Cell Activation Research Articles

Effective cellular and neutralizing immunity against SARS-CoV-2 after mRNA booster vaccination is associated with pDC and B cell activation

IntroductionThe emergence of SARS-CoV-2 variants of concern (VOCs), particularly Omicron, has challenged the efficacy of initial COVID-19 vaccination strategies. Booster immunizations, especially with mRNA vaccines, were introduced to enhance and prolong immune protection. However, the underlying mechanisms of humoral and cellular immunity induced by homologous versus heterologous vaccination regimens remain incompletely understood. This study aimed to elucidate the immune responses, including B cell, plasmacytoid dendritic cell (pDC), and T cell activation, following mRNA booster vaccination.MethodsIn a longitudinal cohort study, 136 individuals received three different vaccination regimens: homologous mRNA, heterologous vector-mRNA-mRNA, or heterologous vector-vector-mRNA vaccinations. Serum and peripheral blood mononuclear cells (PBMCs) were collected at multiple time points up to 64 weeks after initial vaccination. Anti-SARS-CoV-2 IgG titers and neutralization capacity against the wildtype virus and Omicron variant were measured using ELISA and cPass assays. Cellular immunity was assessed by IFN-γ release assays, and flow cytometry was employed to analyze B cell and pDC frequencies, viability, and activation markers. Functional pDC-mediated T cell activation was evaluated in mixed lymphocyte cultures.ResultsmRNA booster vaccination stabilized high anti-SARS-CoV-2 IgG titers and neutralizing activity against wildtype virus across all regimens, with the homologous mRNA group showing the highest antibody titers and Omicron neutralization capacity. Peripheral B cell frequencies and activation markers (MHC class I/II, CD86) were significantly upregulated post-booster. pDCs demonstrated enhanced antigen-presenting capacity and significantly promoted SARS-CoV-2-specific T cell IFN-γ responses in vitro. Despite differences in humoral responses between regimens, breakthrough infection rates up to 25 weeks post-booster were comparable across cohorts, suggesting compensatory mechanisms via cellular immunity.DiscussionOur findings highlight the pivotal role of pDCs and T cells in sustaining effective immunity following mRNA booster vaccination. While homologous mRNA regimens induce superior humoral responses, robust cellular immunity in heterologous regimens may balance protection levels against breakthrough infections. The study underscores the importance of integrated humoral and cellular immune responses, suggesting potential for optimized booster strategies and pDC-targeted vaccine designs to enhance long-term protection against SARS-CoV-2 and emerging variants.

Emerging therapeutics targeting tumor-associated macrophages for the treatment of solid organ cancers.

Over the last decade, immune checkpoint inhibitors (ICIs) like PD-1/PD-L1 or CTLA-4 which reinvigorate T cells for tumor control have become standard-of-care treatment options. In response to the increasingly recognized mechanisms of resistance to T cell activation in immunologically cold tumors, immuno-oncology drug development has started to shift beyond T cell approaches. These include tumor-associated macrophages (TAMs), a major pro-tumor immune cell population in the tumor microenvironment known to silence immune responses. Here we outline anti-TAM therapies in current development, either as monotherapy or in combination with other treatment modalities. We describe emerging drugs targeting TAMs under investigation in phase II and III testing with a focus on their distinguishing mechanism of action which include (1) reprogramming of TAMs toward anti-tumor function and immune surveillance, (2) blockade of recruitment, and (3) reduction and ablation of TAMs. Several new immuno-oncology agents are under investigation to harness anti-tumor functions of TAMs. While robust anti-tumor efficacy of anti-TAM therapies across advanced solid organ cancers remains elusive to-date, TAM reprogramming therapies have yielded benefits in select cancers. The inherent heterogeneity of the diverse TAM population will require enhanced investments into biomarker-driven approaches to fully leverage its therapeutic potential.

Synthesis and anti-hepatic fibrosis activity of novel matrine tricyclic derivatives

Matrine, a component derived from traditional Chinese medicine, exhibits diverse pharmacological effects such as anti-hepatic fibrosis. Here we have investigated novel matrine tricyclic derivatives designed by a molecular fusion strategy for anti-fibrotic effects. Among these new compounds, ZM842 indicated potent inhibitory TGF-β transcriptional activity in a dose-dependent manner by a TGF-β/Smads reported gene assay. TGF-β1-stimulated LX-2 cells were treated with compound ZM842, resulting in a reduction of fibrosis markers, including collagen I and α-SMA, as observed at the protein level. Molecular docking disclosed that compound ZM842 may inhibit the activation of hepatic stellate cells (HSCs) by directly interacting with TGF-β1 and SMAD-3 proteins. In summary, our results suggest that compound ZM842 inhibits the TGF-β1 signaling pathway and HSC activation, indicating its potential as an anti-hepatic fibrosis agent.

