Search Results (190)

The progressive decline in functional β-cell mass in Type 2 Diabetes (T2D) is increasingly recognized not as a simple apoptotic loss, but as a complex erosion of cellular identity termed “dedifferentiation.” Central to this phenotypic shift is the metabolo-epigenetic axis, where mitochondria act as the primary sensing hub, transducing nutrient flux into biochemical signals that govern the chromatin landscape. This review synthesizes current evidence on how mitochondrial metabolites—including Acetyl-CoA, α-ketoglutarate, and NAD+—serve as obligatory co-factors for the epigenetic machinery. We explore how chronic metabolic stress triggers a “Systemic epigenetic destabilization,” leading to the loss of lineage-specific markers and the formation of persistent “metabolic scars.” Furthermore, we discuss the clinical implications of these changes, specifically regarding the phenomenon of metabolic memory and the molecular limits of β-cell reversibility. By integrating foundational transcriptional studies with emerging epigenomic data, we propose that targeting the mitochondrial–epigenetic axis offers a strategic window for re-differentiating failing β-cells and restoring glycemic homeostasis. 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

Immunoglobulin G (IgG) is a central component of humoral immunity in coronavirus disease 2019 (COVID-19); however, increasing evidence suggests that infection-induced IgG repertoires exert immunomodulatory effects beyond classical antiviral functions. In this study, we investigated whether IgG from patients with moderate or severe COVID-19 directly modulates human peripheral γδ T cells and whether these effects are associated with disease severity-dependent IgG idiotype profiles. Purified IgG from non-exposed healthy controls, moderate COVID-19 patients, or severe COVID-19 patients was incubat-ed with peripheral blood mononuclear cells from healthy donors. γδ T cell phenotype, subset distribution, homing markers, and cytokine production were assessed by flow cytometry, while direct IgG–cell interactions were evaluated using fluorescent IgG binding assays. In parallel, proteomic profiling using human proteome microarrays was performed to identify γδ T cell-expressed protein targets recognized by COVID-19-induced IgG. IgG from SARS-CoV-2-infected individuals selectively reduced Vγ9⁺Vδ2⁺ γδ T cells, altered memory differentiation, downregulated CCR5, CCR6, and CD161 expression, and reshaped cytokine production in a severity-dependent manner. COVID-19 IgG bound directly to the γδ T cell membrane without inducing apoptosis, indicating a non-cytotoxic mechanism of modulation. Proteomic analysis revealed a marked expansion and diversification of γδ T cell-associated IgG targets in COVID-19, particularly in severe disease, with enrichment of pathways related to immune signaling and inflammation. Collectively, these findings identify γδ T cells as direct functional targets of SARS-CoV-2-induced IgG repertoires and demonstrate that disease severity shapes IgG idiotype networks with distinct immunomodulatory capacities. This work highlights a previously underappreciated antibody-mediated mechanism contributing to immune dysregulation in COVID-19. Full article

Latent tuberculosis infection (LTBI) represents a major global health concern as it constitutes the principal reservoir for future tuberculosis (TB) disease. Its identification is particularly important in Bacille Calmette–Guérin (BCG)-vaccinated populations, where cross-reactivity of purified protein derivative limits the specificity of the tuberculin skin test and hampers targeted preventive therapy. Early Mycobacterium tuberculosis antigens encoded within the RD1 region, especially ESAT-6, CFP-10 and TB7.7, have enabled the development of antigen-specific interferon-gamma release assays (IGRAs) and recombinant skin tests with improved BCG-independent specificity. This narrative review integrates and critically appraises current evidence on the immunobiological properties of early and latency-associated antigens, the cellular mechanisms underlying T-cell-dependent immune reactivity, and the diagnostic performance of IGRAs and ESAT-6/CFP-10-based skin tests, rather than merely summarizing individual studies. Although these platforms rely on different assay principles (in vitro cytokine release versus in vivo delayed-type hypersensitivity), both measure antigen-specific T-cell memory and do not define the biological stage of infection or reliably distinguish latent from incipient or active TB. Across most adult populations, IGRAs demonstrate high specificity and acceptable sensitivity, whereas reduced sensitivity and higher rates of indeterminate results are observed in young children and immunocompromised individuals. ESAT-6/CFP-10-based skin tests show diagnostic accuracy comparable to IGRAs and may offer operational advantages in resource-limited settings. Latency-associated antigens and host biomarkers such as IP-10, together with multi-analyte immune signatures, represent promising avenues for improving diagnostic sensitivity and prognostic stratification but currently lack sufficient validation for routine clinical use. Overall, RD1-encoded antigens remain central to LTBI immunodiagnosis, while future research should focus on developing stage-resolving and prognostic biomarkers, optimized antigen panels, and standardized interpretive frameworks. Full article

