Frontiers in Immunology最新文献

Introduction: Systemic sclerosis (Scleroderma; SSc) is associated with high morbidity and mortality, particularly in patients with pulmonary arterial hypertension (SSc-PAH) and pulmonary fibrosis (SSc-PF). Effective risk stratification and treatment of SSc remains a significant challenge. This proof-of-concept study aimed to identify potential biomarkers capable of distinguishing between three SSc patient groups, defined by no pulmonary involvement (SSc-NLD; n=30), SSc-PAH (n=30), SSc-PF (n=30) compared to healthy controls (HC; n=30).

Methods: The study employed Olink-based proteomics using the Cardiovascular II and Immuno-oncology panels, and untargeted metabolomic profiling using Ultra-high Performance Liquid Chromatography-Tandem Mass Spectroscopy (UPLC-MS/MS), to discover distinct molecular signatures.

Results: Proteomics analysis revealed significantly elevated levels of MCP-1, MCP-3, and MCP-4 in SSc-PF compared to all other groups. However, no robust discriminatory cytokines were identified for SSc-PAH or SSc-NLD. Validation of systemic MCP-1 and IL-6 by ELISA supported the proteomics findings. IL-33 levels were found to be reduced in the SSc-PAH group. Increased levels of pro-inflammatory sIL-6R were also identified in SSc-PAH and SSc-PF, indicating shared inflammatory pathways. Protein-protein interaction analyses demonstrated greater network complexity in SSc-PF, with pathway analysis suggesting overlapping biological mechanisms across pulmonary groups. Metabolomics analysis uncovered a unique panel of metabolites altered exclusively in SSc-PAH, including quinolinate, dimethylarginines, hydroxyasparagine and orotidine. In contrast, no metabolites were uniquely discriminatory for SSc-PF or SSc-NLD. Metabolite-metabolite interaction networks revealed nicotinate and nicotinamide metabolism as the more significantly enriched metabolic pathways in SSc-PAH. Correlation analyses identified distinct protein-metabolite profiles across groups. Of note is the loss of IL-33-related metabolic associations specific to SSc-PAH.

Discussion: This study identified a candidate biomarker panel comprising three cytokines and ten metabolites capable of differentiating between SSc-PAH, SSc-PF, SSc-NLD, and HC. Biomarkers of SSc-PAH were linked to nicotinate and nicotinamide, as well as tryptophan metabolism, whereas those of SSc-PF reflected immune cell infiltration and fibrosis. These findings highlight the potential biomarker panels for diagnosis and targeted therapeutic development.

Purpose: Abscopal effects (AbE) during combined radiotherapy (RT) and immune checkpoint inhibition (ICI) represent a potential mechanism for systemic tumor control, yet sex-specific differences in these responses remain largely unexplored. We investigated sex-associated signals in outcomes of combined RT-ICI in a multicenter cohort. We analyzed the incidence of AbE and survival outcomes with respect to clinical and biomedical markers.

Methods: In this observational multicenter study, patients with metastatic solid tumors receiving RT-ICI and showing at least one non-irradiated lesion (NIL), assessed using iRECIST criteria, were analyzed. Abscopal response (AR) was defined as ≥30% reduction in NIL size, abscopal progression (AP) as ≥20% increase, and abscopal control (AC) as changes within this range.

Results: Among 3,773 screened patients, 142 met the inclusion criteria (62% male, median age 62 years; 38% female, median age 58 years). AR and AC occurred more frequently in females (24% vs. 14%, 35% vs. 31%). While OS showed no significant difference (p=0.81), Cox regression analyses revealed significant associations of a longer ICI-to-RT-interval (males: HR = 0.903 [0.833-0.978], p=0.012; females: HR = 0.748 [0.621-0.900], p=0.002) and a BMI ≥25 kg/m² with survival in both sexes (males: HR = 4.282 [1.473-12.446], p=0.008; females: HR = 4.801 [1.182-19.502], p=0.028 with survival in both sexes). Elevated C-reactive protein (CRP) (≥5 mg/L) showed prognostic significance only in males (HR = 4.764 [1.184-19.170], p=0.028).