Transforming the Tumor Microenvironment: An Outstanding AIE-Active Photosensitizer to Boost the Effectiveness of Immunotherapy.

Immunotherapy, currently the most promising therapeutic approach for cancer, has shown significant efficacy. However, its clinical effectiveness is often constrained by such factors as tumor heterogeneity, the abundance of M2 macrophages, tumor-vascular hypoxia, and the immunosuppressive microenvironment created by immune checkpoint (IC) complexes. In this work, an effective photosensitizer (TSPA) with aggregation-induced emission (AIE) nature is adopted to counter above limitations. The synthesized TSPA demonstrated potent efficacy in eradicating primary tumors because of their effective generation reactive oxygen species (ROS) after undergoing photodynamic therapy (PDT) process. Moreover, TSPA can improve hypoxic conditions in tumor by normalizing blood vessels, and can instigate immunogenic cell death(ICD), thus stimulating immune cell activation. TSPA demonstrates the ability to reprogram M2 tumor-associated macrophages (TAMs) into the anti-tumor M1 phenotype, thereby increasing the infiltration of M1 macrophages within the tumor. This procedure notably ameliorates the immune microenvironment, effectively suppressing the long-term metastasis of breast cancer (BC). This research notably enhances the efficiency of tumor immunotherapy and is anticipated to emerge as a new strategy for improving the tumor's immunosuppressive microenvironment and overcoming immune evasion.

Invisible appliance promotes bone reconstruction via modulating the periodontal immune microenvironment

ObjectivesRecently, invisible appliances have become popular due to their aesthetics and comfort, but their impact on periodontal health in periodontitis patients has not been fully elucidated. The purpose of this study was to investigate the effectiveness of fixed and invisible appliance treatment for periodontitis in experimental rats while monitoring the dynamics of Th17/Treg cells and osteoclast-related cytokines during treatment.MethodsSD rats were randomly divided into six groups: control, periodontitis model, scaling-0 (basic treatment), no appliance, fixed appliance, and invisible appliance. After successful establishment of ligature-induced periodontitis, rats in the treatment groups were first subjected to supra/subgingival scaling and daily brushing for 2 weeks. Next, except rats in the scaling-0 group, the periodontitis rats were treated with uncorrected, fixed, or invisible appliance, respectively. The CEJ-AC was examined using micro-CT. Osteoclast activation was detected with TRAP staining. The proportion of Th17 and Treg cells was measured by flow cytometry. Subsequently, potential mechanisms were explored by detection of RORγt, Foxp3, RANKL, OPG, and pathogenic bacteria (Pg, Aa, and Tf). Finally, the association between Th17/Treg cells and osteoclast-related indicators as well as pathogenic bacteria was evaluated by correlation analysis.ResultsAmong the three treatments, invisible appliance treatment provided optimal results in controlling periodontal infection while promoting periodontal tissue repair. Specifically, in the early phase of treatment (3–7 days), orthodontic force exerted by the appliance stimulates osteoclast and Th17 cell activation by increasing RANKL and RORγt expression, thereby inducing osteoclast generation and accelerating the amount of tooth movement. In the later stages of treatment (7–21 days), Foxp3 and OPG levels gradually increased to induce the dominant role of Treg cells, controlling osteoclast generation and bone resorption. Meanwhile, the invisible appliance can maintain a low number of pathogenic bacteria during treatment. Finally, Th17 cells showed significant positive correlation with RANKL, Pg, osteoclast percentage, and CEJ–AC; Treg cells were positively correlated with RANKL and OPG; Th17/Treg ratio displayed positive correlation with RANKL/OPG or osteoclast percentage.ConclusionsInvisible appliance has obvious advantages in periodontitis treatment, which can effectively improve periodontal condition and reduce inflammatory response.

