 0.011). A prognostic nomogram integrating risk group, ASA score, MPR, and ypN status showed strong discrimination (C-index = 0.742) and favorable calibration for 2-, 3-, and 4-year OS, with time-dependent AUCs of 0.759, 0.789, and 0.712.

Conclusions: Pre-treatment ALI and TL jointly provide robust and complementary prognostic information in ESCC patients receiving neoadjuvant immunochemotherapy. Low ALI combined with high TL identifies a biologically aggressive subset with poor pathologic response and inferior survival. Integration of ALI and TL may facilitate risk-adapted perioperative strategies and personalized treatment optimization.

Background: Bladder cancer (BLCA) is a prevalent genitourinary malignancy characterized by high recurrence and mortality rates. While mannose metabolism has demonstrated anti-tumor potential across various cancers, its role in BLCA remains underexplored. This study examines the influence of mannose metabolism on BLCA prognosis.

Methods: BLCA-related datasets and genes associated with mannose metabolism (MMRGs) were obtained from public databases. Candidate genes were identified by overlapping differentially expressed genes with MMRGs. Prognostic genes were pinpointed using ten machine learning algorithms and regression analysis to develop a risk model, which was subsequently validated. A nomogram was constructed by integrating the risk score with clinical features, and its predictive accuracy was assessed. We performed functional enrichment, drug sensitivity, reverse transcription-quantitative polymerase chain reaction (RT-qPCR), Western blotting, immunohistochemistry, and immune infiltration analyses. Key cellular components were identified, and further analyses, including pathway enrichment, pseudo-temporal analysis, and cell communication, were performed.

Results: CALR, SLMAP, PFKFB4, and TMTC1 were identified as prognostic genes in BLCA. Notably, the expression of SLMAP and TMTC1 was significantly downregulated in BLCA, whereas PFKFB4 and CALR were upregulated. These findings were consistently validated by RT-qPCR, Western blotting, and immunohistochemical analyses (p < 0.05). The risk model stratified patients into a high-risk group (HRG) and a low-risk group (LRG), with HRG patients exhibiting significantly poorer survival outcomes. The risk score was identified as an independent prognostic factor, and the nomogram demonstrated high diagnostic accuracy. Notable differences between HRG and LRG patients were observed in the "Ribosome" pathway. Additionally, 86 chemotherapeutic drugs exhibited significant differential responses between HRG and LRG, with 23 immune cell types showing differential abundances, including activated dendritic cells (p < 0.05). Single-cell analysis revealed macrophages as key cells in BLCA, which were classified into five subtypes, with CALR, SLMAP, and PFKFB4 influencing their expression.

Conclusion: Four mannose metabolism-related prognostic genes were identified in BLCA, and macrophages were confirmed as critical cells. These findings provide valuable insights for improving prognostic assessment in BLCA.

Staphylococcus aureus second immunoglobulin-binding protein (Sbi) is a unique type 2-promoting virulence factor that induces IL-33 and thymic stromal lymphopoietin (TSLP) release. This mechanism is essential for the development of S. aureus-induced eczema in the widely used NC/Tnd mouse model of human atopic dermatitis (AD). Microbiome shifts in AD suggest that microbiota could modulate the disease. We therefore sought to identify skin bacteria that attenuate S. aureus-induced IL-33/TSLP release from keratinocytes. Micrococcus luteus was unique among skin isolates in its ability to negate cytokine induction. The bioactive factor responsible was identified using fractionation, LC-MS and recombinant proteins, as the serine protease "PA domain protein" (PADP). Immunoblotting and ELISA confirmed Sbi and IL-33 degradation by PADP. This was not observed with the M. luteus type strain which contains a frame shift mutation within the PADP active site. These data provide new insights into the role of skin microbiota in AD and highlights their potential as topical therapeutics.

Introduction: Malaria caused by P. vivax continues to be a serious public health problem, especially in countries like Brazil where P. vivax accounts for more than 80% of diagnosed cases. Since this plasmodial species is characterized as one of the most difficult to eliminate, the development of a specific vaccine for P. vivax may be an essential tool for effective control of the disease. The protein Ripr has been described in P. falciparum as an essential part of the erythrocyte invasion complex. Given the limited number of P. vivax vaccine antigens currently under investigation, this study aimed to characterize, the naturally acquired humoral immune response to Ripr protein of P. vivax.

