Search Results (2,228)

Background: An aberrant immune response against Streptococcus pyogenes combined with yet-unraveled genetic inference can induce acute rheumatic fever (ARF), but factors determining the specific development of rheumatic heart disease (RHD) are obscure. Objectives: To retrospectively assess general and laboratory data at the onset of ARF in a single-centre cohort of children managed between 2004 and 2024, and to evaluate any potential relationship between serum vitamin D and the occurrence of RHD. Patients and Methods: Children with ARF diagnosed according to the revised Jones criteria, hospitalized and managed at the Department of Life Sciences and Public Health in our University, were considered; out of 90 eligible patients with post-streptococcal illness, 11 were not considered because they were diagnosed with post-streptococcal arthritis, while 1 was excluded due to incomplete inpatient data. A total final number of 78 consecutive children with ARF (39 males and 39 females) with a mean age of 10.6 ± 2.7 years was assessed via retrospective evaluation of medical records. Their demographic, clinical, and laboratory variables at disease onset, including C-reactive protein, anti-streptolysin-O titer, and 25-hydroxyvitamin D [25(OH)-vitamin D], were analyzed. Results: Sixty-six children (84.6% of the whole cohort) were found to have echocardiographic evidence of RHD. By dividing patients based on the presence of carditis, at the univariate analysis, we observed serum 25(OH)-vitamin D levels significantly lower in patients with cardiac involvement compared to those without (18 ± 6 versus 38 ± 8 ng/mL, p < 0.001). In addition, the proportion of patients with normal serum vitamin D levels was significantly higher among those without cardiac involvement (92%, p < 0.001). To account for any potential confounding factors, we performed a multivariate analysis using logistic regression, adjusted for sex and age, finding that 25(OH)-vitamin D levels lower than 30 ng/mL were the only variable associated with RHD (OR 27.752; 95%CI: 2.885–266.996). No relationship between vitamin D and the month of the year at diagnosis of ARF and RHD was found. Conclusions: Hypovitaminosis D was identified as a factor potentially associated with RHD occurrence in a single-centre cohort of children with ARF evaluated over two decades. This result may suggest that vitamin D deficiency contributes to the occurrence of carditis in ARF. Full article

Regulated proteolysis via autophagy is essential for cellular homeostasis, yet the specific role of autophagy-related gene 7 (ATG7) in corneal epithelial maintenance remains unclear. Using a conditional knockout mouse model (Atg7^f/f K14Cre^+/−), we investigated the impact of ATG7 deficiency on corneal epithelial autophagy, morphology, and vascular dynamics. Loss of ATG7 disrupted autophagosome formation, evidenced by increased LC3B expression but reduced LC3B-positive puncta and absence of autophagosomes ultrastructurally. Although gross corneal morphology was preserved, ATG7 deficiency led to thickened epithelium and increased peripheral lymphatic vessel sprouting, indicating a pro-inflammatory and pro-lymphangiogenic microenvironment. Proteomic analysis revealed upregulation of RAB8, TM9S3, and RETR3, suggesting activation of compensatory pathways such as exophagy, reticulophagy, and Golgiphagy. Inflammatory and angiogenic components were downregulated, suggesting a moderate loss of inhibitory capacity based on the lymphatic phenotypes observed. At the same time, while these two compensatory changes occur, other proteins that positively regulate lysosome formation are reduced, resulting in a phenotype linked to deficient autophagy. These findings demonstrate that ATG7-mediated autophagy maintains corneal epithelial homeostasis and immune privilege, with implications for understanding corneal inflammation and lymphangiogenesis in ocular surface diseases. Full article