NKG2D triggering hampers DNAM-1-mediated signaling in human NK cells

IntroductionNatural Killer (NK) cells are cytotoxic innate lymphocytes able to detect transformed cells through the balanced action of inhibitory and activating receptors. NKG2D is one of the main activating receptors involved in tumor surveillance thanks to its ability to recognize stress-induced ligands. Of note, the prolonged exposure to NKG2D ligands promotes receptor down-modulation that results in defective activation of NKG2D and other unrelated activating receptors, including DNAM-1 that is also involved in tumor clearance. However, further investigations are necessary to characterize how the NKG2D/DNAM-1 interplay affects NK cell anti-tumor function.MethodsPrimary cultured human NK cells were stimulated with the natural ligand MICA or an anti-NKG2D agonist antibody. The expression of activating and inhibitory receptors as well as DNAM-1-triggered signaling events and cytotoxicity were evaluated by flow cytometry. DNAM-1-mediated granule polarization was evaluated by confocal microscopy.ResultsWe showed that NKG2D crosslinking mediated by the natural ligand MICA or an agonist antibody had different consequences on primary cultured human NK cells. Indeed, MICA stimulation increases the expression of the checkpoint receptor TIGIT that is able to counteract DNAM-1 activation. Stimulation with the agonist antibody, without altering TIGIT expression, directly inhibits DNAM-1-mediated signal transduction and cytotoxic function with a mechanism that required NKG2D endocytosis.DiscussionOur findings contribute to shed light on the functional consequences of NKG2D engagement, demonstrating that a direct impact on DNAM-1-mediated signal transduction occurs independently from the modality of NKG2D crosslinking. Understanding the molecular mechanisms responsible for suppression of NK cell activation may help the development of therapeutic anti-cancer strategies aimed to prevent NK cell dysfunction or to reinvigorate an impaired cytotoxic activity.

An experimental study on the effect of polydatin on retinal ganglion cell apoptosis induced by optic nerve injury

Objective: To investigate the effect of polydatin on retinal ganglion cell (RGC) apoptosis induced by optic nerve injury. Methods: It was an experimental research, conducted from October 2022 to December 2023. Retina-optic nerve explants from C57BL/6 mice were cultured in vitro to simulate optic nerve injury, and a computer-generated random number table was used for complete randomization, assigning the explants to the 0-day uncultured group (immediately detected after sampling), the model group (cultured for 1, 3 or 5 days to establish the injury model), and the polydatin group (with polydatin added throughout the intervention on the basis of the model group). The retinal tissues were collected, and the glial fibrillary acidic protein (GFAP), calcium ion binding protein 1 (Iba1), and ganglion cell marker Brn3a were detected by immunofluorescence staining. The effects of polydatin on the activation of astrocytes and microglia and RGC survival were observed. The expressions of GFAP, Vimentin, Iba1, B-lymphocytoma-2-associated X protein (Bax), lyzed C-caspase 3, and B-lymphocytoma-2 were detected by Western blotting. Real-time fluorescence quantitative PCR was used to detect the mRNA transcription levels of tumor necrosis factor-α (TNF-α), interleukin (IL)-6, and IL-10. One-way analysis of variance and LSD-t test were used for statistical analysis. Results: Immunofluorescence staining showed that compared with the model group, the polydatin group inhibited the activation of astrocytes and microglia and protected the RGCs. With explant culture for 1, 3, and 5 days, the expressions of GFAP (0.74±0.01, 0.70±0.04, 0.68±0.02), Vimentin (0.67±0.02, 1.91±0.09, 1.25±0.05), Iba1 (0.87±0.10, 2.36±0.13, 1.64±0.11), Bax (2.48±0.10, 0.37±0.02, 1.69±0.11), and C-caspase 3 (0.77±0.03, 2.49±0.09, 1.65±0.08) in the polydatin group were lower than those in the model group [GFAP (1.23±0.01, 1.17±0.01, 1.77±0.04), Vimentin (1.21±0.02, 2.67±0.06, 1.42±0.03), Iba1 (1.13±0.02, 3.51±0.07, 2.16±0.08), Bax (3.53±0.12, 1.27±0.06, 3.24±0.15), and C-caspase 3 (1.54±0.08, 3.38±0.17, 2.18±0.08)]. The expression of B-lymphocytoma-2 in the polydatin group (2.41±0.09, 1.67±0.07, 6.84±0.20) was higher than that in the model group (1.73±0.08, 0.96±0.07, 2.36±0.33). The differences were statistically significant (all P<0.05). In addition, the mRNA transcription levels of TNF-α (0.47±0.13, 12.07±0.56, 18.06±2.58) and IL-6 (0.55±0.12, 7.48±1.02, 41.35±7.08) in the polydatin group were lower than those in the model group [TNF-α (4.67±0.52, 26.62±2.62, 42.43±4.97) and IL-6 (1.21±0.06, 15.66±0.62, 67.46±3.78)]. The level of IL-10 (0.52±0.07, 2.98±0.24, 5.61±1.23) in the polydatin group was higher than that in the model group (0.06±0.03, 0.12±0.03, 2.64±0.74). The differences were statistically significant (all P<0.05). Conclusion: Polydatin can inhibit the activation of glial cells and the expression of inflammatory factors induced by optic nerve injury, thus enhancing the survival of RGCs.

