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A widely recognized benefit of gut microbiota is that it provides colonization resistance against enteric pathogens. The gut microbiota and their products can protect the host from invading microbes directly via microbe-pathogen interactions and indirectly by host-microbiota interactions, which regulate immune system function. In contrast, enteric pathogens have evolved mechanisms to utilize microbiota-derived metabolites to overcome colonization resistance and increase their pathogenic potential. This review will focus on recent studies of metabolism-mediated mechanisms of colonization resistance and virulence strategies enteric pathogens use to overcome them, along with how induction of inflammation by pathogenic bacteria changes the landscape of the gut and enables alternative metabolic pathways. We will focus on how intestinal pathogens counteract the protective effects of microbiota-derived metabolites to illustrate the growing appreciation of how metabolic factors may serve as crucial virulence determinants and overcome colonization resistance. [Display omitted] Microbial metabolism is a key player in microbiota-pathogen interactions. Jones et al. describe metabolism-mediated mechanisms of colonization resistance, focusing on nutritional competition, metabolite-mediated inhibition, and modulation of host immune responses. Additionally, the authors explore virulence strategies used by enteric pathogens to overcome metabolism-mediated colonization resistance, enabling them to cause disease. [ABSTRACT FROM AUTHOR]

AbstractBackgroundMethodsResultsConclusionLactoferrin (Lf), a multifunctional glycoprotein known for its roles in immune modulation, iron metabolism, and antimicrobial activity, has limited therapeutic efficacy due to poor bioavailability. Liposomal encapsulation of lactoferrin (LLf) offers a potential solution by improving its stability, absorption, and sustained release, making it a promising candidate for various clinical applications. This study aims to compare the effectiveness of LLf and plain Lf in cellular uptake, proliferation, and wound healing using HEK-293T and Caco-2 cell lines.Cell uptake, proliferation, and wound healing assays were conducted using HEK-293T and Caco-2 cells to evaluate the bioavailability and therapeutic efficacy of LLf compared to plain Lf. The cellular uptake was assessed over a 24-h period using an indirect ELISA method. Cell proliferation was measured using the MTT assay, while wound healing was evaluated using a scratch assay to observe cell migration over 48 h.LLf demonstrated significantly higher cellular uptake in both HEK-293T and Caco-2 cells, with peak internalization at 4 h, compared to plain Lf. In proliferation studies, LLf showed a dose-dependent increase in cell growth, achieving a 71% proliferation rate at 75 µg/mL, while plain Lf reached only 53%. LLf also accelerated wound healing, with nearly complete closure by 48 h, compared to 51.3% closure with plain Lf.The results indicate that liposomal encapsulation significantly enhances lactoferrin’s bioavailability, proliferation-inducing capacity, and wound healing efficacy. LLf’s superior performance in these key areas suggests its potential for broader therapeutic applications, particularly in wound care, immune modulation, and tissue regeneration. Future clinical studies are warranted to validate the therapeutic benefits of LLf in vivo. [ABSTRACT FROM AUTHOR]

The cGAS-STING axis is a promising therapeutic target against cancer. However, most activators require STING signaling in the host, especially within antigen-presenting cells, which are rare in a cold tumor microenvironment. The cGAS-STING cascade is also present within cancer cells but with suppressed activity. Such a paradoxical situation may account for the clinical failures. Herein, we develop a trinity STING-activating nanoparticle (CMTP) coordinated with cGAMP, Mn3+, and porphyrin to awaken autologous STING signaling in cancer cells. CMTP disintegrates into Mn2+ and TCPP upon elevated glutathione in cancer cells, where TCPP triggers mitochondrial DNA leakage, enhancing cGAS enzymatic activity in coordination with Mn2+, while concurrent cGAMP release from framework synergizes to amply STING activity. Consequently, CMTP exploits cancer cells as reservoirs for cGAS-STING signaling to promote DC maturation and T cell priming. A single administration of CMTP demonstrates robust efficacy in both hot MC38 and cold 4 T1 murine tumors. Genetic knockout studies confirm that STING in cancer cells, rather than in the host, is critical for antitumor performance. The feasibility of immune modulation is further validated in resected human patient tissues. This work presents a potent STING-activating nanomedicine based on coordination chemistry and underscores the potential of harnessing cancer cells' autologous cGAS-STING machinery in immunotherapy. A GSH-responsive cGAMP‑manganese-photosensitizer coordination nanoparticle (CMTP) synergizes to amply autologous cGAS-STING signaling in cancer cells and boosts antitumor immune cascade responses. [Display omitted] • CMTP responses to high GSH in cancer cells and reactivates pre-dormant STING axis. • mtDNA leakage cooperates with Mn2+ and cGAMP to amply STING cascade signaling. • A single dose of CMTP elicits robust immune activities against hot and cold tumors. • STING deficiency in cancer cell, but not in the host, abolishes antitumor response. • CMTP activates STING in resected human patient tumor tissues. [ABSTRACT FROM AUTHOR]

