Search Results (338)

Background: Autism spectrum disorder (ASD) is associated with immune dysregulation in a subset of individuals, though findings remain heterogeneous and poorly defined, particularly regarding immune subtypes and metabolic context. Methods: We analyzed whole-blood microarray data from GSE18123 (GPL570: ASD n = 46, controls n = 19; GPL6244: ASD n = 68, controls n = 21) using an integrated immunometabolic framework. CD4⁺ T-cell transcriptional programs were used to assign dominant immune phenotypes (TH1, TH2, TH17, Tfh, FOXP3⁺ Treg, Tr1-like). Metabolic demand was quantified via the τ-axis; execution capacity was assessed using cytosolic and mitochondrial energy compensation ratios (CECR, MECR). Induction–execution mismatch was captured by three Gap metrics (Cytosolic, Warburg, Global). Functional validation correlated these metrics with transcriptional signatures of folate transport, one-carbon metabolism, receptor-mediated micronutrient uptake (LRP2–CUBN–AMN), cobalamin processing, and vitamin D activation across both platforms. Results: Six immunometabolic CD4⁺ subtypes were identified within ASD. τ-axis discrimination was strongest for Tr1-like (AUC = 0.811) and Tfh (AUC = 0.825) states, while TH17 profiles were indistinguishable from controls. Despite variation in metabolic demand, CECR and MECR remained relatively preserved, indicating decoupling between induction and execution capacity. Global Gap values were most negative in Tfh and TH1 states and positive in TH17 and controls. Negative Gap states showed coordinated suppression of ATP-intensive micronutrient acquisition pathways, including folate transport (FOLR1/2, SLC19A1), megalin–cubilin-mediated uptake (r ≈ 0.77–0.79), and vitamin D activation (CYP27B1). Intracellular cobalamin processing was upregulated in proportion to metabolic demand (r > 0.9). Findings were directionally replicated across both datasets. Conclusions: These data demonstrate that ASD exhibits structured immunometabolic heterogeneity characterized by subtype-specific demand–capacity imbalance. The Global Gap framework provides transcriptomic evidence of energetic deficit in Tfh- and Tr1-like-dominant states. Future clinical studies should incorporate subtype-stratified assessment of micronutrient status and metabolic execution capacity. Full article

Background/Objectives: Despite advances in the TNM staging system, prognostic heterogeneity persists in early-stage non-small cell lung cancer (NSCLC). Lymphatic invasion (LI) is a known marker of aggression, but its independent significance in the critical, low-risk Stage I, N0 subgroup—typically ineligible for adjuvant therapy—remains poorly defined. We hypothesized that LI acts as a powerful, yet hidden, risk factor in this highly favourable cohort. Methods: This retrospective cohort study included 988 consecutive patients who underwent curative anatomical resection for NSCLC. All patients underwent complete resection with pathologically confirmed negative surgical margins (R0 resection). Cases were staged according to the 9th Edition of the TNM Classification of Malignant Tumours (TNM-9) and grouped as LI-positive or LI-negative. A critical subgroup analysis focused on 347 truly low-risk patients (TNM Stage I, N0, no vascular or pleural invasion). Overall survival (OS) was evaluated using the Kaplan–Meier method and multivariable Cox proportional hazards models. Results: In the entire cohort (n = 988), LI was present in 40.9% of cases. LI positivity was an independent predictor of worse OS in multivariable analysis (HR: 1.520, 95% CI: 1.004–2.301, p = 0.048). In the low-risk subgroup (n = 347), the presence of LI resulted in a drastic survival divergence, with 5-year OS declining from 96.1% (LI-negative) to 83.8% (LI-positive). Multivariable analysis confirmed LI as an independent adverse prognostic factor in this subgroup (HR: 4.002, 95% CI: 1.567–10.221, p = 0.004). Conclusions: Lymphatic invasion is a robust, independent adverse prognostic factor in resected NSCLC. LI may identify a subset of early-stage N0 NSCLC patients who warrant closer postoperative surveillance and prospective evaluation for adjuvant treatment strategies. Validation in prospective cohorts is required before LI can be formally integrated into staging algorithms or treatment guidelines. Full article

