Search Results (356)

Background/Objectives: Umami peptides enhance flavor and contribute to appetite regulation (satiety) and metabolic health. By signaling to the orbitofrontal cortex, umami has been shown to improve cognitive function in Alzheimer’s disease dementia. This taste boosts the immune system and induces saliva secretion. However, the molecular mechanisms linking umami peptides to systemic physiology remain poorly understood. This study provides the first integrated analysis of neurological, immunological, and endocrinological pathways activated by umami peptides. Methods: Novel umami peptides were identified using machine-learning and deep-learning analyses from a library of marine-derived bioactive peptides. T1R1-T1R3 heterodimer is the dominant receptor for umami taste transmission in humans, expressed on taste cells, intestinal cells, and hypothalamic tanycytes. Molecular docking confirmed the binding of novel ligands to the T1R1-T1R3 receptor complex. New candidates and experimentally validated umami peptides, identified by sensomics approaches from tauco, chicken soup, pufferfish, and dry-cured ham, were analyzed using gene ontology. Results: The functional enrichment analysis revealed crosstalk among key signaling processes, including glutamatergic and opioidergic pathways. In addition to the role of µ1 opioid receptor (OPRM1), hub gene intersections highlight cholecystokinin (CCK), glucagon-like peptide 1 (GLP-1), and the anorexigenic pro-opiomelanocortin (POMC) neurons as potential regulators of the gut–brain axis in satiety signaling. Chemokine-encoding genes, melanin-concentrating hormone (MCH), oxytocin (OXT), and neurotensin (NTS) were other key target genes. Conclusions: The identified targets reveal the coordinated crosstalk between peripheral and central umami signaling that may contribute to the regulation of feeding behavior, satiety, cognition, memory, learning, and immune function. These network-based insights generate hypotheses and guide the design of nutritional and drug-like effectors for metabolic and cognitive health. Full article

With increasing environmental pollution and a high incidence of respiratory infections, pulmonary nodules (PN) are being detected more frequently. Although most are benign, they are often accompanied by chronic inflammation and localized fibrosis, which may predispose patients to progression toward idiopathic pulmonary fibrosis (IPF). However, the biological relationship between benign pulmonary nodules (BPNs) and IPF remains poorly understood. Therefore, this study aims to investigate the shared molecular mechanisms and identify potential biomarkers linking BPN and IPF, with the goal of elucidating the pathogenic transition from BPN to IPF. In this study, microarray data from GEO datasets were systematically analyzed to explore shared molecular mechanisms, immune infiltration characteristics, and potential early intervention strategies linking BPN and IPF. Differential expression analysis, protein–protein interaction (PPI) networks, weighted gene co-expression network analysis (WGCNA), and integrative machine learning approaches identified MME and ANKRD23 as key hub genes associated with the transition from BPN to IPF. Both genes demonstrated strong diagnostic performance, with Area Under the Curve (AUC) values exceeding 0.7, and were significantly correlated with immune cell infiltration, particularly effector memory CD8⁺ T cells. Functional enrichment and gene set enrichment analyses indicated that these genes were mainly involved in immune-related processes in BPN, while in IPF, ANKRD23 was linked to cytoskeletal organization and genomic stability, and MME was enriched in profibrotic pathways such as TGF-β signaling. The diagnostic value of these biomarkers was further validated in a bleomycin-induced IPF mouse model using quantitative polymerase chain reaction (qPCR). In addition, drug–gene interaction prediction and molecular docking analyses highlighted several naturally derived compounds with favorable binding affinity and anti-inflammatory properties, among which folic acid, curcumin, and arbutin emerged as promising candidates for safe early intervention. Collectively, these findings identify MME and ANKRD23 as potential biomarkers for early identification of BPN patients at risk of developing IPF and provide a theoretical basis for early diagnosis and targeted preventive strategies. Full article