Background and Clinical Significance: SLIPPERS syndrome (Supratentorial Lymphocytic Inflammation with Parenchymal Perivascular Enhancement Responsive to Steroids) was first described in 2015 as a variant of CLIPPERS restricted to supratentorial regions. Only a few cases have been reported so far, and its distinction from primary angiitis of the central nervous system (PACNS) remains challenging, as both may present with overlapping clinical, radiological, and histopathological features. We report two patients initially diagnosed with SLIPPERS but finally fulfilling the diagnostic criteria for PACNS, highlighting the complexity of the differential diagnosis. Case Presentation: The first patient was a 49-year-old woman who presented with seizures, memory impairment, and facial neuralgia. MRI showed multiple cortico-subcortical and deep nodular lesions in the left hemisphere with gadolinium enhancement. Brain biopsy revealed a T-cell-predominant lymphocytic vascular infiltrate. She responded to corticosteroids but later relapsed, requiring methotrexate for long-term immunosuppression, with no further recurrences during seven years of follow-up. The second patient was a 64-year-old man with hypertension, dyslipidemia, and alcohol use who developed repeated focal-to-generalized seizures. MRI disclosed multifocal nodular gadolinium-enhancing right hemispheric lesions, with SWI microhemorrhages. Biopsy demonstrated transmural T-cell vasculitic infiltrates. He responded to corticosteroids and methotrexate, but radiological progression at 14 months prompted replacement with cyclophosphamide. Conclusions: There is a considerable clinical, radiological, and histological overlap between SLIPPERS and PACNS. Careful analysis of advanced MRI sequences, particularly angiographic and vessel-wall imaging studies, combined with meticulous histopathological analysis, is essential to avoid misdiagnosis. These similarities suggest that some cases attributed to SLIPPERS may, in fact, correspond to variants of PACNS. Full article

In the context of small, battery-powered systems, a lightweight, reusable architecture is needed for integrated measurement, visualization, and cloud telemetry that minimizes hardware complexity and energy footprint. Existing solutions require high resources. This limits their applicability in Internet of Things (IoT) devices with low power consumption. The present work demonstrates the process of design, implementation and experimental evaluation of a single-cell lithium-ion battery monitoring prototype, intended for standalone operation or integration into other systems. The architecture is compact and energy efficient, with a reduction in complexity and memory usage: modular architecture with clearly distinguished responsibilities, avoidance of unnecessary dynamic memory allocations, centralized error handling, and a low-power policy through the usage of deep sleep mode. The data is stored in a cloud platform, while minimal storage is used locally. The developed system combines the functional requirements for an embedded external battery monitoring system: local voltage and current measurement, approximate estimation of the State of Charge (SoC) using a look-up table (LUT) based on the discharge characteristic, and visualization on a monochrome OLED display. The conducted experiments demonstrate the typical U(t) curve and the triggering of the indicator at low charge levels (LOW − SoC ≤ 20% and CRITICAL − SoC ≤ 5%) in real-world conditions and the absence of unwanted switching of the state near the voltage thresholds. 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

Chimeric antigen receptor (CAR) T-cell therapy has revolutionized the treatment of relapsed or refractory (r/r) diffuse large B-cell lymphoma (DLBCL); however, a significant proportion of patients fail to achieve a durable response, underscoring the need for reliable predictive biomarkers. We characterize T-lymphocyte subpopulations in apheresis samples from 23 r/r large B-cell lymphoma (LBCL) patients who received axicabtagene ciloleucel (axi-cel) to identify pre-treatment cell biomarkers associated with CAR T-cell kinetics and clinical outcomes. Immunophenotyping of T-cells within fresh apheresis samples and monitoring of circulating CAR T-cells were performed by multiparametric flow cytometry. The median peak CAR T-cell count was 45.2 CAR T-cells/mL. Strong CAR-T expanders (≥45.2 CAR T-cells/mL) exhibited higher values of both CD4⁺ (p = 0.011) and CD8⁺ (p = 0.023) central memory T-cells (T_CM; CCR7⁺CD45RA⁻), as well as lower proportions of CD8⁺CD38⁺ T-cells in apheresis samples. In apheresis, a cut-off value of >4.3% of CD8⁺ T_CM predicted strong CAR-T expansion (AUC: 0.80; p = 0.023) and superior progression-free survival (p = 0.04) compared with patients who had CD8⁺ T_CM below the cut-off. Our data suggest that high frequencies of CD8⁺ T_CM cells in apheresis samples may represent a promising pre-treatment biomarker associated with strong CAR-T expansion and superior clinical outcome in r/r LBCL patients following axi-cel. Full article

