Pub Date : 2025-07-30DOI: 10.1038/s41435-025-00349-z
Wared Nour-Eldine, Samia M. Ltaief, Khalid Ouararhni, Nimshitha P. Abdul Manaph, Alberto de la Fuente, Ilham Bensmail, Houari B. Abdesselem, Abeer R. Al-Shammari
Peripheral immune dysregulation is frequently reported in autism spectrum disorder (ASD); however, the underlying molecular mechanisms remain unclear. We recruited a well-defined cohort of young Arab children with ASD, aged 2–4 years, along with matched controls in Qatar. Using a multimodal approach, we integrated transcriptomic, proteomic, and single-cell RNA-seq data analyses from this cohort. Targeted transcriptomic profiling identified differential expression of 50 immune-related genes in the circulating PBMCs of children with ASD, three of which (JAK3, CUL2, and CARD11) negatively correlated with ASD symptom severity. These gene signatures were validated in independent studies using blood and brain tissues from individuals with ASD. Enrichment analysis revealed involvement of these genes in immune function, particularly through TNF signaling pathway. Proteomic analysis highlighted disrupted TNF signaling and upregulated levels of TNFSF10 (TRAIL), TNFSF11 (RANKL), and TNFSF12 (TWEAK) in plasma of individuals with ASD. Single-cell RNA-seq revealed that B cells, CD4 T cells, and NK cells potentially contributed to these upregulations in ASD. Dysregulated TRAIL, RANKL, and TWEAK signaling pathways were specifically observed in CD8 T cells, CD4 T cells, and NK cells of individuals with ASD. These findings provide new insights into immune dysregulation mechanisms in ASD and highlight potential therapeutic targets.
{"title":"A multi-omics approach reveals dysregulated TNF-related signaling pathways in circulating NK and T cell subsets of young children with autism","authors":"Wared Nour-Eldine, Samia M. Ltaief, Khalid Ouararhni, Nimshitha P. Abdul Manaph, Alberto de la Fuente, Ilham Bensmail, Houari B. Abdesselem, Abeer R. Al-Shammari","doi":"10.1038/s41435-025-00349-z","DOIUrl":"10.1038/s41435-025-00349-z","url":null,"abstract":"Peripheral immune dysregulation is frequently reported in autism spectrum disorder (ASD); however, the underlying molecular mechanisms remain unclear. We recruited a well-defined cohort of young Arab children with ASD, aged 2–4 years, along with matched controls in Qatar. Using a multimodal approach, we integrated transcriptomic, proteomic, and single-cell RNA-seq data analyses from this cohort. Targeted transcriptomic profiling identified differential expression of 50 immune-related genes in the circulating PBMCs of children with ASD, three of which (JAK3, CUL2, and CARD11) negatively correlated with ASD symptom severity. These gene signatures were validated in independent studies using blood and brain tissues from individuals with ASD. Enrichment analysis revealed involvement of these genes in immune function, particularly through TNF signaling pathway. Proteomic analysis highlighted disrupted TNF signaling and upregulated levels of TNFSF10 (TRAIL), TNFSF11 (RANKL), and TNFSF12 (TWEAK) in plasma of individuals with ASD. Single-cell RNA-seq revealed that B cells, CD4 T cells, and NK cells potentially contributed to these upregulations in ASD. Dysregulated TRAIL, RANKL, and TWEAK signaling pathways were specifically observed in CD8 T cells, CD4 T cells, and NK cells of individuals with ASD. These findings provide new insights into immune dysregulation mechanisms in ASD and highlight potential therapeutic targets.","PeriodicalId":12691,"journal":{"name":"Genes and immunity","volume":"26 5","pages":"462-474"},"PeriodicalIF":4.5,"publicationDate":"2025-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41435-025-00349-z.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144753199","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-07-28DOI: 10.1038/s41435-025-00346-2
Si Shen, Ran Sun, Tian Wang, Danfang Zhang, Na Che, Xiao Wang, Nan Zhao
Tertiary lymphoid structures (TLSs) are essential for promoting immune responses against tumours. However, the impact of TLS score and its maturation stage on the prognosis of colorectal cancer (CRC) patients has not yet been clarified. The aim of this study was to investigate the relationship between TLS score and its maturation stage and CRC prognosis through a retrospective study. In this study, firstly, high TLS score (≥0.752) was found to be a favourable prognostic factor for the survival of CRC patients using the TCGA database (HR = 0.381, 95% CI = 0.222 ~ 0.656). Secondly, CCL19, CCL21, and CXCL13 were found to be differential genes in the high and low TLS score groups in combination with several databases, and their main function was to chemotaxis TLS