Frontiers in Immunology最新文献

Goblet cell hypersecretion is a hallmark of airway inflammation and is driven by complex neuroimmune regulation involving submucosal glands and goblet cells. Although studies have focused on mast cell degranulation as a critical driver of nasal secretion, the role of goblet cells in this process is relatively under-researched. In allergic airway inflammation, goblet cells exhibit metaplasia and hypersecretion. However, allergen exposure does not directly trigger goblet cell degranulation, raising questions regarding the underlying mechanisms of these reactions. The activation of enteric neurons promotes goblet cell degranulation by stimulating the calcitonin gene-related peptide (CGRP)-receptor active modification protein-1 (RAMP1) axis. Meanwhile, airway goblet cells express various neuropeptide receptors, and their activation by neuropeptides such as substance P and CGRP induces mucus secretion, exacerbating allergic rhinitis-associated hypersecretion. Thus, although previously less recognised, the neuron-goblet cell signalling axis plays a critical role in allergic rhinitis mucus secretion. This review highlights current research on the neuroimmune mechanisms underlying goblet cell metaplasia and degranulation, focusing on allergic rhinitis, so as to guide clinical treatment strategies.

One of the major consequences of schistosomiasis is its impact on brain function, and despite its severity, the underlying mechanism(s) remain inadequately understood, highlighting a knowledge gap in the disease. The symptoms can vary from headaches to profound cognitive impairment. Besides, the potential influence of physical exercise in mitigating cognitive deficits has received little attention. In our study, we utilized a murine model of Schistosoma mansoni infection to investigate the cognitive impact of schistosomiasis. Our aims were multifaceted: to pinpoint the specific cognitive domains affected during the infection in adult mice, to unravel the complex interplay between glial and immune cells within the central nervous system (CNS), and crucially, to explore the potential therapeutic role of regular physical exercise in counteracting the deleterious effects of schistosomiasis on the CNS. Our findings unveiled that while acute infection did not disrupt simple and complex learning or spatial reference memory, it did induce significant deficits in recall memory-a critical aspect of cognitive function. Furthermore, our investigation unearthed profound alterations in the immune and glial cell populations within the CNS. Notably, we observed marked changes in CD4⁺ T cells and eosinophils in the meninges, as well as alterations in glial cell dynamics within the hippocampus and other brain regions. These alterations were characterized by heightened microglial activation, diminished astrocyte reactivity and a shift towards a proinflammatory milieu within the CNS. We also provided insights into the transformative potential of regular moderate physical exercise in partially alleviating cognitive and neuroinflammatory consequences of schistosomiasis. Remarkably, exercise decreased glial cell production of TNFα, suggesting a shift towards a less pro-inflammatory environment. Collectively, our study provided compelling evidence of the intricate interplay between schistosomiasis infection and cognitive function, underscoring the critical need for further exploration in this area. Furthermore, our findings demonstrated the positive effects of physical activities on mitigating the cognitive burden of schistosomiasis, offering new hope for patients afflicted by this debilitating disease.

Objectives: Inflammation is important in the development of systemic lupus erythematosus (SLE). Systemic inflammation response index (SIRI) and systemic immune-inflammation index (SII) are novel clinical markers of inflammation with prognostic value in different diseases. However, the value of SIRI and SII as inflammation predictors in SLE remains unclear. This study explores the SIRI and SII as potential biomarkers for SLE.

Methods: Data from 280 individuals, including newly diagnosed SLE patients and healthy controls, were collected and divided into three groups: SLE without lupus nephritis (NLN) group (n=93), lupus nephritis (LN) group (n=96) and healthy control group (n=91). Differences in SIRI and SII among the three groups were compared. Logistic regression and Pearson linear analysis were used to analyze the predictive value and correlation of SIRI and SII with SLE and systemic lupus erythematosus disease activity index 2000 (SLEDAI-2K). Receiver operating characteristic (ROC) curves evaluated SIRI and SII in predicting SLE, SLE disease activity, and LN.

