Lu Zeng, Charles C White, David A Bennett, Hans-Ulrich Klein, Philip L De Jager
{"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":"https://doi.org/10.1038/s41435-025-00344-4","url":null,"abstract":"<p><p>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<sup>-4</sup>). 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.</p>","PeriodicalId":12691,"journal":{"name":"Genes and immunity","volume":" ","pages":""},"PeriodicalIF":5.0,"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}
Keyu Liu, Li Zhang, Xiuyun Duan, Hailin Jia, Shan Zhou, Mengjie Ma, Xiao Pan, Xiaojing Zhang, Bo Han
{"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":"https://doi.org/10.1038/s41435-025-00343-5","url":null,"abstract":"<p><p>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<sup>+</sup>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.</p>","PeriodicalId":12691,"journal":{"name":"Genes and immunity","volume":" ","pages":""},"PeriodicalIF":5.0,"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}
Yubo Liu, Yiwen Zhou, Ji Zhang, Jingyi Li, Liyun Zou
{"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":"https://doi.org/10.1038/s41435-025-00340-8","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":12691,"journal":{"name":"Genes and immunity","volume":" ","pages":""},"PeriodicalIF":5.0,"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}
Yifei Zhu, Teng Zhou, Yao Zheng, Yanxi Yao, Mingxi Lin, Cheng Zeng, Yuxin Yan, Yifei Zhou, Dou-Dou Li, Jian Zhang
{"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":"https://doi.org/10.1038/s41435-025-00342-6","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":12691,"journal":{"name":"Genes and immunity","volume":" ","pages":""},"PeriodicalIF":5.0,"publicationDate":"2025-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"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":"https://doi.org/10.1038/s41435-025-00341-7","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":12691,"journal":{"name":"Genes and immunity","volume":" ","pages":""},"PeriodicalIF":5.0,"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}
{"title":"Butyrate enhances CD56<sup>bright</sup> 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":"https://doi.org/10.1038/s41435-025-00338-2","url":null,"abstract":"<p><p>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 CD56<sup>bright</sup> and CD69+CD56<sup>dim</sup> NK cells, and represses genes specific for non-classical NK cells. Through flow cytometry, we observed that BUT induces CD69+CD56<sup>dim</sup> NK cells. Finally, we found increased cytotoxicity of BUT-treated CD56<sup>bright</sup> 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.</p>","PeriodicalId":12691,"journal":{"name":"Genes and immunity","volume":" ","pages":""},"PeriodicalIF":5.0,"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}
Brandon J Coombes, Inna G Ovsyannikova, Daniel J Schaid, Nathaniel D Warner, Gregory A Poland, Richard B Kennedy
{"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":"<p><p>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.</p>","PeriodicalId":12691,"journal":{"name":"Genes and immunity","volume":" ","pages":""},"PeriodicalIF":5.0,"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}
{"title":"Mapping the role of cytokine signaling at single-cell and structural resolution in uveal melanoma.","authors":"Hongzhan Lin, Zixia Zhou, Hongyan Sun, Cunzi Li, Ying Lu, Zijing Wu, Lan Zhou, Yumo Wang, Zuhui Pu, Lisha Mou, Ming-Ming Yang","doi":"10.1038/s41435-025-00337-3","DOIUrl":"https://doi.org/10.1038/s41435-025-00337-3","url":null,"abstract":"<p><p>To better understand the complexity of the tumor microenvironment and to identify novel treatment strategies for uveal melanoma (UVM), we analyzed single-cell RNA sequencing (scRNA-seq) data from eight primary UVM eye tissues and three metastatic UVMs in the liver (GSE139829). We integrated this with bulk RNA-seq data from UVM patients derived from TCGA-UVM and GSE84976 cohorts. Our study focused on cytokine signaling in immune-related genes (CSIRGs), revealing distinct cellular compositions, intercellular interactions, and prognostic implications in UVM. We identified 137 cytokine signaling-related genes in UVM, with ISG20 significantly upregulated and linked to advanced stages and poor prognosis. Recognized for immune regulation, ISG20 emerged as a key survival predictor and therapeutic target from a risk model using Cox regression and LASSO, effectively categorizing patients by survival risk. Furthermore, differential drug response analysis revealed distinct sensitivities to drugs between the risk groups. Immune infiltration analysis showed a diverse immune landscape, potentially influencing response to immunotherapy. Structural prediction using AlphaFold 2 technology and molecular docking analyses revealed interactions between ISG20 and the therapeutic candidate decitabine. This study combines scRNA-seq analysis with structural biology approaches to unravel the molecular complexity of UVM, emphasizing the prognostic and therapeutic relevance of CSIRGs, particularly ISG20.