Background: Sepsis is characterized by an excessive immune response. Modulation of the immune response, particularly macrophage polarization, may provide therapeutic benefit. The effects of Caerulomycin A (caeA), a known STAT1 phosphorylation inhibitor, on macrophage polarization and inflammatory markers were explored using a lipopolysaccharide (LPS)-induced sepsis mouse model. Methods: A sepsis model was established in C57BL/6 mice induced by intraperitoneal injection of LPS, and the survival rate of mice was observed after treatment with different doses of caeA to determine the optimal therapeutic dose. For in-vitro assays using the RAW264.7 macrophage cell line, the concentration of caeA that was non-toxic to cell survival was screened using the MTT assay, followed by the analyses by qRT-PCR, ELISA, Western blot and flow cytometry for M1/M2 type macrophage markers (CD86, NOS2, CD206, ARG1) and inflammatory factors (IL-1β, IL-6, TNF-α, IL-4, and IL-10) expression. In addition, the phosphorylation levels of STAT1 and STAT6 in the JAK–STAT signaling pathway were detected. Results: The results of in-vivo experiments showed that caeA treatment (20 mg/kg) significantly increased the survival of LPS-induced septic mice and decreased the expression of M1-type macrophage markers (CD86 and NOS2) and pro-inflammatory cytokines (IL-1β, IL-6, and TNF-α) while increasing the expression of M2-type markers (CD206 and ARG1) and anti-inflammatory cytokines (IL-4 and IL-10) expression. In in-vitro experiments, 20 μM caeA effectively inhibited LPS-induced polarization of M1-type macrophages without affecting the activity of RAW264.7 cells, and caeA significantly inhibited the phosphorylation of STAT1 yet enhanced the phosphorylation level of STAT6, as detected by Western blot. Conclusions: CaeA effectively modulates macrophage polarization and attenuates the inflammatory response in septic mice, possibly by affecting the JAK–STAT signaling pathway. These findings support further exploration of the potential of caeA as a therapeutic agent for sepsis. [ABSTRACT FROM AUTHOR]

The immune system plays a pivotal role in maintaining physiological homeostasis and influencing disease processes. Dysregulated immune responses drive chronic inflammation, which in turn results in a range of diseases that are among the leading causes of death globally. Traditional immune interventions, which aim to regulate either insufficient or excessive inflammation, frequently entail lifelong comorbidities and the risk of severe side effects. In this context, intrinsic immunomodulatory hydrogels, designed to precisely control the local immune microenvironment, have recently attracted increasing attention. In particular, these advanced hydrogels not only function as delivery mechanisms but also actively engage in immune modulation, optimizing interactions with the immune system for enhanced tissue repair, thereby providing a sophisticated strategy for managing chronic inflammation. In this tutorial review, we outline key elements of chronic inflammation and subsequently explore the strategic design principles of intrinsic immunomodulatory hydrogels based on these elements. Finally, we examine the challenges and prospects of such immunomodulatory hydrogels, which are expected to inspire further preclinical research and clinical translation in addressing chronic inflammation. [ABSTRACT FROM AUTHOR]

ABSTRACT Maternal vaccination is essential for safeguarding both mother and foetus from infectious diseases. This study investigated the immunogenicity and efficacy of a maternal ORF‐B2L genetic vaccine in a pregnant rat model, focusing on maternal–neonatal immune modulation, placental and neonatal spleen transcriptomics and the underlying mechanisms contributing to neonatal immune development. Female rats received intramuscular injections of either a gene vaccine (GV) containing 200 μg of recombinant ORF‐B2L DNA and 50 μg of a subunit protein or an empty plasmid as a control. Results showed significantly higher levels of specific anti‐B2L antibodies and Th1 and Th2 cytokine levels in both maternal and neonatal sera from the GV group compared to the control group (p < 0.05). Transcriptome analysis identified 1295 differentially expressed genes (DEGs) in the placenta and 998 DEGs in the neonatal spleen, with upregulated pathways associated with immune cell recruitment, cytokine signalling and hormone regulation in the GV group. Notably, upregulated DEGs such as TLR4, ESR1 and various cytokine/chemokine‐related genes in the placenta suggest enhanced immune regulation and foetal protection. In the neonatal spleen, increased expression of IL‐1β, IL‐6, IL‐10 and CD69 indicates enhanced T and B cell development and pathogen defence. The upregulation of IL‐1β suggests a Th1 response, while elevated IL‐10 indicates a potential Th2‐biased immunity, reflecting a balanced Th1/Th2 response that is crucial for effective adaptive immunity. Overall, maternal ORF‐B2L genetic vaccination induces a robust immune response, enhancing maternal‐foetal protection and shaping neonatal immune responses, offering valuable insights for optimizing maternal vaccination strategies. [ABSTRACT FROM AUTHOR]

Introduction: The COVID-19 pandemic has become a global health crisis, eliciting varying severity in infected individuals. This study aimed to explore the immune profiles between moderate and severe COVID-19 patients experiencing a cytokine storm and their association with mortality. This study highlights the role of PD-1/PD-L1 and the TIGIT/CD226/CD155/CD112 pathways in COVID-19 patients. Methods: We performed a study using flow cytometry to compare the phenotypic and functional characteristics of peripheral blood mononuclear cells in patients with moderate or severe disease and healthy individuals. Soluble immune checkpoint molecule and ligand levels were measured by Luminex. Results: Severe patients show reduced CD8+ T cell frequency, hyperactivation of CD8+ T, NK and NKT cells with concurrent upregulation of immune checkpoint ligands in monocytes. TIGIT expression by CD8+ T and NK cells and PD-1 by NKT cells suggest a spectrum of immune dysfunction, encompassing both hyperactivation and features of exhaustion. This dual phenomenon likely contributes to the impaired viral clearance and the exacerbation of inflammation characteristic of severe disease. Additionally, the study suggests that increased activation and cytotoxicity of NK cells may be associated with fatal outcomes in severe COVID-19 infection. Conclusion: These findings shed light on the intricate immune response regulation in COVID-19, emphasizing the importance of immune checkpoint pathways and activation signatures in disease severity. A novel aspect of this study is that it includes only COVID-19 patients experiencing cytokine storms, allowing for a focused analysis of immune dysregulation during this critical phase of the disease. [ABSTRACT FROM AUTHOR]

