Search Results (2,045)

Diabetes mellitus (DM), characterized by persistent hyperglycemia, not only induces chronic damage and dysfunction across multiple tissues and organs but also increases susceptibility to a broad spectrum of pathogens. Diabetes serves as a significant risk factor for influenza virus infection and associated secondary bacterial pneumonia. This review mainly focuses on the complex pathological and physiological interactions among type 2 diabetes mellitus, influenza and bacterial infections. Chronic hyperglycemia and the resulting immune–metabolic disorders lead to impaired innate and adaptive immune functions. Influenza virus infection further compromises the respiratory barrier, induces an excessive inflammatory response, and depletes immune cells, thereby creating an ideal microenvironment for bacterial colonization. The ensuing bacterial infection synergizes with the virus, forming a vicious cycle of pathogenesis. An integrated strategy combining optimized glycemic control, enhanced vaccination, and early, precise antiviral and antibacterial therapy is paramount for the prevention and treatment of secondary bacterial infections following influenza in patients with diabetes mellitus. Full article

Platelets are anucleated cell fragments representing the second most abundant blood element in circulation, with approximately 100 billion new platelets released from the bone marrow daily in a healthy individual. For over a century, their hemostatic role was considered their primary function; however, the past few decades of research have revealed significant immunological functions in both innate and adaptive immunity. Through the release of mediators stored in platelet granules and the expression and realignment of a diverse array of surface receptors, platelets influence immune cells while simultaneously recognizing, reacting to, and phagocytosing offending pathogens such as viruses and bacteria. Their activation initiates signaling cascades that either amplify platelet responses or drive the activation, recruitment, migration, and maturation of immune cells to sites of infection. This narrative review synthesizes platelet biology, receptor signaling, granule physiology, and platelet interactions with innate and adaptive immune cells to provide an integrated perspective on platelet immunologic function. We examine platelets as frontline immune sentinels and evaluate their capacity to regulate both innate and adaptive immune responses, detailing specific receptors and granule contents as the mechanistic foundation for their immunologic roles. We further explore the molecular mechanisms by which platelets interact with pathogens and immune cells to drive pathogen clearance, inflammation modulation, and the interplay between thrombosis and immunity, including their contributions to chronic inflammatory disease and tumorigenesis. Full article

Atopic dermatitis (AD) is a prevalent chronic inflammatory skin disorder driven by epidermal barrier defects and dysregulated Th2 cell responses. While therapies primarily address adaptive immunity, the role of Natural Killer (NK) cells remains underappreciated. This review analyzes NK cell dysfunctions in AD pathogenesis, evaluating their contributions to compromised skin immunity, microbial dysbiosis, and secondary infections. Accumulating evidence reveals a systemic deficiency of mature, cytotoxic CD56^dim and NKp80+ NK cell subsets in peripheral blood, correlating with disease severity. Within the cutaneous microenvironment, Staphylococcus aureus subverts defenses by utilizing leukocidins to lyse mature NK cells, while superantigens drive an aberrant, pro-inflammatory CD57⁻NKG2+ phenotype, exacerbating inflammation. Furthermore, localized exhaustion of functional NK cells and failure to produce interferon-gamma directly explains AD patients’ unique susceptibility to severe viral complications like eczema herpeticum. Importantly, treatments such as dupilumab and gut microbiota transplantations demonstrate that these NK cell aberrations are reversible, shifting immunity toward a normalized regulatory state. In conclusion, the NK cell compartment represents a vital regulatory axis bridging innate and adaptive immunity. Targeting this axis, particularly through IL-15 superagonists, offers a promising therapeutic frontier to suppress type 2 inflammation and restore antimicrobial defenses. Full article

Background: Host immune responses can be broadly divided into innate and adaptive immunity. Numerous adaptive immune responses have been identified, including TH1, TH2, TH3, TH9, TH17, and TH22 immunity. Within innate immunity, Vγ9-chain γδ T cells are among the most extensively studied immune-cell populations. Knowledge Gap: However, the precise functional classification of these innate and adaptive immunological pathways in responses to different types of pathogens remains incompletely understood. Purpose of the Review: This review proposes an integrated framework for the detailed functional classification of host innate and adaptive immunological pathways. Proposed Framework: Within innate immunity, γδ T cells can be categorized into several functional groups. The clonal anergy and tolerance pathway is associated with Vγ2-chain γδ T cells. The host innate immunological pathway against viruses is associated with Vγ8-chain γδ T cells, whereas the pathway against intracellular microorganisms is associated with Vγ9-chain γδ T cells. The pathway against extracellular microorganisms is associated with Vγ4-chain γδ T cells, the pathway against helminths with Vγ5-chain γδ T cells, and the pathway against insects with Vγ3-chain γδ T cells. Within adaptive immunity, five eradicable immune reactions and four tolerable immune reactions are described. Among the tolerable immune reactions, TH3 is associated with interleukin-35-producing CD4 T cells, whereas TH4 is associated with interleukin-32-producing CD4 T cells. Significance: A more precise functional classification of innate and adaptive immunological pathways may provide a useful conceptual basis for combating infections and hypersensitivity disorders. Full article

