Search Results (819)

Sex-based immunological differences significantly influence the outcome of vaccination, yet the molecular mediators underpinning these differences remain largely elusive. MicroRNAs (miRNAs), key post-transcriptional regulators of gene expression, have emerged as critical modulators of innate and adaptive immune responses. In this study, we investigated the expression profile of selected circulating miRNAs as potential biomarkers of sex-specific humoral responses to the mRNA COVID-19 vaccine in a cohort of health care workers. Plasma samples were collected longitudinally at a defined time point (average 71 days) post-vaccination and analyzed using RT-qPCR to quantify a panel of immune-relevant miRNAs. Anti-spike (anti-S) IgG titers were measured by chemiluminescent immunoassays. Our results revealed sex-dependent differences in miRNA expression dynamics, with miR-221-3p and miR-148a-3p significantly overexpressed in vaccinated female HCWs and miR-155-5p overexpressed in vaccinated males. MiR-148a-3p showed a significant association with anti-S/RBD (RBD: receptor binding domain) IgG levels in a sex-specific manner. Bioinformatic analysis for miRNA targets indicated distinct regulatory networks and pathways involved in innate and adaptive immune responses, potentially underlying the differential immune activation observed between males and females. These findings support the utility of circulating miRNAs as minimally invasive biomarkers for monitoring and predicting sex-specific vaccine-induced immune responses and provide mechanistic insights that may inform tailored vaccination strategies. Full article

Background: Anti-programmed death 1 receptor (PD-1) therapy is a promising treatment strategy for patients with unresectable advanced or recurrent gastric/gastroesophageal junction (G/GEJ) cancer. However, its response rate and survival benefits are still limited; an immunological analysis of the residual tumor after anti-PD-1 therapy would be important. Methods: We evaluated the clinical efficacy of tumor resection (TR) after chemotherapy or anti-PD-1 therapy in patients with unresectable advanced or recurrent G/GEJ cancer and analyzed the immune status of tumor microenvironment (TME) by immunohistochemistry using their surgically resected specimens. Results: Patients treated with TR after anti-PD-1 therapy had significantly longer survival compared to those treated with chemotherapy and anti-PD-1 therapy alone. Expression of human leukocyte antigen (HLA) class I and major histocompatibility complex (MHC) class II on tumor cells was markedly downregulated after anti-PD-1 therapy compared to chemotherapy. Furthermore, the downregulation of HLA class I may be associated with the activation of transforming growth factor-β signaling pathway in the TME. Conclusions: Immune escape from cytotoxic T lymphocytes may be induced in the TME in patients with unresectable advanced or recurrent G/GEJ cancer after anti-PD-1 therapy due to the downregulation of HLA class I and MHC class II expression on tumor cells. TR may be a promising treatment strategy for these patients when TR is feasible after anti-PD-1 therapy. Full article

Several chronic inflammatory processes are currently being studied in relation to other systems to better understand the regulation mechanisms and identify potential therapeutic targets. A significant body of evidence supports the role of the nervous system in regulating various immunological processes. This study investigates the relationship between pterygia and the sympathetic nervous system, focusing on their interaction in the inflammatory response and fibrogenic process. Sixteen surgical specimens of primary pterygia and four conjunctival tissue samples were examined, and their morphology was analyzed using hematoxylin–eosin and Masson’s trichrome stains. The gene expression of adrenergic receptors, as well as inflammatory and fibrogenic cytokines, was also assessed. Additionally, both adrenergic receptors and tyrosine hydroxylase were found to be localized within the tissues according to immunohistochemistry and immunofluorescence techniques. Increased expression of proinflammatory, fibrogenic, and adrenergic genes was observed in the pterygium compared to the healthy conjunctiva. Adrenergic receptors and tyrosine hydroxylase were localized in the basal region of the epithelium and within blood vessels, closely associated with immune cells. Neuroimmunomodulation plays a key role in the pathogenesis of pterygia by activating the sympathetic nervous system. At the intravascular level, norepinephrine promotes the migration of immune cells, thereby sustaining inflammation. Additionally, sympathetic nerve fibers located at the subepithelial level contribute to epithelial growth and the fibrosis associated with pterygia. Full article