maturation. Subsequently, immunohistochemical staining was used to clarify the stage of TLS maturation in 76 clinical samples and to investigate its impact on patients’ survival prognosis. Finally, the validation of TNFRSF17 gene function was completed by cellular experiments. Analysis of the clinical samples showed that patients with higher early TLS (E-TLS) density had shorter survival than those with lower density (P = 0.016). High E-TLS density may be an independent risk factor for CRC (HR = 6.40, 95% CI = 1.82 ~ 22.55). However, the density of secondary follicular-like TLS did not show a significant prognostic effect in this study. In conclusion, patients with high TLS scores had longer survival, higher expression of immune checkpoint genes, and higher expression of TNFRSF17, which promotes T-cell infiltration and adhesion, but highly aggregated E-TLS may hamper patients’ survival prognosis.
{"title":"Impact of tertiary lymphoid structure scores and their stage of maturation on prognosis of colorectal cancer patients","authors":"Si Shen, Ran Sun, Tian Wang, Danfang Zhang, Na Che, Xiao Wang, Nan Zhao","doi":"10.1038/s41435-025-00346-2","DOIUrl":"10.1038/s41435-025-00346-2","url":null,"abstract":"Tertiary lymphoid structures (TLSs) are essential for promoting immune responses against tumours. However, the impact of TLS score and its maturation stage on the prognosis of colorectal cancer (CRC) patients has not yet been clarified. The aim of this study was to investigate the relationship between TLS score and its maturation stage and CRC prognosis through a retrospective study. In this study, firstly, high TLS score (≥0.752) was found to be a favourable prognostic factor for the survival of CRC patients using the TCGA database (HR = 0.381, 95% CI = 0.222 ~ 0.656). Secondly, CCL19, CCL21, and CXCL13 were found to be differential genes in the high and low TLS score groups in combination with several databases, and their main function was to chemotaxis TLS maturation. Subsequently, immunohistochemical staining was used to clarify the stage of TLS maturation in 76 clinical samples and to investigate its impact on patients’ survival prognosis. Finally, the validation of TNFRSF17 gene function was completed by cellular experiments. Analysis of the clinical samples showed that patients with higher early TLS (E-TLS) density had shorter survival than those with lower density (P = 0.016). High E-TLS density may be an independent risk factor for CRC (HR = 6.40, 95% CI = 1.82 ~ 22.55). However, the density of secondary follicular-like TLS did not show a significant prognostic effect in this study. In conclusion, patients with high TLS scores had longer survival, higher expression of immune checkpoint genes, and higher expression of TNFRSF17, which promotes T-cell infiltration and adhesion, but highly aggregated E-TLS may hamper patients’ survival prognosis.","PeriodicalId":12691,"journal":{"name":"Genes and immunity","volume":"26 5","pages":"449-461"},"PeriodicalIF":4.5,"publicationDate":"2025-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144729852","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-07-24DOI: 10.1038/s41435-025-00347-1
Xueqi Qu, Li Lin, Yinhu Li, Yuewen Chen, Yu Chen
N6-methyladenosine (m6A) methylation and abnormal cellular processes are involved in neurodegenerative diseases, including Alzheimer’s disease (AD). However, the functions of molecular signatures associated with m6A modification in AD remain unclear. Here, we show that m6A abundance is elevated in the hippocampus in 6-month-old APP/PS1 mice, an AD mouse model. Comparative analysis of mRNA m6A modification profiles revealed substantial variation in m6A modifications between AD and control mice. Transcripts with differential m6A modification (either hyper- or hypomethylation) were enriched in the regulation of cellular processes, including metabolic alterations, immune responses, synaptic transmission, and responses to stimuli, in both the nervous and immune systems. Moreover, the m6A-associated immune features were involved in microglial signatures, including cytokine signaling, microglial homeostasis, and microglial phagocytosis. Importantly, we identified genes with significant enrichment of m6A modifications in AD mice. Among these, we confirmed that m6A methylation was associated with the gene expression levels of CD9 and Cebpβ. Moreover, these alterations were negatively associated with microglia-mediated phagocytosis in vitro, which in turn impaired activated microglia-induced inflammation. Taken together, these findings suggest that the alteration of m6A modification contributes to the progression of AD by regulating gene expression and microglial function.