Effects of albumin-bound paclitaxel combined with Sophora subprostrate polysaccharide on inflammatory factors and immune function in breast cancer rats

BackgroundTumor occurrence and growth are highly correlated with the degree of inflammation and immunological activity. Reducing the level of inflammation in tumor-bearing body to relieve immune suppression and enhance anti-tumor immune function has become an important strategy for tumor treatment.ObjectiveTo investigate the effect of albumin-bound paclitaxel combined with Sophora subprostrate polysaccharide (SSP) on inhibiting inflammation, reducing immunosuppression, enhancing anti-tumor immune function and slowing the progression of tumor in tumor-bearing rats, and to provide certain scientific basis for the clinical application of combined drugs in tumor.MethodsThe rats were put into three groups at random: normal control, model group, and drug treatment group. After the end of drug intervention, the tumor was taken out and weighed to observe the tumor growth of the rats. Tumor necrosis factor (TNF-α), interleukin (IL) 1β, IL-10, perforin, and granzyme B were found by Western blot in the local tumor tissues of experimental rats. The protein expression levels of Arginase-1 (Arg-1) and Cyclooxygenase 2 (COX-2) were determined. HE staining was used to observe the inflammatory infiltration of the tumor. Using flow cytometry, the proportions of anti-tumor immune cells—CD8 + T cells, NK cells, and immunosuppressive cells—in local tumor tissues were evaluated. In addition, spleen T cells isolated from normal rats were co-cultured with spleen myeloid derived suppressor cells (MDSC) from tumor-bearing rats in the model group and the combined treatment group. Cell Trace Far Red was used to identify T cell proliferation, flow cytometry was used to determine the level of T cell activation from CD25 expression, and in vivo immunosuppression in tumor-bearing rats was examined.ResultsThe combined therapy group experienced a considerable decrease in tumor weight as compared to the model group. TNF-α and IL-1p levels in the vicinity of the tumor tissues reduced following intervention, although IL-10 levels, which are anti-inflammatory cytokines, did not significantly change. The results of the HE staining revealed that the intervention group's tumor had less inflammatory infiltration than the model group did. After intervention, the percentages of CD8 + T cells and NK cells in local tumor tissues increased. Additionally, the intervention group's levels of protein expression for perforin and granzyme B were considerably higher than those of the model group. In the nearby tumor tissues, there were lots of MDSC. Following the intervention, the proportion of MDSC in the local tumor tissues was significantly reduced, and the expansion of MDSC was reduced. Additionally, the intervention group's COX-2 and Arg-1 protein expression levels in the tumor-specific tissues were significantly lower than those of the model group. The outcomes of in vitro co-culture demonstrated that rats in the combination group had higher levels of T cell proliferation and activation than animals in the model group.ConclusionsAlbumin-bound paclitaxel combined with Sophora subprostrate polysaccharide can reduce the local inflammation level, promote the proportion of CDB + T cells and NK cells and cell killing function, reduce the proportion of MDSC and immunosuppressive level, enhance the anti-tumor immune function of tumor-bearing mice, and slow the growth of tumors.

MiR-129-5p alleviates depression and anxiety by increasing astrocyte ATP production partly through targeting deubiquitinase Mysm1.

Major depressive disorder (MDD) is a major global mental concern that severely affects quality of life, yet current pharmacological treatments remain limited in their effectiveness. Long-term chronic stress has been shown to increase the incidence of depression and anxiety. Micro RNAs (miRNAs) have been revealed to participate in the pathological process of depression and represent promising therapeutic targets. In this study, we found that microRNA-129-5p (miR-129-5p) was significantly decreased in the brains of depressive mice. Overexpression of miR-129-5p in the hippocampus effectively alleviated depressive-like behaviors and reduced the activation of microglial cells and astrocytes. In addition, ATP levels in depressive mice were significantly increased following miR-129-5p overexpression. The antidepressant effects of miR-129-5p were reversed when ATP function was blocked with the non-specific P2 receptor antagonist suramin. In vitro experiments revealed that miR-129-5p overexpression enhanced ATP production in astrocytes. Furthermore, using a dual-luciferase reporter assay, we found that miR-129-5p directly targeted Mysm1. When overexpressed in astrocytes, miR-129-5p significantly suppressed Mysm1 expression, promoted phosphorylation of p53 and AMPK, and enhanced the expression of PGC1α, factors previously associated with ATP production. Our findings highlight the crucial role of miR-129-5p in regulating depression, suggesting that miR-129-5p overexpression may serve as an effective strategy for antidepressant treatment.