The COVID-19 pandemic, caused by SARS-CoV-2, has led to a wide range of acute and chronic disease manifestations. While most infections are mild, a significant number of patients develop severe illness marked by respiratory failure, thromboinflammation, and multi-organ dysfunction. In addition, post-acute sequelae—commonly known as long-COVID—can persist for months. Recent studies have identified the emergence of diverse autoantibodies in COVID-19, including those targeting nuclear antigens, phospholipids, type I interferons, cytokines, endothelial components, and G-protein-coupled receptors. These autoantibodies are more frequently detected in patients with moderate to severe disease and have been implicated in immune dysregulation, vascular injury, and persistent symptoms. This review examines the underlying immunological mechanisms driving autoantibody production during SARS-CoV-2 infection—including molecular mimicry, epitope spreading, and bystander activation—and discusses their functional roles in acute and post-acute disease. We further explore the relevance of autoantibodies in maternal–fetal immunity and comorbid conditions such as autoimmunity and cancer, and we summarize current and emerging therapeutic strategies. A comprehensive understanding of SARS-CoV-2-induced autoantibodies may improve risk stratification, inform clinical management, and guide the development of targeted immunomodulatory therapies. Full article

Background/Objective: Early-onset neonatal sepsis (EOS), defined as infection occurring within the first 72 h after birth, remains a major contributor to neonatal morbidity and mortality worldwide. Although advances in perinatal care have improved overall outcomes, the diagnosis of EOS continues to be challenging. Clinical presentations are often nonspecific, laboratory confirmation is often delayed, and immune responses vary considerably among neonates. Expanding our understanding of the molecular mechanisms underlying EOS is essential in enhancing early detection, refining risk stratification, and guiding therapeutic strategies. This systematic review aims to synthesize the available information on the molecular pathways involved in EOS, focusing on pathogen-induced inflammation, systemic immune responses, sterile inflammatory processes, interactions between infectious and non-infectious pathways, as well as emerging molecular diagnostic approaches. Methods: A comprehensive review of original research articles and reviews published between January 2015 and January 2025 was conducted; studies were included based on their focus on human neonates and their analysis of molecular or immunological mechanisms relevant to EOS pathogenesis, immune dysregulation, or novel diagnostic strategies. Results: Pathogen-driven inflammation typically involves the activation of Toll-like receptors (TLRs), the recruitment of neutrophils, and the release of pro-inflammatory cytokines such as IL-6, IL-1β, and TNF-α, particularly in response to vertical transmission of organisms like Escherichia coli and Streptococcus agalactiae. Systemic inflammatory responses are marked by cytokine dysregulation, contributing to multi-organ dysfunction. Sterile inflammation, often initiated by hypoxia–reperfusion injury or intrauterine stress, amplifies susceptibility to sepsis. Interactions between immune, metabolic, and endothelial pathways further exacerbate tissue injury. Recent advances, including transcriptomic profiling, microRNA-based biomarkers, and immune checkpoint studies, offer promising strategies for earlier diagnosis and individualized therapeutic options. Conclusions: EOS arises from a complex interplay of infectious and sterile inflammatory mechanisms. A deeper molecular understanding holds promise for advancing correct diagnostics and targeted therapies, aiming to improve neonatal outcomes. Full article

