International immunology最新文献

Studies have been exploring the connection between the intake of vitamins and the development of food allergy, with a particular focus on folic acid (FA). However, the impact of FA supplementation on food allergy remains a subject of debate. In the present study, the anti-allergic properties of FA and its possible mechanism of action were investigated. In a Brown Norway rat food allergy model, we found that FA downregulated the expression of specific antibodies, while influencing the Th1/Th2 balance. Furthermore, FA was found to reduce the release of particulate matter such as histamine and mast cell proteinase. Transcriptomic analysis provided evidence that FA intervention could reverse gene expression changes induced by food allergies. The gene Hsp90, responsible for producing heat shock proteins (HSP), emerged as a potential key gene involved in the process. In vitro RBL-2H3 cell-based assays suggested that FA might affect HSP90 expression through the glucocorticoid receptor (GR), leading to a reduction in effector cell degranulation. Overall, the results of this study indicate that FA has an alleviating effect on food allergies, with high doses of FA exhibiting more pronounced effects. Moreover, FA's impact on HSP90 expression through GR seems to contribute to a decrease in degranulation during the effector phase.

This review presents an overview of the emerging roles of epigenomic regulation in immune cell function, with a particular focus on its relevance in inflammatory bowel diseases (IBD). Epigenetic mechanisms, including DNA methylation, histone modification, chromatin remodeling, and non-coding RNAs, are essential in directing immune cell development, activation, and lineage commitment. Advances in genomics and epigenomics have highlighted the dynamic nature of gene regulation as the cornerstone of immune homeostasis and adaptability. We summarize recent insights into enhancer dynamics, three-dimensional chromatin architecture, transcription factor signaling, and microRNA (miRNA)-mediated regulation that reshape our understanding of immune-mediated diseases. These findings not only deepen our knowledge of disease pathogenesis but also offer promising targets for therapeutic intervention. In this context, miRNAs have emerged as key post-transcriptional regulators with significant diagnostic and therapeutic potential for IBD. The field of immune epigenomics is advancing rapidly, offering powerful tools for dissecting complex immune responses and guiding the development of precise therapies for chronic inflammatory conditions.

Intracellular bacteria can survive in vivo, evading host immunity and antibiotics. Salmonella persists in organs such as spleen by invading in the phagocytic cells. However, it remains controversial which specific cell populations, e.g., macrophages, monocytes, neutrophils or dendritic cells, harbor the bacteria during persistent infection. To address this question, we employed a persistent infection mouse model using attenuated Salmonella expressing an acid tolerant fluorescent protein. We found that the bacteria predominantly resided in monocytes. Although these cells expressed Ly-6G, a typical marker for neutrophils, they did not exhibit a polymorphonuclear morphology. Furthermore, Salmonella primarily and preferentially invaded monocytes over other phagocytic cell types. Importantly, Salmonella was able to survive in monocytes even in the presence of antibiotics. Our findings demonstrate that monocytes serve as a critical survival niche for Salmonella in vivo, allowing the bacteria to evade both host immunity and antibiotics.

In early life, the immune and nervous systems are highly plastic and engage in complex, bidirectional communication that is critical for establishing postnatal immune tolerance, gut and brain development, and responses to environmental challenges. The developing gut microbiota exerts its influence on both systems via microbial metabolites to modulate immune responses and neural function. Early disruptions in the gut microbiota, in part due to preterm delivery or antibiotic treatment, are linked to long-term immune or neurodevelopmental impairments. In this review, we provide an overview of the current understanding how the microbiota crosstalk with immune cells regulates in the development and function of the nervous system.