Background/Objective: This study is a cross-sectional investigation of long-term immune responses measured at different time intervals after COVID-19 infections, vaccinations, or combined exposure. The focus is on immune reactivity against recombinant spike (S) and nucleocapsid (N) protein antigens. Materials and Methods: Serum antibody levels were assessed up to four to four and a half years after infection or immunization, including virus-specific immunoglobulin G (IgG), IgA and IgM antibodies, as well as neutralizing antibodies against the S-protein. Cellular immunity was assessed by analyzing peripheral blood mononuclear cells (PBMC; n = 43 in first cohort, n = 32 in second cohort), including T-helper memory and cytotoxic subsets, and cytokine production after in vitro stimulation with recombinant SARS-CoV-2 proteins. A multiplex cytokine assay was used to analyze effector and regulatory immune responses. Results: Virus-specific IgG antibodies persisted for years after exposure to SARS-CoV-2, with IgG against the receptor-binding domain (RBD) correlating most strongly with neutralizing activity. Vaccinated individuals demonstrated higher IgA responses, whereas antibodies to the N-protein were associated with previous infection. No IgM antibodies were detected in any subjects, suggesting an immune response based on memory rather than ongoing infection. PBMCs from individuals with a history of both COVID-19 exposure and vaccination exhibited enhanced responsiveness, characterized by increased frequencies of memory T cells compared to vaccination alone. Stimulating with the S-protein induces higher cytokine production, including IFN-gamma, TNF-alfa, and IL-12(p70), compared with stimulation by the N-protein. Cytokines such as IL-10 and TGF-beta are also elevated, suggesting immune regulation rather than persistent inflammation. Conclusions: SARS-CoV-2 infection and vaccination are associated with persistent humoral and cellular immune responses detectable several years after exposure. Individuals with hybrid immunity exhibit broader and functionally enhanced immune reactivity, indicating more robust long-term immune memory. Future studies should focus on the long-term consequences of hybrid immunity and optimize other vaccine strategies, including recombinant antigen vaccines. Full article

We prospectively evaluated whether cytotoxic T-lymphocyte (CTL) activation and T-cell receptor (TCR) Vβ clonality predict treatment-free remission (TFR) after tyrosine kinase inhibitor (TKI) cessation in chronic-phase chronic myeloid leukemia (CML). Forty-five patients with sustained deep molecular response (DMR) were enrolled (On-TKI, n = 38; Off-TKI, n = 7) and underwent one-year immuno-monitoring from consent. The primary endpoint was 12-month TFR, defined as retention of MR4. Overall, 32/45 patients (71%) maintained TFR at 12 months. Longer TKI exposure and stable DMR were associated with TFR; notably, patients fulfilling “≥7 years of TKI plus ≥1 year of DMR” and exhibiting CTL activation features—CD8 > CD4, memory > effector, and/or highly activated CTL clones on TCR Vβ repertoire—showed the highest likelihood of durable TFR. By contrast, NK cells, effector Tregs, and G-/M-MDSCs did not discriminate TFR status in this cohort. Although antigen specificity against CML stem cells was not directly tested, the memory-dominant CTL phenotype is consistent with immune control after antigen reduction. These findings suggest that a simple, clinically accessible strategy based on flow cytometric CTL profiling and TCR Vβ clonality may help inform TKI discontinuation decisions in CML. External validation is warranted to confirm transportability and refine clinical thresholds. Full article