Background/Objectives: HXP-GPOVac is a locally produced, inactivated Newcastle disease virus-based (NDV-HXP-S) COVID-19 vaccine manufactured in Thailand. This phase II trial compared its safety and immunogenicity with the mRNA vaccine BNT162b2 in adults aged 18–75 years. Methods: In this randomized, double-blind, active-controlled trial registered with the Thai Clinical Trials Registry (TCTR20220819003), 300 participants were assigned 3:1 to receive HXP-GPOVac or BNT162b2 on Days 1 and 29. Solicited adverse events (AEs) were recorded for 7 days after each dose, AEs were summarized through 28 days after each dose, and serious adverse events (SAEs), medically attended AEs (MAAEs), and adverse events of special interest (AESIs) were collected through Day 197. Humoral immunogenicity was assessed by pseudovirus 50% neutralization titers (NT₅₀) and anti-spike IgG concentrations at baseline, Day 29, Day 43, and Day 197. Seroconversion was defined as a ≥4-fold increase from baseline. A predefined subset underwent interferon-γ (IFN-γ) and interleukin-5 (IL-5) ELISpot assays to assess cell-mediated immune responses. The primary immunogenicity analysis assessed non-inferiority of HXP-GPOVac compared with BNT162b2 based on the NT₅₀ geometric mean titer ratio, with a prespecified non-inferiority margin of 0.5. Results: Solicited AEs were predominantly mild and occurred more frequently after the first dose in both groups; one or more solicited local or systemic AEs were reported by 23.7% (95% CI: 18.3–29.8) of HXP-GPOVac recipients and 44.7% (95% CI: 33.3–56.6) of BNT162b2 recipients after the first dose. AEs through 28 days after vaccination and SAEs were uncommon; MAAEs occurred in 17.0% of HXP-GPOVac recipients and 22.4% of BNT162b2 recipients, and none were considered related to vaccination. In the HXP-GPOVac group, NT₅₀ geometric mean titers increased from 5.6 at baseline to 65.5 at Day 29 and 505 at Day 43, declining to 63.6 at Day 197. Anti-spike IgG geometric mean concentrations rose from 7.5 BAU/mL at baseline to 102.7 BAU/mL at Day 29 and 514.6 BAU/mL at Day 43, decreasing to 61.0 BAU/mL at Day 197. BNT162b2 induced higher antibody levels at all time points. The NT₅₀ GMT ratio (HXP-GPOVac/BNT162b2) at Day 43 was 0.51 (95% CI: 0.39–0.67); the lower bound did not exceed the prespecified non-inferiority margin of 0.5, and non-inferiority was not established. Seroconversion rates at Day 43 were 97.6% for HXP-GPOVac and 97.1% for BNT162b2 (neutralizing antibody) and 98.6% and 97.1%, respectively (anti-spike IgG). ELISpot analyses demonstrated increased IFN-γ responses after the second dose without evidence of Th2-dominant skewing. Conclusions: HXP-GPOVac was well tolerated and induced substantial humoral and cellular immune responses, with high seroconversion rates and balanced T-cell polarization. Although absolute antibody levels were lower than those induced by BNT162b2 and the prespecified non-inferiority criterion was not met, these findings support continued evaluation of the inactivated NDV-HXP-S vaccine platform. Full article

Pancreatic ductal adenocarcinoma (PDAC) remains highly lethal and largely refractory to immune checkpoint inhibition because limited antigen-specific priming, myeloid suppression, dense desmoplasia, and abnormal vasculature enforce immune exclusion. CD40 links CD4+ T-cell help through CD40L/CD154 to antigen-presenting-cell (APC) licensing and CD8+ T-cell priming, making CD40 agonism a rational strategy to stimulate antitumor immunity in PDAC. CD40 is expressed on APCs and has also been reported on subsets of PDAC tumor cells, cancer-associated fibroblasts, and endothelial cells, indicating that CD40 agonists may affect immune activation, stromal/vascular remodeling, and context-dependent tumor-cell-intrinsic signaling. TRAF-dependent CD40 signaling activates canonical and non-canonical NF-kB, MAPK, and PI3K/AKT pathways, promoting APC maturation, IL-12-associated Th1 programming, macrophage repolarization, and matrix remodeling; tumor-intrinsic effects remain more variable, ranging from apoptotic to pro-survival programs. Clinically, CD40 agonists have shown pharmacodynamic immune engagement and manageable toxicity, mainly in combinations with chemotherapy, checkpoint inhibitors, and vaccine platforms, but efficacy remains inconsistent, and randomized validation is incomplete. Baseline CD40 expression has not reliably predicted benefit. Future development should prioritize spatially resolved tumor-immune profiling, longitudinal pharmacodynamic biomarkers, optimized sequencing, and agent-specific dosing strategies. This review integrates CD40 expression, signaling, and clinical evidence in PDAC to support more rational, biomarker-guided development of CD40-directed immunotherapy. Full article