The ubiquitin ligase protein tripartite-motif containing 56 (TRIM56) positively regulates Toll-like receptor-3 (TLR3) signaling by forming a complex with Toll-Interleukin-1 receptor domain-containing adapter protein inducing interferon (IFN)-beta (TRIF), independent of its E3 ligase activity. Whether TRIM56 modulates other TLR pathways in innate antiviral immunity, however, is unclear. Herein, we show ectopic expression of TRIM56 augments activation of IFN regulatory factor-3 (IRF3)-dependent promoters following stimulation by lipopolysaccharide (LPS) in HEK293-TLR4-MD2-CD14 cells while leaving activation of NF-κB-dependent promoter unaffected, suggesting TRIM56 specifically promotes immune signaling through the TLR4-TRIF axis but not the MYD88 arm downstream of this TLR. Confirming its impact on endogenous antiviral responses in immune sentinel cells naturally harboring the TLR4 pathway, we demonstrated enforced expression of TRIM56 enhanced LPS-induced expression of IFN-beta and IFN-stimulated genes (ISGs) and establishment of an antiviral state in bone marrow-derived macrophages. Importantly, depletion of endogenous TRIM56 impaired LPS-induced antiviral gene expression and cellular antiviral defense. Altogether, these data add to understanding of the role of TRIM56 in TLR-mediated innate immune responses. Given that TRIM56 is an ISG and that many immune adjuvants and some viral proteins activate TLR4, the findings of this study could have implications for designing immunotherapies, especially those against viral infections. Full article

Sex- and gender-based immune differences have often been interpreted through a male–female biological binary, overlooking how endocrine signaling dynamically shapes immune function. Gender-affirming hormone therapy (GAHT) offers a unique physiological model to disentangle the effects of sex steroids from chromosomal background and examine immune plasticity in contexts relevant to reproductive health. This hormone-informed framework proposes that estradiol and testosterone regulate immune set-points across innate, adaptive, metabolic, and mucosal compartments. Through genomic and non-genomic signaling via androgen and estrogen receptors (AR, ERα/β), these hormones drive distinct immune outcomes: testosterone dampens type I interferon responses in plasmacytoid dendritic cells and reshapes monocyte inflammatory profiles, while estradiol promotes macrophage polarization and enhances T helper1 (Th1) responses. Hormonal effects are closely coupled to cellular metabolism: androgen signaling acts as a “metabolic brake” on Th17 cells by limiting glutaminolysis, a process reinforced by epigenetic remodeling, and is reflected in shifts in the circulating metabolome, positioning metabolomics as a sensitive tool for monitoring hormone-driven immune adaptation. Regardless, hormones also reshape mucosal barriers and reproductive microbiome composition. GAHT alters vaginal and gut microbial communities and their metabolism, influencing mucosal immunity, local inflammation, and reproductive tract homeostasis, with potential implications for fertility preservation, susceptibility to reproductive tract infections, and long-term genital mucosal health. Collectively, this evidence underscores that human immunity is highly responsive to endocrine context. This review synthesizes evidence linking endocrine trajectories, tissue microenvironments, reproductive biology, and social determinants of health, aiming to advance understanding of immune plasticity and contribute to a more inclusive framework of human immune diversity. Full article