Background: Axillary lymph node (ALN) metastasis is a critical prognostic determinant in breast cancer (BC) that informs surgical management. However, surgically clearing the axilla carries morbidity, so less invasive methods of risk-stratifying patients are needed. ALN fine needle aspiration (FNA) is currently used to detect BC metastases, but these samples also contain immune cells. Methods: Cells obtained via FNA from BC-patient-derived ALNs were analysed using flow cytometry. Results: FNA acquires sufficient leukocytes for comprehensive immunophenotyping of reactive, patient-derived ALNs. All CD4⁺ and CD8⁺ T-cell subsets (naïve, terminal effector, central memory, and effector memory) and rarer (<2%) natural killer (NK) and plasmacytoid dendritic cell (pDC) populations are represented. Importantly, the immune-cell profile of one reactive ALN appears to reflect the immune status of the patient’s axilla. Furthermore, FNA captures immune differences between patients with ≤1 or ≥2 metastatic ALNs. Increased numbers of naïve CD4⁺ T cells, but fewer terminal effector, central memory, and effector memory subpopulations, were obtained from patients with ≥2 metastatic ALNs. Moreover, despite their sparse distribution pattern on whole-section immunohistochemistry (WSI), FNA revealed that CD56⁺ NK cell activation receptors were decreased in patients with ≥2 metastatic ALNs. Finally, FNA captured a decrease in pDCs in patients with ≤1 metastatic ALNs, despite their clustered distribution pattern on WSI. Conclusions: FNA is not only feasible for sampling leukocytes from reactive, patient-derived ALNs, but also identifies immune-cell profiles that reflect axillary tumour burden in BC. Thus, this technique could be used to risk-stratify BC patients in the future. Full article

Acute Appendicitis (AA) is the commonest abdominal digestive surgical emergency, but its etiology is not clarified. Based on histologic observations, an allergic cause has been proposed. In a type I hypersensitivity allergic reaction, there is a Th2 immune response characterized by Th2 cells, eosinophils, basophils, IgE, IL-4, IL-5, and IL-13 serum elevation. Recent studies showed a local appendicular endoluminal and parietal Th2 immune response in acute phlegmonous appendicitis. We performed a prospective single-center study where we evaluated the Th2 blood immune response in 38 patients with acute phlegmonous appendicitis, 27 patients with acute gangrenous appendicitis, and 18 patients with the clinical picture of AA, who underwent appendectomy but had negative histology for AA (negative appendectomy group). Higher levels of basophils were found in phlegmonous appendicitis (p = 0.03), and higher levels of eosinophils were found in the control group (p = 0.003). Effector memory CD4 T cells re-expressing CD45RA were higher in gangrenous (p = 0.020) and central memory CD4 T cells in phlegmonous appendicitis (p = 0.004). The number of Th2 circulating cells was higher in gangrenous appendicitis (p = 0.037), while Th1 circulating cells were higher in phlegmonous appendicitis (p = 0.028). IL-4 blood concentrations were elevated in acute gangrenous appendicitis (p = 0.029). No significant differences were found in the levels of IgE, IL-5, or IL-13 in any of the groups. Thus, a Th2 response was not detected in patients’ serum with phlegmonous appendicitis. Serum levels of IgE, IL-5, and IL-13 were not different among patients with acute phlegmonous appendicitis, acute gangrenous appendicitis, and the negative appendectomy group. These findings are in contrast to our previous work in which we evaluated the Th2 response at the local level, at the appendicular luminal aspect and appendicular wall, in phlegmonous appendicitis and control groups, and we unequivocally showed a Th2 response in phlegmonous appendicitis. Thus, in patients with phlegmonous appendicitis, the local Th2 response is not reflected in the serum levels of immune cells and cytokines. Full article

