Search Results (1,375)

The utilization of immunomodulatory nanomaterials, i.e., leveraging their unique properties to enhance immune responses, represents a transformative approach for the treatment of various diseases. Recent advancements in nanotechnology have enabled the design of nanomaterials capable of delivering immunomodulatory agents in a targeted manner, such as cytokines, antibodies, and nucleic acids, to specific cells or tissues involved in immune regulation. These nanomaterials, including nanoparticles, liposomes, nanogels, nanoemulsions, dendrimers, MXenes and extracellular vesicles, have been increasingly tailored to modulate immune responses with precision and efficacy. This targeted approach not only enhances therapeutic outcomes but also reduces off-target effects, minimizing systemic toxicity. In this review, an overview of immunomodulatory nanomaterials and their biomedical applications are highlighted. Herein, we have discussed different types of nanomaterials and their design strategies, interactions with different immune system components (macrophages, dendritic cells (DCs), neutrophils, T lymphocytes (CD4⁺ helper T-cells, CD8⁺ cytotoxic T-cells, regulatory T-cells/Tregs, and memory T-cells), and B lymphocytes), and immunomodulation mechanisms. Furthermore, nanomaterial-based immunomodulation strategies to enhance cancer immunotherapy, wound healing, and bone regeneration and the treatment of infectious diseases, autoimmune diseases, and allergy and are discussed in detail. In addition to therapeutic applications, selected nanomaterial platforms demonstrate significant potential in pharmaceutical formulations by improving drug stability, controlled release, and bioavailability, as well as in cosmetology through skin-targeted delivery, anti-inflammatory activity, immune protection, and enhanced tissue regeneration. Finally, clinical trial updates, challenges and future prospects are outlined. Key findings indicate that lipid-based, polymeric, inorganic nanoparticles and dendrimers provide complementary advantages for immunomodulation, including efficient delivery, controlled release, multifunctionality, and precise immune targeting. Despite safety, regulatory, and scalability challenges, these systems show strong potential for advancing precision and personalized medicine. Taken together, these innovations hold great promise for personalized medicine approaches, wherein nanomaterials can be tailored to individual patient profiles for more effective and precise disease treatment and prevention strategies. This review focuses primarily on the mechanistic interactions between immunomodulatory nanomaterials and immune cells, including macrophages, dendritic cells, neutrophils, T lymphocytes, and B lymphocytes, rather than providing an exhaustive treatment of physicochemical optimization parameters such as particle size or surface modification chemistry, which fall outside the defined scope of this work. Full article

Background/Objectives: Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by progressive cognitive decline and chronic neuroinflammation. Increasing evidence suggests that the imbalance between pro-inflammatory Th17 cells and anti-inflammatory regulatory T (Treg) cells plays a critical role in AD pathogenesis. However, a comprehensive synthesis of how natural compounds modulate Th17/Treg balance in AD remains lacking. This review aims to summarize current preclinical evidence on Th17/Treg dysregulation and evaluate the immunomodulatory potential of natural compounds in AD. Methods: This review focuses on preclinical evidence derived from experimental AD models and related inflammatory models to evaluate how natural compounds modulate Th17/Treg balance, neuroinflammation, and cognitive function, with an emphasis on underlying molecular and immunometabolic mechanisms. Results: Th17/Treg imbalance contributes significantly to AD-associated neuroinflammation and disease progression. Representative natural compounds, including paeoniflorin, quercetin, and ganoderic acid A, have demonstrated the ability to rebalance Th17/Treg responses, suppress neuroinflammation, and improve neuronal survival in experimental models. These compounds are highlighted due to their relatively stronger evidence in AD-related models and more clearly defined immunomodulatory mechanisms. These effects are partially mediated through modulation of key signaling pathways and immunometabolic reprogramming. Conclusions: Targeting Th17/Treg balance with natural compounds represents a promising multi-target immunomodulatory strategy for AD. However, most current evidence is derived from preclinical or non-AD models, and clinical validation remains limited. Future studies should prioritize AD-specific models and translational research to evaluate therapeutic potential in humans. Full article