Hemophilia, an X-linked recessive bleeding disorder, results from mutations in the F8 or F9 genes, leading to factor VIII (hemophilia A) or factor IX (hemophilia B) deficiency. While conventional treatment relies on regular factor replacement therapy, gene therapy has emerged as a promising alternative, offering the potential for sustained endogenous factor production after a single administration. This review provides an in-depth analysis of recent advances in gene therapy for both hemophilia A and B, with a focus on AAV-mediated liver-directed approaches and other approved modalities. Key limitations—such as vector immunogenicity, hepatic toxicity, waning transgene expression, and limited re-dosing capacity—are discussed. Additional gene delivery platforms, including lentiviral and retroviral vectors, genome editing techniques (e.g., CRISPR/Cas9), and non-viral systems like transposons and lipid nanoparticles, are also examined. Although gene therapy for hemophilia B demonstrates greater clinical durability, hemophilia A presents unique challenges due to factor VIII’s size, poor expression efficiency, and the need for higher vector doses. Future efforts will focus on overcoming immune barriers, improving delivery technologies, and developing approaches suitable for pediatric patients and individuals with pre-existing immunity. This review provides not only a descriptive overview but also a critical comparison of gene therapy approaches for hemophilia A and B. We emphasize that the durability of response is currently superior in hemophilia B, whereas hemophilia A still faces unique barriers, including declining FVIII expression and higher immunogenicity. By analyzing cross-platform challenges (AAV, lentiviral, CRISPR, and emerging LNPs), we highlight the most promising strategies for overcoming these limitations and provide a forward-looking perspective on the future of gene therapy. Full article

Background: As the member of the B7 family, V-set and immunoglobulin domain-containing 4 (VSIG4) plays an essential role in regulating immune responses against bacterial infection, autoimmune disease, and chronic viral infection. However, the role of VSIG4 in acute viral infections remains largely unclear. Methods: Here, we constructed a gene-targeted VSIG4-deficient mouse model and then infected it with influenza to explore the detailed VSIG4-involved mechanism. Results: Our results demonstrated that the gene-deficient mice exhibited reduced survival rates, ranging from 25% to 50%, after being infected with different influenza virus strains. At the sites of infection, an increased number of CD8⁺ T cells, along with heightened expression of pro-inflammatory cytokines, e.g., Il-6 and TNFα, may have contributed to tissue damage. The recombinant VSIG4 protein slightly improved protection from the influenza challenge, suggesting regulatory functions of VSIG4 during infection. Using in vitro cell models, we show that the type C lectin receptor pathway member DC-SIGNR1 (CD209) is an essential factor during acute virus infection. The affinity and CO-IP tests indicated an interaction between CD209 and VSIG4, but not through protein modification. Conclusions: Therefore, VSIG4 functionally protected mice by regulating the type C lectin receptor pathway to inhibit excessive Th1 immune responses and inflammation. Our findings highlight the importance of considering immune homeostasis in the development of therapies for severe infections. Full article

Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system that affects women more frequently than men. This sex gap has widened over the past century, and appears to be shaped by lifestyle factors more than biological factors. This narrative review examines the evidence for sex-specific differences in lifestyle risk factors and their impact on both MS susceptibility and disease progression, with implications for diagnosis, monitoring, and treatment. Smoking, obesity, vitamin D deficiency, ultraviolet radiation exposure, and Epstein–Barr virus infection all interact with sex-related biological pathways to influence MS risk. Women appear to be more vulnerable to the pathogenic effects of smoking and obesity, both independently and in synergy with genetic risk alleles, while vitamin D and UV exposure confer stronger protective effects in females than in males. EBV infection also exhibits sex-dependent immune responses, shaped by hormonal regulation and host–virus genetic interactions. Sex-related lifestyle factors also modulate MS progression. Women experience more inflammatory activity and relapses, whereas men more often develop a progressive phenotype with greater neurodegeneration. Hormonal changes during female reproductive phases, such as pregnancy, breastfeeding, menopause, and hormone-based therapies, critically influence disease activity and progression in MS. Obesity, smoking, vitamin D status, diet, and gut microbiota further interact with sex hormones and genetic background, contributing to variable disease trajectories, also modulated by social determinants such as education level. These findings underscore the need to integrate into clinical practice the evaluation of lifestyle factors in a sex-specific way for diagnosis, monitoring, and treatment of MS. Full article