The placenta is a unique organ with various immunological and endocrinological roles that modulate maternal and fetal physiology to promote maternal-fetal tolerance, pregnancy maintenance, and parturition at term. During pregnancy, the hormone prolactin (PRL) is constitutively secreted by the placenta and is necessary for implantation, progesterone support, fetal development, and overall immune modulation. While PRL is essential for pregnancy, studies suggest that elevated levels of serum PRL (hyperprolactinemia) are associated with adverse pregnancy outcomes, including miscarriage, preterm birth, and preeclampsia. However, there is a lack of mechanistic studies to support these observations. Here we investigated the impact of elevated levels of PRL on placental cells and evaluated PRL effects on the JAK2/STAT5 inflammatory signaling cascade. Elevated levels of exogenous PRL enhances PRL and PRL-receptor expression, along with JAK2/STAT5 signaling in primary decidual mononuclear cells and the placental trophoblast cell line, JEG-3. Following PRL exposure, the STAT5 isoform, STAT5B, is preferentially activated and there is a significant upregulation in the secretion of pro-inflammatory cytokines, IL-6 and IL-1β. This inflammatory cascade is supported via PRL-induced reduction of SOCS1 and SOCS2. Furthermore, LPS exacerbates PRL expression and JAK2/STAT5 signaling, leading to increased secretion of IL-6 and TNF-α. These results highlight the inflammatory roles of elevated PRL at the maternal-fetal interface, underscoring the need for further mechanistic studies to elucidate its functions in pregnancy. [ABSTRACT FROM AUTHOR]

Parasitic infection is a complex process involving interactions among various immune cells. Regulatory B cells (Breg cells), a subset of B lymphocytes with immunosuppressive functions, play a role in modulating immune responses during infection to prevent excessive immune activation. This article reviews the origin, phenotype, and immunoregulatory mechanisms of Breg cells. We summarize the immunomodulatory roles of Breg cells in various parasitic infections. We also discuss the potential applications of activating Breg cells through parasitic infections and their derived molecules in the treatment of certain allergic, autoimmune, and inflammatory diseases. The aim is to provide new perspectives for the future treatment of parasitic diseases and other related conditions. [ABSTRACT FROM AUTHOR]

The deregulation of immune responses is what causes food allergy (FA) to occur. FA's cause is still unknown. The goal of this study is to investigate the mechanism how the impaired production of IL-10 occurs in peripheral naive B cells of patients with FA. Samples from patients with FA and healthy controls (HC) were used to isolate CD19+ CD45R+ naive B cells from peripheral blood mononuclear cells (PBMC). Lipopolysaccharide (LPS) exposure was used to assess the expression of interleukin-10 (IL-10) in B cells. Although the FA and HC groups had similar total B cell counts, the FA patients had fewer IL-10+ B cell counts than the HC group. In peripheral B cells, the concentrations of IL-10 were inversely related to the concentrations of specific IgE, Th2 and Th1 cytokines in the serum. In patients with FA, peripheral B cells experienced impaired immune-suppressive functions. Galectin-9 could restore the defective induction of IL-10 expression in naive B cells of FA patients. In conclusion, FA patients with naive B cells experience impaired IL-10 induction. The induction of IL-10 in naive B cells of FA patients can be restored by galectin-9 treatment, which triggers B cells to differentiate into immune regulatory B cells. [ABSTRACT FROM AUTHOR]

Peptidoglycan (PGN) is the primary component of bacterial cell walls, consisting of linear glycan chains formed by alternating linkages of N‐acetylglucosamine (NAG) and N‐acetylmuramic acid (NAM) through glycosidic bonds. It exhibits biological activity in various aspects, making it a biologically significant macromolecule with extensive industrial application. This review aims to explore the latest research advancements in the extraction techniques, structural characterization, functions, and applications of PGN. The review compares the advantages and limitations of traditional chemical lysis methods with modern mechanical‐assisted and bio‐assisted extraction techniques, discusses chemical composition analysis techniques and structural characterization methods of PGN. The review emphasizes the potential of PGN in immune modulation, specific recognition, and adsorption functions. Furthermore, the review examines potential applications of PGN in vaccine development, the livestock industry, the removal of harmful substances, and protein bioprocessing. In the end, based on the current development trend, future research directions for PGN are proposed, including in‐depth studies on the mechanisms of PGN in different hosts and its immunomodulatory effects in various disease models. It is expected that a comprehensive reference framework for the research and application of PGN will be provided through this review, offering ideas and directions for further development and utilization. [ABSTRACT FROM AUTHOR]

Type 1 diabetes mellitus (T1DM) is a growing global health concern that affects approximately 8.5 million individuals worldwide. T1DM is characterized by an autoimmune destruction of pancreatic β cells, leading to a disruption in glucose homeostasis. Therapeutic intervention for T1DM requires a complex regimen of glycaemic monitoring and the administration of exogenous insulin to regulate blood glucose levels. Advances in continuous glucose monitoring and algorithm-driven insulin delivery devices have improved the quality of life of patients. Despite this, mimicking islet function and complex physiological feedback remains challenging. Pancreatic islet transplantation represents a potential functional cure for T1DM but is hindered by donor scarcity, variability in harvested cells, aggressive immunosuppressive regimens and suboptimal clinical outcomes. Current research is directed towards generating alternative cell sources, improving transplantation methods, and enhancing cell survival without chronic immunosuppression. This Review maps the progress in cell replacement therapies for T1DM and outlines the remaining challenges and future directions. We explore the state-of-the-art strategies for generating replenishable β cells, cell delivery technologies and local targeted immune modulation. Finally, we highlight relevant animal models and the regulatory aspects for advancing these technologies towards clinical deployment. Type 1 diabetes mellitus affects 8.5 million people globally and is characterized by autoimmune destruction of pancreatic β cells. This Review discusses cell replacement therapies for T1DM and outlines the challenges and future directions Key points: Stem cell-derived islets have advanced as a viable renewable source of cells for transplantation in type 1 diabetes mellitus (T1DM). Although these cells are being tested in the clinical setting, challenges remain to be addressed regarding cell safety, composition and function. Genetic engineering of renewable β cells can reduce immunogenicity, lower metabolic needs and bolster hypoxia resistance. However, the effect on β cell performance requires further elucidation. Local immunomodulation via in situ delivery of immunomodulatory molecules and adjuvant cells is emerging as a promising approach for abrogating the need for systemic immunosuppression in β cell transplantation. Current preclinical results suggest that immunoprotected islet cell grafts in a retrievable subcutaneous site could restore normoglycaemia for at least 1 year or longer without systemic immunosuppression. Despite the potential of new technologies, the development of cell therapy treatments must pragmatically focus on generating therapies that are not only effective and safe but also align with the real-world dynamics of patients' lives and the capabilities of health-care systems. [ABSTRACT FROM AUTHOR]