Human T-cell leukemia virus type 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a chronic inflammatory disease driven by HTLV-1-infected CD4⁺ T cells; however, the phenotypic and functional characteristics of disease-associated T-cell subsets remain incompletely understood. We analyzed samples using flow cytometry (n = 3–5 per group) and RNA-seq (n = 13), focusing on CADM1^highCD4⁺ T cells enriched for HTLV-1-infected cells to evaluate a transferrin receptor (TfR)-expressing subset. TfR⁺CADM1^highCD4⁺ T cells were detected in both asymptomatic carriers and patients with HAM, but their frequency among CD4⁺ T cells was higher in HAM patients. These cells exhibited a Treg-like phenotype with higher Foxp3 and CTLA-4 expression than TfR⁻ cells and showed increased Ki-67 positivity, consistent with proliferation. Despite this phenotype, they produced interferon-γ, indicating inflammatory potential, while Foxp3 expression was lower in HAM patients than in asymptomatic carriers, suggesting a more inflammatory phenotype. Furthermore, TfR transcript levels (RNA-seq TPM) correlated with clinical indicators of disease activity, including neopterin and CXCL10 protein levels, and the Osame motor disability score. Collectively, these findings suggest that TfR identifies a proliferative, Foxp3-low, Treg-like inflammatory CD4⁺ T-cell subset that is associated with disease activity in HAM. Full article

Autoimmune diseases arise from the failure of self-tolerance. The recognition of self-antigen peptide–MHC (pMHC) complexes by the T-cell receptor (TCR) is the fundamental event triggering autoimmune pathogenesis. While traditional immunosuppressants provide broad systemic effects, they often compromise global immunity. Emerging molecular strategies aim to selectively disrupt the trimolecular complex—comprising the TCR, the antigenic peptide, and the MHC molecule—to induce antigen-specific tolerance. This review highlights the pMHC–TCR interaction as the primary molecular checkpoint for antigen-specific intervention. We discuss the structural basis of these interactions and their potential to redefine the therapeutic landscape for autoimmune diseases (ADs). We examine the molecular drivers of tolerance breakdown—including genetic susceptibility, molecular mimicry, post-translational modifications (PTMs), and ectopic MHC II expression—that shape the autoreactive T-cell landscape. This review examines current advancements in biological and pharmacological interventions, such as pMHC-decorated nanoparticles and soluble pMHC, to reprogram pathogenic T-cell response. We also explored CAR-T therapy strategies for autoimmune diseases, such as CAR-Treg, designed to precisely modulate pMHC-TCR signaling. Collectively, these precision interventions in immunological synapse assembly during autoimmune response are considered the basis for safer, antigen-specific immunotherapy capable of restoring self-tolerance without global immunosuppression. Full article

Chronic pain is increasingly understood as a neuroimmune disorder rather than a purely neuronal condition, in which immune mediators and immune-like signaling within the nervous system regulate nociceptive gain across peripheral tissues, dorsal root ganglia (DRG), spinal cord, and supraspinal networks. Seminal and recent syntheses show that microglia, macrophages, cytokines/chemokines, and innate immune sensors can initiate and maintain maladaptive plasticity and central sensitization, helping explain the frequent clinical dissociation between structural pathology, systemic inflammatory markers, and pain severity. However, immune biology is bidirectional: alongside pronociceptive pathways, a growing literature describes active “pain-resolving” programs that terminate sensitization and restore homeostasis, including regulatory T cell (Treg)–IL-10 signaling and specialized pro-resolving mediators (SPMs). A structured search of PubMed/MEDLINE, supplemented by Europe PMC and PubMed Central, was performed, and citation chasing through broad scholarly indices was used to identify high-impact reviews, meta-analyses, and translational mechanistic studies. Systematic biomarker syntheses in low back pain, neck pain, and fibromyalgia indicate modest and heterogeneous systemic inflammatory signals, underscoring the need for mechanistic endotyping and stage-specific interventions. Based on this evidence, a clinically oriented framework is presented that distinguishes immune-driven pain amplification from impaired resolution and outlines practical implications for assessment, biomarker interpretation, and precision-oriented trial design. Full article

