EBioMedicine最新文献

{"title":"Monocyte/macrophage-derived interleukin-15 mediates the pro-inflammatory phenotype of CD226⁺ B cells in type 1 diabetes.","authors":"Jingyue Li, Xin Liang, Mingjiu Zhao, Wenjun Luo, Juan Huang, Yang Xiao, Jiaqi Huang, Bin Zhao, Zhiguang Zhou","doi":"10.1016/j.ebiom.2025.105946","DOIUrl":"10.1016/j.ebiom.2025.105946","url":null,"abstract":"<p><strong>Background: </strong>Type 1 diabetes (T1D) is characterised by the autoimmune-mediated destruction of pancreatic β-cells. Although traditionally viewed as a disease dominated by T cells, recent studies have emphasised the crucial role of B cells in the development of T1D. Genome-wide association studies (GWAS) have revealed that CD226 is related to susceptibility to several autoimmune diseases, including T1D. Our recent work identified a pathogenic role of CD226⁺ CD8⁺ T cells in T1D. However, the involvement of CD226⁺ B cells in T1D development remains unclear.</p><p><strong>Methods: </strong>The expression and functional characteristics of CD226⁺ B cells in T1D patients and non-obese diabetic (NOD) mice were detected by flow cytometry. RNA sequencing and molecular biology experiments were performed to reveal regulatory mechanisms. In addition, in vivo interventions were conducted to explore potential preventive and therapeutic targets for T1D.</p><p><strong>Findings: </strong>The percentage of CD226⁺ B cells is increased and positively correlated with disease severity in T1D. CD226⁺ B cells from T1D patients and NOD mice exhibit increased capability for activation, proliferation, and production of pro-inflammatory cytokines along with heightened glycolytic metabolism. Mechanistic studies have revealed that interleukin-15 (IL-15) secreted by monocytes or macrophages promotes the inflammatory response of CD226⁺ B cells. Importantly, the use of an anti-CD132 monoclonal antibody (anti-CD132) or an anti-IL-15 monoclonal antibody (anti-IL-15), which blocks IL-15 signalling, effectively prevented the disease onset of T1D. Furthermore, combination therapy with anti-CD3 monoclonal antibody (anti-CD3) and anti-CD132 synergistically reversed hyperglycemia in cyclophosphamide-accelerated NOD mice.</p><p><strong>Interpretation: </strong>Our study demonstrates a novel role of the monocyte/macrophage-IL-15-CD226⁺ B cell axis in T1D immunopathogenesis and provides potential targets for T1D immunotherapy.</p><p><strong>Funding: </strong>This work was supported by the Noncommunicable Chronic Diseases-National Science and Technology Major Project (2023ZD0507300, 2023ZD0507303, 2023ZD0508200, and 2023ZD0508201), the Natural Science Foundation of China (82570973, 82170795, 82470814, 82100949, and 82470931), the Scientific Research Program of FuRong Laboratory (2024PT5105) and the Central South University Research Programme of Advanced Interdisciplinary Studies (2023QYJC008).</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"120 ","pages":"105946"},"PeriodicalIF":10.8,"publicationDate":"2025-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12466144/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145074596","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"IL-13 decreases susceptibility to airway epithelial SARS-CoV-2 infection but increases disease severity in vivo via eicosanoid signalling.","authors":"Shreya Ghimire, Biyun Xue, Kun Li, Ryan M Gannon, Christine L Wohlford-Lenane, Andrew L Thurman, Huiyu Gong, Grace C Necker, Jian Zheng, David K Meyerholz, Stanley Perlman, Paul B McCray, Alejandro A Pezzulo","doi":"10.1016/j.ebiom.2025.105920","DOIUrl":"10.1016/j.ebiom.2025.105920","url":null,"abstract":"<p><strong>Background: </strong>Treatments available to prevent progression of virus-induced lung diseases, including coronavirus disease 2019 (COVID-19) are of limited benefit once respiratory failure occurs. The efficacy of approved and emerging cytokine signalling-modulating antibodies is variable and is affected by disease course and patient-specific inflammation patterns. Therefore, understanding the role of inflammation on the viral infectious cycle is critical for effective use of cytokine-modulating agents.</p><p><strong>Methods: </strong>The role of the type 2 cytokine IL-13 on SARS-CoV-2 binding/entry, replication, and host response was investigated in primary HAE cells in vitro and in a model of mouse-adapted SARS-CoV-2 infection in vivo using single-cell and bulk RNA-sequencing approaches. Additionally, the responses were quantified using immunofluorescence, histopathology, immunohistochemistry and LC-MS/MS assays.</p><p><strong>Findings: </strong>IL-13 protected airway epithelial cells from SARS-CoV-2 infection in vitro by decreasing the abundance of ACE2-expressing ciliated cells rather than by neutralisation in the airway surface liquid or by interferon-mediated antiviral effects. In contrast, IL-13 worsened disease severity in mice; the effects were mediated by eicosanoid signalling and were abolished in mice deficient in the phospholipase A₂ enzyme PLA2G2D.