This study is a narrative review of natural killer (NK) cells in Behcet disease (BD). BD is an inflammatory disorder with manifestations in mucosal tissues. Unlike autoimmune diseases that generate autoantibodies, BD is believed to be an autoinflammatory disease triggered by innate immune cells rather than adaptive cells. Hyperactivation of neutrophils causes vasculitis and thrombosis, and they migrate into cutaneous and ocular lesions. Dominance of M1 macrophages promotes the differentiation of Th1 cells. Moreover, the cross-reaction of bacterial heat shock proteins induces production of cytokines such as IL-4 and IFN-γ in γδT cells, which alters the balance between Th1 and Th2 phenotypes. Nevertheless, NK cells play more critical roles in BD pathogenesis than other innate immune cells because not only is their activity precisely controlled by the interaction between ligands and receptors, but NK1 shift also elicits Th1 dominance. The genetic factors associated with BD are HLA-B51 and major histocompatibility complex class I-related chain A (MICA), which stimulate NK receptors as ligands. Improperly processed peptides dysregulate their interaction with NK receptors, triggering the inflammatory response. NK1 and NK2 subsets represent cytokine production in relapse and remission periods; however, the cytotoxicity of NK cells in relapse is lower than that in remission periods. It still remains unclear how NK cells are activated recurrently and expand cytokine production. This review highlights the regulation of gene expression encoding NK receptors, tissue-resident NK cells, and adaptive NK cells to discuss their potential for relapse. Splicing variants and readthrough genes encoding NK receptors easily alter cytokine production. Moreover, tissue-resident NK cells in mucosal tissues and adaptive NK cells that memorize the virus infection have the potential to trigger hyperactivation in relapse. Full article

Background: Growth factor therapy often fails in diabetic foot ulcers (DFUs). The reason remains unclear. Standard differential expression analysis may miss functionally critical genes with modest expression changes. Methods: We performed a secondary computational analysis of a longitudinal DFU transcriptomic dataset (Dryad; 17 patients, 117 serial biopsy samples, 12-week follow-up). Co-expression networks were built separately for healed (n = 37) and non-healed (n = 80) samples. Virtual gene knockout (VGK) was used to rank genes by topological impact on network cohesion. Single-cell analysis (GSE165816) assessed the association between endogenous KIF13A expression and keratinocyte migration-related signatures. A conceptual Hill-equation simulation was used to illustrate the transport-signaling threshold relationship. Drug repurposing used DSigDB enrichment. An independent bulk DFU cohort (GSE134431) was used for external validation. Results: KIF13A showed no differential expression (log₂FC = 0.173, p = 0.263) yet ranked first by VGK topological impact. In keratinocytes, high KIF13A expression correlated with greater migration scores versus zero-detection cells (p = 0.0058). A clear threshold effect emerged: below the 30th expression percentile, EGF, PDGF, and FGF pathway activation scores remained near baseline. In a structural-equation model, transport activity negatively predicted inflammation (standardized β = −0.92, p < 0.001). HIF1A showed the strongest positive correlation with KIF13A in keratinocytes (Spearman ρ = 0.26, p < 0.001), and FOS showed a negative correlation in the single-cell analysis (ρ = −0.16, p < 0.001) and in the bulk longitudinal cohort (ρ = −0.32, p < 0.001, n = 117). Recurrent AKR1B1-related drug signatures nominated the aldose-reductase pathway, and epalrestat was therefore prioritized as a hypothesis-generating candidate compound rather than a direct top-ranked enrichment hit. External validation confirmed consistent upregulation of KIF13A (Fold-Change = 1.58, adj. p = 0.0075), EPN1, and CLIP1 in DFU tissue. Despite population-level upregulation, a subset of cells fell below the functional signaling threshold. Conclusions: These computational findings suggest that KIF13A-associated vesicle transport impairment may represent a candidate systems-level bottleneck for growth-factor responsiveness in DFUs, a network-level pattern not captured by standard differential-expression analysis. Epalrestat, an AKR1B1 inhibitor prioritized through recurrent AKR1B1-related drug signatures, is presented as a candidate compound for further evaluation. As the present analysis is observational and computational, the findings should be interpreted as hypothesis-generating; experimental perturbation studies and prospective clinical validation are required. Full article