{"title":"N6-methyladenosine RNA modification regulates microglial phagocytosis in the APP/PS1 mouse model of Alzheimer’s disease","authors":"Xueqi Qu, Li Lin, Yinhu Li, Yuewen Chen, Yu Chen","doi":"10.1038/s41435-025-00347-1","DOIUrl":"10.1038/s41435-025-00347-1","url":null,"abstract":"N6-methyladenosine (m6A) methylation and abnormal cellular processes are involved in neurodegenerative diseases, including Alzheimer’s disease (AD). However, the functions of molecular signatures associated with m6A modification in AD remain unclear. Here, we show that m6A abundance is elevated in the hippocampus in 6-month-old APP/PS1 mice, an AD mouse model. Comparative analysis of mRNA m6A modification profiles revealed substantial variation in m6A modifications between AD and control mice. Transcripts with differential m6A modification (either hyper- or hypomethylation) were enriched in the regulation of cellular processes, including metabolic alterations, immune responses, synaptic transmission, and responses to stimuli, in both the nervous and immune systems. Moreover, the m6A-associated immune features were involved in microglial signatures, including cytokine signaling, microglial homeostasis, and microglial phagocytosis. Importantly, we identified genes with significant enrichment of m6A modifications in AD mice. Among these, we confirmed that m6A methylation was associated with the gene expression levels of CD9 and Cebpβ. Moreover, these alterations were negatively associated with microglia-mediated phagocytosis in vitro, which in turn impaired activated microglia-induced inflammation. Taken together, these findings suggest that the alteration of m6A modification contributes to the progression of AD by regulating gene expression and microglial function.","PeriodicalId":12691,"journal":{"name":"Genes and immunity","volume":"26 5","pages":"438-448"},"PeriodicalIF":4.5,"publicationDate":"2025-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41435-025-00347-1.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144698353","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-07-16DOI: 10.1038/s41435-025-00344-4
Lu Zeng, Charles C. White, David A. Bennett, Hans-Ulrich Klein, Philip L. De Jager
Myeloid cells, including monocytes, macrophages, and microglia, play major roles in innate and adaptive immune responses. Alzheimer’s disease (AD) and inflammatory bowel disease (IBD) susceptibility loci are both enriched for genes expressed in myeloid cells, so we assessed whether these myeloid pathways may be shared. Leveraging genome-wide association study results, we investigated the causal effect of IBD (including ulcerative colitis and Crohn’s disease) variants on AD and its endophenotypes. Microglia and monocyte expression Quantitative Trait Locus (eQTLs) were used to examine the functional consequences of IBD and AD variants. Our results revealed that the sets of genes and pathways implicated in AD and IBD susceptibility are largely distinct. Specifically, AD loci were enriched for microglial eQTLs, while IBD loci were enriched for monocyte eQTLs. Nonetheless, genetically determined IBD was associated with a modest protective effect against AD (p < 0.03), whereas CD susceptibility was linked to a modest increase in amyloid accumulation (β = 7.14, p = 0.02) and AD risk. UC susceptibility, on the other hand, was associated with increased TDP-43 deposition (β = 7.58, p value = 6.11 × 10−4). Thus, the relationship between gastrointestinal inflammatory diseases and AD is complex, but there is evidence for a modest role of IBD susceptibility on AD risk that could yield valuable therapeutic insights.