Results: The SIRI and SII values were significantly higher in the LN group compared to the NLN group (p<0.01). SII had the largest area under the ROC curve for predicting LN (AUC: 0.6775, 95%CI: 0.6020 - 0.7531). Logistic regression analysis showed SIRI and SII as independent risk factors for LN. Pearson linear analysis indicated SIRI and SII were positively correlated with SLEDAI-2K (r_SIRI=0.25, r_SII=0.24, p<0.05).

Conclusions: SIRI and SII are biomarkers of disease activity and renal involvement in SLE patients that can be used to evaluate and predict for SLE occurrence, disease activity, and lupus nephritis occurrence assessment.

Objective: Insomnia is increasingly recognized as a significant factor in the development of various autoimmune diseases, including autoimmune uveitis (AU). We investigated insomnia-associated genes that may contribute to AU pathogenesis and sought to identify potential biomarkers for insomnia-associated AU.

Methods: Microarray data related to insomnia and AU were downloaded from the Gene Expression Omnibus (GEO) database and analyzed. The GEO2R tool was used to identify differentially expressed genes (DEGs) that were common between insomnia and AU. Weighted gene co-expression network analysis (WGCNA), protein-protein interaction (PPI), functional enrichment, and CMap analyses were then performed to identify pathogenic genes, underlying mechanisms, and potential therapeutic drugs for insomnia-associated AU. Least absolute shrinkage and selection operator regression was employed to screen for candidate biomarkers, and their diagnostic performance was evaluated using receiver operating characteristic (ROC) curves and quantitative polymerase chain reaction (qPCR). Finally, molecular docking was applied to verify binding activities.

Results: We identified 138 up-regulated and 85 down-regulated DEGs that were common to insomnia and AU. PPI network analysis highlighted 10 key genes, CMap analysis identified 30 compounds, and WGCNA revealed 54 key genes and 30 compounds. Intersection of the above-mentioned key genes and compounds identified six genes and five compounds. After verification by qPCR and ROC curve analysis, IFI44 and IRF9 were confirmed as hub genes. Finally, two compounds were selected based on docking scores of less than -7 kcal/mol.

Conclusion: Our study demonstrated involvement of the viral response in both insomnia and AU and identified the diagnostic significance of IFI44 and IRF9 in these conditions. These findings provide novel insights for future diagnostic and therapeutic strategies to treat insomnia-associated AU.

Background: The combination of programmed cell death 1 (PD-1)/programmed death ligand 1 (PD-L1) inhibitors with chemotherapy (CT) is currently under evaluation as a first-line treatment for advanced or recurrent endometrial cancer (EC). This study sought to assess the efficacy and safety of this therapeutic combination in patients with advanced or recurrent EC.

Methods: We performed an exhaustive review of randomized controlled trials (RCTs) up to September 25, 2024, examining the efficacy and safety of combining PD-1/PD-L1 inhibitors with CT versus CT alone (or plus placebo) in advanced or recurrent EC. Efficacy was measured by progression-free survival (PFS) and overall survival (OS), while safety was assessed by the incidence of any grade or grade ≥ 3 adverse events (AEs). We calculated hazard ratios (HRs) for PFS and OS, as well as risk ratios (RRs) for AEs, each accompanied by 95% confidence intervals (CIs). To evaluate heterogeneity, we employed Cochran's Q test, I² statistics, and 95% prediction intervals (PIs). Trial sequential analysis (TSA) was conducted using R Version 4.3.1, STATA Version 12.0, and TSA Version 0.9.5.10 Beta software.