</p><p><strong>Interpretation: </strong>IL-13-induced inflammation differentially affects multiple steps of COVID-19 pathogenesis. IL-13-induced inflammation may be protective against initial SARS-CoV-2 airway epithelial infection; however, it enhances disease progression in vivo. Blockade of IL-13 and/or eicosanoid signalling may be protective against progression to severe respiratory virus-induced lung diseases.</p><p><strong>Funding: </strong>Carver Trust COVID-19 Grant; CF Foundation Iowa RDP; NIH 1R01HL163024; K01HL140261; NIH R01AI129269; NIH P01AI060699; NIH Grant P30 DK-54759; Cystic Fibrosis Foundation PEZZUL20A1-KB; Stead Family Foundation.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"120 ","pages":"105920"},"PeriodicalIF":10.8,"publicationDate":"2025-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12466150/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145074683","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Authors' reply to letter regarding \"Inflammaging links life's essential 8 to white matter brain aging\".","authors":"Tianzhou Ma, Zhenyao Ye, Li Feng, Shuo Chen","doi":"10.1016/j.ebiom.2025.105909","DOIUrl":"https://doi.org/10.1016/j.ebiom.2025.105909","url":null,"abstract":"","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"120 ","pages":"105909"},"PeriodicalIF":10.8,"publicationDate":"2025-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145063297","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Fitness costs of mobilised colistin resistance gene 3 (mcr-3): systematic review, epidemiological study, and functional analysis.","authors":"Lujie Liang, Yaxin Li, Lin Wang, Wenli Wang, Yihao Zhang, Hui Zhao, Yaxuan Wang, Lingxuan Lyu, Jiachen Li, Dianrong Zhou, Zhe Hu, Lizhen Luo, Guanxiu Wang, Jia Wan, Lin Xu, Meisong Li, Min Dai, Meiting Yang, Shun Xiong, Lan-Lan Zhong, Fang Bai, Siyuan Feng, Guo-Bao Tian","doi":"10.1016/j.ebiom.2025.105923","DOIUrl":"https://doi.org/10.1016/j.ebiom.2025.105923","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;The rapid evolution and dissemination of mobilised colistin resistance gene (mcr) family has revealed as a severe threat to the global public health. Nevertheless, dramatic reduction in the prevalence of mcr-1, the major member of mcr family, was observed after the withdrawal of colistin in animal fodder in China since 2017, demonstrating that colistin acts as a selective stress to promote the dissemination of mcr-1. As the second largest lineage, mcr-3 was firstly discovered in 2017 and has been identified from numerous sources. However, whether the spreading of mcr-3 is driven by colistin remains unknown.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;To this end, we investigated the global prevalence of mcr-3 from 2005 to 2022 by an up-to-date systematic review, along with a nation-wide epidemiological study to establish the change of mcr-3 prevalence in China before and after 2017. To investigate the fitness cost imposed by MCR-3 upon bacterial host, in vitro and in vivo competitive assays were employed, along with morphological study and fluorescent observation. Moreover, by replacing non-optimal codons with optimal codons, synonymous mutations were introduced into the 5'-coding regions of mcr-3 to study mechanisms accounting for the distinct fitness cost conferred by MCR-1 and MCR-3. Furthermore, by combining AlphaFold and molecular dynamics (MD) simulation, we provided a complete characterisation on the putative lipid A binding pocket localised at the linker domain of MCR-3. Crucially, inhibitors targeting at the putative binding pocket of MCR-1 or MCR-3 were identified from small molecules library using the pipeline of virtual screening.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Findings: &lt;/strong&gt;The global prevalence of mcr-3 increased continuously from 2005 to 2022. The average prevalence was 0.18% during 2005-2014 and rapidly increased to 3.41% during 2020-2022. The prevalence of mcr-3 in China increased from 0.79% in 2016 to 5.87% in 2019. We found that the fitness of mcr-3-bearing Escherichia coli and empty plasmid control was comparable but higher than that of mcr-1-positive strain. Although the putative lipid A binding pocket of MCR-3 was similar to that of in MCR-1, mcr-3 occupies remarkable codon bias at the 5'-end of coding region that disrupted the stability of mRNA, further reduced its protein expression in E. coli, resulting in the low fitness burden of bacterial host. Moreover, the 5'-end codon usage frequency appeared as a critical factor related with the evolution of mcr family. Furthermore, based on the similar lipid A binding pocket among MCR family protein, we identified three MCR inhibitors targeting at such pocket by screening from small-molecule library, which effectively restored the colistin susceptibility of mcr-bearing E. coli.