Background: Lung cancer is the top cause of cancer-related mortality globally, and chemo-immunotherapy is a core therapeutic strategy for it. The novel bacterial composite vaccine (Neo-BCV) we developed previously can activate anti-tumor immunity. This study explored its synergistic anti-tumor effect with cisplatin (CDDP), along with the underlying immunomodulatory mechanisms and molecular regulatory networks. Methods: A murine Lewis lung cancer (LLC) model was established to evaluate the efficacy of the combination therapy. Flow cytometry and multiplex cytokine assay were used to detect immune cell subsets and functional molecules in the spleen, serum and tumor tissues. RNA-sequencing (RNA-seq) was used to elucidate the molecular regulatory networks following the combination therapy in the tumor tissues. Body weight, blood indexes, serum biochemistry and H&E staining were monitored to verify biosafety. Results: Neo-BCV combined with CDDP achieved an 87.77% tumor growth inhibition rate, showing the most significant anti-tumor effect. The combination promoted DC maturation, enhanced effector immune cell infiltration, reduced immunosuppressive cells, upregulated Th1-type cytokines and downregulated CD8⁺ T cell surface PD-1. RNA-seq confirmed enrichment of multiple immune effector pathways, supporting tumor immune microenvironment remodeling. The combination alleviated CDDP-induced weight loss, had no obvious adverse effects on physiological indicators, and exhibited good biosafety. Conclusions: Neo-BCV combined with CDDP achieves enhanced anti-tumor efficacy and favorable biosafety in murine lung cancer models by regulating immune cell subsets and activating immune-related molecular pathways, providing a solid preclinical basis for its clinical translation in lung cancer treatment. Full article

Background/Objectives: The GMZ2.6c malaria vaccine candidate is a multi-stage P. falciparum chimeric protein that contains a fragment of the sexual stage Pfs48/45-6c protein genetically fused to GMZ2, which is an asexual stage vaccine construct consisting of conserved domains of Glutamate-Rich Protein (GLURP) and Merozoite Surface Protein-3 (MSP-3). Previous studies showed that GMZ2.6c is widely recognized by antibodies from individuals living in endemic areas of Brazil and that levels of anti-GMZ2.6c increase with malaria exposure and may contribute to immunity against the parasite. As cell-mediated responses are crucial for parasite control and protection, identifying antigens that elicit antigen-specific T cell recall in naturally exposed populations is the key to vaccine development. This study aimed to evaluate the cellular immune response against GMZ2.6c and its components (MSP-3, GLURP, and Pfs48/45) and to identify promiscuous T cell epitopes in individuals exposed to malaria in the Brazilian Amazon, considering the impact of active P. falciparum infection on antigen-specific T cell recall. Methods: This study was carried out using peripheral blood mononuclear cells (PBMCs) from individuals with active P. falciparum infection (PFI) and non-infected individuals exposed to malaria (NI) from Cruzeiro do Sul and Mâncio Lima, Acre State, and Guajará, Amazonas State. The PBMCs were stimulated with GMZ2.6c and its components, and cellular activation, CD4⁺ and CD8⁺ memory T cell subsets, and cytokine production were evaluated by flow cytometry. IFN-γ-secreting T cells were quantified by ELISpot using predicted T cell epitopes. Results: The individuals infected by P. falciparum displayed more CD8⁺ T cell activation in response to MSP-3 and Pfs48/45 and an increase in CD4⁺ T_CM cells and a reduction in CD4⁺ T_EM cells following stimulation with Pfs48/45 and GMZ2.6c. The PBMCs from both groups showed elevated production of IL-6 and TNF after stimulation with GMZ2.6c, MSP-3, and Pfs48/45, but only the non-infected individuals had high levels of IL-10. T cell epitope prediction identified sequences within MSP-3, GLURP, and Pfs48/45 that elicited IFN-γ responses in both the non-infected and P. falciparum-infected individuals. Conclusions: Individuals exhibit cellular immune responses to MSP-3 and Pfs48/45 that are recalled following GMZ2.6c stimulation. P. falciparum infection may modulate immune response, inducing a prominent pro-inflammatory response. Conversely, in the absence of the parasite, the individuals displayed balanced Th1/Th2 cytokine production. Several promiscuous T cell epitopes were able to recall IFN-γ responses. Further studies are needed to fully ascertain the potential of GMZ2.6c as a protective candidate vaccine against malaria. Full article