{"title":"Genetic insights into the association between inflammatory bowel disease and Alzheimer’s disease","authors":"Lu Zeng, Charles C. White, David A. Bennett, Hans-Ulrich Klein, Philip L. De Jager","doi":"10.1038/s41435-025-00344-4","DOIUrl":"10.1038/s41435-025-00344-4","url":null,"abstract":"Myeloid cells, including monocytes, macrophages, and microglia, play major roles in innate and adaptive immune responses. Alzheimer’s disease (AD) and inflammatory bowel disease (IBD) susceptibility loci are both enriched for genes expressed in myeloid cells, so we assessed whether these myeloid pathways may be shared. Leveraging genome-wide association study results, we investigated the causal effect of IBD (including ulcerative colitis and Crohn’s disease) variants on AD and its endophenotypes. Microglia and monocyte expression Quantitative Trait Locus (eQTLs) were used to examine the functional consequences of IBD and AD variants. Our results revealed that the sets of genes and pathways implicated in AD and IBD susceptibility are largely distinct. Specifically, AD loci were enriched for microglial eQTLs, while IBD loci were enriched for monocyte eQTLs. Nonetheless, genetically determined IBD was associated with a modest protective effect against AD (p < 0.03), whereas CD susceptibility was linked to a modest increase in amyloid accumulation (β = 7.14, p = 0.02) and AD risk. UC susceptibility, on the other hand, was associated with increased TDP-43 deposition (β = 7.58, p value = 6.11 × 10−4). Thus, the relationship between gastrointestinal inflammatory diseases and AD is complex, but there is evidence for a modest role of IBD susceptibility on AD risk that could yield valuable therapeutic insights.","PeriodicalId":12691,"journal":{"name":"Genes and immunity","volume":"26 5","pages":"429-437"},"PeriodicalIF":4.5,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144649291","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-07-08DOI: 10.1038/s41435-025-00343-5
Keyu Liu, Li Zhang, Xiuyun Duan, Hailin Jia, Shan Zhou, Mengjie Ma, Xiao Pan, Xiaojing Zhang, Bo Han
The precise pathological immune subsets and molecular changes in myocarditis, especially fulminant myocarditis (FM), have not been elucidated. We present a systemic analysis of immunological signatures and cell communications from pediatric PBMCs during the acute and recovery phases of FM using scRNA-seq. The peripheral immune profile in acute FM exhibited significant dysregulation in the proportion and function of immune cells. Several unique cell types, regulatory B cells, MAIT cells, adaptive NK cells, and CD8+Tpex cells, were identified in peripheral blood. Transcriptomic analysis revealed elevated expression of chemokine receptor CXCR4 and S100A family genes across nearly all cell types in the FM acute phase, as well as MHC-II molecules in antigen-presenting cells. TCR and BCR analysis showed remarkable clonal amplification and skewed V gene usage. Ligand receptor analysis highlighted active communication between myeloid cells and other immune cells. Furthermore, plasma proteomics analysis identified 36 differentially expressed proteins that interact with peripheral immune cells. Notably, anti-inflammation factors IL-10 and TGFB1 demonstrated significant potential in regulating the activity of downstream target genes involved in the immune response of peripheral immune cells. These findings enhance the understanding of the immune landscape of pediatric FM and provide valuable insights for developing potential diagnostic and therapeutic strategies.