The effective suppression of inflammation using disease-modifying therapies is essential in the treatment of multiple sclerosis (MS). Anti-CD20 monoclonal antibodies are commonly used long-term as maintenance therapies, largely due to the lack of reliable biomarkers to guide dosing and evaluate treatment response. However, prolonged use increases the risk of infections and other immune-mediated side effects. The unique ability of brain-derived blood extracellular vesicles (EVs) to cross the blood–brain barrier and reflect the central nervous system (CNS) immune status has sparked interest in their potential as biomarkers. This study aimed to assess whether blood-derived L1CAM⁺ EVs could serve as biomarkers of treatment response to rituximab (RTX) in patients with relapsing-remitting MS (RRMS). Serum samples (n = 25) from the baseline (month 0) and after 6 months were analyzed from the RTX arm of the ongoing randomized clinical trial OVERLORD-MS (comparing anti-CD20 therapies in RRMS patients) and were compared with serum samples from healthy controls (n = 15). Baseline cerebrospinal fluid (CSF) samples from the same study cohort were also included. EVs from both serum and CSF samples were characterized, considering morphology, size, and concentration, using transmission electron microscopy (TEM) and nanoparticle tracking analysis (NTA). The immunophenotyping of EV surface receptors was performed using flow cytometry with the MACSPlex exosome kit, while label-free quantitative proteomics of EV protein cargo was conducted using a proximity extension assay (PEA). TEM confirmed the presence of EVs with the expected round morphology with a diameter of 50–150 nm. NTA showed significantly higher concentrations of L1CAM⁺ EVs (p < 0.0001) in serum total EVs and EBNA1⁺ EVs (p < 0.01) in serum L1CAM⁺ EVs at baseline (untreated) compared to in healthy controls. After six months of RTX therapy, there was a significant reduction in L1CAM⁺ EV concentration (p < 0.0001) and the downregulation of TNFRSF13B (p = 0.0004; FC = −0.49) in serum total EVs. Additionally, non-significant changes were observed in CD79B and CCL2 levels in serum L1CAM⁺ EVs at baseline compared to in controls and after six months of RTX therapy. In conclusion, L1CAM⁺ EVs in serum showed distinct immunological profiles before and after rituximab treatment, underscoring their potential as dynamic biomarkers for individualized anti-CD20 therapy in MS. Full article

Background/Objectives: Melanoma is an aggressive skin cancer influenced by genetic and immunological factors. The PDCD1 gene encodes PD-1, a receptor involved in immune evasion and therapeutic response. This study aimed to evaluate the association of PDCD1 variants (rs2227982, rs36084323, rs7421861) and its relative gene expression with melanoma in a Mexican population. Methods: An analytical cross-sectional study was conducted with 262 samples: 131 from melanoma patients (newly diagnosed and treatment-naïve) and 131 from cancer-free controls. Genotyping was performed using real-time PCR. PDCD1 expression was assessed by qPCR, normalized with GAPDH, using the 2^−ΔΔCt method and the Pfaffl model. Statistical comparisons included allele/genotype frequencies, expression levels, and clinicopathological associations. Results: No significant association was found between the studied PDCD1 variants and melanoma susceptibility. However, PDCD1 was significantly overexpressed in melanoma samples (2.42-fold increase; p < 0.01), consistent across both quantification methods. Significant associations were also observed between histopathological subtype and Breslow thickness, and between subtype and anatomical site (p < 0.01). Conclusions: Although PDCD1 variants showed no association with melanoma risk, the gene’s overexpression highlights its potential relevance in melanoma immunobiology. These findings contribute to the molecular characterization of melanoma in the Mexican population and support future research on PDCD1 as an immunological biomarker. Full article

Adeno-associated virus (AAV) vectors face a critical translational challenge in ocular gene therapy due to pre-existing neutralizing antibodies (NAbs) whose seroprevalence limits patient eligibility. Standard NAb detection using non-ocular cell models (Human Embryonic Kidney 293T) may inadequately predict retinal transduction inhibition due to cell type-related variations in receptor usage and immunogenicity. This study established parallel NAb detection platforms utilizing human retinal pigment epithelial (ARPE-19) cells and standard 293T cells to systematically evaluate clinical serum samples against ophthalmologically relevant AAV serotypes (2, 5, 8, 9) via luciferase reporter-based transduction inhibition assays. Comparative analysis demonstrated ARPE-19 exhibited 42–48% higher NAb titers against AAV5/9 compared to 293T cells, with distinct serotype-biased neutralization hierarchies observed between cellular models. Furthermore, female-derived sera exhibited significantly elevated NAbs against particular serotypes in the ARPE-19 system. Critically, inter-serotype cross-neutralization correlation patterns differed substantially between cellular platforms. These findings demonstrate that physiologically relevant retinal cellular models provide essential immunological profiling data, revealing NAb characteristics obscured in standard assays. Consequently, employing retinal cell-based platforms is crucial for optimizing AAV serotype selection, patient stratification, and predicting clinical outcomes in ocular gene therapy. Full article