Aberrant pathogenic immune responses drive autoimmune uveitides; however, comprehensive leukocyte profiling in the conditions remains limited. Here, this exploratory pilot study aimed to elucidate the immunodynamics of ocular sarcoidosis (OS) and Vogt–Koyanagi–Harada disease (VKH) to identify blood diagnostic biomarkers during their acute phases. We performed a prospective observational analysis of ten newly diagnosed, treatment-naïve OS patients and seven VKH patients during their acute phases, along with eight healthy controls (HCs). Mass cytometry was utilized to quantify the proportions of 37 distinct leukocyte subsets. In OS group, the proportion of CD8⁺ naive was lower than in both VKH and control groups. Furthermore, the proportions of CD8⁺ central memory and γδ T cells were decreased compared to HC group. Hierarchical cluster analysis categorized the leukocyte subsets into four principal clusters: Cluster A (Th17-like, monocytes, neutrophils, etc.), Cluster B (Tregs, B cells, NK cells, basophils, etc.), Cluster C (CD8⁺ T cells, Th1-like, Th2-like, DCs, etc.), and Cluster D (CD4⁺ terminal effector, CD8⁺ terminal effector, and CD66b⁻ neutrophils). Compared to HC group, the abundance of Cluster A was relatively high in OS group, and the abundance of cluster B was relatively high in VKH group. In OS group, the proportions of CD8⁺ T cells and CD8⁺ terminal effector correlated negatively with serum ACE and sIL-2R levels. ROC curve analysis estimated that CD4⁺/CD8⁺ ratio (cut-off value: ≥3.46), the proportion of monocytes (≥9.41%), and the decreased proportions of CD3⁺ T cells (≤43.9%) and CD8⁺ T cells (≤10.0%) in peripheral blood may serve as potential blood biomarkers for diagnosing OS. The exploratory pilot study provides a comprehensive and simultaneous data of leukocyte subset proportions in the acute phase of OS and VKH, and our preliminary findings suggest that the proportions of specific leukocyte subsets may represent potential candidates for blood-based biomarkers in the diagnosis of OS. Full article

Inflammation at the superior airway level has multiple manifestations, and allergic rhinitis and chronic rhinosinusitis with or without polyps are two of the most frequent and troublesome of them, with innate and adaptive immunity being implicated. Dendritic cells, epithelial cells, neutrophils, macrophages, mucosal mast cells, eosinophils, basophils, innate lymphoid cells (ILCs), and NK cells are the players in innate immunity, while regulatory T (Treg), TH1, TH2, TH17, T follicular helper, and B cells are components of the adaptative immune system. Th9 cells, a subset of T helper cells discovered in 2008 that produce interleukin-9 (IL-9), play a vital role in the adaptive immune response and have advantageous and harmful effects in different diseases due to the induction pattern. We queried international databases for current, up-to-date information regarding the interplay between interleukin 9 (IL-9) and helper T cells (especially Th9 cells), and by other immune cells. Interleukin-9 has multiple immunological functions, acting on various target cells through its specific receptor (IL-9R), such as the following: the regulation of allergic (Th2-type) immune responses; effects on epithelial and mucosal cells, mast cells, and eosinophils; chronic inflammation; and autoimmunity. Thus, there is a further need to translate laboratory findings into clinical practice regarding IL-9. Full article

