Search Results (2,301)

Systemic lupus erythematosus (SLE) is a severe autoimmune disease characterized by autoantibody production and multi-organ involvement. Anifrolumab, a monoclonal antibody targeting the type I interferon (IFN) receptor, has been approved for the treatment of SLE. Our aim was to investigate the long-term effects of inhibited type I IFN signaling on circulating follicular helper T subsets (T_FH), follicular regulatory T cells (T_FR), and B lymphocyte subpopulations, reflecting the ongoing germinal center reactions in SLE patients. Peripheral blood samples were obtained from ten SLE patients before the initiation of anifrolumab treatment, and at months 6 and 12 of the intervention period. Flow cytometry analysis was performed to assess the frequencies of circulating T_FH cell subsets, T_FR cells, and certain B cell subpopulations. Serological parameters, including autoantibody levels and complement components, were determined as part of the routine diagnostic evaluation. We observed a significant and sustained reduction in the percentage of activated circulating T_FH cells. Notably, the frequency of CXCR3⁻CCR6⁺ T_FH17 cells decreased, whereas the proportion of CXCR3⁺CCR6⁻ T_FH1 cells increased significantly. Furthermore, the proportion of the IgD⁻CD27⁻ double-negative B lymphocytes was also significantly reduced. These findings suggest that anifrolumab therapy attenuates T_FH cell activation, which may contribute to its clinical efficacy by modulating germinal center responses in SLE. Full article

Background/Objective: Candidemia is a serious complication following intensive chemotherapy and is associated with high mortality in pediatric patients. This study aimed to identify the factors associated with 28-day mortality in pediatric patients with candidemia. Methods: We retrospectively analyzed 63 pediatric patients diagnosed with acute leukemia and candidemia following intensive chemotherapy. Clinical characteristics, laboratory findings, and epidemiological data were collected. Antifungal susceptibility data were available for 60 patients. Kaplan–Meier survival analysis was used to estimate the 28-day mortality rate, and Cox regression was performed to identify prognostic factors. Results: The 28-day mortality rate among the 63 patients (57.1% male, median age 9.74 years) was 36.5%. Candida tropicalis was the predominant species (96.8%). Antifungal susceptibility rates were 100% for amphotericin B and caspofungin and 22.2% for fluconazole. The factors independently associated with reduced 28-day mortality were an absolute lymphocyte count (ALC) ≥ 0.2 G/L at the time of candidemia diagnosis (5.3% vs. 50% mortality; hazard ratio [HR] = 0.08; 95% confidence interval [CI], 0.01–0.61), the use of antifungal prophylaxis (AFP) (26.3% vs. 52%; HR 0.31; 95% CI, 0.13–0.74), and granulocyte transfusion (GTX) combined with granulocyte colony-stimulating factor (G-CSF) (20% vs. 47.4%; HR = 0.31; 95% CI, 0.11–0.85). Conclusions: Our findings suggest that an ALC ≥ 0.2 G/L, AFP, and the administration of a GTX combined with G-CSF may be considered favorable prognostic factors. Full article

FMC63-CAR T cell therapy targeting CD19 protein on malignant B-cells is effective in patients with relapsed or refractory diffuse large B-cell lymphoma (r/r DLBCL), with complete response rates of 43–54%. Common germline variants of the immune-checkpoint regulator CTLA-4 may elicit different responses to CAR-T cell therapy. The CTLA4 gene single-nucleotide polymorphism rs231775 coding threonine or alanine at amino acid position 17 of the CTLA-4 protein was prevalent in 55% of the studied DLBCL patients. In a retrospective comparative analysis of clinical outcome, there were significant differences in CTLA4 A17hom vs. T17Ahet and T17hom carriers with four-year progression-free survival at 77%, 59%, and 30% (p = 0.019), four-year overall survival was 79%, 41%, and 33% (p = 0.049), the relapse rates were 20%, 37%, and 56% (p = 0.025), and the death rates 20%, 54%, and 52% (p = 0.049). Conclusions: CTLA4 rs231775 polymorphism may impact the treatment outcome in FMC63-anti-CD19 CAR-T cell therapy, with an association of the CTLA4 minor allele A17 to favorable treatment outcome. Full article