In our previous studies, methylated CpG oligodeoxynucleotides (ODN) derived from Bifidobacterium longum subsp. infantis have demonstrated immunomodulatory effects through the induction of regulatory T cells (Tregs). To define the structural determinants underlying this effect, we synthesized four CpG ODNs varying in methylation degree, CpG motif placement, and backbone length. These include (1) ODN-A (2m-V1), a 20-nucleotide CpG oligodeoxynucleotide incorporating two 5-methylcytosines at positions 4 and 12 within centrally placed CpG motifs; (2) ODN-B (um-V2), a 20-nucleotide CpG oligodeoxynucleotide with a backbone structure identical to ODN-A but unmethylated; (3) ODN-C (2m’-V3), a 20-nucleotide CpG oligodeoxynucleotide with a backbone structure identical to ODN-A, but with two 5-methylcytosines shifted to positions 7 and 15; (4) ODN-D (3m-V4), a 27-nucleotide CpG oligodeoxynucleotide with an extended backbone structure, this time with three 5-methylcytosines at positions 3, 11, and 19. Using a murine model of an OVA-induced allergy, we show that methylated ODN-A (2m-V1) and ODN-D (3m-V4) markedly reduce serum anti-OVA IgE, clinical symptoms, eosinophilic infiltration, and Th2/Th17 responses, while promoting splenic Treg expansion and IL-10 production. In contrast, unmethylated ODN-B (um-V2) and a positionally altered methylated ODN-C (2m’-V3) both failed to suppress allergic inflammation, and, in contrast, enhanced the Th2/Th17 response and induced robust in vitro Toll-like receptors TLR7/8/9 expression in native splenocytes. These findings suggest that both methylation and motif architecture critically influence the immunologic profile of CpG ODNs. Our results provide mechanistic insights into CpG ODN structure/function relationships and support the therapeutic potential of select methylated sequences for restoring immune tolerance in allergic diseases. Full article

T-cell receptors (TCRs) exhibit degeneracy, enabling individual TCRs to recognize multiple altered peptide ligands (APLs) derived from a single cognate antigen. This characteristic has been involved in the pathogenesis of autoimmune diseases through cross-reactivity between microbial and self-antigens. Cytotoxic T lymphocytes (CTLs), which recognize peptide–MHC class I complexes via TCRs, play a critical role in the immune response against viral infections. However, the extent to which TCR degeneracy within a population of virus-specific CTLs contributes to effective viral control remains poorly understood. In this study, we investigated the magnitude and functional relevance of TCR degeneracy in CTLs targeting an immunodominant epitope of human T-cell leukemia virus type 1 (HTLV-1) in patients with HTLV-1-associated myelopathy (HAM). Using peripheral blood mononuclear cells (PBMCs) from these patients, we quantified TCR degeneracy at the population level by comparing CTL responses to a panel of APLs with responses to the cognate epitope. Our findings demonstrated that increased TCR degeneracy, particularly at the primary TCR contact residue at position 5 of the antigen, was inversely correlated with HTLV-1 proviral load (p = 0.038, R = −0.40), despite similar functional avidity across patient-derived CTLs. Viral sequencing further revealed that CTLs with high TCR degeneracy exerted stronger selective pressure on the virus, as indicated by a higher frequency of nonsynonymous substitutions within the epitope-encoding region in patients with highly degenerate TCR repertoires. Moreover, TCR degeneracy was positively correlated with the recognition rate of epitope variants (p = 0.018, R = 0.76), suggesting that CTLs with high TCR degeneracy exhibited enhanced recognition of naturally occurring epitope variants compared to those with low TCR degeneracy. Taken together, these results suggest that virus-specific CTLs with high TCR degeneracy possess superior antiviral capacity, characterized by broadened epitope recognition and more effective suppression of HTLV-1 infection. To our knowledge, this is the first study to systematically quantify TCR degeneracy in HTLV-1-specific CTLs and evaluate its contribution to viral control in HAM patients. These findings establish TCR degeneracy as a critical determinant of antiviral efficacy and provide a novel immunological insight into the mechanisms of viral suppression in chronic HTLV-1 infection. Full article