Bacterial wilt is a highly destructive disease affecting a wide range of crops, with no effective chemical control methods currently available. Consequently, the development of microbial strategies for disease management has become increasingly important. Among these, plant immunity-intensifying microbes have demonstrated promising efficacy in controlling bacterial wilt. However, the influence of environmental factors, particularly light intensity, on the effectiveness of these microbes remains unclear. Light intensity is a critical regulator of the photosynthetic system and plant biochemical functions, including defense responses. In this study, we specifically utilized Arabidopsis plants grown under distinct light intensities to systematically examine how light conditions affect the induction of plant immune responses and the occurrence of bacterial wilt. Our findings revealed that Arabidopsis grown under high light intensity exhibited significantly stronger immune responses and reduced disease severity, compared to plants grown under low light intensity. Further, application of Bacillus amyloliquefaciens PMB05, a plant immunity-intensifying strain, resulted in more pronounced immune signaling and disease control efficacy under high light conditions. Experiments using salicylic acid (SA)-deficient mutants demonstrated that disruption of the SA pathway abolished the enhanced suppression of bacterial wilt conferred by B. amyloliquefaciens PMB05 under high light intensity, indicating that the SA pathway is indispensable for PMB05-mediated disease resistance. Moreover, the validation experiments in tomato plants supported these results, with B. amyloliquefaciens PMB05 significantly reducing bacterial wilt development under high light intensity. Collectively, our study demonstrates that growing plants under varying light intensities provides critical insights into how environmental conditions modulate the effectiveness of plant immunity-intensifying microbes, offering a potential strategy for integrated disease management in crops. Full article

Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease in which environmental factors modulate genetically determined immune dysregulation. Vitamin D has emerged as a plausible modifier of disease expression because its active metabolite signals through the vitamin D receptor on innate and adaptive immune cells and influences antigen presentation, cytokine balance, and lymphocyte differentiation. This narrative review synthesizes current evidence on vitamin D status and supplementation in SLE with attention to organ-specific domains. Observational studies consistently report high rates of hypovitaminosis D in SLE and associations with less favorable clinical profiles, including higher global and renal disease activity, adverse cardiometabolic features, greater infection vulnerability, and neuropsychiatric manifestations. Preclinical models demonstrate neuroprotective and barrier-stabilizing actions of vitamin D analogs, supporting biological plausibility. Interventional trials indicate that supplementation safely corrects deficiency and shows signals of benefit for selected outcomes (e.g., modest activity reductions or fatigue in specific contexts), although effects on interferon signatures, complement, and autoantibodies are heterogeneous and often limited. Overall, current evidence supports optimization of vitamin D status as a low-risk adjunct in comprehensive SLE care while highlighting the need for adequately powered, organ-focused randomized trials using standardized measurements and prespecified endpoints to define causality, therapeutic targets, and long-term safety. Full article

Multiple sclerosis (MS) is a chronic autoimmune neurodegenerative disorder characterized by progressive demyelination and axonal degeneration within the central nervous system, driven by complex genomic and epigenomic dysregulation. Its pathogenesis involves aberrant DNA methylation patterns at CpG islands of numbers of genes like OLIG1 and OLIG2 disrupting protein expression at myelin with compromised oligodendrocyte differentiation. Furthermore, histone modifications, particularly H3K4me3 and H3K27ac, alter the promoter regions of genes responsible for myelination, affecting myelin synthesis. MS exhibits chromosomal instability and copy number variations in immune-regulatory gene loci, contributing to the elevated expression of genes for pro-inflammatory cytokines (TNF-α, IL-6) and reductions in anti-inflammatory molecules (IL-10, TGF-β1). Vitamin D deficiency correlates with compromised immune regulation through hypermethylation and reduced chromatin accessibility of vitamin D receptor (VDR) dysfunction and is reported to be associated with dopaminergic neuronal loss. Vitamin D supplementation demonstrates therapeutic potential through binding with VDR, which facilitates nuclear translocation and subsequent transcriptional activation of target genes via vitamin D response elements (VDREs), resulting in suppression of NF-κB signalling, enhancement of regulatory T-cell (T_reg) responses due to upregulation of specific genes like FOXP3, downregulation of pro-inflammatory pathways, and potential restoration of the chromatin accessibility of oligodendrocyte-specific gene promoters, which normalizes oligodendrocyte activity. Identification of differentially methylated regions (DMRs) and differentially expressed genes (DEGs) that are in proximity to VDR-mediated gene regulation supports vitamin D supplementation as a promising, economically viable, and sustainable therapeutic strategy for MS. This systematic review integrates clinical evidence and eventual bioinformatical meta-analyses that reference transcriptome and methylome profiling and identify prospective molecular targets that represent potential genetic and epigenetic biomarkers for personalized therapeutic intervention. Full article