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Interpretation: &lt;/strong&gt;We found that the prevalence of mcr-3 increased continuously during 2016-2019 in China, demonstrating that the withdrawal of colistin in husbandry failed to pr","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"120 ","pages":"105923"},"PeriodicalIF":10.8,"publicationDate":"2025-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145058304","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"New standards in HER2-low testing: the CASI-01 comparative methods study.","authors":"David J Dabbs, Emina Torlakovic, Søren Nielsen, Suzanne C Parry, Jing Yu, Catherine Stoos, Beth Clark, Henrik Høeg, Jeppe Thagaard, Seshi R Sompuram, Stephen P Naber, Yukako Yagi, James Sayre, Kodela Vani, Mélissande Cossutta, Francoise Soussaline, Alexandre Papine, Nils A t'Hart, Matthias J Szabolcs, Bharat Jasani, Mary Kinloch, Luis Chiriboga, Keith Miller, Steve Bogen","doi":"10.1016/j.ebiom.2025.105919","DOIUrl":"https://doi.org/10.1016/j.ebiom.2025.105919","url":null,"abstract":"<p><strong>Background: </strong>The introduction of Trastuzumab deruxtecan (T-Dxd) has exposed clinically significant limitations in accurately detecting HER2-low expression testing when using immunohistochemistry (IHC) assays originally developed to detect HER2 over-expression. While HER2 testing is widely used to determine T-Dxd eligibility, no HER2-low assay was ever validated against HER2 protein expression.</p><p><strong>Methods: </strong>To address this pressing need, the Consortium for Analytic Standardization in Immunohistochemistry (CASI) conducted the CASI-01 study, involving 54 IHC laboratories across Europe and the U.S. The study aimed to identify optimal assay conditions for accurate HER2 testing, differentiating between HER2 overexpression (3+) for Trastuzumab eligibility and HER2-low expression (1+ or ultra-low) for T-Dxd eligibility. The conventional FDA-cleared HER2 assay (\"predicate\") was compared with higher-sensitivity assays using pathologist versus image analysis readouts. HER2 overexpression was validated against HER2 gene amplification via in situ hybridisation (ISH), while HER2-low accuracy was evaluated using newly introduced HER2 reference standards and a novel IHC parameter-dynamic range.</p><p><strong>Findings: </strong>CASI-01 revealed variability in predicate HER2 assays, with detection thresholds ranging from 30,000 to 60,000 among laboratories. Despite this variability, these assays demonstrated high accuracy for identifying HER2 overexpression (3+), with 85.7% (18/21) sensitivity (95% confidence limits 63.66-96.95%) and 100% (49/49) specificity (95% confidence limits 92.75-100%), though sensitivity may have been limited by the use of older tissue specimens, with loss or reduced expression levels of the HER2 protein. However, these same assays exhibited poor dynamic range for detecting HER2-low scores. Enhanced analytic sensitivity of IHC assays combined with image analysis overcame this limitation with HER2-low scores, achieving a six-fold improvement (p = 0.0017).</p><p><strong>Interpretation: </strong>IHC assays with detection thresholds in the range of 30,000-60,000 HER2 molecules per cell yield accurate results for determination of Trastuzumab eligibility (HER2 3+) but fail to demonstrate the dynamic range for accurate HER2-low scores. Enhanced analytic sensitivity of HER2 assays combined with image analysis addresses this critical gap in HER2-low testing. More generally, CASI-01 introduces pivotal advancements in precision medicine: (a) the importance of reporting IHC analytic sensitivity and ability to demonstrate an assay dynamic range, and (b) image analysis can surpass pathologist readout accuracy in specific clinical contexts.</p><p><strong>Funding: </strong>This work was supported by the National Cancer Institute of the National Institutes of Health under Award Number R44CA268484.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"120 ","pages":"105919"},"PeriodicalIF":10.8,"publicationDate":"2025-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145058389","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A comprehensive single-cell atlas of three centenarian cohorts unveils unique natural killer cell signatures and enhanced mutual interactions among peripheral immune cells.","authors":"Bin Wang, Zehao Zhang, Qing Ouyang, Min Zhang, Mingda Duan, Hongyan Hu, Qingtao Zhang, Xinye Jin, Jie Zhang, Qing Luo, Ding Sun, Hao Li, Zeyu Qu, Xiangmei Chen, Zhifeng Gu, Yizhi Chen","doi":"10.1016/j.ebiom.2025.105922","DOIUrl":"https://doi.org/10.1016/j.ebiom.2025.105922","url":null,"abstract":"<p><strong>Background: </strong>Centenarians are considered as an optimal population for studying healthy ageing. However, immune features associated with super longevity have only been investigated in a few small studies using a single research method.