Gliomas are aggressive brain tumors with poor prognosis. The contribution of Toxoplasma gondii (T. gondii)-related transcriptional programs to glioma remains unclear. We identified T. gondii infection-related genes from neuroepithelial cell transcriptomes, mapped them to TCGA and CGGA glioma datasets, and validated their expression via RT-qPCR. A prognostic signature (TGRisk) was constructed via Cox and LASSO regression and validated across independent cohorts. Functional, immune, and drug sensitivity analyses were conducted. Forty infection-related genes were identified, enriched in stress responses, microRNA regulation, ribosome biogenesis, and metabolism. The 13-gene TGRisk model significantly separated survival between high- and low-risk groups. A nomogram combining TGRisk with clinical features improved prediction accuracy. High-risk tumors showed immune activation and higher infiltration of CD8⁺ T cells, Tregs, macrophages, and neutrophils, while low-risk tumors showed enhanced neuronal signaling and NK cell activity. Drug sensitivity prediction suggested low-risk patients were more responsive to temozolomide and bortezomib, whereas high-risk patients were more sensitive to dasatinib and ruxolitinib. We developed a novel T. gongdii infection-related gene signature that stratifies glioma patients by prognosis, immune features, and therapeutic vulnerabilities. These findings suggest host–T. gondii interactions and a potential biomarker for patient stratification and personalized therapy. Full article

Background: The chemokine CCL5 exhibits a complex role in cancer immunotherapy, yet its dual immunomodulatory functions in non-small cell lung cancer (NSCLC) remain poorly understood. Methods and Results: Based on a newly analyzed clinical cohort of 33 advanced NSCLC patients receiving anti-PD-1 therapy combined with platinum-based chemotherapy, we found that elevated baseline peripheral blood CCL5 levels significantly predicted shorter overall survival (27.6 months vs. not reached, HR = 2.779, p = 0.038) and a higher incidence of immune-related pneumonitis (p = 0.0072). These clinical observations were supported by the re-analysis of a previously published single-cell RNA sequencing (scRNA-seq) dataset (n = 8), which indicated that high CCL5 expression in peripheral blood T/NK cells was associated with a lower major pathological response (p = 0.029). To explore the underlying mechanisms, we conducted detailed analyses using a large, publicly available tumor scRNA-seq dataset (GSE243013, n = 234). These analyses revealed that high intratumoral CCL5 simultaneously promoted the recruitment of both immune effector cells (CD8⁺ T cells, NK cells) and immunosuppressive populations (Tregs, MDSCs). This paradoxical immune landscape correlated with elevated immune checkpoint expression and significantly higher TIDE scores (1.47 vs. 0.83, p < 0.001). CellChat and SCENIC network analyses identified intensified T cell–myeloid communication and key transcription factors (e.g., FOXP3, EOMES) mediating this dichotomy. Conclusions: This hypothesis-generating study raises the possibility that CCL5 orchestrates paradoxical immune responses and may serve as a biomarker in NSCLC. Further validation in larger prospective, independent cohorts is required. Full article

Background: Treatment response to neoadjuvant therapy in rectal cancer exhibits a considerable degree of interpatient heterogeneity. Select components of the tumour immune microenvironment have been identified as predictive biomarkers of therapeutic response, for which more evidence is required for future clinical prediction models. Aim: The research aimed to identify key tumour immune microenvironment biomarkers predictive of the response to neoadjuvant therapy through the systematic appraisal of existing literature. Methods: A structured search was performed across PubMed, Ovid Embase, and Cochrane databases to retrieve primary studies investigating the association between the tumour immune microenvironment and pathological complete response (pCR) or tumour regression grade (TRG) in patients with rectal cancer. Studies were screened against predefined inclusion and exclusion criteria. Results: Fifteen studies satisfied the inclusion criteria, with cohorts ranging between 24 and 298 participants with predominantly stage II–III disease. Considerable heterogeneity was observed in both types and methods of quantification of biomarkers. Biomarkers assessed in pretreatment biopsies included tumour-infiltrating lymphocytes (TILs), investigated by subtype (cluster of differentiation (CD)8+, CD4+, forkhead box protein 3+ (FOXP3)) or as a composite measure, as well as programmed death-ligand 1 (PD-L1), PD-1+, natural killer (NK) cells, CD163+, and CD68+. Findings showed that high densities of TILs—particularly the CD8+ subtype—consistently correlated with improved tumour regression. FOXP3+ and CD163+ were inconsistently associated with reduced treatment response. NK cells and CD68+ cells were less frequently investigated and yielded non-significant findings. Conclusions: CD8+ TILs have the potential to serve as predictive biomarkers of therapeutic response to neoadjuvant treatment in patients with rectal cancer. Inconsistent findings with FOXP3+ Tregs and CD163+ macrophages reinforce the need for their further investigation. Full article