The fungal component of microbiota, known as the mycobiome, inhabits different body niches such as the skin and the gastrointestinal, respiratory, and genitourinary tracts. Much information has been gained on the bacterial component of the human microbiota, but the mycobiome has remained somewhat elusive due to its sparsity, variability, susceptibility to environmental factors (e.g., early life colonization, diet, or pharmacological treatments), and the specific in vitro culture challenges. Functionally, the mycobiome is known to play a role in modulating innate and adaptive immune responses by interacting with microorganisms and immune cells. The latter elicits anti-fungal responses via the recognition of specific fungal cell-wall components (e.g., β-1,3-glucan, mannan, and chitin) by immune system receptors. These receptors then regulate the activation and differentiation of many innate and adaptive immune cells including mucocutaneous cell barriers, macrophages, neutrophils, dendritic cells, natural killer cells, innate-like lymphoid cells, and T and B lymphocytes. Mycobiome disruptions have been correlated with various diseases affecting mostly the brain, lungs, liver and pancreas. This work reviews our current knowledge on the mycobiome, focusing on its composition, research challenges, conditioning factors, interactions with the bacteriome and the immune system, and the known mycobiome alterations associated with disease. Full article

Background: Regulatory T cells (Tregs) are the main suppressor cells that maintain immune tolerance and prevent autoimmunity. Changes in Treg number or function are implicated in a wide range of autoimmune and inflammatory (AI/I) diseases, with or without underlying inborn errors of immunity (IEI). Understanding the phenotypic profiles of Treg subsets and their associations with immune dysregulation is crucial to identifying potential robust and holistic biomarkers for disease activity. Methods: We examined peripheral blood mononuclear cells from 40 patients diagnosed with various autoimmune/inflammatory diseases, including those with genetically confirmed inborn errors of immunity (IEIs), and compared these samples to those from 38 healthy controls of the same age. Utilizing multiparametric flow cytometry, we measured multiple Treg sub-populations and investigated their correlations with lymphocyte subset profiles and the diversity of autoantibodies. We applied advanced statistical and machine learning techniques, such as t-SNE, k-means clustering, and ROC analysis, to analyze immunophenotypic patterns in the patients. Results: Among all Treg sub-populations, only CD4⁺CD127^lowCD25^highFOXP3⁺ Tregs showed a significant decrease in patients compared to healthy controls (p < 0.05), while other Treg phenotypes did not differ. FOXP3 expression showed reduced intensity in patients and demonstrated diagnostic potential (AUC = 0.754). Notably, this Treg subset negatively correlated with CD19⁺ B cell percentages and positively correlated with the diversity of circulating autoantibodies. Unsupervised clustering revealed three distinct immunophenotypic profiles, highlighting heterogeneity among patients and underlining FOXP3-centered immune dysregulation. Conclusions: Our results presented that patients have an impairment in the CD4⁺CD127^lowCD25^highFOXP3⁺ regulatory T cell subset, which is identified by significantly decreased frequency and decreased expression of FOXP3. Immunological heterogeneity among patients was further uncovered by unsupervised clustering, highlighting the critical role that FOXP3-centered regulatory failure plays in the pathophysiology of illness. The combined evaluation of these three immunological factors, centered around FOXP3, holds promise as an integrative tool for monitoring disease progression across various autoimmune and immunodeficient contexts. Full article

CD8+ T lymphocytes (CTLs) act as serial killers of infected or malignant cells by releasing large amounts of interferon-gamma (IFNγ) and granzymes. Although IFNγ is a pleiotropic cytokine with diverse immunomodulatory functions, its precise spatiotemporal regulation and role in CTL-mediated cytotoxicity remain incompletely understood. Using wild-type and granzyme B-mTFP knock-in mice, we employed a combination of in vitro approaches, including T cell isolation and culture, plate-bound anti-CD3e stimulation, degranulation assays, flow cytometry, immunofluorescence, and structured illumination microscopy, to investigate IFNγ dynamics in CTLs. IFNγ expression in CTLs was rapid, transient, and strictly dependent on T cell receptor (TCR) activation. We identified two functionally distinct IFNγ-producing subsets: IFNγ^high (IFNγ^hi) and IFNγ^low (IFNγ^lo) CTLs. IFNγ^hi CTLs exhibited an effector/effector memory phenotype, significantly elevated CD107a surface expression (a marker of lytic granule exocytosis), and higher colocalization with cis-Golgi and granzyme B compared to IFNγ^lo CTLs. Furthermore, CRTAM, an early activation marker, correlated with IFNγ expression in naive CTLs. Our findings establish a link between elevated IFNγ production and enhanced CTL cytotoxicity, implicating CRTAM as a potential regulator of early CTL activation and IFNγ induction. These insights provide a foundation for optimizing T cell-based immunotherapies against infections and cancers. Full article