Results: Our analysis incorporated 6 studies, encompassing a total of 2,954 patients. The combination of PD-1/PD-L1 inhibitors with CT significantly improved PFS (HR = 0.617, 95% CI: 0.506-0.752; 95% PI: 0.334-1.140) and OS (HR = 0.774, 95% CI: 0.664-0.902; 95% PI: 0.553-1.083) compared to CT alone (or plus placebo) in the overall population. Subgroup analysis based on mismatch repair (MMR) status revealed pronounced benefits in PFS and OS for patients with deficient MMR (dMMR) (PFS: HR = 0.344, 95% CI: 0.269-0.438; 95% PI: 0.231-0.510; OS: HR = 0.371, 95% CI: 0.245-0.562; 95% PI: 0.025-5.461) compared to those with proficient MMR (pMMR) (PFS: HR = 0.772, 95% CI: 0.627-0.950; 95% PI: 0.394-1.512; OS: HR = 0.996, 95% CI: 0.692-1.435; 95% PI: 0.021-47.662). Although there was no observed difference in the incidence of any grades AEs (RR = 0.994, 95% CI: 0.982-1.006; 95% PI: 0.978-1.009), the risk of grade ≥ 3 AEs was elevated in the group receiving PD-1/PD-L1 inhibitors in combination with CT (RR = 1.132, 95% CI: 1.023-1.252; 95% PI: 0.836-1.532).

Conclusion: The combination of PD-1/PD-L1 inhibitors with CT significantly improved PFS and OS in advanced or recurrent EC patients, with particularly pronounced benefits observed in those with dMMR. Clinicians can tailor treatment strategies according to individual patient characteristics to optimize therapeutic outcomes, while remaining alert to the possibility of AEs in clinical practice.

Systematic review registration: https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42024595455.

Acute myeloid leukemia (AML) remains a devastating diagnosis in clear need of therapeutic advances. Both targeted dendritic cells (DC) and particularly leukemia-derived dendritic cells (DC_leu) can exert potent anti-leukemic activity. By converting AML blasts into immune activating and leukemia-antigen presenting cells, DC/DC_leu-generating protocols can induce immune responses against AML blasts. Such protocols combine approved response modifiers (i.e., GM-CSF and PGE₁/OK-432/PGE₂) that synergistically improve the conversion of AML blasts into (mature) DC/DC_leu. To guide potential clinical application of these response modifiers, we analyzed three different DC-generating protocols that combine a constant GM-CSF dose with varying concentrations of PGE₁ (Kit-M), OK-432 (Kit-I), and PGE₂ (Kit-K). Here, we specifically aimed to assess how different response modifier concentrations impact DC/DC_leu generation, immune cell activation and leukemic blast lysis. We found that all immunomodulatory kits were effective in generating mature and leukemia-derived DCs from healthy and leukemic whole blood. For Kit-M, we noted optimal generation of DC-subsets at intermediary concentration ranges of PGE₁ (0.25-4.0 µg/mL), which facilitated upregulation of activated and memory T-cells upon mixed lymphocyte culture, and efficient anti-leukemic activity in cytotoxicity assays. For Kit-I, we observed DC/DC_leu generation and enhanced T- and immune cell activation across a broader range of OK-432 concentrations (5-40 µg/mL), which also facilitated improved leukemic blast killing. In conclusion, our results highlight that Kit-mediated DC/DC_leu generation, immune cell activation and blast lysis are dependent on the concentration of response modifiers, which will guide future clinical development. Overall, DC_leu-based immunotherapy represents a promising treatment strategy for AML patients.