Graft-versus-host disease (GVHD) is one of the principal complications seen in the recipients of allogenic hematopoietic stem cell transplantation (allo-HSCT), and persists as a leading cause of post-transplant morbidity and mortality. Increasing evidence highlights the crucial influence of the gut microbiome (GM) on transplant outcomes. Microbial dysbiosis, characterized by reduced bacterial diversity and pathogenic overgrowth, is strongly associated with higher rates of complications and mortality. Patients with lower microbial diversity exhibit poorer overall survival (OS) and an increased incidence of acute GVHD (aGVHD). Conversely, restoration of beneficial commensal communities has been shown to enhance immune homeostasis, mitigate GVHD severity, and decrease infection risk. Emerging therapeutic strategies now focus on modulating the intestinal microbiome through dietary interventions, probiotics, prebiotics, and fecal microbiota transplantation (FMT). It has been demonstrated that bacterial metabolites, such as short-chain fatty acids (SCFAs) from the diet, especially a diet rich in fibers, reduce the occurrence/severity of GVHD by inducing regulatory T cells (Tregs), which release anti-inflammatory cytokines and regulate the host immune system. Hence, the implementation of dietary fibers (DFs) could increase beneficial commensals, Treg induction, and improve outcomes such as GVHD and OS in recipients of allo-HCT. Hereupon, this review addresses how a fiber-rich diet modulates GM composition, reinforces epithelial barrier integrity, and improves the efficacy of Treg-based immunotherapy by stabilizing their regulatory phenotype and increasing their functional persistence, ultimately leading to a reduction in GI complications associated with GVHD. Unlike prior reviews that primarily cover the microbiome–GVHD axis or Treg therapies in isolation, this review emphasizes fermentable dietary fibers as a mechanistically grounded, clinically actionable strategy to support Treg stability and persistence via microbiota-derived metabolites. We integrate mechanistic evidence with emerging clinical feasibility data and ongoing trials of prebiotic supplementation in allogeneic HSCT. Full article

Myocardial fibrosis is a key pathological process driving the progression of cardiovascular diseases toward heart failure, closely linked to persistent inflammation and immune dysregulation. Among CC chemokines, CCL17 has emerged as an important mediator connecting immune cell dynamics with fibrotic remodeling. This review outlines current understanding of the cellular sources, regulatory mechanisms, and functional roles of CCL17, with particular attention to its impact on regulatory T cell (Treg) recruitment through ligand-biased signaling. Beyond this mechanism, CCL17 likely operates within a broader inflammatory network, with potential interactions involving CCR2⁺ macrophages and IL-17-related pathways. Experimental studies show that disruption of CCL17 signaling attenuates fibrosis and improves cardiac function, while clinical data link elevated circulating CCL17 to cardiac dysfunction and adverse outcomes. However, the absence of clinical trials and the redundancy of chemokine networks remain key challenges for translation. Overall, CCL17 may serve as a biomarker and therapeutic target, although its clinical application will require a more integrated, network-based understanding. 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: Aralia echinocaulis has therapeutic effects on rheumatoid arthritis (RA), with total polysaccharide and glycoside (TPGs) as main active components. RA pathogenesis involves gut microbiota dysbiosis and immune–metabolic crosstalk, but the role of microbiota-derived succinate in RA remains unclear. Objective: This study explored the role of succinate-GPR91 signaling in intestinal dendritic cells (DCs) in the context of RA and the therapeutic mechanism of A. echinocaulis TPGs. Methods: Collagen-induced arthritis (CIA) mice were treated with TPGs or exogenous succinate. Paw edema, inflammation, gut succinate levels, the Th17/regulatory T (Treg) balance, and DC activation via succinate-GPR91 were detected, and GPR91-targeting siRNA and CD4+ T-cell coculture assays for verification. Results: TPGs alleviated symptoms in CIA mice and restored the Th17/Treg balance by reducing intestinal succinate levels. Succinate activated DCs via GPR91 to promote Th17 differentiation, while TPGs suppressed DC maturation and Th17-driven inflammation, supporting the involvement of a gut-centric immunometabolic axis in RA. Conclusions: TPGs ameliorate RA by targeting the succinate-GPR91-Th17 pathway, identifying succinate as a novel RA target and TPGs as a potential microbiota-modulating agent. Full article