Methods: ELISA assays were performed using plasma samples from individuals naturally exposed to malaria in the Brazilian Amazon in order to determine levels of IgM, IgG and IgG subclasses against PvRipr. In addition, linear B-cell epitopes within the protein were identified.

Results and discussion: Our results demonstrated that PvRipr is naturally immunogenic, as more than 60% of the individuals presented IgM or IgG antibodies against recombinant PvRipr. The profile of IgG subclasses was also investigated and higher frequencies of seropositive individuals for IgG1 and IgG2 were observed. After in silico prediction, a total of four linear B cell epitopes were identified in PvRipr, from these sequences, B-PvRipr_(879-888) and B-PvRipr_(923-958) had higher frequencies of seropositive individuals and reactivity indexes in comparison to the other tested epitopes. Moreover, levels of IgG antibodies specific for these two epitopes were strongly correlated with the levels of IgG antibodies against recombinant PvRipr and especially with IgG3 antibodies, a cytophilic subclass widely cited in the protective immune response against malaria.

Background: Hepatocellular carcinoma (HCC) patients with Clonorchis sinensis (Cs) infection tend to exhibit a poorer prognosis compared to those without infection. Nevertheless, the molecular mechanisms underlying Cs-associated HCC, particularly those linked to metastatic progression, remain poorly understood. This study therefore seeks to elucidate the role of C. sinensis infection in promoting metastasis.

Methods: Through a clinical retrospective analysis, we compared overall survival and metastasis incidence between HCC patients with and without Cs infection. To explore the underlying mechanisms, we conducted integrated multi-omics analyses-including RNA-seq, miRNA-seq, ATAC-seq, WGBS-seq, oxWGBS-seq, and ChIP-seq-to profile 369 metastasis-related genes in Cs ⁺ and Cs ^- HCC tumors. The expression of three key metastasis-related genes was further validated by RT-qPCR, and Transwell and wound-healing assays were performed in vitro to confirm the pro-metastatic effect of Cs infection on HCC cells.

Results: In HCC patients, Cs infection was associated with poorer overall survival and an increased metastasis rate. We identified 20 metastasis-related genes, with SPP1, MMP2, and VCAM1 as central hubs, together with 41 interacting miRNAs and 71 accessible promoter regions. Histone modifications-particularly H3K9ac, H3K27ac and H3K4me3-were correlated with chromatin accessibility in the promoters of these genes. Molecular experiments further demonstrated that Cs infection enhances the metastatic potential of HCC.

Conclusions: Our study reveals that Cs infection promotes HCC metastasis through gene and epigenetic alterations, providing mechanistic insights and identifying potential targets for early intervention.

Background: Atopic dermatitis (AD) is a chronic, pruritic, inflammatory skin disorder. While the stem of Schisandra chinensis has been extensively studied for its pharmacological properties, including anti-inflammatory, antioxidant, and hepatoprotective effects, its therapeutic potential in AD remains to be elucidated. This study therefore aimed to investigate the effects of Schisandra chinensis stem extract (SCSE) against AD and to explore its underlying mechanism of action.

Methods: Chemical profiling of SCSE via UPLC-Q-Exactive-Orbitrap-MS revealed 45 constituents, with lignans comprising 80%. The primary active component was identified through activity-guided assays employing hyaluronidase inhibition and HPLC. The therapeutic efficacy of SCSE and its constituent Schisandrin B (Sch B) was assessed in an AD mouse model. Furthermore, network pharmacology predicted the involved signaling pathways, and these predictions were subsequently validated experimentally.

Results: Sch B was identified as the core active component. Both SCSE and Sch B significantly improved skin barrier function in AD mice, as evidenced by reduced transepidermal water loss (TEWL) and upregulation of key barrier proteins (Filaggrin, Loricrin, and Claudin-1). They also alleviated pruritus by suppressing Transient Receptor Potential Vanilloid 1 (TRPV1) and mitigated the allergic-inflammatory response, as shown by reduced Immunoglobulin E (IgE) levels and inhibited release of mast cell (MC) mediators (IL-4, IL-6, TNF-α). These effects were potentially mediated through modulation of the NF-κB pathway.

Conclusion: By simultaneously mitigating skin barrier dysfunction, immune inflammation, and pruritus, SCSE and Sch B hold promise as therapeutic candidates capable of disrupting the self-perpetuating cycle of AD. These findings position SCSE and Sch B as a novel therapeutic strategy for this disease.