Previous research has linked both endothelial protein changes and vitamin D with infertility. This study was undertaken to investigate the association of proteins associated with endothelial function and vitamin D status in the luteal phase at day 21 in a group of non-obese women prior to in vitro fertilization (IVF) with either unexplained infertility (UI) or male factor infertility (MFI). Twenty-five non-obese Caucasian women from a UK academic center with MFI (n = 14) and UI (n = 11) were recruited. Blood was withdrawn at day 21 of the menstrual cycle at the time of mock embryo transfer. Vitamin D parameters were measured by tandem mass spectroscopy. Off-rate Modified Aptamer (SOMA)-scan plasma protein measurement was undertaken for 20 protein markers of endothelial dysfunction. Baseline demographics did not differ between groups and parameters of response following IVF did not differ. Vitamins D₂ and D₃, and 1,25 Vitamin D₃ did not differ between groups. In UI, markers of endothelial activation/dysfunction were investigated; vascular cell adhesion molecule 1 (VCAM-1) decreased and this is associated with endothelial stress; vascular endothelial growth factor (VEGF) decreased and this may suggest impaired endometrial angiogenesis; while intercellular adhesion molecule 1 (ICAM-3) increased (p < 0.05) and is associated with increased immunological activity. A marker of vascular integrity, angiopoietin-1, increased while soluble angiopoietin-1 receptor (sTie-2) decreased (p < 0.05), suggesting increased vascular development. Endothelial markers of inflammation, coagulation, and endothelial progenitor cells were unchanged. Vitamin D and its metabolites show no relationship to UI, but endothelial activation/dysfunction and vascular integrity changes in VCAM-1, VEGF, sICAM-3, angiopoietin-1, and sTie-2 may contribute to UI, though the mechanisms through which they work require further evaluation; however, these protein changes have been associated with endometriosis, raising the suggestion that subclinical/undiagnosed endometriosis may have contributed to UI in these subjects. Full article

Natural killer (NK) cells play a key role in the innate immune response against viral infections. Their activity is regulated by a balance of activating and inhibitory signals, which are modulated by interactions with HLA class I molecules, including HLA-E. The HLA-B 21M/T dimorphism influences the availability of HLA-B leader peptides that stabilize HLA-E expression and modulate NK cell function via the NKG2A/CD94 receptor. To investigate the association between the HLA-B –21M/T dimorphism and the clinical severity of COVID-19, we analyzed a cohort of hospitalized patients with primary SARS-CoV-2 infection, who were genotyped for the HLA-B –21M/T dimorphism. Clinical data, lymphocyte counts, the neutrophil-to-lymphocyte ratio (NLR), and inflammatory markers were compared across genotypes. Contrary to previous studies suggesting a protective effect of the M/M genotype, we found no significant association between the HLA-B –21M/T dimorphism and COVID-19 severity, lymphocyte parameters, or inflammatory biomarkers. Our findings do not support a role for the HLA-B –21M/T dimorphism in modulating COVID-19 outcomes. These results underscore the complexity of NK cell regulation and highlight the need for integrative studies combining genetic, immunological, and functional data to better understand host factors influencing disease progression. Full article

Background: Vaccines have revolutionized disease prevention, yet their effectiveness is challenged by variable immunogenicity, individual response differences, and emerging variants. Biomimetic strategies, inspired by natural immune processes, offer new avenues to enhance vaccine performance. Objectives: This narrative review examines how bioinspired approaches—grounded in evolutionary medicine, immunology, and host–microbiota interactions—can improve vaccine immunogenicity and long-term protection. We further examine the evolutionary foundations of immune responses, highlighting how an evolutionary perspective can inform the development of durable, broadly protective, and personalized vaccines. Furthermore, mechanistic insights at the molecular and cellular level are explored, including Toll-like receptor (TLR) engagement, dendritic cell activation pathways, and MHC-I/MHC-II-mediated antigen presentation. These mechanisms are often mimicked in biomimetic systems to enhance uptake, processing, and adaptive immune activation. Results: The review highlights how immunosenescence, maternal immunity, genetic variation, and gut microbiota composition influence vaccine responses. Biomimetic platforms—such as nanoparticle carriers and novel adjuvants—enhance antigen presentation, boost adaptive immunity, and may overcome limitations in traditional vaccine approaches. Additionally, co-administration strategies, delivery systems, and microbiota-derived immunomodulators show promise in improving vaccine responsiveness. Conclusions: Integrating biomimetic and evolutionary principles into vaccine design represents a promising path toward safer, longer-lasting, and more effective immunizations Full article