Primary Sjögren’s disease (SjD) is characterized by lymphocyte infiltration into exocrine glands. Mitochondrial dysfunction is a critical pathological mechanism underlying SjD, and mitophagy plays a vital role in clearing damaged mitochondria. This study used bioinformatic analysis to explore the potential roles of mitophagy-related genes in SjD pathogenesis and immune infiltration. Bioinformatic analysis was performed on the SjD microarray datasets to identify differentially expressed genes (DEGs). Mitophagy-related DEGs were selected and analyzed using functional enrichment, protein–protein interaction (PPI) networks, and machine learning (Least Absolute Shrinkage and Selection Operator [LASSO] and Random Forest) to identify hub genes. Their diagnostic value was assessed by receiver operating characteristic (ROC) curves. Immune infiltration and its correlation with hub genes were also evaluated. Hub gene expression in the salivary glands of patients was validated using qRT-PCR. Regulatory networks were also predicted. Three hub genes (GABARAPL1, PINK1, and SQSTM1) were identified. They showed high diagnostic specificity and were downregulated in SjD salivary glands. Immune infiltration analysis revealed increased levels of activated natural killer (NK) cells, memory B cells, plasma cells, CD8+ T cells, Tfh cells, and M1 macrophages, but decreased levels of Tregs and M2 macrophages. Hub gene expression was correlated with specific immune cell subsets. Regulatory network predictions highlighted potential upstream regulators and therapeutic compounds. This study identified three mitophagy-related hub genes linked to immune dysregulation in SjD, providing novel insights into disease mechanisms and potential therapeutic targets. Full article

Temporomandibular disorders (TMDs) are multifactorial conditions traditionally attributed to excessive mechanical loading on the temporomandibular joint, leading to clinical manifestations ranging from joint sounds to structural deformation. Contributing factors include trauma, occlusal abnormalities, psychological stress, and bruxism. However, immune and molecular alterations associated with early disease activity are not systematically integrated into structure-centered TMD frameworks. Emerging evidence indicates that temporomandibular joint osteoarthritis (TMJOA) involves activation of innate immunity caused by damage-associated molecular patterns (DAMPs) generated through mechanical loading, together with non-antigen-specific adaptive immune responses, including macrophage polarization and T helper 17 (Th17) and regulatory T (Treg) cell imbalance. Inflammatory and mechanical inputs converge through shared signaling modules and mechanoresponsive transcriptional programs, promoting extracellular matrix degradation, fibrotic remodeling, and subchondral bone remodeling. This review synthesizes the current immunopathological and mechanobiological evidence and introduces temporomandibular immunologic disease (TMID) as a mechanism-oriented framework, characterized by a reinforcing cycle between mechanically induced tissue damage and immune activation within the temporomandibular joint (TMJ) microenvironment. TMID complements TMJOA and Diagnostic Criteria for Temporomandibular Disorders (DC/TMD) structural diagnostic categories while excluding antigen-specific autoimmune arthritides such as rheumatoid arthritis, thus functioning as a mechanistic overlay framework for the integration of immuno-mechanical signaling networks in immune-active, mechanically driven TMJ pathology. Full article

Alveolar echinococcosis (AE), caused by Echinococcus multilocularis larvae, is a severe zoonotic disease mimicking tumors, primarily affecting the liver with high mortality if untreated. Host immunity plays a pivotal role, shifting from Th1/Th17-mediated clearance to Th2/Treg-driven tolerance, enabling parasite survival. Liver macrophages, including Kupffer cells, polarize towards M2 phenotype under parasite antigens (e.g., phytic acid, exosomes), promoting immunosuppression, fibrosis, and T cell exhaustion via IL-10/TGF-β. This reshapes the tumor-like immune microenvironment with M2 macrophages recruiting Tregs, suppressing NK/DC functions, and fostering angiogenesis/fibrosis. Current treatment remains centered on surgery and benzimidazole therapy, both of which have notable limitations. Experimental immunomodulatory strategies, drug repurposing approaches, and targeted delivery systems may offer future therapeutic opportunities, but these concepts remain largely preclinical, unproven in AE, and require careful evaluation for safety and efficacy. Full article