Herpes simplex virus type 2 (HSV-2) is the primary pathogen responsible for genital herpes. Predominantly transmitted via sexual contact, HSV-2 not only poses significant physical and psychological burdens on infected individuals but also substantially elevates the risk of HIV acquisition and represents a potentially fatal threat to newborns. Following primary infection, HSV-2 establishes lifelong latent infection within the sacral ganglia. Currently, there are no vaccines or therapeutics capable of eradicating this latent virus reservoir or effectively preventing initial infection. The core impediment to developing such interventions lies in the incomplete elucidation of the protective immune mechanisms against HSV-2 and its precise molecular pathogenesis. The host immune response against HSV-2 hinges critically on the coordinated interplay between innate and adaptive immunity. The innate immune system, serving as the first line of defense, acts to curtail early viral replication and initiate adaptive responses. This is achieved through mechanisms, including the genital mucosal barrier, activation of Toll-like receptors (TLRs), the cGAS-STING signaling pathway, interferon (IFN)-mediated antiviral effector functions, and activation of innate immune cells such as natural killer (NK) cells and dendritic cells (DCs). Crucially, however, HSV-2 counteracts these host defenses by expressing immune modulatory proteins (e.g., ICP0, ICP27, ICP35) that target key host antiviral signaling pathways, thereby affecting immune evasion. Within the adaptive immune response, neutralizing antibodies generated by the humoral immunity can provide localized protection at mucosal sites, but their protective efficacy is limited due to sophisticated viral immune evasion mechanisms. Cellular immunity, particularly mediated by CD4+ T cells, constitutes the core mechanism for viral clearance and suppression of recurrent outbreaks. Notably, tissue-resident memory T cells (TRMs) play a pivotal role in controlling the reactivation of latent HSV-2 within the ganglia. This review integrates current research advances to delineate the innate and adaptive immune mechanisms engaged during HSV-2 infection from the perspective of the dynamic host–virus interplay, with an ultimate aim to provide a theoretical foundation informing the rational development of preventive vaccines and therapeutic agents against HSV-2. Full article

Etrasimod is an oral selective sphingosine-1 phosphate receptor modulator, and its anti-inflammatory mechanism of action in inflammatory bowel diseases is not completely understood. It targets pro-inflammatory immune cells expressing sphingosine-1-phosphate receptors during their migration from the lymphatic system to the circulation and intestinal mucosa. Reductions in certain lymphocyte subsets in the peripheral blood have been reported, but its effects in lymph nodes remain unknown. This study investigated changes in leukocyte subpopulations in peripheral lymph nodes and blood in Crohn’s disease patients treated with etrasimod. Moderate-to-severe Crohn’s disease patients participated in this randomized, double-blind study, within the phase 2 CULTIVATE clinical trial. At baseline and after 14 weeks of etrasimod treatment, peripheral blood and inguinal lymph node biopsies were obtained. Isolated peripheral blood mononuclear cells and lymph node leukocyte populations were analyzed at single cell level using mass cytometry at both timepoints. The immunophenotyping revealed 15 innate and adaptive major immune cell populations, as well as 14 subpopulations of CD4+ and CD8+ T-cells. In peripheral lymph nodes, etrasimod resulted in significant accumulation of naïve, central memory, and effector memory CD4+ T-cells (+10.7%, +4.2%, and +2.3%, respectively; all p = 0.03), as well as naïve CD8+ T-cells (+4.2%; p = 0.03). Conversely, these subsets were reduced in peripheral blood (−6.2%, −6.0%, −2.0%, and −2.2%, respectively; all p = 0.03). Naïve and memory B-cells decreased in the circulation (−1.7%, p = 0.057; −0.6%, p = 0.03, respectively) but were unchanged in the lymph nodes. Innate immune cell populations remained mostly unaffected in both compartments. Our data indicate that etrasimod’s pharmacodynamic effect is related primarily with the attenuation of the T-cell mediated inflammation with minor changes in B-cells. However, additional follow-up studies are needed for the validation of these observations in the context of Crohn’s disease. Full article