Alpha-enolase (ENO1) is a multifunctional protein frequently overexpressed in solid tumors, where elevated levels are associated with aggressive behavior and poor prognosis. Beyond its canonical glycolytic role, ENO1 participates in immunoregulatory processes through distinct subcellular pools. Intracellular ENO1 shapes tumor-associated metabolic programs, while surface-exposed ENO1 functions as a plasminogen receptor and can engage innate immune signaling pathways. Post-translational modifications—particularly citrullination and phosphorylation—generate structurally altered epitopes that expand ENO1 antigenicity and enable adaptive immune recognition, including coordinated humoral and T-cell responses in cancer patients. These determinants of ENO1 immunogenicity have downstream consequences within the tumor microenvironment: immune-accessible ENO1 modulates myeloid cell recruitment, dendritic cell maturation, and macrophage polarization, while ENO1-dependent metabolic and signaling programs contribute to immune suppression and escape through multiple interconnected axes. Together, these mechanisms position ENO1 at the interface between tumor metabolism and immune regulation. Preclinical evidence demonstrates that ENO1-directed strategies—including antibody-based targeting, DNA vaccination, and vaccines incorporating post-translationally modified ENO1 peptides—can generate productive antitumor immunity and synergize with checkpoint blockade, supporting the rationale for ENO1 as an immunotherapeutic target. This review synthesizes current evidence within an integrated framework linking ENO1 dysregulation to its immunological consequences in cancer and discusses translational implications for ENO1-centered immunotherapy and immunoprevention. Full article

Background and Objectives: Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease in which persistent synovial inflammation and joint damage are influenced not only by immune dysregulation but also by environmental, genetic, and epigenetic factors. Vitamin D is a secosteroid hormone and has emerged as a key immunomodulatory hormone, with reported effects on innate and adaptive immune responses, with potential relevance to RA clinical activity and treatment. This narrative review synthesizes mechanistic and clinical evidence enlightening vitamin D’s immunomodulatory role in RA pathogenesis and management. Methods: A comprehensive literature search was carried out on PubMed and MEDLINE databases using Medical Subject Headings (MeSH) terms: “Vitamin D”, “Cholecalciferol”, “Arthritis, Rheumatoid”, “Seasons”, “Epigenomics”, “DNA Methylation”, and “Therapy”. The narrative review highlights evidence published mainly in the last 5 years on the link between vitamin D and RA, focusing on epigenetic interactions, circannual rhythms, and therapeutic implications. Results: Emerging data suggest that vitamin D-related epigenetic mechanisms (e.g., DNA methylation, histone acetylation, and microRNA regulation) and genetic polymorphisms have been associated with disease susceptibility and treatment outcomes. Latitude and seasonal fluctuations in serum 25-hydroxyvitamin D levels correlate with variations in RA disease activity, although results remain heterogeneous across studies. Overall, the available evidence supports an association between vitamin D deficiency and greater RA disease activity, while its adequate supplementation has been associated with improvements in inflammatory markers and selected clinical outcomes, especially when tailored to baseline status and individual risk factors, such as limited dietary intake and sunlight exposure. Conclusions: Current evidence emphasizes the need for further studies using standardized methods and larger, geographically diverse cohorts to define how best to leverage seasonal vitamin D variations in RA management, considering also the range of concomitant epigenetic modifiers that may influence the effects of vitamin D on the management of RA patients. Full article

Neonates and infants exhibit fundamentally distinct immune responses compared to adults, resulting in increased susceptibility to infectious diseases and reduced vaccine efficacy. These age-specific responses are characterized by developmental constraints affecting both adaptive and innate immunity. T cell-independent (TI) responses to polysaccharide vaccines are severely impaired due to reduced transmembrane activator and calcium-modulating cyclophilin ligand interactor (TACI) expression on neonatal B cells, while T cell-dependent (TD) responses are compromised by Th2 bias in the CD4+ T cell compartment, and by restricted T follicular helper (Tfh) cell development. Emerging data suggest that cytokines such as IL-6 have completely opposite effects on Tfh cell development between adults and neonates. Germinal center (GC) B cell responses are further constrained by delayed follicular dendritic cell (FDC) maturation, impaired B cell receptor (BCR) signaling, and elevated frequencies of IL-10-producing regulatory B cells. The overall immunosuppressive phenotype associated with early age extends to the neonatal innate immune system as exhibited by altered dendritic cell (DC) subset distribution, decreased IL-12p70 production, lower expression of MHC class II and co-stimulatory molecules, and increased IL-10 secretion. To overcome these immune constraints, various adjuvants that are shown to enhance immune response to vaccines in adults are considered for early age vaccines. Although some of these adjuvants show promising results in animal experiments, mechanistic studies need to be conducted in detail since adult and neonatal in vivo environments may dictate different outcomes between the two age groups, especially because early-life adjuvant exposure may have long-lasting effects on immune system programming. Elucidation of age-specific immune responses to vaccines and adjuvants will help develop age-tailored strategies to develop safe and effective pediatric vaccines. Full article