Thyroid cancer is the most common malignancy of the endocrine system and represents a biologically heterogeneous disease driven by the interplay between endocrine regulation, oncogenic signaling pathways, and tumor microenvironment dynamics. Although most follicular cell-derived thyroid cancers follow an indolent clinical course, a subset progresses toward aggressive, therapy-refractory phenotypes, underscoring the need for refined molecular understanding and improved biomarkers. This review comprehensively examines the molecular determinants of thyroid cancer progression, with particular emphasis on Thyroid Hormone (TH) signaling, the Mitogen-Activated Protein Kinase (MAPK) and Phosphoinositide 3-Kinase (PI3K)/AKT pathways, and the emerging role of microRNAs (miRNAs). We discuss how oncogenic alterations, most notably the ^V600EBRAF mutation, act as central drivers of tumor initiation and aggressiveness by sustaining MAPK/ERK signaling, promoting dedifferentiation, metabolic reprogramming, immune evasion, and resistance to targeted therapies. The cooperative role of PI3K/AKT signaling in reinforcing survival, invasion, and treatment resistance is highlighted, emphasizing the network-level integration of oncogenic pathways rather than linear dependency on single drivers. In parallel, thyroid hormones exert context-dependent effects on tumor biology through both genomic actions mediated by nuclear thyroid hormone receptors and non-genomic mechanisms initiated at the integrin αvβ3 receptor, linking endocrine status to cancer progression and therapeutic response. Finally, we review the expanding evidence supporting miRNAs as critical regulators of thyroid carcinogenesis and as promising diagnostic, prognostic, and predictive biomarkers. The clinical validation of miRNA-based panels and circulating miRNAs offers new opportunities to improve preoperative risk stratification, reduce overtreatment, and guide personalized therapeutic strategies. Collectively, these insights support a multidimensional framework for understanding thyroid cancer progression and highlight future directions for precision oncology. Full article

Lyme disease (LD) is classically defined as a tick-borne infection caused by Borrelia burgdorferi sensu lato (Bbsl). However, accumulating evidence indicates that, beyond microbial persistence, Bbsl infection can initiate sustained immune dysregulation and post-infectious inflammatory phenotypes in a subset of patients. This narrative review integrates open-access experimental, translational, and clinical data and discusses LD within the spectrum of infection-triggered, immune-mediated processes. We review key immunopathogenic mechanisms, including dysregulated innate immune activation, type I interferon (IFN-I) signaling, T helper 1 and T helper 17 (Th1/Th17) polarization with regulatory T-cell (Treg) insufficiency, antigen persistence (notably borrelial peptidoglycan), and pathways linking infection to autoimmunity such as molecular mimicry, epitope spreading, and human leukocyte antigen (HLA)-restricted susceptibility. These mechanisms are integrated with immune-mediated clinical manifestations affecting the central nervous system (CNS), peripheral nervous system (PNS), musculoskeletal system, heart, skin, and hematologic compartment. Finally, we discuss translational implications for diagnosis, biomarker-guided stratification, and emerging therapeutic strategies that extend beyond antimicrobial therapy, while addressing current controversies and limitations. This framework supports a mechanistic model in which Lyme disease-associated morbidity in selected patients reflects persistent immune activation and dysregulated host responses triggered by infection. Full article

Background: Renal allograft rejection remains a major challenge in transplantation. Current diagnostic approaches, including biopsies, are invasive and may fail to detect subclinical immune activation, potentially contributing to progressive graft dysfunction. Reliable, non-invasive biomarkers capable of monitoring immune activation and distinguishing rejection phenotypes are therefore needed. Methods: In this retrospective study, we evaluated serum neopterin as a biomarker of immune activation and graft status over 12 months following transplantation. Associations between neopterin levels and immune parameters, including natural killer (NK)-to-CD3⁺CD16/CD56⁺ T cell ratios, cytokines (IFN-γ and IL-10), and CD4⁺CD25⁺FoxP3⁺ T cell frequencies, were assessed. A total of 211 first renal allograft recipients were followed longitudinally, including patients with acute rejection (AR) and matched stable graft (SG) recipients. Serum neopterin was quantified by enzyme immunoassay, and immunophenotyping, mRNA expression, and cytokine profiling were performed on peripheral blood samples. Results: Serum neopterin levels were significantly elevated in AR compared to SG recipients, with a threshold of 57 nmol/L distinguishing AR with 81% sensitivity and 80% specificity. While IFN-γ demonstrated higher diagnostic performance in cross-sectional analysis, neopterin showed a more sustained elevation over time, remaining increased in AR recipients even at later post-transplant time points. Neopterin correlated positively with IFN-γ, but not IL-10, and inversely with CD4⁺CD25⁺FoxP3⁺ T cell frequency. NK cells were enriched during rejection, whereas CD3⁺CD16/CD56⁺ T cells were more prominent in graft stability. The NK-to-CD3⁺CD16/CD56⁺ T cell ratio was highest during acute cellular rejection. Conclusions: Neopterin reflects Th1-associated immune activation in renal allograft recipients and provides a temporally stable, non-invasive marker of immune status. Although it does not outperform IFN-γ levels at the time of rejection, its stability and sustained elevation suggest a complementary role in longitudinal monitoring. Integration of neopterin with immune parameters, including cytokine profiles and cellular subsets, may enhance the assessment of graft immunological status and support clinical decision-making. Full article