Aberrant expression of CNTRL was associated with poor prognosis, immune response and progression in glioma

This study investigated the biological functions and prognostic significance of centromere protein L (CNTRL) in glioma. mRNA expression data and clinical information were obtained from TCGA, CGGA, and an independent cohort of 207 glioma patients. CNTRL expression levels were quantified using qRT-PCR. Functional analyses, including Gene Ontology and KEGG pathway enrichment, were conducted to elucidate the biological roles of CNTRL. Kaplan–Meier survival curves and Cox regression analyses were applied to evaluate its association with overall survival, and a nomogram was constructed to predict individual survival. Additionally, the tumor microenvironment and immune cell infiltration were analyzed. Glioma cell lines were transfected with CNTRL-targeting shRNA to explore its functional role in cell proliferation, migration, and invasion, utilizing CCK-8, colony formation, scratchy and Transwell assays. The results revealed that CNTRL is ubiquitously expressed in brain tissues and is significantly upregulated in glioma. Higher CNTRL expression was positively correlated with increased tumor grade and were associated with poor prognosis in glioma patients. Furthermore, univariate and multivariate Cox regression analyses identified CNTRL as an independent prognostic factor for glioma survival. The nomogram model integrating CNTRL expression and clinical parameters demonstrated robust predictive performance for patient survival. Functional enrichment analyses suggested that CNTRL is involved in key cellular processes such as cell cycle, DNA repair, and chromatin remodeling. CNTRL expression was positively associated with enhanced immune cell infiltration and activation within the tumor microenvironment, as well as with the expression of immune checkpoint molecules, implicating its potential role in immune evasion mechanisms. In vitro, CNTRL knockdown significantly inhibited glioma cell proliferation, migration, and invasion. Notably, suppression of CNTRL led to reduced expression of the cell cycle regulator WEE1 in glioma cells. This study provides comprehensive evidence that CNTRL contributes to glioma progression by regulating the cell cycle and immune-related processes. Targeting CNTRL could represent a promising therapeutic strategy for glioma. These findings underscore the potential of CNTRL as a prognostic biomarker and a therapeutic target in glioma management.

Identifying brain-penetrant small-molecule modulators of human microglia using a cellular model of synaptic pruning.

Microglia dysregulation is implicated across a range of neurodevelopmental and neurodegenerative disorders, making their modulation a promising therapeutic target. Using PBMC-derived induced microglia-like cells (piMGLCs) in a scalable assay, we screened 489 CNS-penetrant compounds for modulation of microglial phagocytosis of human synaptosomes in a validated assay for microglia-mediated synaptic pruning. Compounds from the library that reduced phagocytosis by ≥2 standard deviations across the library without cytotoxicity were validated in secondary screens, with 28 of them further confirmed to reduce phagocytosis by 50% or more. These compounds comprise a wide range of therapeutic classes with different mechanisms of action, including immunosuppressants, kinase inhibitors, antipsychotics, and epigenetic modulators. Image-based morphological measurements were calculated to measure the degree of ramified vs. ameboid morphotypes as an indicator of activation state. Additionally, transcriptomic profiling indicated divergent effects on cell signaling, metabolism, activation, and actin dynamics across confirmed compounds. In particular, multiple CNS-penetrant small molecules with prior FDA approval or demonstration of safety in vivo demonstrated modulatory effects on microglia. For example, identified drugs such as the tyrosine kinase inhibitors lapatinib, alectinib, and lazertinib and the epigenetic modulator vorinostat have been approved for various cancer treatments and are being investigated for other indications; however, they have not been extensively studied in patients for neurodevelopmental and neurodegenerative disorders. These potential disease-modifying agents represent high-priority candidates for repositioning studies in neurodevelopmental, neuroinflammatory, or neurodegenerative disorders.

EYA3 regulation of NF-κB and CCL2 suppresses cytotoxic NK cells in the premetastatic niche to promote TNBC metastasis.