Background/Objectives: Toxoplasmosis caused by Toxoplasma gondii still poses a serious threat to public health in most countries and regions. Currently, the lack of effective vaccines necessitates the urgent development of a safe and effective vaccine. Methods: In this study, we combined the inactivated T. gondii vaccine with a colloidal manganese salt (Mn jelly [MnJ]) adjuvant. Results: This triggered a powerful innate immunity, significantly increased the number of CD4⁺ and CD8⁺ T cells secreting interferon γ (IFN-γ) in mice, and enhanced the generation of CD8⁺ central memory T cells and CD8⁺ effector memory T cells. Compared to the control groups, mice in experimental groups produced more specific IgG, and produced high levels of IL-2, IL-12 and IFN-γ. The survival rate of mice in experimental groups reached 50%, while all control group mice died within 9 days during T. gondii acute infection. Furthermore, the burden of brain cysts in experimental group mice was also significantly reduced by 90.77% compared to the control group during chronic infection. Conclusions: These results suggested that the incorporation of an MnJ adjuvant significantly enhances the immunoprotective efficacy of inactivated T. gondii vaccine, positioning this formulation as a promising candidate for development against toxoplasmosis. Full article

Child maltreatment (MALT) is a devastating form of early-life adversity (ELA) and a primary risk for mental and physical illness. It is difficult to disentangle postnatal caregiving effects from heritable factors. Here we investigated the long-term effects of maternal care using a cross-fostering design to control for biological/heritable factors on immune function and inflammation during adolescence in a translational and naturalistic macaque model of MALT. We studied the impact of MALT on the immunophenotype of peripheral blood mononuclear cells (PBMCs) and assessed glucocorticoid receptor expression and function during adolescence. MALT was associated with elevated expression of NR3C1, the gene that encodes for the glucocorticoid receptor, in PBMCs. Glucocorticoid receptor function was not altered by MALT when examined for response to dexamethasone (DEX). In addition, MALT led to a reduction in the percentage of naïve CD4⁺ T cells and an increase in the percentage of central memory (Tcm) CD4⁺ T cells. These results suggest that MALT-exposed adolescents show residual effects of MALT on CD4⁺ T cells and increased expression of NR3C1 without demonstration of increased function of the glucocorticoid receptor. Taken together, these results suggest that ELA has enduring implications for cellular glucocorticoid receptor biology and CD4⁺ T cells. Full article

The brain and the immune system communicate in many ways and interact directly at neuroimmune interfaces at brain borders, such as hippocampus, choroid plexus, and gateway reflexes. The first part of this review described intercellular communication (synapses, extracellular vesicles, and tunneling nanotubes) during homeostasis and neuroimmunomodulation upon dysfunction. This second part compares spatial orientation, learning, and memory function in both systems. The hippocampus, deep in the medial temporal lobes of the brain, is reported to play a central role in all three functions. Its medial entorhinal cortex contains neuronal spatial cells (place cells, head direction cells, boundary vector cells, and grid cells) that facilitate spatial navigation and allow the construction of cognitive maps. Sensory input (about 100 megabytes per second) via engram neurons and top down and bottom up information processing between the temporal lobes and other lobes of the brain are described to facilitate learning and memory function. Output impulses leave the brain via approximately 1.5 million fibers, which connect to effector organs such as muscles and glands. Spatial orientation in the immune system is described to involve gradients of chemokines, chemokine receptors, and cell adhesion molecules. These facilitate immune cell interactions with other cells and the extracellular matrix, recirculation via lymphatic organs (lymph nodes, thymus, spleen, and bone marrow), and via lymphatic fluid, blood, cerebrospinal fluid, and tissues. Learning in the immune system is summarized to include recognition of exogenous antigens from the outside world as well as endogenous blood-borne antigens, including tumor antigens. This learning process involves cognate interactions through immune synapses and the distinction between self and non-self antigens. Immune education via vaccination helps the process of development of protective immunity. Examples are presented concerning the therapeutic potential of memory T cells, in particular those derived from bone marrow. Like in the brain, memory function in the immune system is described to be facilitated by priming (imprinting), training, clonal cooperation, and an integrated perception of objects. The discussion part highlights evolutionary aspects. Full article