</p><p><strong>Methods: </strong>In this study, single-cell RNA sequencing (scRNA-seq), mass cytometry, and flow cytometry analysis were used to analyse the immune feature of peripheral blood mononuclear cells (PBMCs) from 17 centenarians (CENs), 9 of their offsprings (COs), and 14 of their offsprings' spouses or neighbours (controls, CTs) from Lingao County of China. scRNA-seq data from the other two cohorts were downloaded from public databases.</p><p><strong>Findings: </strong>Comprehensive analysis of 31 CENs, 17 COs, and 26 CTs from these three cohorts revealed decreased percentages of B cells and CD4⁺ T cells and an increased percentage of natural killer (NK) cells in PBMCs from CENs, compared with CTs. Moreover, NK cells from CENs exhibited relatively \"young\" signatures, including cell subset distribution and key membrane receptor expression. Enhanced RUNX3 expression in NK cells was observed in CENs, with reinforced interactions between NK and T cells, which promoted T cell function by modulating MHC-I, CD99 and MIF signalling.</p><p><strong>Interpretation: </strong>CENs exhibit unique immunological features, especially NK cells with young protein expression signatures and immune functions.</p><p><strong>Funding: </strong>This study was funded by the Sanya Science and Technology Innovation Special Project (No. 2022KJCX02), National Natural Science Foundation of China (No. 32141005, 82270769), Specific Research Fund of the Innovation Platform for Academicians of Hainan Province, and National Key Research and Development Program of China (Nos. 2022YFC3602900, 2022YFC3602902, 2022YFC3602903).</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"120 ","pages":"105922"},"PeriodicalIF":10.8,"publicationDate":"2025-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145058399","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Brain-clinical signatures of basal ganglia-related dysfunctional reorganisation in Parkinson's disease.","authors":"Lili Chen, Lianglong Sun, Junyan Sun, Junling Wang, Dongling Zhang, Mingrui Xia, Tao Wu","doi":"10.1016/j.ebiom.2025.105917","DOIUrl":"https://doi.org/10.1016/j.ebiom.2025.105917","url":null,"abstract":"<p><strong>Background: </strong>The hierarchical organisation of functional networks is crucial for integration and segregation, and its dysregulation is implicated in neurodegenerative progression. The basal ganglia (BG) is the communication hub of the BG-thalamo-cortical circuit, and its dysfunction drives the progression of clinical symptoms in Parkinson's disease (PD). However, network-level functional reorganisation of BG disruption remains unclear.</p><p><strong>Methods: </strong>In this cross-sectional study, we applied functional gradient analysis based on a diffusion map embedding algorithm to delineate macroscale functional architectures of BG in 102 PD patients and 88 healthy controls (HCs). Partial least squares correlation analysis was employed to investigate the relationship between gradient alterations and clinical symptoms in PD.</p><p><strong>Findings: </strong>The first functional gradient of BG extended from caudate nucleus to putamen, whereas second gradient was anchored at dorsal and ventral caudate nucleus. In PD patients, the first gradient showed significant global compression with the progression from unilateral to bilateral motor symptoms. The second gradient exhibited local disruptions in nucleus accumbens and putamen, driven by reduced connectivity with multiple functional systems. Gradient scores of these two nuclei displayed significant lateralisation in PD, regardless of motor deficit dominance. Dysfunctional gradients in PD are associated with motor deficits and emotional symptoms.</p><p><strong>Interpretation: </strong>Our findings reveal that functional gradient reorganisation is a network-level signature of early-stage PD, linking functional reorganisation in BG circuit to clinical symptoms. The hemispheric asymmetry of gradient patterns may inform ongoing research on PD lateralisation.</p><p><strong>Funding: </strong>National Natural Science Foundation of China (Nos. 82071423 and 82021004) and Beijing Natural Science Foundation (No. JQ23033).