Triple-negative breast cancer cells must evade immune surveillance to metastasize to distant sites, yet this process is not well understood. The Eyes absent (EYA) family of proteins, which are crucial for embryonic development, become dysregulated in cancer, where they have been shown to mediate proliferation, migration, and invasion. Our study reveals an unusual mechanism by which EYA3 reduces the presence of cytotoxic natural killer (NK) cells in the premetastatic niche (PMN) to enhance metastasis, independent of its effects on the primary tumor. We find that EYA3 up-regulates nuclear factor κB signaling to enhance CCL2 expression, which, in contrast to previous findings, suppresses cytotoxic NK cell activation in vitro and their infiltration into the PMN in vivo. These findings uncover an unexpected role for CCL2 in inhibiting NK cell responses at the PMN and suggest that targeting EYA3 could be an effective strategy to reactivate antitumor immune responses to inhibit metastasis.

Development of a prognostic model for osteosarcoma based on macrophage polarization-related genes using machine learning: implications for personalized therapy

While neoadjuvant chemotherapy combined with surgical resection has improved the prognosis for patients with osteosarcoma, its impact on metastatic and recurrent cases remains limited. Immunotherapy is emerging as a promising alternative. However, the relationship between the phenotype of tumor-associated macrophages and the prognosis of osteosarcoma remains unclear. Differentially expressed gene during macrophage polarization were identified using the Monocle package. Weighted gene co-expression network analysis was conducted to select genes regulating macrophage polarization. The least absolute shrinkage and selection operator algorithm and multivariate Cox regression were used to construct long-term survival predictive strategies. Multiple machine learning algorithms identified target genes for pan-cancer analysis. Lentiviral transfection created stable strains with target gene knockdown, and CCK-8 and transwell migration assays verified the target gene's effects. Western blot and flow cytometry assessed the impact of target genes on macrophage polarization. A total of 141 genes regulating macrophage polarization were identified, from which eight genes were selected to construct prognostic models. Significant differences between high-risk and low-risk groups were observed in immune cell activation, immune-related signaling pathways, and immune function. The prognostic model and target gene were validated to provide more precise immunotherapy options for osteosarcoma and other tumors. BNIP3 knockdown decreased osteosarcoma cell proliferation and migration and promoted macrophage polarization to the M2 phenotype. The constructed prognostic model offers precise immunotherapy regimens and valuable insights into mechanisms underlying current studies. Furthermore, BNIP3 may serve as a potential immunotherapeutic target for osteosarcoma and other tumors.

Serum Amyloid A: A Double-Edged Sword in Health and Disease

Despite more than fifty years since its discovery in the 1970s, Serum Amyloid A (SAA)’s true biological functions remain enigmatic. The research so far has primarily associated SAA with chronic inflammatory conditions such as cardiovascular disease, obesity, and type 2 diabetes; its role in acute inflammation is less understood. Unlike the modest elevations observed in chronic conditions, SAA levels surge dramatically during acute inflammatory responses. Notably, approximately 2.5% of hepatic protein synthesis is devoted to SAA production during acute inflammation—despite the high energy demands required for synthesizing pro-inflammatory cytokines and immune cell activation—leaving its precise necessity unclear. Elucidating SAA’s physiological role in acute inflammation is crucial to determine the therapeutic potential of SAA inhibition for chronic inflammatory diseases, such as atherosclerosis and abdominal aortic aneurysms. The evidence suggests that SAA may play a protective role in acute inflammation, positioning it as a “double-edged sword”: detrimental in chronic inflammation, yet potentially beneficial in acute settings. This review explores the divergent roles of SAA in chronic versus acute inflammation, proposing that while SAA inhibition could offer therapeutic benefits for chronic conditions, it might pose risks during acute inflammation. As the primary transporter of SAA in circulation, high-density lipoprotein (HDL) has been shown to become dysfunctional in chronic inflammation, at least partly due to SAA’s effects. However, we propose that SAA may confer functional properties to HDL during acute inflammatory states, such as sepsis, thereby highlighting the context-dependent nature of its impact.