Background: The escalating prevalence of food allergies, alongside the global call for environmentally sustainable dietary transitions, has drawn attention to plant-based dietary models—particularly those inspired by the EAT-Lancet Commission. These frameworks not only reduce reliance on animal-sourced foods, benefiting planetary health, but may also play a role in modulating immune tolerance and allergic responses. Methods: This scoping review followed PRISMA guidelines and included 53 peer-reviewed studies published between 2000 and 2024, retrieved from PubMed, Scopus, and Google Scholar. Eligible articles were classified into two thematic domains: prevention of food allergy onset (n = 31) and modulation of allergic symptoms in sensitized individuals (n = 22). Included studies comprised randomized controlled trials (n = 6), observational studies (n = 17), systematic reviews and meta-analyses (n = 11), and narrative/scoping reviews (n = 19). Results: Sustainable plant-based diets were consistently associated with a lower incidence of allergic sensitization and reduced symptom severity. These effects were partly due to the exclusion of common allergens (e.g., dairy, eggs, and shellfish) but more importantly due to immunomodulatory mechanisms. Fermentable fibers can enhance short-chain fatty acid (SCFA)-producing bacteria (e.g., Faecalibacterium prausnitzii), elevating butyrate and acetate levels, which interact with G-protein-coupled receptors 43 and 109A (GPR43 and GPR109A) to induce regulatory T cells (Tregs) and reinforce epithelial integrity via tight junction proteins such as occludin and claudin-1. Polyphenols (e.g., quercetin and luteolin) can inhibit Th2-driven inflammation by stabilizing mast cells and downregulating IL-4 and IL-1. Conclusions: Following sustainable dietary guidelines such as those proposed by the EAT-Lancet Commission may confer dual benefits: promoting environmental health and reducing the burden of allergic diseases. By emphasizing plant-based patterns rich in fiber and polyphenols, these diets support microbiota-mediated immune education, mucosal barrier function, and immunological tolerance. When properly supervised, they represent a promising tool for allergy prevention and symptom management. Larger randomized trials and long-term population studies are needed to confirm and operationalize these findings in clinical and public health contexts. Full article

Among the molecules implicated in inflammation-associated tumorigenesis, Chitinase 3-like 1 (CHI3L1/YKL-40/Brp-39) has emerged as a particularly compelling target due to its multifaced roles in immune regulation, tissue remodeling, and cancer progression. Elevated CHI3L1 expression is observed in various human cancers and corresponding animal models. CHI3L1 directly promotes tumor cell proliferation and angiogenesis and also contributes to immune evasion by establishing an immunosuppressive environment in inflamed tissues. Mechanistically, CHI3L1 exerts its effects through the modulation of STAT3, MAPK, and PI3K/Akt signaling pathways and by interacting with cell surface receptors, such as IL-13Rα2 and RAGE. Studies using transgenic and knockout mouse models have revealed a strong association between CHI3L1 expression and cancer progression. In models of colon and lung cancer, CHI3L1 overexpression correlates with increased tumor size and number, whereas CHI3L1 deficiency markedly suppresses tumor formation. However, its involvement appears to be context-dependent and varies among different epithelial tumor types. These findings suggest that CHI3L1 is a potential therapeutic target and diagnostic biomarker for inflammation-associated cancers. Animal studies provide valuable insights into the immunological mechanisms of CHI3L1-mediated tumorigenesis but also highlight the need for cautious interpretation due to inherent technical limitations. Full article