</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"120 ","pages":"105917"},"PeriodicalIF":10.8,"publicationDate":"2025-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145052392","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Smouldering disease in paediatric-onset multiple sclerosis.","authors":"Massimo Filippi, Monica Margoni, Brenda Banwell, Tanuja Chitnis, Russell Dale, Giulia Fadda, Yael Hacohen, Lauren B Krupp, Paolo Preziosa, E Ann Yeh, Emmanuelle Waubant, Maria A Rocca","doi":"10.1016/j.ebiom.2025.105921","DOIUrl":"https://doi.org/10.1016/j.ebiom.2025.105921","url":null,"abstract":"<p><p>Smouldering disease in multiple sclerosis (MS) refers to chronic central nervous system processes that occur beyond acute inflammation, driving long-term disability. Although current therapies effectively reduce relapse rates and MRI lesions, many individuals experience progression independent of relapse activity. While clinical progression is uncommon during childhood or adolescence, growing evidence suggests that subclinical progressive disease biology is already active even in this young age group, warranting early intervention to preserve function. Conventional MRI, while critical for diagnosis, lacks sensitivity for subtle damage. Advanced MRI techniques, including detection of chronic active lesions, global and focal brain damage, hold promise for early identification. Fluid biomarkers, such as neurofilament light chain and glial fibrillary acidic protein, provide non-invasive measures of neuroaxonal injury and ongoing chronic inflammation. This review summarises the role of MRI and fluid biomarkers in detecting smouldering disease in paediatric-onset MS and their application in supporting therapeutic decision-making.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"120 ","pages":"105921"},"PeriodicalIF":10.8,"publicationDate":"2025-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145052438","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"TIM-3 ameliorates host responses to Salmonella infection by controlling iron driven CD4⁺ T cell differentiation and interleukin-10 formation.","authors":"Christa Pfeifhofer-Obermair, Natascha Brigo, Chiara Volani, Piotr Tymoszuk, Egon Demetz, Sabine Engl, Günter Weiss","doi":"10.1016/j.ebiom.2025.105910","DOIUrl":"https://doi.org/10.1016/j.ebiom.2025.105910","url":null,"abstract":"<p><strong>Background: </strong>Iron loading increases infection risk in being a nutrient for invading siderophilic bacteria and by modulating immune functions including the expression of the immune checkpoint regulator T-cell immunoglobulin-and-mucin-containing-domain-3 (TIM-3). TIM-3 affects specific immune cell functions including T-helper cell differentiation but also T cell dysfunction, and immune exhaustion. Given the prevalence of iron overload specifically in patients at higher risk for infection such as those suffering from hemo-oncological diseases, we investigated TIM-3's role in immune control of bacterial sepsis.</p><p><strong>Methods: </strong>A sepsis model was employed in wildtype and Tim3^-/- mice with transgenic expression of a functional natural resistance associated macrophage protein 1 (NRAMP1). This creates a chronic inflammation model with enhanced resistance to infections with Gram negative Salmonella typhimurium, enabling to study T cell immune responses over time.</p><p><strong>Findings: </strong>Dietary iron supplementation reduced mouse survival, which was further exaggerated by TIM-3 deletion. This indicates that TIM-3 dependent immune regulation was essential for effective host defence against Salmonella. TIM-3 deletion increased the production of immune-deactivating interleukin (IL) -10 as a result of impaired interleukin-12 receptor (IL-12R)-dependent CD4⁺ cytotoxic T cell signalling and development which subsequently reduced the production of anti-microbial interferon gamma (IFNγ). Anti-IL-10 treatment in iron-loaded Tim3^-/- mice improved Salmonella control and restored CD4⁺ T cell mediated IFNγ production.</p><p><strong>Interpretation: </strong>Our study uncovers TIM-3 as a crucial regulator of T cell driven immune control of bacterial infection and identifies the underlying treatable pathways, which is of major importance to better combat infection related mortality in subjects with iron overload syndromes.</p><p><strong>Funding: </strong>Christian-Doppler-Society, FWF (I-3321, W-1253).</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"120 ","pages":"105910"},"PeriodicalIF":10.8,"publicationDate":"2025-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145052448","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Multi-region ultrasound-based deep learning for post-neoadjuvant therapy axillary decision support in breast cancer.","authors":"Ziyin Li, Ning Mao","doi":"10.1016/j.ebiom.2025.105916","DOIUrl":"https://doi.org/10.1016/j.ebiom.2025.105916","url":null,"abstract":"","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"120 ","pages":"105916"},"PeriodicalIF":10.8,"publicationDate":"2025-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145033122","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}