</p>","PeriodicalId":12691,"journal":{"name":"Genes and immunity","volume":" ","pages":""},"PeriodicalIF":5.0,"publicationDate":"2025-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144257947","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}
Luna Hong, Yijiao Huang, Fengzhan Ye, Shan Wang, Yongqiang Wang, Jie Luo, Zongjiang Zhou, Junpu Wang, Xiaoqing Yuan, Nan Zhou
{"title":"Tumor-associated macrophages-induced lncRNA RP11-627G18.1 promotes breast cancer metastasis.","authors":"Luna Hong, Yijiao Huang, Fengzhan Ye, Shan Wang, Yongqiang Wang, Jie Luo, Zongjiang Zhou, Junpu Wang, Xiaoqing Yuan, Nan Zhou","doi":"10.1038/s41435-025-00339-1","DOIUrl":"https://doi.org/10.1038/s41435-025-00339-1","url":null,"abstract":"<p><p>Tumor-associated macrophages (TAMs) promote the transition of breast cancer cells from an epithelioid to a mesenchymal phenotype (EMT) and facilitate breast cancer metastasis, but the role of lncRNA in this process is poorly understood. We employed bioinformatics analysis to identify TAMs-related lncRNAs involved in EMT, migration and metastasis of breast cancer cells. LncRNA RP11-627G18.1 was identified as a TAMs-induced lncRNA in breast cancer cells and was further evaluated using RT-qPCR. The roles of lncRNA RP11-627G18.1 in EMT and migration were further explored using RNA interference, western blot, immunofluorescence, wound healing, and transwell assays. We discovered that TAMs-related lncRNA RP11-627G18.1 is positively correlated with EMT, metastasis, and poor prognosis in breast cancer. In vitro studies showed that lncRNA RP11-627G18.1 was induced by TAMs in breast cancer cells, accompanied by enhanced EMT and migration. Knockdown of lncRNA RP11-627G18.1 reversed EMT and inhibited the migration of breast cancer cells. TAMs-induced lncRNA RP11-627G18.1 promoted EMT, migration of breast cancer cells, and tumor metastasis, suggesting it as a promising biomarker and therapeutic target for breast cancer.</p>","PeriodicalId":12691,"journal":{"name":"Genes and immunity","volume":" ","pages":""},"PeriodicalIF":5.0,"publicationDate":"2025-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144257948","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}
Genes and immunityPub Date : 2025-06-01Epub Date: 2025-05-06DOI: 10.1038/s41435-025-00329-3
Xin-Tao Yu, Jian Cui, Xing-Guo Yang, Xiang Gao, Lei Yu
{"title":"Novel modulation of T effector memory cells-expressing CD45RA by prednisone in inoperable advanced type B thymoma patients.","authors":"Xin-Tao Yu, Jian Cui, Xing-Guo Yang, Xiang Gao, Lei Yu","doi":"10.1038/s41435-025-00329-3","DOIUrl":"10.1038/s41435-025-00329-3","url":null,"abstract":"<p><p>Due to the covert onset of thymoma, nearly 30% of patients are diagnosed at stage III or IV, losing the opportunity for surgical treatment. We have initiated the application of prednisone in treating refractory thymoma and explored biomarkers to identify potential cases that might benefit from prednisone treatment. In a study involving 96 patients with thymoma, we confirmed a significant tumor shrinkage with prednisone acetate treatment. A reduced diameter ratio indicated that type B1 and B2 thymomas exhibited the most obvious response to prednisone acetate, especially type B2 thymoma. However, the reduced diameter ratio was < 30% in type A, AB, and B3 thymomas. Immunofluorescence and flow cytometry of tumor tissues indicated that TEMRA (T Effector Memory-Expressing CD45RA) cells primarily exist in type B thymoma. However, the percentage of interleukin-8 + TEMRA cells decreased only in B1 and B2 thymoma tissues after prednisone acetate treatment. These findings are particularly significant for patients with type B thymoma with stage III or IV.</p>","PeriodicalId":12691,"journal":{"name":"Genes and immunity","volume":" ","pages":"222-228"},"PeriodicalIF":5.0,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12170332/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143983988","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}