Fasciola gigantica (F. gigantica) is a vital parasite that causes fasciolosis. Liver fluke infections affect livestock animals, and the Fasciola species (Fasciola spp.) vaccine has been tested for many types of these diseases. Currently, computer-based vaccine design represents an attractive alternative for constructing vaccines. Thus, this study aimed to design the epitopes of linear B-cells (BCL) and helper T lymphocytes (HTL) using an immunoinformatic approach and to investigate in silico and the mice’s immune response. A non-conserved host region, overlapping F. gigantica cathepsin B proteins (FgCatB), and the highest conserved residue percentages were the criteria used to construct epitopes. The GPGPG linker was used to link epitopes in the multi-epitope Fasciola gigantica cathepsin B (MeFgCatB) peptide. The MeFgCatB peptide has high antigenicity, non-allergenicity, non-toxicity, good solubility, and a high-quality structure. The molecular docking between the MeFgCatB peptide and Toll-like receptor 2 (TLR-2) was evaluated. The IgM, IgG1, and IgG2 levels were elevated in silico. In mice, the MeFgCatB peptide was synthesized and administered as an injection. The MeFgCatB-specific IgG1 and IgG2a levels were elevated after week 2, showing a predominance of IgG1. The rFgCatB1, rFgCatB2, and rFgCatB3 were detected using the MeFgCatB peptide-immunized sera. The MeFgCatB peptide-immunized sera were detected at approximately 28–34 kDa in the whole body. In addition, the MeFgCatB immunized sera can positively signal at the caecal epithelium in the NEJ, 4WKJ, and adult stages. In summary, the MeFgCatB peptide is able to induce mixed Th1/Th2 immune responses with Th2 dominating and to detect the native protein of F. gigantica. The MeFgCatB peptide should help against F. gigantica in future experiments. Full article

Background: The spleen is the primary reservoir of immune cells in mammals. Diverse stimuli can disrupt spleen homeostasis, resulting in spleen injury and immune dysfunction. This study employed a porcine model to assess the therapeutic potential of salvianolic acid B (SAB) against lipopolysaccharide (LPS)-induced splenic injury. Methods: Seventy-two male weanling piglets were randomly assigned to one of four groups: CON-SS, SAB-SS, CON-LPS, and SAB-LPS. The CON-SS and CON-LPS groups received a basal diet, while SAB-SS and SAB-LPS groups received a SAB-supplemented diet. After 14 d, the CON-SS and SAB-SS groups received an intraperitoneal injection of sterile saline, whereas the CON-LPS and SAB-LPS groups were injected with LPS. Blood and spleen tissues were harvested 6 h post-injection for biochemical analysis. Results: LPS induced systemic immune disorders in piglets, as evidenced by increased immune organ indices and decreased white blood cell, lymphocyte, and basophil counts in blood (p < 0.05). LPS also caused histoarchitectural disruption, cell apoptosis, oxidative stress, and inflammation in the spleen (p < 0.05). Conversely, SAB improved splenic histopathology and reduced splenic apoptosis and pro-inflammatory mediators in piglets (p < 0.05). SAB significantly mitigated peroxidation accumulation by facilitating the nuclear translocation of nuclear factor erythroid 2-related factor 2 and strengthening the antioxidant system, and inhibited nucleotide-binding oligomerization domain, leucine-rich repeat and pyrin domain-containing 3 (NLRP3) inflammasome activation (p < 0.05). Mechanistically, SAB attenuated LPS-induced splenic oxidative stress and NLRP3 inflammasome activation by restoring mitochondrial structure and function (p < 0.05). Conclusions: This research unveils that SAB alleviates LPS-induced spleen disorder by reinforcing antioxidant system and suppressing NLRP3 inflammasome, highlighting SAB’s potential as a prospective therapeutic agent for spleen disorders. Full article