Recent outbreaks of the ZIKA virus (ZIKV) in Brazil and Puerto Rico have been linked to an increase in the incidence of fetal microcephaly and Guillain-Barre syndrome. In addition, although a causal relationship remains unproven, ZIKV has been found in the brains of multiple sclerosis (MS) patients, prompting interest in a possible link. The present study aimed to elucidate the role of ZIKV in the pathogenesis of MS. ZIKV-infected mice with experimental autoimmune encephalomyelitis (EAE) exhibited aggravated EAE symptoms with significant demyelination of the central nervous system (CNS). Moreover, ZIKV infection promoted pathogenic T cell infiltration into the CNS by enhancing the expression of chemokines for C-C motif chemokine receptor 2 (CCR2) in astrocytes, which was dependent on TRAF6 signaling. Propagermanium, a CCR2 inhibitor, prevented ZIKV-induced exacerbation of EAE in mice. These findings highlight the critical role of TRAF6 signaling in the progression of neurological disorders caused by ZIKV infection.

Autoimmune sialadenitis is a hallmark of IgG4-related disease (IgG4-RD) and Sjögren syndrome (SS). The single-stranded RNA sensor TLR7 has been shown as a driver of sialadenitis. Although TLR7 is activated by ssRNA degradation products such as nucleosides and oligoribonucleotides, the role of these ligands in sialadenitis development remains unclear. Here, we demonstrate that lysosomal accumulation of endogenous nucleosides is sufficient to drive autoimmune sialadenitis. Loss-of-function genetic variations in the nucleoside transporter SLC29A3 cause lysosomal nucleoside accumulation, leading to constitutive activation of TLR7 and TLR8 in monocytes and macrophages. Consequently, macrophages infiltrate multiple organs in mice and humans. In Slc29a3‒/‒ mice, submandibular glands (SMGs) were impaired in saliva production. SLC29A3-deficiency specifically damaged Aqp5+ acinar and intercalated duct cells in SMGs, while sparing neighboring cells such as ductal and myoepithelial cells. Although macrophages accumulated in both the spleen and SMGs, lymphocyte infiltration and production of chemokines including CXCL9, CXCL13, and CCL5 occurred selectively in SMGs. In IgG4-RD patients, these chemokines were also produced in SMGs, highlighting parallels between sialadenitis in Slc29a3‒/‒ mice and IgG4-RD. These findings indicate that constitutive TLR7 activation by nucleosides is a key mechanism driving autoimmune sialadenitis.

Humanized mice are invaluable models for investigating human cell engraftment in vivo post-transplantation. Mice engrafted with human red blood cells (hRBCs) are useful for examining the physiological roles of hRBCs in vivo, including studies on blood disorders, immune responses, and transfusion-related research. These models hold promise for malaria infection studies and vaccine development. However, engrafted hRBCs in vivo in immunodeficient mice presents challenges that must be addressed to establish effective in vivo models. In this study, we explored the rejection mechanisms of hRBCs in immunodeficient NOD/Shi-scid-IL2rγnull (NOG) mice and developed a novel model for long-term RBC engraftment. We observed rapid depletion of fluorescent-labeled hRBCs in the liver, but not in other organs, of NOG mice, with Gr-1midCD68+ mouse macrophages play a significant role in the elimination of hRBCs in the liver. To counteract this, we created thymidine kinase (TK) transgenic (Tg) mice under the human CD68 promoter (NOG-pCD68-TK Tg), which, upon administration of valganciclovir (VGCV), led to the successful depletion of macrophages. Consequently, hRBCs showed significantly prolonged engraftment in NOG-pCD68-TK Tg mice compared to non-Tg mice following macrophage depletion, maintaining engraftment for up to 14 days post-transplantation. This study elucidates the erythrophagocytosis mechanisms of hRBCs in mice and establishes NOG-pCD68-TK Tg mice as a valuable model for the long-term engraftment of hRBCs, potentially advancing in vivo hRBC research.