Conclusion: Our findings suggest the possibility of sex-specific patterns in AbE occurrence. Additionally, our analyses identified sex-associated prognostic factors, including the importance of ICI-to-RT interval and BMI in both sexes and the male-specific prognostic value of CRP. These observations warrant further research and consideration in designing personalized RT-ICI combination strategies.

[This corrects the article DOI: 10.3389/fimmu.2025.1723346.].

Background: Abdominal aortic aneurysm (AAA) is a severe vascular disease that can lead to rupture and life-threatening hemorrhage. The role of ferroptosis in AAA pathogenesis remains insufficiently understood. This study aims to investigate the role of ferroptosis in AAA by identifying ferroptosis-associated molecular subtypes and examining their relationship with immunological characteristics using an artificial neural network (ANN) model.

Methods: We analyzed three publicly available datasets (GSE7084, GSE47472, and GSE57691) to identify differentially expressed ferroptosis-related genes (FRGs) and employed consensus clustering to classify AAA samples into two subtypes. Immune infiltration was assessed with the CIBERSORT algorithm, and a diagnostic artificial neural network (ANN) model based on subtype-specific genes was developed to discriminate ferroptosis-associated molecular subtypes and derive the NeuraAAA score.

Results: Nine differentially expressed FRGs were identified, and the model incorporated three key genes (oncostatin M, heme oxygenase-1, and interleukin-6), achieving high diagnostic accuracy (AUC = 0.988). Consensus clustering stratified AAA samples into two ferroptosis-associated subtypes with distinct immune profiles, with the C1 subtype showing higher immune infiltration and immune scores than C2. The derived NeuraAAA score was elevated in the immune-enriched subtype and correlated with immune-cell infiltration, and a nomogram integrating NeuraAAA and immune score showed good calibration. Immunofluorescence confirmed increased expression of all three genes in AAA specimens.

Conclusion: Our study reveals the heterogeneous role of ferroptosis in AAA pathogenesis, demonstrating that ferroptosis-associated subtypes are linked to variations in the immune microenvironment. These findings provide new insights into AAA pathophysiology and suggest potential targets for subtype-specific therapeutic strategies, contributing to advances in precision medicine for AAA treatment.

Renal cell carcinoma (RCC) is an immunogenic tumor in which tumor-associated neutrophils (TANs) and neutrophil extracellular traps (NETs) represent a functionally important component of the tumor microenvironment. Recent studies have revealed pronounced phenotypic heterogeneity of RCC-infiltrating neutrophils, including interferon-responsive, immunosuppressive PMN-MDSC-like, pro-angiogenic, and NET-forming subsets that cannot be adequately described by the classical N1/N2 model. Their polarization is shaped by ELR⁺ CXC chemokines (CXCL1, CXCL8), cytokine signals, systemic inflammation, hypoxia driven by VHL/HIF pathways, and tumor-intrinsic oncogenic alterations such as PTEN loss, ERβ- and c-Myc-dependent programs, as well as epigenetic remodeling. TANs exert predominantly pro-tumor functions in RCC, promoting T-cell exclusion and exhaustion, supporting angiogenesis and stromal remodeling, and facilitating epithelial-mesenchymal transition, venous invasion and metastasis. NETs, enriched in hypoxic and necrotic tumor regions and in venous tumor thrombi, further contribute to vascular occlusion, metastatic dissemination and local immune dysfunction, and are reflected by distinct transcriptional signatures. Clinically, high TAN density, activation markers and neutrophil/NET-associated gene signatures are consistently associated with aggressive tumor behavior, early recurrence, poor survival and resistance to VEGF-TKIs and immune checkpoint inhibitors. Emerging data also link neutrophil-rich stromal inflammation with the tumor resident microbiome, suggesting composite TAN-microbiome biomarkers for refined risk stratification. In this review, we summarize current knowledge on phenotypic diversity, regulatory circuits and functional programs of TANs and NETs in RCC, and discuss their prognostic and predictive significance, as well as therapeutic strategies aimed at chemokine blockade, complement modulation, NET inhibition and neutrophil re-education.