Background: Olmesartan-induced enteropathy is a rare complication of a widely used angiotensin II receptor blocker. Patients usually present with chronic diarrhea and weight loss. Histologically, villous atrophy and intraepithelial lymphocyte infiltrates within the duodenum confirm the diagnosis. The prognosis is usually good after withdrawal of the offending drug. Case presentation: Here, we report the case of a 76-year-old woman who developed a severe form of Olmesartan-induced enteropathy complicated by acute kidney injury and acute recurrence after drug rechallenge. After definite cessation of the drug, the patient did not experience any gastrointestinal (GI) symptom recurrence after 6 months of follow-up. However, she experienced chronic kidney disease stage G3b. Histological analysis did not show any villous atrophy or intraepithelial lymphocyte infiltrates within the duodenum or the colon biopsy. Discussion and conclusion: This case highlights the broad spectrum of clinical manifestations and histological findings in Olmesartan-induced enteropathy. It also highlights the importance of rapid diagnosis in order to limit organ damage such as chronic kidney disease. Full article

A novel therapeutic approach, inverse vaccination, is being developed to combat autoimmune diseases and other inflammatory conditions. It aims to educate the immune system to recognize self-components as innocuous and stop reacting against them. Inverse vaccination, also referred to as tolerogenic vaccination, introduces autoantigens into the immune system to induce immune tolerance to the nominal antigen. In contrast to conventional vaccination, which aims to train the immune system to identify a pathogen as a potential threat that needs to be eradicated, inverse vaccination is designed to educate the immune system to recognize that an antigen is harmless and, consequently, extinguish the inflammatory attack of the tissues that contain the autoantigen. This article discusses recent progress in using inverse vaccination to design therapeutic interventions in several autoimmune diseases by deprivation of co-stimulatory signaling, tagging autoantigens to trigger immune tolerance in the liver, and mRNA vaccination. Also discussed is a tolerogenic feedback loop implicating B lymphocytes in inverse vaccination. Full article

This study identifies the novel effects of soluble factors derived from murine erythroblasts on lymphoid cell phenotypes. These effects were observed following the treatment of splenic mononuclear cells with erythroblast-conditioned media received from both healthy mice and mice subjected to hematopoiesis-activating conditions (hypoxia, blood loss, and hemolytic anemia), suggesting a common mechanism of action. Using flow cytometry, we elucidated that erythroblast-derived soluble products modulate T cell differentiation by promoting Treg development and increasing PD-1 surface expression on B cells. The immunoregulatory potential of erythroblasts is subpopulation-dependent: CD45+ erythroblasts respond to hemolytic stress by upregulating the surface expression of immunosuppressive molecules PDL1 and Galectin-9, while CD45- erythroblasts primarily increase TGFb production. These findings highlight the regulatory role of erythroblasts in modulating immune responses. Full article

Cutaneous melanoma is an aggressive cancer with an increasing incidence worldwide, highlighting the need for research into its pathogenesis. The tumor microenvironment (TME) plays a critical role in melanoma progression and consists of cellular components and an extracellular matrix (ECM) rich in cytokines and signaling molecules. The most abundant stromal cells within the TME are cancer-associated fibroblasts (CAFs), which remodel the ECM and modulate immune responses. Among immune cells, tumor-associated macrophages (TAMs) predominate, and their polarization toward the M2 phenotype supports tumor progression. Tumor-infiltrating lymphocytes (TILs) have diverse functions, including cytotoxic T-cells, helper T-cells that modulate immune response, B-cells forming tertiary lymphoid structures (TLS), and regulatory T-cells with immunosuppressive properties. Dendritic cells (DCs) also play a complex role in the TME. A notable subpopulation are mature regulatory dendritic cells (mregDCs), which contribute to immune evasion. All of these TME components may drive tumorigenesis. Advancements in melanoma treatment—including immunotherapy and targeted therapies—have significantly improved outcomes in advanced-stage disease. In parallel, emerging approaches targeting the tumor microenvironment and gut microbiome, as well as personalized strategies such as neoantigen vaccines and cell-based therapies, are under active investigation and may further enhance therapeutic efficacy in the near future. Full article