Tolerogenic vaccines represent a therapeutic approach to induce antigen-specific immune tolerance to disease-relevant antigens. As general immunosuppression comes with significant side effects, including heightened risk of infections and reduced anti-tumor immunity, antigen-specific tolerance by vaccination would be game changing in the treatment of immunological conditions such as autoimmunity, anti-drug antibody responses, transplantation rejection, and hypersensitivity. Tolerogenic vaccines induce antigen-specific tolerance by promoting tolerogenic antigen presenting cells, regulatory T cells, and regulatory B cells, or by suppressing or depleting antigen-specific pathogenic T and B cells. The design of tolerogenic vaccines vary greatly, but they all deliver a disease-relevant antigen with or without a tolerogenic adjuvant. Tolerogenic adjuvants are molecules which mediate anti-inflammatory or immunoregulatory effects and enhance vaccine efficacy by modulating the immune environment to favor a tolerogenic immune response to the vaccine antigen. Tolerogenic adjuvants act through several mechanisms, including immunosuppression, modulation of cytokine signaling, vitamin signaling, and modulation of immunological synapse signaling. This review seeks to provide a comprehensive examination of tolerogenic adjuvants currently utilized in tolerogenic vaccines, describing their mechanism of action and examples of their use in human clinical trials and animal models of disease. [ABSTRACT FROM AUTHOR]

Immunogenic cell death (ICD) spatiotemporally regulates damage-associated molecular patterns (DAMPs) derived from dying cancer cells to signal the immune response. Intriguingly, these DAMPs and cytokines also induce cellular responses in non-immune cells, particularly cancer cells. Several ICD-modulating natural products and miRNAs have been reported to regulate the DAMP, cytokine, and cell death responses, but they lack systemic organization and connection. This review summarizes the impacts of natural products and miRNAs on the DAMP and cytokine responses and cancer cell death responses (apoptosis, autophagy, ferroptosis, necroptosis, and pyroptosis). We establish the rationale that ICD inducers of natural products have modulating effects on miRNAs, targeting DAMPs and cytokines for immune and cancer cell death responses. In conclusion, DAMP, cytokine, and cell death responses are intricately linked in cancer cells, and they are influenced by ICD-modulating natural products and miRNAs. [ABSTRACT FROM AUTHOR]

Vibrio parahaemolyticus is a significant pathogen affecting shrimp and crab farming, particularly strains carrying genes associated with acute hepatopancreatic necrosis syndrome. However, the immune response of Eriocheir sinensis to V. parahaemolyticus infection remains unclear. To address this knowledge gap, an experiment was conducted to establish a V. parahaemolyticus infection model. This model aimed to compare pathological damage and enzyme activity changes in E. sinensis hepatopancreas tissue at various infection time points, and to examine transcriptome changes in individuals exhibiting different clinical symptoms of infection. The results showed that intramuscular injection of 1.78 × 106 CFU/mL of V. parahaemolyticus for 24 hours resulted in a 50% mortality rate among the experimental animals. Pathological findings revealed that the infection led to a change in color of the hepatopancreas tissue from bright yellow to white, diffuse tissue cell distribution, and hepatopancreatic necrosis. Additionally, there was a significant increase in the activities of alanine aminotransferase and aspartate aminotransferase in the hepatopancreas (P < 0.01). Furthermore, the activities of superoxide dismutase, total antioxidant capacity, phenoloxidase, alkaline phosphatase, and acid phosphatase initially increased and then decreased. RNA-seq analysis revealed 11,662 differentially expressed genes compared to the susceptible group and control group, with 6,266 genes up-regulated and 5,396 genes down-regulated. When comparing the susceptible group to the disease-resistant group, 13,515 differentially expressed genes were identified, with 7,694 genes up-regulated and 5,821 genes down-regulated. Finally, comparison between the disease-resistant group and control group yielded 13,515 differentially expressed genes, with 7,631 genes up-regulated and 3,111 genes down-regulated. Differential gene enrichment analysis revealed pathways such as phagosomes, cancer pathways, proteoglycans in cancer, ribosomes, protein processing in the endoplasmic reticulum, starch and sucrose metabolism, and lysosome signaling pathways. Furthermore, 342 immune-related genes with differential expression were identified, primarily enriched in 22 pathways linked to cell signaling. These genes play a crucial role in defense against bacterial invasion and immune response regulation through various signaling pathways. Overall, this study provides valuable insights into the defense mechanisms and understanding of Chinese mitten crab immunity against bacterial infection by examining changes in mRNA, enzyme activity, and hepatopancreatic damage during infection. [ABSTRACT FROM AUTHOR]