Integrated transcriptomic and immune profiling reveals crucial molecular pathways and hub genes associated with postoperative delirium in elderly patients

BackgroundPostoperative delirium (POD) manifests as severe mental disorientation, often experienced by elderly patients undergoing surgery, significantly hindering recovery and deteriorating the quality of life. Despite numerous clinical studies, the molecular mechanisms behind POD in elderly patients are still not well understood, requiring further investigation to identify potential biomarkers and therapeutic targets.MethodsThis study amalgamates Gene Set Variation Analysis (GSVA), Weighted Gene Co-expression Network Analysis (WGCNA), differential expression analysis, and immune infiltration assessments to identify molecular pathways and hub genes linked to the initiation of POD in the elderly. Gene expression data were sourced from the GSE163943 dataset in the Gene Expression Omnibus (GEO) database. A total of 18,894 protein-coding genes were extracted for analysis.ResultsWe constructed a gene co-expression network using WGCNA and performed GSVA to investigate the link between POD and different types of cell death. The results indicated that POD is positively associated with pyroptosis and parthanatos, while negatively correlated with oxidative stress and disulfidptosis. Differential expression analysis revealed 145 differentially expressed genes (DEGs), including 83 downregulated and 62 upregulated genes. Analysis of functional enrichment revealed that DEGs were enriched in activities like neuron projection development, axonogenesis, and synapse organization, with KEGG pathway analysis identifying neuroactive ligand-receptor interaction and neurodegeneration pathways. Gene Set Enrichment Analysis (GSEA) further revealed the upregulation of the apoptosis pathway and the downregulation of neuroactive ligand-receptor interaction. Protein–protein interaction (PPI) network analysis identified 10 hub genes, including COL18A1, CD63, and LTF. Immune infiltration analysis indicated that the occurrence of POD is strongly associated with immune cell activation, particularly in T cells and macrophages.ConclusionOverall, this research primarily examines the intricate interplay between cell death processes and alterations in the immune microenvironment throughout the development of geriatric POD, pinpointing essential genes that provide vital theoretical support for further studies on geriatric POD. However, this discovery is only an initial one derived from analyzing the datasets. Upcoming research ought to evaluate and scrutinize additional datasets and conduct essential experiments to guarantee the precision and widespread relevance of the analytical findings.

Asymmetric Dimethylarginine Disrupts Tumor Antigen Presentation in Breast Cancer

Asymmetric dimethylarginine (ADMA), an endogenous methylated amino acid, has been implicated in tumor progression; however, its influence on tumor immunity, particularly dendritic cell (DC) function and antigen presentation, remains unclear. In this study, we examined the effects of ADMA on tumor antigen uptake, processing, and presentation in DCs using the murine dendritic cell line DC2.4 as a model. Our results reveal that ADMA treatment significantly reduces the phagocytic uptake of tumor antigens derived from EO771 and Py230 breast cancer cell lysates. Additionally, ADMA exposure leads to a marked downregulation of key genes involved in antigen processing and presentation, including MHC I, MHC II, TAP1, TAP2, ERp57, and CD80. This suppression at the transcriptional level corresponds with decreased surface protein expression of MHC I, MHC II, and CD80, as confirmed by flow cytometry. Furthermore, ADMA-treated DC2.4 cells exhibit impaired tumor antigen presentation on their surface. Consequently, these functional impairments result in a diminished capacity to activate CD4+ T cells, as evidenced by a 41.18% decrease in CD25 expression and a 30.28% reduction in IFN-γ secretion. Similarly, CD8+ T cell activation is compromised, as indicated by a 32.26% decrease in IFN-γ production, although CD25 expression remains unaffected. Collectively, our findings identify ADMA as a potential immunosuppressive factor that disrupts antigen uptake, processing, and presentation in DCs, thereby modulating T cell activation. These insights suggest a potential mechanism through which ADMA may contribute to immune evasion within the tumor microenvironment.

Dynamics and immunological signature of γδ T cells following antiretroviral therapy initiation in acute HIV-1 Infection

Early antiretroviral therapy (ART) is essential for controlling HIV-1 replication and boosting immune function. γδ T cells, as a vital component of the innate immune system, are implicated in the antiviral response. However, their immunological profile during acute HIV-1 infection and the early stages of ART remains unclear. This study aimed to delineate the immunological landscape of γδ T cells in individuals with acute HIV-1 infection undergoing early ART. We enrolled 65 participants who initiated ART immediately post-diagnosis and assessed the phenotypes and functions of γδ T cells using flow cytometry. We demonstrated that early ART significantly increased the frequency of Vδ2 T cells, while the Vδ1 T cell frequency remained stable and showed an inverse relationship with CD4+ T cell counts after ART. Early ART normalized the activation and PD-1 expression in Vδ1 and Vδ2 T cells, aligning with healthy controls (HCs) levels. Nevertheless, the proliferation of these cells, particularly within the PD-1+ subset, remains elevated post-ART. We also noted a reduction in perforin secretion in PD-1+ Vδ1 and Vδ2 T cells of people living with HIV (PLWH). Furthermore, Vδ1 T cells were identified as the predominant regulatory T cells, with TGF-β production and co-expression of CD127 and CXCR4, negatively correlated with CD8+ T cell activation. Our study elucidates the dynamic immunological characteristics of γδ T cells in acute HIV-1 infection and early ART, contributing to the understanding of their role in HIV-1 pathogenesis and the potential for γδ T cell-based immunotherapeutic strategies.