CD4+ helper T (Th) cell subsets play an essential role in the regulation of adaptive immunity. Th9, Th17, and regulatory T (Treg) cells require transforming growth factor-beta (TGF-β) for their differentiation; however, their respective functions are highly distinct. Recent studies have highlighted the critical role of cellular metabolism in initiating clonal expansion and facilitating the effector differentiation of Th cells. Upon antigen exposure, naïve CD4+ T cells undergo metabolic reprogramming to fulfill their bioenergetic and biosynthetic demands. This process involves a shift from fatty acid oxidation to glycolysis, which ensures a sufficient energy supply for activation and proliferation. Lipid metabolism plays a pivotal role in modulating the differentiation and function of Th17, Treg, and Th9 cells. This review explores the influence of metabolic pathways on key transcription factors, including retinoic-acid-related orphan receptor gamma t (RORγt) and SMADs, and emphasizes their regulatory roles in Th cell differentiation. Furthermore, it discusses emerging therapeutic strategies aimed at targeting cellular metabolism to address autoimmune and inflammatory diseases associated with these T-cell subsets.

Tolerogenic adjuvants can enhance allergy vaccine efficacy. We previously showed that intranasal administration of recombinant Toxoplasma gondii serine protease inhibitor 1 (rTgPI-1) with ovalbumin alleviates asthma symptoms in mice. This study investigates the immunomodulatory mechanisms of rTgPI-1, focusing on its effect on dendritic cells (DCs). Bone marrow-derived DCs (BMDCs) were generated in the presence of rTgPI-1 and analyzed for their phenotype. rTgPI-1 exposed BMDCs showed reduced CD80, CD86, and MHCII, increased PDL-1 and CD45Rb, and a higher IL-10/IL-12 ratio. These BMDCs induced fewer CD69⁺CD4⁺ T cells, decreased proliferation and secretion of IL-17 and IL-4, and increased CD4⁺FoxP3⁺ T cells. In vivo, intranasal co-administration of rTgPI-1 with allergen in asthmatic mice reduced CD80high/CD86high DCs, expanded lung CD4⁺FoxP3⁺ regulatory T cells, and decreased the cDC2 subset, correlating with reduced IL-4 levels. Importantly, nafamostat mesylate-a synthetic serine protease inhibitor previously shown to alleviate asthma symptoms-failed to induce FoxP3⁺ T cells both in vitro and in vivo, underscoring the unique tolerogenic activity of rTgPI-1. Finally, stimulation of peripheral blood mononuclear cells from mite-allergic patients with house dust mite extract in the presence of rTgPI-1 led to reduced allergen-specific IL-4 and IL-5 secretion. These findings demonstrate that rTgPI-1 promotes a semimature, tolerogenic DC phenotype, suppresses T cell activation, and fosters regulatory T cell differentiation. Moreover, rTgPI-1 selectively modulates DC subsets in vivo. The observed effects on patient-derived PBMCs support its potential for further preclinical development as an adjuvant for allergen-specific immunotherapy.

Talin protein as a mechanosensitive cytoskeleton protein connects the extracellular matrix to the cytoskeleton by linking to integrins and actin, thereby mediating the conversion of mechanical signals into biochemical signals and influencing disease progression. The biological significance of Talin2 in asthma is not well understood. The aim of this study was to elucidate the role of Talin2 in asthma. Mice sensitized and challenged with ovalbumin (OVA) or saline and MRC-5 cells were used to investigate the role of Talin2 in the pathogenesis of bronchial asthma. In addition, Talin2 levels were measured in the plasma of control subjects and asthmatic patients. The relationships between Talin2 and clinical variables in asthmatic patients were also examined. Plasma Talin2 levels were higher in asthmatic patients than control subjects. In asthmatic patients, Talin2 levels correlated with FEV1 % pred., FVC % pred., and FEV1/FVC, and the blood neutrophils and lymphocyte proportion. The receiver operating characteristic curves for Talin2 levels differed between control subjects and asthmatic patients. Talin2, Kindlin2, Integrin β1 and F-actin levels were significantly increased in MRC-5 cells exposed to Der p 1, but decreased in MRC-5 cells treated with talin2 siRNA. The BALF and serum levels of cytokines (IL-4, IL-5, and TNF-α) were elevated in OVA mice compared to the control mice. Talin2, Kindlin2, Integrin β1, and F-actin protein expression in lung tissue was significantly higher in OVA mice than control mice. These results suggest that Talin2 be involved in the pathogenesis of asthma, and may be a marker for asthma.