Autoimmune gastritis (AIG) is a chronic, organ-specific autoimmune disease characterized by progressive destruction of gastric parietal cells driven by autoreactive CD4⁺ T-cells, epithelial stress pathways, and microbial factors. Parietal cell loss results in achlorhydria, intrinsic factor deficiency, and vitamin B12 malabsorption, ultimately leading to pernicious anemia. Compensatory hypergastrinemia promotes enterochromaffin-like (ECL) cell hyperplasia and contributes to the development of type 1 gastric neuroendocrine neoplasms (gNENs). These clinical consequences are well recognized, yet the cellular and molecular mechanisms driving mucosal atrophy and neoplastic transformation remain incompletely defined. Recent advances highlight the role of endoplasmic reticulum stress, impaired autophagy, innate immune effectors, and dysbiosis in perpetuating inflammation and epithelial injury. The frequent coexistence of AIG with other autoimmune disorders further adds to its clinical complexity. Therapeutic options remain limited, spanning vitamin B12 replacement and endoscopic management to emerging targeted approaches. Netazepide, a gastrin/CCK2 receptor antagonist, is the only agent tested in clinical trials, whereas interventions targeting ER stress, autophagy, immune tolerance, or microbiome composition are still in the preclinical stage. Clarifying these mechanisms is crucial to improve biomarker development, optimize surveillance, and identify targeted therapies to prevent neoplastic transformation. Full article

To further investigate the role of PKCλ/ι in Schistosoma japonicum-induced hepatic fibrosis, we employed a CD4⁺ T-cell-specific PKCλ/ι conditional knockout (KOSJ) mouse model, with wild-type (WTSJ) mice used as controls. Transcriptomic profiling of hepatic mRNA was used to reveal the immune regulatory mechanisms underlying the role of PKCλ/ι in the hepatic fibrosis caused by S. japonicum infection. Flow cytometry, RT–qPCR and ELISA were used to analyze the effects of PKCλ/ι on Tfh and Tfr cells, and single-cell RNA sequencing was used to elucidate the interactions between Tfr and B cells. The results showed that PKCλ/ι deficiency led to altered BCR signaling gene expression, reduced germinal center activity, and decreased anti-SEA antibody levels. Tfh cells and key factors including IL-21, CXCR5, and ICOS were downregulated, while Tfr cells and IL-10⁺ B cells increased. Additionally, hepatic neutrophils decreased and Treg/Tfr ratios rose, with enhanced IL-10-mediated cellular crosstalk. These findings indicate that PKCλ/ι deficiency attenuates liver fibrosis by inhibiting Tfh differentiation, promoting Tfr function, and activating IL-10-producing Breg cells, suggesting its potential as a therapeutic target. Full article