Hematopoietic stem cell transplant (HSCT) is a curative therapy for acute lymphoblastic leukemia (ALL), but its success is limited by chronic graft-versus-host disease (cGvHD) and disease relapse. A central challenge is uncoupling the graft-versus-leukemia (GvL) effect from cGvHD. Early changes in the bone marrow microenvironment following HSCT may offer a predictive window into these divergent outcomes. We conducted a retrospective, single-center, exploratory study on 14 pediatric ALL HSCT patients. Applying single-cell antibody-sequencing (AbSeq) on archived bone marrow aspirates collected 60–100 days post-HSCT, we evaluated immune patterns associated with the development of cGvHD or ALL relapse after day 114. cGvHD after day 114 was associated with upregulation of the endoplasmic reticulum (ER) stress transcription factor XBP1 in transitional B cell and IgM memory B cell populations, a mincle^highPD1⁻ neutrophil population, and exhausted LAG3⁺ effector memory T cells (T_EM). ALL relapse after day 114 was associated with higher CD22, CD24, and ARG1 expression in M(IL-4)-like macrophages and exhausted TIGIT⁺ T_EM. Results from this exploratory study suggest that marrow immune signatures of B cell ER stress preceding later development of cGvHD and macrophage-mediated immune evasion preceding relapse may potentially be early biomarkers for separating GvL from cGvHD in ALL HSCT. Validation with larger cohorts is warranted. Full article

Type I interferons (IFN-I) are pleiotropic cytokines best known for their antiviral impacts. However, they are known to also impact immune responses outside of viral infection through directly signaling many populations of innate and adaptive immune cells. Here, we focus on the complex body of findings from viral, bacterial, and parasitic infection models, cancer and autoimmunity studies, as well as in vitro experiments using human and murine T cells, demonstrating that IFN-I can be directly sensed by CD4 T cells. Such signaling has been shown to influence many central aspects of antigen-specific CD4 T cell responses, including proliferation, apoptosis, effector subset differentiation, and memory formation. These effects are frequently divergent and sometimes opposing, likely reflecting how differences in variables related to the IFN-I signal, overall inflammatory milieu, and the CD4 T cell integrate to shape outcomes. Indeed, we discuss findings supporting a framework in which dynamic engagement of canonical and non-canonical signaling pathways downstream of IFN-I, which are contingent on a cell’s activation state, play a key role in determining whether and how IFN-I promotes, restrains, or otherwise reprograms CD4 T cell fates. Together, these observations highlight the impressive scope of regulation that IFN-I signals to CD4 T cells can exert, parallel to its actions on other immune and non-immune cell types. They also suggest that harnessing such signaling could offer powerful therapeutic strategies to shape CD4 T cell immunity in diverse context-dependent situations. Full article

Systemic lupus erythematosus (SLE) is a severe autoimmune disease that is challenging to treat due to poor understanding of its pathogenesis and etiology. Clearly understanding and dissecting the therapeutic effects of potential treatment in animal models are important. It has been shown that human alpha-1 antitrypsin (hAAT) holds therapeutic potential for the treatment of autoimmune diseases including lupus. However, the mechanism underlying its protective effect requires further investigation. In the present study, we used a chronic graft-versus-host disease-induced lupus mouse model to test the effect of hAAT on lupus development. We performed adoptive transfer of MHC I-aβ mismatched bm12 splenocytes into hAAT transgenic mice and showed that hAAT significantly blocked the production of anti-dsDNA IgG autoantibodies. Mechanistically, hAAT inhibited T cell activation and proliferation, including that of effector memory T (Tem) and T follicular helper (Tfh) cells. In addition, hAAT suppressed germinal center formation and functions. These results advanced the current understanding of hAAT functions and provide a new insight for the treatment of SLE. Full article

Acute Trypanosoma cruzi infection induces an exuberant immune response; however, the host is unable to clear the parasite, and the infection progresses to a chronic phase. T and B cells play a crucial role in controlling infections. Although the parasite constitutes a myriad of antigenic determinants capable of activating many T and B cell clones, some antigens trigger a large proportion of CD8 T cells, implying TCR cross-reactivity targeting these determinants. Polyclonal activation may result in an inefficient immune response against the parasite, diverting it to less critical antigenic determinants, allowing infection persistence, and increasing the risk of autoimmunity. Cross-reactivity has been demonstrated in CD8 T cells but not in CD4 T cells. Herein, we demonstrate, by cytometry, that CD4+ T cells, carrying the DO11.10 transgenic TCR, which are responsive to OVA, are activated during the T. cruzi acute infection, becoming effector memory T cells that produce cytokines such as IFN-γ, TNF-α, IL-4, and IL-10. In addition, prior oral exposure to OVA altered cytokine production by these transgenic T cells upon infection. We also demonstrate that T. cruzi induces Foxp3 expression in a sizable pool of transgenic T cells. Full article