Geometric Adjustment of T Cell-Sensitive Nanorobots for Enhanced Stability.

Personalized dendritic cell (DC) based vaccines offer promising immunotherapeutic approaches for cancers and infectious diseases by leveraging living DCs to stimulate a patient's immune system through interactions with T cells. However, conventional DC-based vaccines face significant challenges, including limited stability and short storage lifespan of the living cells. To overcome these limitations, smart artificial nanorobots, termed nano-bone marrow dendritic cell (BMDC)-originated T cell activators (nano-BOTs) are developed by incorporating 1-dimensional (1D) nanoparticles to enhance stability and activation efficacy. The use of 1D nanoparticles enables precise modulation of the geometric properties, resulting in significantly improved interactions with effector T cells. This innovative approach addresses the inherent limitations of traditional DC-based vaccines and amplifies their ability to activate effector T cells. The advanced nanorobots exhibit exceptional stability and therapeutic potential, representing a transformative step toward personalized DC-based vaccines in future biological therapeutics.

Characterization of serotype-specific Dengue virus T cell inhibition.

Dengue virus (DENV) serotype -2 and -3 infections are associated with more severe disease outcomes than -1 and -4, though a biological explanation for this has not been identified. DENV serotype effects on human T cell activation were assessed by measuring T cell receptor (TCR)-mediated IL-2 release following TCR stimulation. DENV envelope (env) proteins were expressed in Jurkat CD4+ T cell lines and regions inhibiting TCR inhibition mapped by mutagenesis. TCR-signaling pathway inhibition was characterized by total internal reflection fluorescence microscopy and immunoblot. Reverse genetics validated env mapping results. T cell incubation with DENV-1 and -4 inhibited TCR signaling whereas DENV-2 and -3 did not. Inhibition did not require viral replication. DENV env protein expression inhibited TCR by interfering with activation of proximal TCR signaling events. Amino acids (aa's) 49 to 62 of DENV 1 env were sufficient to inhibit TCR signaling, with env aa's 55 and 66 being critical. Reverse genetics confirmed that substitution of DENV-2 and -3 aa's 55 and 66 into DENV-1 and -4 reversed TCR inhibition, and DENV-1 aa 55 and 66 introduced into DENV-2 and -3 enhanced TCR inhibition. DENV-2 and -3 are associated with more severe clinical disease than DENV-1 and -4; however, no biological explanation for this difference has been previously identified. We found that DENV-1 and -4 viral particles and env proteins blunt T cell responses by interfering with proximal TCR signaling while DENV-2 and -3 do not, potentially explaining DENV pathogenic outcomes in primary and secondary infection.

Pathogenic Role of Age‐Associated B Cells in Autoimmune Disorders and Myasthenia Gravis

ABSTRACTAge‐associated B cell (ABC) is a distinctive B cell subset characterized by CD11c and T‐bet expression that accumulates with aging and in autoimmune conditions. This review summarizes current understanding of ABCs in the immunological function and autoimmune pathogenesis of autoimmune diseases, including myasthenia gravis (MG). ABCs arise when B cells are stimulated via B cell receptors and innate immune receptors (notably TLR7/9), in the presence of cytokines secreted by Th1 cells. ABCs behave as antigen‐presenting cells, secrete inflammatory cytokines, and can differentiate into antibody‐secreting cells. In autoimmune disorders, ABCs are thought to undergo expansion, efficiently present self‐antigens to T cells, generate inflammatory mediators, and contribute to autoantibody production. Contemporary single‐cell transcriptomic investigations of MG patients experiencing myasthenic crisis have identified clonally expanded ABC‐like populations. These cells potentially contribute to MG pathogenesis through multiple mechanisms: enhancing T cell activation, sustaining autoreactive plasma cell development, and producing inflammatory cytokines. The increased number of ABCs in late‐onset MG suggests a link between aging and autoimmunity. Targeting ABC development may be a useful treatment approach for antibody‐mediated autoimmune diseases such as MG. Understanding ABCs helps explain how aging affects autoimmunity.