Despite the tremendous advances that have been made in biomedical research, cancer remains one of the leading causes of death worldwide. Several therapeutic approaches have been suggested and applied to treat cancer with impressive results. Immunotherapy based on targeting immune checkpoint signaling pathways proved to be one of the most efficient. In this review article, we will focus on the recently discovered TNFα‐TNFR2 signaling pathway, which controls the immunological and pro‐angiogenic properties of many immunoregulatory and pro‐angiogenic cells such as endothelial progenitor cells (EPCs), mesenchymal stem cells (MSCs), and regulatory T cells (Tregs). Due to their biological properties, these cells can play a major role in cancer progression and metastasis. Therefore, we will discuss the advantages and disadvantages of an anti‐TNFR2 treatment that could carry two faces under one hood. It interrupts the immunosuppressive and pro‐angiogenic behaviors of the above‐mentioned cells and interferes with tumor growth and survival. [ABSTRACT FROM AUTHOR]

Objective: To explore the biological relationship between the regulatory signal pathways involved in differentially expressed genes and recurrent spontaneous abortion (RSA) by analyzing the gene expression microarray data of unexplained RSA. Methods: The gene expression profile data of chorionic villi from unexplained recurrent abortion with normal karyotype and selective induced abortion were compared. Differentially expressed genes were analyzed by the "Limma" package in R Studio, and Gene Ontology(GO) and Kyoto Encyclopedia of Genes and Genomes(KEGG) pathway enrichment analysis were carried out with "Cluster Profiler" and "org.hs.eg.db" packages. Finally, hub genes were identified through constructing the protein-protein interaction (PPI) network from the differentially expressed gene dataset in the STRING database. And the hub genes were verified by RT-PCR. The expression of TH1 and TH2 cytokines representing IL-2, IL-10 and their receptors related to hub gene immune regulation were detected by enzyme-linked immunosorbent assay (ELISA) and western blot (WB), respectively. Results: A total of 295 differentially expressed genes were identified in the dataset GSE22490, with a significance level of P < 0.05 and an absolute log-fold change > 1.0, which included 166 up-regulated genes and 129 down-regulated genes. Go and KEGG enrichment analysis of these differentially expressed genes (P < 0.05,FDR < 0.05) revealed significant involvement in the regulation of inflammatory and immune responses. The PPI analysis revealed that the hub genes FCGR3A, TLR2, BTK, CLEC7A and CD163 were centrally located in the network cluster which were composed of the proteins encoded by differentially expressed genes associated with RSA. The mRNA levels of FCGR3A, TLR2 and CLEC7A in the RSA group were significantly higher than those in the NC group (P < 0.05). The protein expression level of TLR2 was also significantly increased in the RSA group (P < 0.05). The level of IL-2 in the RSA group was significantly higher than that in the NC group (P < 0.05), while the protein expression level of its receptor was not different(P > 0.05). There was no significant difference in the expression levels of IL-10 and its receptor between the two groups (P > 0.05). Conclusion: Abnormal immune response plays an important role in unexplained RSA. The imbalance in immune regulation may be one of the most important reasons behind this phenomenon. These findings provide a foundation for further research into the mechanisms underlying RSA. [ABSTRACT FROM AUTHOR]

Despite the progress in conventional treatments for head and neck squamous cell carcinoma (HNSCC), the 5-year survival rate remains below 70%. Enhancing immunotherapy outcomes through personalized treatment strategies, particularly by identifying immune-related biomarkers, is critical. The ASXL family are associated with malignancies, but their relationship with HNSCC has not been elucidated. In this study, we found that high expression of ASXL2 is associated with better prognosis in HNSCC patients. Analysis revealed a significant positive correlation between ASXL2 and immune infiltration. Functional analysis suggests that ASXL2 co-expressed genes in HNSCC patients are enriched in the JAK-STAT signaling pathway, and patients with high expression show an even greater enrichment in T cell and B cell receptor signaling pathways. Utilizing the NPC single-cell dataset, ASXL2's widespread expression in the tumor microenvironment was confirmed, and its co-expressed genes were found to be highly associated with immune cell function. Experimental validation showed a correlation between ASXL2 expression and T cell secretion of interferon-γ (IFNγ), confirming that high ASXL2 expression facilitates T cell activation. Overall, our findings underscore the important role of ASXL2 in immune activation, suggesting its potential as a promising biomarker for tailoring immunotherapy strategies in HNSCC patients. [ABSTRACT FROM AUTHOR]

The cytokine homologs, particularly transforming growth factor (TGF)-β, is a crucial immunomodulatory molecule and involved in growth and developmental processes in several helminths. In this study, the basic properties and functions of T. spiralis TGF-β homolog 2 (TsTGH2) were characterized using bioinformatics and molecular biology approaches. Bioinformatics analyses indicated that TsTGH2 belongs to the TGF-β subfamily. Recombinant TsTGH2 (rTsTGH2) expressed in Escherichia coli was used to produce a polyclonal antibody (pAb) in mice. Western blot and immunolocalization using pAb detected native TsTGH2 in crude worm antigens from muscle larvae and adults, showing it was mainly localized in the body wall muscles and the epithelia of the ovary and uterus. To assess the interplay between TsTGH2 and the human TGF-β signaling pathway, rTsTGH2 produced in a HEK293T cell was incubated with the SBE luciferase-HEK293 cell. The result indicated a significant increase in luciferase activity after treatment with rTsTGH2 compared to untreated control (p < 0.05). In conclusion, these findings are the first to characterize the basic properties and functions of TGF-β homologs in T. spiralis, demonstrating their interaction with the human TGF-β receptor. Further investigation is required to identify and optimize an appropriate expression system or conditions for TsTGH2. Additionally, studies are needed to clarify the specific role of native TsTGH2 in parasite development and host immunomodulation. [ABSTRACT FROM AUTHOR]