Background/Objectives: Cholangiocarcinoma (CCA) is characterized by a heterogeneous immune microenvironment, where the prognostic significance of CD8⁺ tissue-resident memory T (T_RM) cell activation and spatial positioning remains to be fully elucidated. This study investigated how the activation phenotypes and their spatial distribution relative to tumor cells influence anti-tumor immunosurveillance and predict clinical outcomes in CCA. Methods: Multiplex immunohistochemistry (mIHC) and single-cell RNA sequencing (scRNA-seq) were employed to characterize naïve (PD-1⁻CD103⁺CD8⁺) and exhausted (PD-1⁺CD103⁺CD8⁺) subsets. G-cross function analysis was utilized to quantify the spatial proximity between these specific T_RM subsets and tumor cells, correlating the spatial interaction with patient overall survival. Results: scRNA-seq profiling revealed that PD-1⁻CD103⁺CD8⁺ T_RM cells were enriched in genes associated with lymphocyte activation and cytotoxicity, while PD-1⁺CD103⁺CD8⁺ T_RM cells exhibited an exhaustion signature. Spatially, PD-1⁻CD103⁺CD8⁺ T_RM cells exhibited increased interactions with tumor cells, whereas PD-1⁺CD103⁺CD8⁺ T_RM cells showed reduced engagement. Therefore, the close proximity of PD-1⁻CD103⁺CD8⁺ T_RM cells to tumor cells was identified as a significant predictor of favorable clinical outcomes. Conclusions: The activation state of CD8⁺ T_RM cells combined with their spatial localization constitutes a critical prognostic factor in CCA. Effective anti-tumor immunosurveillance relies on the direct engagement of naïve T_RM cells with tumor cells. These findings highlight the potential of PD-1-targeted immunotherapies to remodel the spatial proximity of the tumor microenvironment, potentially promoting the redistribution of effector cells into tumor-proximal regions. Full article

The early identification of patients with highly active multiple sclerosis (HAMS) is crucial for guiding therapeutic decisions and initiating high-efficacy treatment strategies. This study aimed to characterize peripheral immune profiles that can distinguish between patients who are candidates for intensive therapy at disease onset and in later stages. Using spectral flow cytometry, we identified distinct immune signatures to differentiate early-stage patients from those with refractory, long-standing disease. In newly diagnosed individuals, decreased herpesvirus entry mediator (HVEM) expression on effector T helper (Th) cells distinguished HAMS from non HAMS cases. In contrast, patients with therapeutic resistance exhibited reduced CD28 expression on naïve regulatory and CD8⁺ T cells. Disability progression was associated with elevated HVEM on classical monocytes, decreased CD70 on CD56^bright natural killer cells (NK), and lower programmed cell death protein 1 (PD-1) expression on memory Th cells. Notably, CD28 expression on terminal effector CD8⁺ T cells and HVEM levels on plasmablasts emerged as strong predictors of progression independent of relapse activity, while higher PD-1 memory Th cell frequencies predicted clinical stability. This study identifies two panels of immune biomarkers: one distinguishing candidates for early high-efficacy intervention, and another defining patients with refractory disease. The immunological landscape of HAMS evolves across disease stages. In addition, we defined progression-associated markers detectable at the outset of follow-up, enabling the timely recognition of patients at heightened risk of disability accumulation, discriminating between neurodegeneration-driven and inflammation-driven mechanisms of progression. Full article