Introduction: Parkinson's disease (PD) is a progressive neurodegenerative disorder marked by chronic neuroinflammation and loss of dopaminergic neurons. The neurotoxin MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) selectively targets dopaminergic neurons, effectively replicating the pathological features of PD. Lupeol, a natural pentacyclic triterpenoid, has been shown to exhibit neuroprotective properties in various models by reducing oxidative stress, inflammation, and apoptosis. This study aimed to investigate the neuroprotective effects of lupeol in an MPTP-induced mouse model of PD.

Methods: Male mice were administered MPTP (30 mg/kg, i.p.) for seven days to induce PD-like pathology. Lupeol (50 mg/kg) was administered as a potential therapeutic intervention. Behavioral assessments were conducted to evaluate motor function. Biochemical analyses were performed to measure dopamine and tyrosine hydroxylase (TH) levels. Immunohistochemical and molecular approaches were used to assess glial activation, oxidative stress, and apoptotic signaling pathways in the substantia nigra pars compacta (SNpc) and striatum.

Results: Lupeol treatment significantly improved MPTP-induced motor impairments and restored dopamine and TH levels. Additionally, lupeol reduced neuroinflammation, by decreasing microglial activation, astrocyte reactivity, and lower levels of inflammatory mediators. Oxidative stress markers, including reactive oxygen species (ROS) and lipid peroxidation (LPO), were diminished in SNpc and striatum following lupeol treatment. Furthermore, lupeol upregulated antioxidant defense mechanisms by increasing the expression of Nrf-2 and HO-1. Apoptotic markers, such as Cytochrome C, Bax, and Caspase-3, were downregulated, indicating reduced neuronal apoptosis.

Conclusion: The current study suggests that lupeol exerts neuroprotective effects by inhibiting glial cell activation, thereby reducing neuroinflammation, oxidative stress, and apoptosis in an MPTP-induced PD mouse model.

The global prevalence of erectile dysfunction (ED) continues to rise, which has become an important issue affecting the physical and mental health of men. Existing evidence suggests that ED is closely related to various immune-mediated skin diseases. This review elaborates on the epidemiological characteristics, potential mechanisms, and clinical management strategies of ED associated with immune-mediated skin diseases. It discusses the future research directions and challenges in this field. Epidemiological studies consistently show that the prevalence of ED in such patients is higher than that in the general population, indicating that immune-mediated skin diseases may significantly increase the risk of ED. Its pathogenesis is complex and diverse, involving the interaction of multiple pathways. In terms of clinical management, a multidisciplinary collaborative model is advocated, with the active control of the inflammatory activity of the primary skin disease as the cornerstone of treatment. The treatment of ED should be individualized, combined with psychological intervention and lifestyle optimization, to comprehensively improve the treatment effect. Future research should further explore its molecular mechanisms and conduct large-sample, prospective clinical trials to optimize treatment strategies and ultimately enhance patients' sexual health and overall quality of life (QoL).

The development of endometrial cancer is a gradual malignant transformation process driven by multiple factors, and the immune microenvironment is closely related to clinical outcomes and immunotherapy responses. Under physiological conditions, the immune microenvironment of the normal endometrium undergoes periodic reshaping under the regulation of estrogen and progesterone, maintaining the balance between immune defense and reproductive capacity. However, continuous exposure to risk factors, such as non-antagonistic estrogen, may trigger endometrial intraepithelial neoplasia. During this period, the immune microenvironment becomes dysregulated, supporting malignant progression. For example, estrogen-stimulated interactions between endothelial cells and macrophages, elevated neutrophil/lymphocyte ratios, and the accumulation of regulatory T cells all combine to cause dysregulation of immune microenvironment. The abnormal immune microenvironment that occurs in the precancerous lesion stage interacts with systemic and genetic carcinogenic factors, ultimately shaping the unique immune microenvironment of each molecular subtype of endometrial cancer. POLE-mutated and MSI-H subtype endometrial cancer are immune-infiltrated tumors, whereas the copy-number high subtype is immune-suppressive tumor and the copy-number low subtype is immune-desert tumor. However, still little is known about the immune dysregulation that occurs during the precancerous stage and its impact on subsequent malignant progression. This review systematically describes the changes in the immune microenvironment during the process from normal endometrium to endometrial cancer, emphasizing that endometrial intraepithelial neoplasia is a key stage of immune imbalance, thus paving the way for early immune intervention and precise immunotherapy.