{"title":"Peripheral immune imbalance in pediatric fulminant myocarditis revealed by single-cell sequencing and plasma proteomics","authors":"Keyu Liu, Li Zhang, Xiuyun Duan, Hailin Jia, Shan Zhou, Mengjie Ma, Xiao Pan, Xiaojing Zhang, Bo Han","doi":"10.1038/s41435-025-00343-5","DOIUrl":"10.1038/s41435-025-00343-5","url":null,"abstract":"The precise pathological immune subsets and molecular changes in myocarditis, especially fulminant myocarditis (FM), have not been elucidated. We present a systemic analysis of immunological signatures and cell communications from pediatric PBMCs during the acute and recovery phases of FM using scRNA-seq. The peripheral immune profile in acute FM exhibited significant dysregulation in the proportion and function of immune cells. Several unique cell types, regulatory B cells, MAIT cells, adaptive NK cells, and CD8+Tpex cells, were identified in peripheral blood. Transcriptomic analysis revealed elevated expression of chemokine receptor CXCR4 and S100A family genes across nearly all cell types in the FM acute phase, as well as MHC-II molecules in antigen-presenting cells. TCR and BCR analysis showed remarkable clonal amplification and skewed V gene usage. Ligand receptor analysis highlighted active communication between myeloid cells and other immune cells. Furthermore, plasma proteomics analysis identified 36 differentially expressed proteins that interact with peripheral immune cells. Notably, anti-inflammation factors IL-10 and TGFB1 demonstrated significant potential in regulating the activity of downstream target genes involved in the immune response of peripheral immune cells. These findings enhance the understanding of the immune landscape of pediatric FM and provide valuable insights for developing potential diagnostic and therapeutic strategies.","PeriodicalId":12691,"journal":{"name":"Genes and immunity","volume":"26 4","pages":"394-412"},"PeriodicalIF":4.5,"publicationDate":"2025-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144591096","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-07-05DOI: 10.1038/s41435-025-00340-8
Yubo Liu, Yiwen Zhou, Ji Zhang, Jingyi Li, Liyun Zou
The long-term persistence of naive T lymphocytes is maintained by a state of relative quiescence. Upon antigenic stimulation, these naive T cells undergo rapid activation and proliferation, differentiating into effector cells with specific clonal expansion. Recently, in-depth studies have revealed a fundamental difference in the metabolic requirements of distinct T cell subsets. The fate of CD4 + T cells is influenced by glucose-mediated glycolysis and oxidative phosphorylation (OXPHOS). In this context, key enzymes and various glycolytic intermediates, in conjunction with transcription factors and cytokines, play a crucial role in CD4 + T cell differentiation and function. In our study, we investigated the mechanisms underlying glycolytic reprogramming in CD4 + T cells, with a particular focus on the role of glycolytic enzymes in modulating cytokines and transcription factors that govern T cell differentiation.Our aim is to provide novel insights into the treatment of clinically relevant immune diseases by thoroughly elucidating the characteristics and potential regulatory mechanisms of glucose metabolism in CD4 + T cells.
{"title":"Regulation of CD4 + T cell differentiation and function by glucose metabolism","authors":"Yubo Liu, Yiwen Zhou, Ji Zhang, Jingyi Li, Liyun Zou","doi":"10.1038/s41435-025-00340-8","DOIUrl":"10.1038/s41435-025-00340-8","url":null,"abstract":"The long-term persistence of naive T lymphocytes is maintained by a state of relative quiescence. Upon antigenic stimulation, these naive T cells undergo rapid activation and proliferation, differentiating into effector cells with specific clonal expansion. Recently, in-depth studies have revealed a fundamental difference in the metabolic requirements of distinct T cell subsets. The fate of CD4 + T cells is influenced by glucose-mediated glycolysis and oxidative phosphorylation (OXPHOS). In this context, key enzymes and various glycolytic intermediates, in conjunction with transcription factors and cytokines, play a crucial role in CD4 + T cell differentiation and function. In our study, we investigated the mechanisms underlying glycolytic reprogramming in CD4 + T cells, with a particular focus on the role of glycolytic enzymes in modulating cytokines and transcription factors that govern T cell differentiation.Our aim is to provide novel insights into the treatment of clinically relevant immune diseases by thoroughly elucidating the characteristics and potential regulatory mechanisms of glucose metabolism in CD4 + T cells.","PeriodicalId":12691,"journal":{"name":"Genes and immunity","volume":"26 4","pages":"287-296"},"PeriodicalIF":4.5,"publicationDate":"2025-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144567347","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-07-03DOI: 10.1038/s41435-025-00342-6
Yifei Zhu, Teng Zhou, Yao Zheng, Yanxi Yao, Mingxi Lin, Cheng Zeng, Yuxin Yan, Yifei Zhou, Dou-Dou Li, Jian Zhang
Folic acid plays a crucial role in cellular regulation and metabolism, commonly included in dietary supplements. Despite this, its involvement in colorectal cancer (CRC), particularly in metabolic pathways and immune evasion, remains poorly understood. We developed the FMRG_score system using machine learning algorithms on TCGA and GEO data to assess modification patterns influencing clinical outcomes and immune characteristics in CRC. The system’s reliability was validated across multiple external immunotherapy cohorts. We examined associations between FMRG-related features and clinical traits, mutation profiles, biological functions, immune infiltration, therapy responses, and drug sensitivities. By integrating in vitro and in vivo experiments with bioinformatics, we built a nine-gene risk model linked to folate metabolism for CRC prognosis. Notably, CYP26A1, a key gene in the model, was upregulated in CRC tissues, promoting cell proliferation, migration, invasion, and contributing to an immunosuppressive tumor microenvironment. Significant differences in clinical traits, immune infiltration, checkpoint expression, therapy response, and drug sensitivity were observed between risk groups. This folate-based scoring system provides a novel tool for evaluating CRC prognosis, tumor microenvironment, and response to immunotherapy. We also propose CYP26A1 as a potential oncogene in CRC, offering new therapeutic insights.