PEDV is a highly contagious enteric pathogen that can cause severe diarrhea and death in neonatal pigs. Despite extensive research, the molecular mechanisms of host's response to PEDV infection remain unclear. In this study, differentially expressed genes (DEGs), time-specific coexpression modules, and key regulatory genes associated with PEDV infection were identified. The analysis revealed 2,275, 1,492, and 3,409 DEGs in infected vs. mock-treated pigs at 12 h, 24 h, and 48 h, respectively. Time series analysis revealed that the upregulated genes were involved mainly in antiviral pathways such as the viral defense response and the regulation of immune system processes. Protein–protein interaction network analysis identified the top 20 core genes in the interaction network, which included six upregulated genes (TFRC, SUOX, RMI1, CD74, IFIH1, and CD86) and 14 downregulated genes (FOS, CDC6, CDCA3, PIK3R2, TUFM, VARS, ASF1B, POLD1, MCM8, POLA1, CDC45, BCS1L, RAD51, and RPA2). In addition, GSEA enrichment analysis revealed that pathways such as DNA replication and homologous recombination involving RAD51, CDC6, and RPA2 were significantly inhibited during viral infection. Our findings not only reveal dynamic changes in the transcriptome profile of PEDV-infected IPEC-J2 cells but also provide novel insights into the mechanism of PEDV infection of the host. [ABSTRACT FROM AUTHOR]

Immunosenescence, the slow degradation of immune function over time that is a hallmark and driver of aging, makes older people much more likely to be killed by common infections (such as flu) than young adults, but it also contributes greatly to rates of chronic inflammation in later life. Such micro nutrients are crucial for modulating effective immune responses and their deficiencies have been associated with dysfunctional immunity in the elderly. In this review, we specifically focused on the contribution of major micro nutrients (Vitamins A, D and E, Vitamin C; Zinc and Selenium) as immunomodulators in ageing population especially related to inflame-ageing process including autoimmunity. This review will cover these hologenomic interactions, including how micro nutrients can modulate immune cell function and/or cytokine production to benefit their hosts with healthy mucous-associated immunity along with a sustainable immunologic homeostasis. For example, it points out the modulatory effects of vitamin D on both innate and adaptive immunity, with a specific focus on its ability to suppress pro-inflammatory cytokines synthesis while enhancing regulatory T-cell function. In the same context, also zinc is described as important nutrient for thymic function and T-cell differentiation but exhibits immunomodulatory functions by decreasing inflammation. In addition, the review will go over how micro nutrient deficiencies increase systemic chronic low-grade inflammation and, inflammaging as well as actually enhance autoimmune pathologies in old age. It assesses the potential role of additional targeted nutritional supplementation with micro nutrients to counteract these effects, promoting wider immune resilience in older adults. This review collates the current evidence and highlights the role of adequate micro nutrient intake on inflammation and autoimmunity during ageing, providing plausible origins for nutritional interventions to promote healthy immune aging. [ABSTRACT FROM AUTHOR]

The cGAS-STING signaling pathway is a critical component of the innate immune response, playing a significant role in various diseases. As a central element of this pathway, STING responds to both endogenous and exogenous DNA stimuli, triggering the production of interferons and pro-inflammatory cytokines to enhance immune defenses against tumors and pathogens. However, dysregulated activation of the STING pathway is implicated in the pathogenesis of multiple diseases, including autoinflammation, viral infections, and cancer. Traditional Chinese Medicines (TCMs), which have a long history of use, have been associated with positive effects in disease prevention and treatment. TCM formulations (e.g., Lingguizhugan Decoction, Yi-Shen-Xie-Zhuo formula) and active compounds (e.g., Glabridin, Ginsenoside Rd) can modulate the cGAS-STING signaling pathway, thereby influencing the progression of inflammatory, infectious, or oncological diseases. This review explores the mechanisms by which TCMs interact with the cGAS-STING pathway to regulate immunity, focusing on their roles in infectious diseases, malignancies, and autoimmune disorders. [ABSTRACT FROM AUTHOR]

Introduction: The abscopal effect, a systemic anti-tumor response triggered by localized treatment, has gained attention but remains poorly understood. This study evaluates the efficacy and consistency of focused ultrasound (FUS) combined with immunotherapy in inducing the abscopal effect. Methods: A systematic review and meta-analysis were conducted on preclinical studies using solid tumor models. Data on tumor response, immune modulation, and survival outcomes were analyzed to assess the combination therapy's effectiveness. Results: FUS combined with immunotherapy enhanced anti-tumor responses at local and distant sites, with evidence of immune activation and increased abscopal effect rates. However, heterogeneity across tumor models and protocols was observed. Discussion: The findings provide a theoretical basis for FUS-immunotherapy combinations in cancer treatment, while emphasizing the need for standardized protocols and further research to elucidate underlying mechanisms. Systematic review registration: https://www.crd.york.ac.uk/prospero/ , identifier CRD42023460710. [ABSTRACT FROM AUTHOR]