Background: Age-related cognitive impairment (ARCI) is an urgent public health concern with limited therapeutic options. Soluble fermentable dietary fiber (SFDF) is a safe, accessible nutritional factor that may support cognition through microglial remodeling and antioxidant defense, but its dose-response effects and cellular mechanisms remain unclear.

Methods: We combined three levels of evidence (1). In 2,350 older adults from NHANES (2011-2014), weighted regression and spline modeling assessed the association between total dietary fiber intake and cognitive performance. (2) In a D-galactose-induced aging mouse model, inulin supplementation (as a representative SFDF) was tested for effects on behavior, cytokines, and oxidative stress. (3) We analyzed an independent single-nucleus RNA-seq dataset of naturally aged mice receiving a 5% SFDF intervention to characterize microglial state remodeling.

Results: Higher total dietary fiber intake was nonlinearly associated with better cognition, with ~15 g/day as the threshold for maximal benefit. In mice, SFDF improved memory and learning, alleviated anxiety-like behavior, reduced IL-6, TNF-α, and lipid peroxidation, and enhanced antioxidant defenses. Single-nucleus analyses indicated that the 5% SFDF intervention was associated with a shift toward a reparative Mic.7 microglial subtype enriched for immune regulation and oxidative defense programs.

Conclusions: These convergent population, animal, and single-cell findings support a model in which higher total dietary fiber intake is associated with better late-life cognition, and SFDF interventions can attenuate aging-related neuroimmune activation and oxidative stress in experimental systems, highlighting dietary fiber as a scalable nutritional strategy to support healthy cognitive aging.

Introduction: Inborn errors of immunity (IEI) are particularly prevalent in regions with high rates of consanguinity, yet the genetic profiles in these populations are underreported. This study aims to describe the clinical and molecular characteristics of IEI in a highly consanguineous population and investigate the impact of genetic diagnosis on patient management.

Method: This retrospective study included 52 patients with suspected IEI, as defined by the IUIS criteria. Clinical, immunological, and demographic data were recorded. Genetic analyses were performed primarily using next-generation sequencing (NGS) gene panels, and all pathogenic variants were confirmed by Sanger sequencing. Variants were interpreted in accordance with the ACMG guidelines.

Results: A total of 52 patients were included in the study, with 92% of the individuals born to consanguineous parents, comprising 28 females and 24 males. The mean age at diagnosis was 4.63 ± 2.5 years. The median duration of follow-up was three years. The overall incidence was 0.3% representing the proportion of patients diagnosed with IEI among those referred to our center during the study period. A high rate of consanguineous marriage was observed, reported in 92% of the cases. The most frequently represented category was Predominantly Antibody Deficiencies (PAD), accounting for 20 patients (38.5%), including 12 cases (23%) of transient hypogammaglobulinemia of infancy (THI) and 7 cases (13%) of selective IgA deficiency. Among the 52 patients, 3 (5.8%) were diagnosed with severe combined immunodeficiency (SCID): 1 patient had ADA deficiency, and two patients had DNA ligase IV deficiency (LIG4). Additionally, 14 patients (26%) were diagnosed with combined Immunodeficiencies (CID). Thirty patients were treated with IVIG, and 3 patients underwent HSCT. A molecular diagnosis was established in 33 patients (63%). Genetic findings influenced clinical management in 82% of variant-positive cases, including decisions regarding HSCT, targeted therapy, and genetic counseling.

Conclusion: This study highlights the distinctive genetic characteristics of IEI in a population with high consanguinity, emphasizing the need to incorporate molecular diagnostics into standard immunology practice, particularly in areas where recessive disorders are prevalent.