{"title":"Folate metabolism-associated CYP26A1 is a clinico-immune target in colorectal cancer","authors":"Yifei Zhu, Teng Zhou, Yao Zheng, Yanxi Yao, Mingxi Lin, Cheng Zeng, Yuxin Yan, Yifei Zhou, Dou-Dou Li, Jian Zhang","doi":"10.1038/s41435-025-00342-6","DOIUrl":"10.1038/s41435-025-00342-6","url":null,"abstract":"Folic acid plays a crucial role in cellular regulation and metabolism, commonly included in dietary supplements. Despite this, its involvement in colorectal cancer (CRC), particularly in metabolic pathways and immune evasion, remains poorly understood. We developed the FMRG_score system using machine learning algorithms on TCGA and GEO data to assess modification patterns influencing clinical outcomes and immune characteristics in CRC. The system’s reliability was validated across multiple external immunotherapy cohorts. We examined associations between FMRG-related features and clinical traits, mutation profiles, biological functions, immune infiltration, therapy responses, and drug sensitivities. By integrating in vitro and in vivo experiments with bioinformatics, we built a nine-gene risk model linked to folate metabolism for CRC prognosis. Notably, CYP26A1, a key gene in the model, was upregulated in CRC tissues, promoting cell proliferation, migration, invasion, and contributing to an immunosuppressive tumor microenvironment. Significant differences in clinical traits, immune infiltration, checkpoint expression, therapy response, and drug sensitivity were observed between risk groups. This folate-based scoring system provides a novel tool for evaluating CRC prognosis, tumor microenvironment, and response to immunotherapy. We also propose CYP26A1 as a potential oncogene in CRC, offering new therapeutic insights.","PeriodicalId":12691,"journal":{"name":"Genes and immunity","volume":"26 4","pages":"376-393"},"PeriodicalIF":4.5,"publicationDate":"2025-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12353796/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144553329","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-07-01DOI: 10.1038/s41435-025-00341-7
Xiusheng Qu, Qingdong Wang, Hongbin Qiu
Gouty arthritis (GA) is a common inflammatory disease which has no effective treatments. Pyroptosis has been reported to exacerbate the progression of GA. We aimed to explore the molecular mechanism by which S-nitrosylated NEDD4 accelerates GA progression by regulating pyroptosis. In our study, we found NOD1 knockdown inhibited pyroptosis and reduced c-Caspase-1, NLRP3, ASC, and GSDMD-N expression, IL-1β and IL-18 levels, and XOD activity in GA in vivo and in vitro. In addition, NOD1 knockdown alleviated inflammatory symptoms of joint tissues in GA mice model. Moreover, downregulation of NEDD4 caused by S-nitrosylation modification at C365 site upregulated NOD1 expression by reducing ubiquitination and degradation of NOD1. Furthermore, iNOS promoted NOD1 expression by mediating S-nitrosylation of NEDD4 thereby inducing GA in vitro. In conclusion, S-nitrosylation of NEDD4 promoted NLRP3-mediated pyroptosis by upregulating NOD1 expression, which ultimately accelerated the development of GA. We are the first to report the expression patterns of NEDD4 and NOD1 in GA, and demonstrated firstly that S-nitrosylation of NEDD4 inhibited ubiquitination-mediated degradation of NOD1, thereby modulating pyroptosis in GA. By elucidating how S-nitrosylation of NEDD4 orchestrates NOD1-mediated pyroptosis, this work opens avenues for developing first-in-class therapies for GA.