RIN4 is a crucial regulator of plant immunity, playing a role in both PAMP-triggered immunity (PTI) and effector-triggered immunity (ETI). While the impact of post-translational modifications (PTMs) on RIN4 has been extensively studied, their specific effects on plant immune response regulation and the underlying mechanisms have remained unclear. In this study, we investigated the phosphorylation of RIN4 at threonine-166 (RIN4T166) in Arabidopsis transgenic lines expressing various RIN4 variants. Our pathological and molecular genetic analyses reveal that RIN4T166 phosphorylation disrupts its localization to the plasma membrane (PM) and represses plant defense activation. We found that RIN4's PM tethering relies on Exo70B1-mediated exocytosis and the integrity of the host cytoskeletal actin network. Phosphorylation at RIN4T166 disrupts its PM localization due to reduced binding affinity with Exo70B1. This disruption was further evidenced by the 35S::RIN4T166D/rin124 transgenic line, which exhibited suppressed PTI responses similar to the exo70b1 mutant. Our findings demonstrate that RIN4's subcellular localization is regulated by phosphorylation, suggesting that plants use a sophisticated network of signaling processes to precisely control the timing and localization of immune signaling activation. This study uncovers a mechanism by which PTI is repressed through RIN4 phosphorylation, providing new insights into the spatial regulation of RIN4 within plant immune signaling pathways. [ABSTRACT FROM AUTHOR]

The northern snakehead (Channa argus) is a valuable aquaculture species across certain Asian countries, contributing significantly to economic prosperity and dietary needs. However, its productivity faces significant challenges, particularly from diseases such as nocardiosis, caused by Nocardia seriolae. To date, the majority of research efforts have focused on describing the observed phenomena related to N. seriolae infection. However, there remains a notable gap in knowledge concerning the infectivity of N. seriolae and the immune response it elicits. To better understand the modulation of the immune responses to N. seriolae infection in snakeheads, we investigated the splenic proteome profiles. Specifically, we compared the profiles between uninfected northern snakehead specimens and those infected with N. seriolae at 96 h using the label-free data-independent acquisition methodology. A total of 700 differentially expressed proteins (DEPs) were obtained. Of these, 353 proteins exhibited upregulation, whereas 347 proteins displayed downregulation after the infection. The DEPs were mapped to the reference canonical pathways in Kyoto Encyclopedia of Genes and Genomes database, revealing several crucial pathways that were activated following N. seriolae infection. Noteworthy, among these were pathways such as ferroptosis, complement and coagulation cascades, chemokine signaling, tuberculosis, natural killer cell-mediated cytotoxicity, and Th17 cell differentiation. Furthermore, protein–protein interaction networks were constructed to elucidate the interplay between immune-related DEPs. These results revealed expression changes in multiple signaling pathways during the initial colonization phase of N. seriolae. This discovery offers novel insights into the infection mechanisms and host interaction dynamics associated with N. seriolae. [ABSTRACT FROM AUTHOR]

Background: Fascioliasis is a zoonotic parasitic disease caused by Fasciola hepatica and Fasciola gigantica, which poses a serious threat to global public health and livestock farming. Fasciola gigantica secretes and excretes various components to manipulate the immune response, thereby enhancing its invasion, migration, and survival in vivo. However, the roles of specific components in immune modulation, such as asparagine endopeptidase, remain unknown. Methods: The transcriptional abundance of members of the asparagine endopeptidase family (also known as the legumain family) from F. gigantica was analyzed. Two highly transcribed asparagine endopeptidases in metacercariae, juveniles and adults were cloned, and their recombinant proteins—recombinant F. gigantica legumain (rFgLGMN-1) and (rFgLGMN-2)—were expressed in prokaryotic expression system. Their regulatory effects on buffalo peripheral blood mononuclear cells (PBMCs), including proliferation, migration, total nitric oxide (NO) production, cytokine secretion, and phagocytosis were explored in vitro. Results: Ten members of the legumain family were detected in F. gigantica, among of which FgLGMN-1 and FgLGMN-2 exhibited high transcription levels in juveniles and adults. The isolation of sequences indicated that FgLGMN-1 encodes 409 amino acids, while FgLGMN-2 encodes 403 amino acids. Both recombinant FgLGMN-1 (rFgLGMN-1) and rFgLGMN-2 were recognized by serum from buffaloes infected with F. gigantica. Both rFgLGMN-1 and rFgLGMN-2 inhibited the proliferation of PBMCs, and rFgLGMN-1 also inhibited the migration of PBMCs. While rFgLGMN-1 increased the production of total NO, rFgLGMN-2 decreased NO production. Both rFgLGMN-1 and rFgLGMN-2 increased the transcription of the cytokines interleukin-10 and transforming growth factor β. The effect of rFgLGMN-1 and rFgLGMN-2 on the phagocytosis of PBMCs varied depending on their concentrations. Conclusions: rFgLGMN-1 and rFgLGMN-2 modulate several cellular and immunological functions of PBMCs, and exhibited distinct regulatory effects on these in vitro, which indicated that they may play roles in immune modulation and facilitate fluke development. However, due to uncertainties associated with in vitro experiments, further studies are necessary to elucidate the precise functions of these legumains. [ABSTRACT FROM AUTHOR]

ENPP1/CD203a is a membrane-bound ectonucleotidase capable of hydrolyzing ATP, cGAMP and other substrates. Its enzymatic activity plays an important role in the balance of extracellular adenine nucleotides and the modulation of purinergic signaling, in soft tissue calcification, and in the regulation of the cGAS/STING pathway. However, a detailed analysis of ENPP1 surface expression on human immune cells has not been performed. Here, we selected VHH domains from human ENPP1-immunized alpacas to generate heavy-chain antibodies targeting ENPP1, and analyzed cell surface expression on all circulating immune cell subsets using flow cytometry. We find high expression of ENPP1 in CD141high conventional dendritic cells (cDC1), while ENPP1 was not detectable on other dendritic cells and monocytes. In the lymphocytic compartment, only CD56bright natural killer cells and mucosal-associated invariant T cells (MAIT) express ENPP1. In contrast, all other T cell subpopulations, CD56dim natural killer cells and B lymphocytes do not or only minimally express ENPP1. In summary, we describe highly cell type-specific expression of ENPP1 in the immune system using a newly generated heavy-chain antibody. This reagent will help to decipher the function of ENPP1 in the regulation of the immune response, allow a quick identification of ENPP1-deficiency and of ENPP1-positive tumors, and constitutes the basis for targeted anti-tumor intervention. [ABSTRACT FROM AUTHOR]