Objectives: This study aimed to assess the effects of voluntary exercise on type 1 diabetes mellitus (T1D) development and splenic immunological profiles in non-obese diabetic (NOD) mice, a spontaneous model of human T1D. Methods: Prediabetic female NOD mice were randomly assigned to sedentary or exercise groups, with mice in the exercise group given 10-week wheel access and sedentary mice receiving none. Late-time mice were monitored to diabetes onset or 24 weeks of age; early-time mice were analyzed immediately post-intervention. Blood glucose, food intake, water consumption, and body mass were monitored weekly. At the endpoints, splenocyte counts, T and B cell subsets, and mitogen-stimulated cytokine production were analyzed using flow cytometry. Results: Mice in the exercise group ran an average of 20.76 ± 0.22 km/day. By the late-time endpoint, 75% of mice in the exercise group remained non-diabetic versus 35% of sedentary mice (p = 0.006). Mice in the exercise group demonstrated lower blood glucose (p = 0.015), visceral fat mass (p = 0.035), and water intake (p < 0.001) but higher food intake (p = 0.001), with no difference in body mass (p = 0.389) compared to sedentary mice. No differences were observed in splenocyte counts or Th, Tc, Treg, or B cell populations at either time point (p ≥ 0.185). Early-time point cytokines also did not differ between groups (p ≥ 0.08). Conclusions: Voluntary exercise reduces T1D incidence and mitigates hyperglycemia in NOD mice, suggesting a protective effect against disease progression. Despite the benefits, physical activity did not alter splenic Tcell subsets or inflammatory cytokines, demonstrating systemic immunomodulation may not be the primary driver of benefit. Our results indicate that voluntary exercise protects against T1D through tissue-specific or metabolic mechanisms, which warrant further mechanistic investigation. Full article

Polycystic ovary syndrome (PCOS) is associated with reproductive, metabolic, and inflammatory disturbances. Alterations in T-cell subpopulations—particularly increased T helper 17 cells (Th17) and decreased regulatory T cells (Treg)—have been reported in PCOS; however, data on normoandrogenic phenotype D remain limited. Hypoxia-inducible factor 1α (HIF-1α), a key regulator of hypoxic response, also influences immune and metabolic processes and may affect the Treg/Th17 balance. To assess Treg and Th17 abundance, HIF-1α expression within these cells, and their ratios in women with phenotype D PCOS compared with healthy controls. The study included 49 women with phenotype D PCOS and 40 controls comparable in terms of age and BMI. Anthropometric, hormonal, metabolic, and inflammatory parameters were evaluated. Peripheral T-cell subsets and intracellular HIF-1α expression were analyzed by multiparameter flow cytometry. Absolute numbers of Treg and Th17 cells did not differ between groups. However, PCOS patients showed significantly higher Treg/Th17 and HIF-1α-positive Treg/HIF-1α-positive Th17 ratios. HIF-1α-positive Treg cells correlated positively with adiposity and insulin resistance markers; however, after False Discovery Rate (FDR) correction, correlations no longer remained statistically significant. Despite normoandrogenemia, PCOS patients exhibited higher hs-CRP levels. Phenotype D PCOS is characterized by altered immune cell ratios rather than absolute T-cell differences, suggesting distinct immunological features and persistent low-grade inflammation. Full article