{"title":"S-nitrosylated NEDD4 exacerbates gouty arthritis by upregulating NOD1 to induce pyroptosis","authors":"Xiusheng Qu, Qingdong Wang, Hongbin Qiu","doi":"10.1038/s41435-025-00341-7","DOIUrl":"10.1038/s41435-025-00341-7","url":null,"abstract":"Gouty arthritis (GA) is a common inflammatory disease which has no effective treatments. Pyroptosis has been reported to exacerbate the progression of GA. We aimed to explore the molecular mechanism by which S-nitrosylated NEDD4 accelerates GA progression by regulating pyroptosis. In our study, we found NOD1 knockdown inhibited pyroptosis and reduced c-Caspase-1, NLRP3, ASC, and GSDMD-N expression, IL-1β and IL-18 levels, and XOD activity in GA in vivo and in vitro. In addition, NOD1 knockdown alleviated inflammatory symptoms of joint tissues in GA mice model. Moreover, downregulation of NEDD4 caused by S-nitrosylation modification at C365 site upregulated NOD1 expression by reducing ubiquitination and degradation of NOD1. Furthermore, iNOS promoted NOD1 expression by mediating S-nitrosylation of NEDD4 thereby inducing GA in vitro. In conclusion, S-nitrosylation of NEDD4 promoted NLRP3-mediated pyroptosis by upregulating NOD1 expression, which ultimately accelerated the development of GA. We are the first to report the expression patterns of NEDD4 and NOD1 in GA, and demonstrated firstly that S-nitrosylation of NEDD4 inhibited ubiquitination-mediated degradation of NOD1, thereby modulating pyroptosis in GA. By elucidating how S-nitrosylation of NEDD4 orchestrates NOD1-mediated pyroptosis, this work opens avenues for developing first-in-class therapies for GA.","PeriodicalId":12691,"journal":{"name":"Genes and immunity","volume":"26 4","pages":"365-375"},"PeriodicalIF":4.5,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144539981","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Gut bacteria-derived metabolites, such as butyrate (BUT), induce T regulatory cells through inhibition of histone deacetylases (HDAC). Natural killer (NK) cells are innate lymphocytes with important effector and regulatory functions; little is known on the effect of BUT on NK cells. Here we aimed at evaluating whether BUT affects the epigenetic landscape of human NK cells. We found that BUT inhibits HDAC on human NK cells. Through ATAC sequencing, we demonstrated that BUT affects the chromatin accessibility of human NK cells, influencing, among others, genetic pathways related to immune regulation, response to viruses, chromatin remodeling and genes encoding for micro-RNAs. We identified, through analysis of published transcriptomic data, genes specific for NK-cell functional clusters, and we overlapped results of ATAC-sequencing, finding that BUT activates genes specific for CD56bright and CD69+CD56dim NK cells, and represses genes specific for non-classical NK cells. Through flow cytometry, we observed that BUT induces CD69+CD56dim NK cells. Finally, we found increased cytotoxicity of BUT-treated CD56bright NK cells towards CD25+ and CD69+ T cells, despite a trend towards decreased suppressor function towards total autologous CD4+ T cells. In conclusion, we show that BUT affects the epigenetic landscape of human NK cells, their phenotype and regulatory function.