Background/Objectives: Sepsis is a life-threatening condition characterized by an uncontrolled immune response due to systemic infections. It is responsible for millions of deaths worldwide. Although inflammasomes play an important role in host defense, they have a detrimental role in sepsis induced by LPS or Gram-negative bacteria. We aimed to revise the molecular mechanisms of inflammasome activation in sepsis by LPS and Gram-negative bacteria other than cytokine release as treatments blocking TNF-α and IL-1 cytokines have been ineffective even though cytokine storm is associated with lethality. Results: Studies with knockout mice deficient in inflammasome-derived cytokines have shown contrasting results on the role of these proinflammatory cytokines in the lethality of LPS- and Gram-negative-induced sepsis. However, DAMPs released after non-canonical inflammasome activation such as extracellular DNA, histones, HMGB1, and tissue factor result in disseminated-intravascular coagulation (DIC) and mortality in mice. Blocking these products in preclinical studies with animal models showed improved clinical scores and survival after LPS-induced sepsis or polymicrobial sepsis induced by Cecal Ligation and Puncture. Conclusions: Even though immunomodulatory drugs have shown inconclusive results as therapies for sepsis, blocking DAMPs associated with DIC may be considered for clinical trials in the future, especially in patients presenting biomarkers of coagulopathies. Full article

Zinc (Zn), a naturally occurring trace element ubiquitous in the Earth’s crust, soil, and water, is indispensable for human health due to its physiological and nutritive benefits. In this scenario, Zn is pivotal for maintaining homeostasis against toxic effects exerted by heavy metals (HMs) through bioaccumulation and metabolic interference. Zinc is an enticing cofactor for miscellaneous biochemical enzymes such as Zn metalloenzymes, which mediate crucial cellular processes, including cell proliferation, protein synthesis, immune modulation, epigenetic regulation, and nucleic acid synthesis. Recently, several research studies have focused on the thorough investigation of Zn supplementation in controlling HM toxicity by competing for binding sites and boosting protective mechanisms in humans. The current article discusses the upper limits for various toxic HMs in staple crop foods, as provided by globally recognized organizations. Clinical studies recommend a daily dose of 11 mg of Zn for healthy men and 8–12 mg for women in healthy and pregnancy conditions. However, during Zn deficiency, therapeutic supplementation is expected to be adjustable, and the dosage is increased from 15 to 30 mg daily. This review discusses the dysregulation of specific Zn importers and transporters (ZIPs/ZnTs) due to their clinical significance in immune system dysfunction as well as the progression of a myriad of cancers, including prostate, breast, and pancreas. Moreover, this review emphasizes indispensable in vitro and in vivo studies, as well as key molecular mechanisms related to Zn supplementation for treating toxicities exacerbated by HMs. Full article

Misregulation of C-C chemokine receptor 7 (CCR7) has been linked to multiple autoimmune diseases including systemic lupus erythematosus, multiple sclerosis, and ankylosing spondylitis. As a G-protein-coupled receptor, located on the cell membrane, CCR7 can be targeted by inhibiting one of its two ligands, C-C chemokine ligand 19 (CCL19), to regulate its function. In this study, we examined signaling events downstream of CCL19 binding that provide a mechanism for regulation of the immune response. We used a CCR7 antagonist, CCL19_8-83, in immune studies in vivo, as a platform for a pharmaceutical to define the molecular events that are involved in regulating the humoral adaptive immune response. We found that in the presence of a T-cell-dependent antigen, C57BL/6 mice treated during antigen exposure with CCL19_8-83 generated significantly higher levels of IgG1, the dominant isotype in extracellular bacterial infections that can activate complement, and IgG2c, the dominant isotype during viral and intracellular bacterial infections. Inhibiting ERK5 signaling downstream of CCR7 activation by CCL19, or disruption of CCL19 expression in CCL19^−/− mice, also resulted in higher levels of IgG1 when compared to control mice. Differences in levels of IL-4 or other cytokines or lymphocyte types between wild-type and ERK5-deficient T cells did not account for antibody levels. Since pertussis-toxin-induced inhibition of lymphocyte chemotaxis is linked to elevated levels of IgG, we examined the effect of ERK5 on chemotaxis to CCR7 ligand CCL19. We found that disruption of ERK5 in T cells, or global disruption of CCL19 or CCR7, inhibited chemotaxis of T cells to CCL19, a mechanism that enhances sensitization during the exposure to an immunogen. Since CCR7 and its ligands have been linked to autoimmunity, these studies may provide insight into mechanisms that can be targeted to control autoimmune responses. Full article