Recent advances in vaccinology have accelerated the shift from conventional live-attenuated and inactivated vaccines toward subunit and nucleic acid-based platforms. Although these next-generation vaccines offer improved safety, rapid adaptability, and manufacturing flexibility, their relatively low intrinsic immunogenicity often requires efficient adjuvants and delivery systems. Nanoparticle-based vaccine platforms have therefore emerged as versatile tools capable of protecting antigens, improving targeted delivery, and modulating both innate and adaptive immune responses. This review summarizes the major classes of nanovaccine platforms, including lipid and polymeric nanoparticles, self-assembling protein nanostructures such as virus-like particles and ferritin nanocages, saponin-based self-assembling complexes, and inorganic nanomaterials. Particular attention is given to how vaccine performance is determined not only by material composition but also by nanoparticle physicochemical properties, biodistribution, cellular uptake, and mechanisms of immune activation. We further discuss the major challenges limiting clinical translation, including scalable manufacturing, safety evaluation, quality control, regulatory requirements, and long-term biocompatibility. Finally, emerging strategies involving hybrid and personalized nanovaccine platforms are highlighted, illustrating how nanotechnology and immunoengineering are transforming vaccine development for both prophylactic and therapeutic applications. Full article

Hydrogen sulfide (H₂S) is a vital gasotransmitter essential for maintaining redox homeostasis and modulating inflammatory responses. Herein, we examined a collection of Drosophila melanogaster knockout (KO) lines generated in our laboratory, lacking key genes involved in transsulfuration (cbs, cse) and sulfide metabolism (tst1), to elucidate the role of this adaptive system in immunity. Genetic ablation of these pathways results in profound H₂S deficiency and hyperhomocysteinemia, leading to chronic oxidative stress. This leads to constitutive activation of major immune pathways—including IMD, Toll, and JAK-STAT—even in the absence of infection, a hallmark of chronic inflammation. Indeed, transcriptomic analysis and qRT-PCR studies revealed significant upregulation of these pathways in double (cbs; cse) and triple (cbs; cse; tst1) KO flies under control conditions. Following septic injury with Bacillus subtilis, double and triple KO flies exhibited increased expression of antimicrobial peptides (AMPs) and pattern recognition receptors compared to control and TST1-/- single KO lines. Notably, double and triple KO lines showed more prolonged immune activation. The triple KO flies exhibited the worst survival rate following septic injury. These results demonstrate that H₂S deficiency causes chronic inflammation through the sustained activation of immune pathways, highlighting sulfur metabolism as a crucial regulator of homeostasis and innate immunity in Drosophila. Full article

Epigenetic regulation plays a central role in shaping innate immune responses following immunostimulant exposure. In this study, we characterized the epigenetic landscape of four histone modifications, H3K27ac, H3K27me3, H3K4me1, and H3K4me3, in the anterior kidney of Ictalurus punctatus (channel catfish) following β-glucan exposure. Using chromatin immunoprecipitation sequencing (ChIP-seq), we generated chromatin state maps and examined the regulatory potential of these histone marks in relation to transcriptional responses. Genes showing increased expression associated with H3K4me3 up-peaks included regulators of metabolism, signaling, pathogen recognition, and immune regulation, while H3K27ac and H3K4me1 marks were linked to genes involved in apoptosis, cytoskeletal dynamics, autophagy, cell adhesion, and stress responses. In contrast, H3K27me3-associated gene repression appeared to fine-tune immune activation by selectively maintaining transcriptional restraint at specific loci. Further transcriptional regulatory-related genes were significantly enriched, suggesting metabolic adaptation following β-glucan exposure. Collectively, these findings define the epigenetic landscape of key histone marks in channel catfish following β-glucan exposure and reveal coordinated chromatin and transcriptional remodeling, consistent with mechanisms of trained immunity. This work provides novel insight into conserved epigenetic features of innate immune memory in teleost fish and supports the use of β-glucan as a functional immunomodulator in aquaculture. Full article