{"title":"Butyrate enhances CD56bright NK cell-driven killing of activated T cells and modulates NK cell chromatin accessibility","authors":"Federico Carlini, Margherita Squillario, Valentina Casella, Matteo Capaia, Valeria Lusi, Davide Bagnara, Monica Colombo, Serena Palmeri, Federico Ivaldi, Fabrizio Loiacono, Antonio Uccelli, Michele Piana, Alice Laroni","doi":"10.1038/s41435-025-00338-2","DOIUrl":"10.1038/s41435-025-00338-2","url":null,"abstract":"Gut bacteria-derived metabolites, such as butyrate (BUT), induce T regulatory cells through inhibition of histone deacetylases (HDAC). Natural killer (NK) cells are innate lymphocytes with important effector and regulatory functions; little is known on the effect of BUT on NK cells. Here we aimed at evaluating whether BUT affects the epigenetic landscape of human NK cells. We found that BUT inhibits HDAC on human NK cells. Through ATAC sequencing, we demonstrated that BUT affects the chromatin accessibility of human NK cells, influencing, among others, genetic pathways related to immune regulation, response to viruses, chromatin remodeling and genes encoding for micro-RNAs. We identified, through analysis of published transcriptomic data, genes specific for NK-cell functional clusters, and we overlapped results of ATAC-sequencing, finding that BUT activates genes specific for CD56bright and CD69+CD56dim NK cells, and represses genes specific for non-classical NK cells. Through flow cytometry, we observed that BUT induces CD69+CD56dim NK cells. Finally, we found increased cytotoxicity of BUT-treated CD56bright NK cells towards CD25+ and CD69+ T cells, despite a trend towards decreased suppressor function towards total autologous CD4+ T cells. In conclusion, we show that BUT affects the epigenetic landscape of human NK cells, their phenotype and regulatory function.","PeriodicalId":12691,"journal":{"name":"Genes and immunity","volume":"26 4","pages":"342-351"},"PeriodicalIF":4.5,"publicationDate":"2025-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144283593","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-06-10DOI: 10.1038/s41435-025-00335-5
Brandon J. Coombes, Inna G. Ovsyannikova, Daniel J. Schaid, Nathaniel D. Warner, Gregory A. Poland, Richard B. Kennedy
In this report, we provide a follow-up analysis of a previously published genome-wide association study (GWAS) evaluating the effect of genetic polymorphisms on inter-individual variations in cell-mediated immune responses to mumps vaccine. Here we report the results of a polygenic score (PGS) analysis showing how common variants can predict mumps vaccine response. We found higher PGS for IFNγ, IL-2, and TNFα were predictive of higher post-vaccine IFNγ (p value = 2e-6), IL-2 (p = 2e-7), and TNFα (p = 0.004) levels, respectively. Control of immune responses after vaccination is complex and polygenic in nature. Our results suggest that the PGS-based approach enables better capture of the combined genetic effects that contribute to mumps vaccine-induced immunity, potentially offering a more comprehensive understanding than traditional single-variant GWAS. This approach will likely have broad utility in studying genetic control of immune responses to other vaccines and to infectious diseases.
{"title":"Polygenic prediction of cellular immune responses to mumps vaccine","authors":"Brandon J. Coombes, Inna G. Ovsyannikova, Daniel J. Schaid, Nathaniel D. Warner, Gregory A. Poland, Richard B. Kennedy","doi":"10.1038/s41435-025-00335-5","DOIUrl":"10.1038/s41435-025-00335-5","url":null,"abstract":"In this report, we provide a follow-up analysis of a previously published genome-wide association study (GWAS) evaluating the effect of genetic polymorphisms on inter-individual variations in cell-mediated immune responses to mumps vaccine. Here we report the results of a polygenic score (PGS) analysis showing how common variants can predict mumps vaccine response. We found higher PGS for IFNγ, IL-2, and TNFα were predictive of higher post-vaccine IFNγ (p value = 2e-6), IL-2 (p = 2e-7), and TNFα (p = 0.004) levels, respectively. Control of immune responses after vaccination is complex and polygenic in nature. Our results suggest that the PGS-based approach enables better capture of the combined genetic effects that contribute to mumps vaccine-induced immunity, potentially offering a more comprehensive understanding than traditional single-variant GWAS. This approach will likely have broad utility in studying genetic control of immune responses to other vaccines and to infectious diseases.","PeriodicalId":12691,"journal":{"name":"Genes and immunity","volume":"26 4","pages":"413-417"},"PeriodicalIF":4.5,"publicationDate":"2025-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144266086","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
京公网安备 11010802042870号
京ICP备2023020795号-1
扫码关注我们
求助内容：
应助结果提醒方式：