Introduction: Dry Eye Syndrome (DES) is a multifactorial disorder of the ocular surface, characterized by complex interactions between environmental factors, immune dysregulation, and potential genetic predispositions. Vitamin D deficiency, known for its immunomodulatory properties, has increasingly been implicated in the pathogenesis of DES; however, the underlying mechanisms remain insufficiently elucidated. Of particular interest is the vitamin D receptor (VDR) gene, whose polymorphisms may influence the bioavailability and biological activity of vitamin D. Objective: The aim of this study was to investigate the association between serum 25-hydroxyvitamin D [25(OH)D₃] levels and selected polymorphisms in the VDR gene (Taq, Fok, Apa, and Bsm) in patients with DES and to analyze their potential clinical and genetic interactions. Methods: This prospective observational study included 60 patients with a confirmed diagnosis of DES. Serum 25(OH)D₃ levels were measured, and genotyping of four VDR single-nucleotide polymorphisms (SNPs) was performed using PCR followed by restriction fragment length polymorphism analysis. Genotype distributions were assessed in relation to vitamin D status using appropriate statistical tests and Hardy–Weinberg equilibrium analysis. Results: Over 85% of patients exhibited insufficient or deficient vitamin D levels. Among the analyzed SNPs, only the ApaI polymorphism (rs7975232) showed a statistically significant association with vitamin D status (p = 0.0384), with the homozygous AA genotype being more prevalent among patients with hypovitaminosis. The remaining polymorphisms (TaqI, FokI, BsmI) did not reach statistical significance; however, potential trends were observed that may warrant further investigation in larger cohorts. Conclusion: The findings suggest a potential role for VDR gene variability in the regulation of systemic vitamin D levels in patients with DES. Identification of specific genotypes may contribute to the development of personalized diagnostic and therapeutic strategies, particularly for patients with treatment-resistant forms of the disease. These results support the integration of genetic biomarkers and nutritional parameters into modern ophthalmologic practice. Full article

Background: Tumor-associated macrophages (TAMs) are important contributors to tumor progression and metastasis. Therefore, the identification of molecules that mediate these cells’ tumor-promoting functions is highly warranted. VSIG4 has been proposed as a macrophage immune checkpoint. Hence, we aim to investigate this marker in preclinical models. Methods: Publicly available scRNAseq datasets of human colorectal (CRC) and triple-negative breast (TNBC) carcinomas and their murine counterparts were reanalyzed to investigate the expression of VSIG4 in the different TAM populations. Moreover, tumors were grown in Vsig4-deficient mice to evaluate the effect on primary tumor characteristics. Finally, since liver Kupffer cells and large peritoneal macrophages are at least partly VSIG4-high, and are implicated in metastasis to those organs, the dissemination of CRC cancer cells to those sites was assessed in the Vsig4-deficient mice. Results: We demonstrate that VSIG4 expression in human CRC and TNBC is mostly restricted to TAMs, and that its expression correlates with a worse prognosis. However, a striking finding was that no Vsig4 mRNA nor protein could be detected in the microenvironment of primary CRC and TNBC murine tumors, resulting in a similar tumor growth in wild type versus Vsig4-deficient mice. Moreover, no major differences were observed in metastatic tumor load in the liver and peritoneal cavity, apart from a reduced metastasis to the omentum in Vsig4-deficient animals. Conclusions: Murine cancer models are not suitable to investigate the role of VSIG4 in primary tumors and VSIG4 deficiency did not alter liver nor peritoneal cavity metastasis in murine models, with the exception of the omentum. Full article