The immune status of dogs is shaped by continuous exposure to antigenic and various environmental stimuli, which together influence the development, regulation, and effectiveness of immune responses. Stress-related immune alterations may not be evident at the systemic level but can emerge at cellular and molecular scales. Therefore, this study aimed to comprehensively characterize the hematological and immunological profiles of dogs in different environments. We evaluated lymphocyte responses under basal conditions and following CD3/CD28-mediated in vitro activation, with subsequent long-term culture. Gene expression analyses targeted markers of early T cell activation, cytotoxic effector function, cytokine signaling, and inhibitory immune regulation. The memory phenotype of T lymphocytes was evaluated after blood collection and prolonged in vitro culture. In addition, hematological and biochemical profiles were assessed, including basic parameters, cortisol, and C-reactive protein. Our results revealed that client-owned dogs exhibited lower baseline expression of activation markers, especially in comparison with the short-term stay group, indicating an early immune activation state upon entry to the shelter environment. Furthermore, T lymphocytes from short- and long-term shelter dogs exhibited marked differences in the distribution of naïve and effector-memory subsets as well as different expansion capacity. These alterations persisted during prolonged in vitro culture, indicating that stress duration and environmental antigen exposure differentially shape immune responsiveness. In summary, chronic stress modulates canine immune status in a time-dependent manner, highlighting the importance of integrated cellular and molecular approaches in assessing the impact of environmental stressors on dogs’ health and welfare. Full article

Inducible costimulator (ICOS) is a costimulatory immune checkpoint receptor expressed on activated T-cells, while the ICOS ligand (ICOSL) is expressed on antigen-presenting cells. The ICOS–ICOSL axis promotes the survival of memory and effector T-cells and induces several immune responses. In addition, the ICOS–ICOSL interaction induces cell proliferation, cell survival, and cytokine production. The roles of ICOS and ICOSL in cutaneous T-cell lymphoma (CTCL) are unclear. In this study, we examined the roles of ICOS and ICOSL in CTCL. The tumor cells co-expressed ICOS and ICOSL, and the upregulated expression of ICOS and ICOSL reflected disease severity. Anti-ICOS and anti-ICOSL neutralizing antibodies inhibited both the in vitro and in vivo proliferation of CTCL cell lines. The anti-ICOSL neutralizing antibodies induced apoptosis and suppressed CCR4 expression on tumor cells, inhibiting CCR4–CCL17-mediated migration. These results suggest that the ICOS–ICOSL axis plays an essential role in CTCL pathogenesis, and targeting the ICOS–ICOSL axis could be a viable strategy for treating CTCL. Full article

Background and Objective: Patients with stage III clear cell renal cell carcinoma (ccRCC) have a high risk for disease recurrence post-nephrectomy. To mitigate overtreatment, there is a pressing need to determine who benefits from immune checkpoint inhibition (ICI) around the time of surgical resection. We performed digital spatial analysis of both gene and protein expression in stage III ccRCC tumors, some of which had preoperative ICI exposure. Methods: Nephrectomy specimens from stage III ccRCC patients were analyzed using the Nanostring GeoMx Digital Spatial Profiler. Differential expression analysis was performed and validated using NCT02210117 trial data to identify genes associated with both ICI and clinical response. A gene score was then generated to predict overall survival in patients from The Cancer Genome Atlas (TCGA). Key Findings and Limitations: In a small cohort of 19 patients, RNA expression significantly differed based on preoperative ICI exposure and recurrence status—CD8+ effector and central-memory T-cell signatures were less prevalent in the treatment-naïve with recurrence group. Three out of four patients with preoperative immune checkpoint inhibition recurred. External validation yielded a four-gene set (GZMK, GZMA, ITGAL, and IL7R), where higher expression levels predicted better overall survival in the TCGA cohort (p = 0.005). Conclusions and Clinical Implications: Preoperative ICI favorably altered the tumor microenvironment to resemble that of treatment-naïve patients without recurrence but did not translate to improved survival. Upon external validation, the genes GZMK, GZMA, ITGAL, and IL7R were modifiable with ICI and associated with improved overall survival. Further investigation is needed to assess if patients with low baseline expression of these genes may benefit from ICI around the time of surgery. Full article