The zinc finger protein 36 (ZFP36) family, including ZFP36/tristetraprolin (TTP), ZFP36 CCCH-type-like 1 (ZFP36L1), and ZFP36 CCCH-type-like 2 (ZFP36L2), consists of conserved CCCH-type tandem zinc-finger RNA-binding proteins. These proteins recognize AU-rich elements (AREs) in target mRNAs and promote deadenylation, decay, and translational repression. In this review, we use the term post-transcriptional immune checkpoint in a restricted conceptual sense: ZFP36 family proteins are intracellular, RNA-level negative regulators that tune the magnitude, duration, and resolution of immune effector programs, rather than classical receptor-ligand immune checkpoints such as programmed cell death protein 1 (PD-1)/ programmed death-ligand 1 (PD-L1) or cytotoxic T-lymphocyte-associated protein 4 (CTLA-4). We summarize structural features, ARE-recognition mechanisms, mRNA decay pathways, translational repression mechanisms, and post-translational regulation of the ZFP36 family, while explicitly distinguishing mechanisms established for ZFP36 from those inferred for ZFP36L1 and ZFP36L2. We then review cell-type-specific roles in innate and adaptive immunity, including myeloid inflammatory responses, barrier tissue inflammation, innate lymphoid cell function, T cell activation and effector differentiation, regulatory T cell stability, B cell development, and antiviral immunity. In cancer, ZFP36 family members show context-dependent functions that should be separated into tumor-cell-intrinsic effects and immune-microenvironment-dependent effects. They suppress tumor progression by destabilizing pro-inflammatory, angiogenic, metabolic, and epithelial–mesenchymal transition (EMT)-associated transcripts, yet may also restrict antitumor immune responses or promote immune evasion in selected tumor contexts. Finally, we discuss autoimmune and inflammatory diseases, allergic disorders, transplant immunity, neuroimmune relevance, and therapeutic strategies, emphasizing the current evidentiary limits, preclinical status, and safety concerns of ZFP36 family modulation. Full article

Systemic lupus erythematosus (SLE) is a chronic autoimmune disorder characterized by the loss of self-tolerance to nuclear and cytoplasmic antigens, triggering immune activation and tissue inflammation. Lupus nephritis (LN) is a major determinant of disease-related morbidity, disability, chronic kidney disease progression, kidney failure, and mortality in SLE, affecting approximately 30% of patients at diagnosis and up to 50–60% within the first decade. This review examines the disease’s pathogenic mechanisms, emphasizing the innate immune system’s role in the loss of self-tolerance and subsequent activation of the adaptive immune response. Mechanisms include dysregulated cell death pathways, impaired clearance of nucleic acid-containing debris and immune complexes, and involvement of antigen-presenting cells and other innate immune cells. These processes lead to the clonal expansion of autoreactive lymphocytes, generating effector T cells, memory B cells, and plasma cells that produce autoantibodies, resulting in renal injury. The review further explores the immunological processes driving kidney damage, beginning with autoantibody binding and immune complex deposition, followed by complement-mediated microvascular injury, kidney stromal cell activation, and leukocyte recruitment. Lastly, it discusses LN treatment strategies, from traditional to novel targeted therapies, with a focus on their systemic immunologic impacts and the protection of podocytes. Full article

Background: Chronic rhinosinusitis with nasal polyps, CRSwNP, represents one of the most clinically relevant models of type 2 inflammation in the upper airways. Its pathogenesis is not sustained by a single mechanism but by the continuous interaction between epithelial barrier damage, immune activation and tissue remodeling. Although several systemic biomarkers are currently used in clinical practice, they do not always reflect the inflammatory processes occurring directly within the sinonasal mucosa. Objective: This review discusses nasal cytology as a local and clinically accessible read-out of type 2 inflammation and epithelial barrier dysfunction in CRSwNP. Particular attention is given to the relationship between cytological patterns, underlying immune mechanisms and the use of biologic therapies. Methods: A narrative review of the literature was conducted, focusing on epithelial barrier abnormalities, type 2 inflammatory pathways, cytological phenotypes and available monoclonal antibodies. The clinical relevance of these elements was considered, with particular regard to patient stratification and therapeutic decision-making. Results: Epithelial barrier disruption promotes the release of alarmins such as TSLP, IL-25 and IL-33. These mediators activate both innate and adaptive type 2 immune responses and contribute to the persistence of mucosal inflammation. Nasal cytology allows direct assessment of the local inflammatory infiltrate and makes it possible to identify eosinophilic, mast cell-predominant and mixed eosinophil–mast cell patterns. These profiles appear to mirror different inflammatory settings. In particular, the coexistence of eosinophils and mast cells may identify patients with more severe, persistent or recurrent disease. When integrated into clinical tools such as clinical–cytological grading (CCG), nasal cytology may improve disease stratification, support follow-up and help orient biologic therapy according to the level of the inflammatory cascade predominantly involved. These cytological profiles may also support biologic treatment selection, therapeutic monitoring, and future tapering strategies by reflecting the predominant inflammatory pathway active at the mucosal level. Conclusions: Nasal cytology is a direct, reproducible and clinically useful approach for evaluating local inflammation in CRSwNP. By providing information from the mucosal site of disease, it complements systemic biomarkers and may support personalized therapeutic strategies and biologic treatment selection in CRSwNP. Full article