Sleep deprivation impairs immune function, and melatonin has emerged as a key mediator in this process. This narrative review analyzes 50 studies published between 2000 and 2025 to determine the extent to which reduced melatonin synthesis contributes to immune dysregulation. Consistent sleep loss lowers melatonin levels, which correlates with elevated proinflammatory cytokines (e.g., IL-6 and TNF-α), increased oxidative stress, and reduced immune cell activity, including that of natural killer (NK) cells and CD4+ lymphocytes. Melatonin regulates immune pathways, including NF-κB signaling. It also supports mitochondrial health and helps maintain gut barrier integrity. These effects are particularly relevant in vulnerable populations, including older adults and shift workers. Experimental findings also highlight melatonin’s therapeutic potential in infections like SARS-CoV-2, where it modulates inflammatory responses and viral entry mechanisms. Despite the heterogeneity of study methodologies, a consistent correlation emerges between circadian disruption, melatonin suppression, and immune imbalance. These findings underscore melatonin’s dual role as a chronobiotic and immunomodulator. Addressing sleep loss and considering melatonin-based interventions may help restore immune homeostasis. More clinical trials are needed to determine the best dosing, long-term efficacy, and population-specific strategies for supplementation. Promoting healthy sleep is crucial for preventing chronic inflammation and diseases associated with immune dysfunction. Full article

Background/Objectives: Head and neck squamous cell carcinoma (HNSCC) is the seventh most common cancer, with limited responsiveness to immune checkpoint inhibitors (ICIs). Cancer vaccine therapy is a promising novel immunotherapeutic approach that stimulates tumor-specific T cells. Receptor tyrosine kinase-like orphan receptor 1 (ROR1), which is overexpressed in malignant tumors but minimally expressed in normal tissues, presents a promising target for immunotherapy. This study aimed to evaluate ROR1 as a target for helper T lymphocyte (HTL)-based peptide vaccine immunotherapy in HNSCC. Methods: ROR1 expression in HNSCC tissues was assessed by immunohistochemistry. A novel ROR1-derived epitope (ROR1_403–417) was identified and used to generate ROR1-reactive HTLs. Functional assays measuring IFN-γ and granzyme B secretion, as well as direct cytotoxicity, were performed. The effects of ICIs on HTL activity were also examined. The presence of ROR1-reactive T cells in the peripheral blood of patients with HNSCC was evaluated. Results: ROR1 positivity rates in HNSCC tissues were significantly higher (80.0%) than those in healthy controls (16.7%), and high ROR1 expression correlated with advanced clinical stages. HTL lines recognized the ROR1_403–417 peptide in a human leukocyte antigen (HLA)-DR-restricted manner, secreted effector cytokines, and exhibited direct cytotoxicity against ROR1+ tumor cells. Dual PD-L1/PD-L2 blockade further enhanced HTL responses. ROR1-reactive T cells were detected in the peripheral blood of patients with HNSCC. Conclusions: ROR1 represents a promising target for immunotherapy in HNSCC. The ROR1_403–417 peptide can elicit ROR1-reactive HTLs that exhibit antitumor responses against HNSCC cell lines, which can be enhanced by ICIs. These findings support the potential of ROR1-targeted peptide vaccine therapy for HNSCC. Full article

The traditional paradigm of multiple sclerosis (MS) as a T cell-mediated disorder has been challenged by the effectiveness of monoclonal antibodies (mAbs) targeting CD20-expressing lymphocytes. Although these are mostly represented by B cells, the CD20 marker is expressed by 2–6% of T cells (CD20+ T), which are effectively depleted in serum and cerebrospinal fluid of MS patients by anti-CD20 mAbs. CD20+ T cells are characterized by a pro-inflammatory phenotype and increased potential for migrating and invading the central nervous system (CNS) compared to CD20− T cells. Furthermore, CD20+ T cells are detected within brain inflammatory lesions from MS patients and actively participate in the experimental MS model. This review aims to summarize the current knowledge on CD20+ T cells, from their identification and characterization to evidence of depletion by disease-modifying treatments (DMTs), likely contributing to therapeutic efficacy. Conflicting hypotheses on the origin and development of CD20+ T cells will also be discussed, as well as evidence from clinical and preclinical studies supporting their pathogenetic role in MS. Full article