The omentum is a common site of peritoneal metastasis in various cancers, including gastric cancer. It contains immune cell aggregates known as milky spots, which provide a microenvironment for peritoneal immunity by regulating innate and adaptive immune responses. In this study, we investigated gene expression profiles in cells from omental milky spots of patients with gastric cancer (n = 37) by RNA sequencing analysis and classified the patients into four groups (G1-4). Notably, significant differences were observed between the groups in terms of macroscopic type, lymphatic invasion, venous invasion, and pathological stage (pStage). G3, which was enriched in genes related to acquired immunity, showed earlier tumor stages (macroscopic type 0, Ly0, V0, and pStage I) and a better prognosis. In contrast, G4 showed enrichment of genes related to neutrophils and innate immunity; G1 and G2 showed no enrichment of innate or adaptive immune-related genes, suggesting an immune desert microenvironment. Cytometric analysis revealed significantly more T and B cells and fewer neutrophils in G3. Accordingly, the immune microenvironment in omental milky spots may vary depending on the stage of gastric cancer progression. When univariate Cox proportional hazards regression models were used to search for prognostically relevant genes specific to G3, 23 potential prognostic genes were identified as common genes associated with relapse-free survival and overall survival. In addition, the multivariate Cox proportional hazards model using these prognostic genes and clinicopathological information showed that combining the B cell marker CD19 and Ly had a high predictive accuracy for prognosis. Based on this study's results, it is possible that tumor progression, such as lymphatic and/or venous infiltration of tumor cells, may affect the immune cell composition and proportions in omental milky spots of patients with gastric cancer and analysis of gene expression in omental milky spots may help to predict gastric cancer prognosis.

Introduction: Influenza-associated pulmonary aspergillosis (IAPA) is a severe complication of influenza infection that occurs in critically ill patients and results in higher mortality compared to influenza infection alone. Interleukin-17 (IL-17) and the Type 17 immune signaling pathway cytokine family are recognized for their pivotal role in fostering protective immunity against various pathogens. In this study, we investigate the role of IL-17 and Type 17 immune signaling components during IAPA.

Methods: Wild-type mice were challenged with influenza A H1N1 (flu) and then exposed to Aspergillus fumigatus ATCC42202 resting conidia on day 6 post-influenza infection, followed by the quantification of cytokines and chemokines at 48 h post-fungal infection.

Results and discussion: The gene and protein expression levels revealed that IL-17 and Type 17 immune cytokines and antimicrobial peptides are downregulated during IAPA compared to mice singularly infected solely with A. fumigatus. Restoration of Type 17 immunity was not sufficient to provide protection against the increased fungal burden observed during IAPA. These findings contrast those observed during post-influenza bacterial super-infection, in which restoration of Type 17 immune signaling protects against exacerbation seen during super-infection. Our study highlights the need for future studies to understand the immune mechanisms that increase susceptibility to fungal infection.

Introduction: Macrophages play an important role in disease progression of pediatric cholestatic liver disease, particularly biliary atresia (BA); however, the restorative versus pathogenic role for precise macrophage subsets remains poorly defined. We aimed to distinguish the transcriptional profiles and roles of defined macrophage subset(s) in murine BA.

Methods: We used multiparameter flow cytometry and RNA-sequencing analysis to profile recruited CD11b^hiCD64+ hepatic macrophages by cell surface expression of MHCII and Ly6c in the Rhesus rotavirus (RRV)-induced murine model of BA versus saline controls. Modulation of macrophage numbers via intra-peritoneal injections of clodronate-loaded liposomes was performed to determine the association between macrophage numbers and histologic injury (Ishak score).

Results: Ly6c+ macrophages demonstrated the greatest increase in numbers and percent of total macrophages in murine BA versus saline controls whereas MHCII+ macrophages decreased. Transcriptional changes in murine BA MHCII+ macrophages included reduced expression of the Kupffer cell gene signature, lower expression of genes involved in homeostatic processes, and increased expression of genes involved in inflammatory processes. Ly6c+ macrophages in murine BA showed increased expression for Hif1a and other genes involved in the cellular response to hypoxia. Among all subsets, the number of Ly6c+ macrophages exhibited the strongest correlation with severity of histologic liver injury by Ishak score.

Conclusions: Our data identify specific pathways upregulated in Ly6c vs MHCII+ macrophage subsets in murine BA. Transcriptional similarities between murine BA and human cholestatic macrophages may enable translation of future mechanistic studies to new macrophage subset-specific therapies.