Background: Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is a rare single-gene X-linked immunodeficiency disease caused by mutations in the forkhead box protein 3 (FOXP3) gene. The typical clinical manifestations of IPEX mainly include severe atopic dermatitis, insulin-dependent type 1 diabetes mellitus, and intractable diarrhea. Case presentation: Here, we report a boy with intractable diarrhea diagnosed with early-onset IPEX syndrome due to the c.434C > T (p.Ala145Val) mutation in exon 4 of the FOXP3 gene. The patient experienced intractable diarrhea and severe weight loss, and his clinical symptoms could not be alleviated by conventional supportive and anti-infection treatment. Sirolimus, an immunosuppressant, preferentially inhibits effector T cells while allowing the proliferation of Tregs and is used to treat IPEX patients and alleviate intractable diarrhea. Conclusion: We reviewed the literature on the use of sirolimus for the treatment of IPEX syndrome over the past two decades. [ABSTRACT FROM AUTHOR]

Autoimmune diseases, characterized by the immune system's attack on the body's own tissues, affect millions of people worldwide. Current treatments, which primarily rely on broad immunosuppression and symptom management, are often associated with significant adverse effects and necessitate lifelong therapy. This review explores the next generation of therapies for immune-mediated diseases, including chimeric antigen receptor (CAR) T cell and regulatory T cell (Treg)-based approaches, which offer the prospect of targeted, durable disease remission. Notably, we highlight the emergence of CD19-targeted CAR T cell therapies, and their ability to drive sustained remission in B cell-mediated autoimmune diseases, suggesting a possible paradigm shift. Further, we discuss the therapeutic potential of Type 1 and FOXP3+ Treg and CAR-Treg cells, which aim to achieve localized immune modulation by targeting their activity to specific tissues or cell types, thereby minimizing the risk of generalized immunosuppression. By examining the latest advances in this rapidly evolving field, we underscore the potential of these innovative cell therapies to address the unmet need for long-term remission and potential tolerance induction in individuals with autoimmune and immune-mediated diseases. [ABSTRACT FROM AUTHOR]

Herpes simplex virus type 2 (HSV-2) and helminth infections are among the most widespread infectious diseases in sub-Saharan Africa (SSA). Helminths are known to modulate host immune responses and consequently impact the severity and outcomes of unrelated diseases, including allergies, autoimmune conditions, and infectious diseases. In this way, helminths may modulate essential immune responses against HSV-2 during co-infection and may alter susceptibility to and pathology of HSV-2. However, the epidemiology of STH/HSV-2 co-infections is understudied, and whether helminths influence the host immune response to HSV-2 is not well understood. In this perspective piece, we briefly examine the current knowledge on helminth immune modulation of important pathogens that are endemic to SSA, arguing that it is important to explore HSV-2 and helminth co-infections to elucidate potential interactions between HSV-2 and helminths. This is particularly relevant in SSA, where both pathogens are highly prevalent. [ABSTRACT FROM AUTHOR]

Interleukin-6 (IL-6) expression in mesenchymal stem cells (MSCs) has been shown to play a pivotal role in modulating cartilage regeneration and immune responses, particularly in the context of diseases that involve both degenerative processes and inflammation, such as osteoarthritis (OA). However, the precise mechanism through which IL-6 and other immune-regulatory factors influence the therapeutic efficacy of autologous adipose-derived stem cells (ASCs) transplantation in OA treatment remains to be fully elucidated. This study aims to investigate the relationship between IL-6 expression in autologous ASCs isolated from OA patients and their impact on immune modulation, particularly focusing on the regulation of Receptor Activator of Nuclear factor Kappa-Β Ligand (RANKL), a key mediator of immune-driven cartilage degradation in OA. Autologous ASCs were isolated from the stromal vascular fraction (SVF) of adipose tissue obtained from 22 OA patients. The isolated ASCs were cultured and characterized using reverse transcription polymerase chain reaction (RT-PCR), enzyme-linked immunosorbent assay (ELISA), and flow cytometry to the phenotype and immune regulatory factors of MSCs. Based on IL-6 expression levels, ASCs were divided into high and low IL-6 expression groups. These groups were then co-cultured with activated peripheral blood mononuclear cells (PBMCs) to evaluate their immune-modulatory capacity, including the induction of regulatory T cells, inhibition of immune cell proliferation, and regulation of key cytokines, such as interferon-gamma (IFN-γ). Additionally, RANKL expression, a critical factor in osteoclastogenesis and cartilage degradation, was assessed in both ASC groups. High IL-6-expressing ASCs demonstrated a significantly greater capacity to inhibit immune cell proliferation and IFN-γ production compared to their low IL-6-expressing counterparts under co-culture conditions. Moreover, the group of ASCs with high IL-6 expression showed a marked reduction in RANKL expression, suggesting enhanced potential to control osteoclast activity and subsequent cartilage defect in OA. Conclusion: Autologous ASCs with elevated IL-6 expression exhibit enhanced immunomodulatory properties, particularly in regulating over-activated immune response and reducing osteoclastogenesis through RANKL suppression. These findings indicate that selecting ASCs based on IL-6 expression could enhance the therapeutic efficacy of ASC-based treatments for OA by mitigating immune-driven joint inflammation and cartilage degradation, potentially slowing disease progression. [ABSTRACT FROM AUTHOR]