Pub Date : 2025-09-13DOI: 10.1016/j.cellimm.2025.105024
Yixuan Ma , Yue Zhou , Miao Yu
T follicular helper (Tfh) cells constitute a functionally specialized subset of CD4+ T lymphocytes that orchestrate germinal center (GC) responses, critically regulating B cell destination and the development of long-term humoral immunity. Emerging evidence implicates Tfh cells as key mediators in the pathogenesis of multiple fibrotic disorders across multiple organ systems, including systemic sclerosis (SSc), hepatic fibrosis, chronic kidney disease, idiopathic pulmonary fibrosis (IPF) and IgG4-Related Disease (IgG4-RD). This review synthesizes current understanding of Tfh cell biology in fibrosis, aiming to provide deeper insights into their involvement in pathogenesis and identify potential new therapeutic targets.
{"title":"Follicular helper T cells and fibrotic diseases","authors":"Yixuan Ma , Yue Zhou , Miao Yu","doi":"10.1016/j.cellimm.2025.105024","DOIUrl":"10.1016/j.cellimm.2025.105024","url":null,"abstract":"<div><div>T follicular helper (Tfh) cells constitute a functionally specialized subset of CD4+ T lymphocytes that orchestrate germinal center (GC) responses, critically regulating B cell destination and the development of long-term humoral immunity. Emerging evidence implicates Tfh cells as key mediators in the pathogenesis of multiple fibrotic disorders across multiple organ systems, including systemic sclerosis (SSc), hepatic fibrosis, chronic kidney disease, idiopathic pulmonary fibrosis (IPF) and IgG4-Related Disease (IgG4-RD). This review synthesizes current understanding of Tfh cell biology in fibrosis, aiming to provide deeper insights into their involvement in pathogenesis and identify potential new therapeutic targets.</div></div>","PeriodicalId":9795,"journal":{"name":"Cellular immunology","volume":"418 ","pages":"Article 105024"},"PeriodicalIF":2.9,"publicationDate":"2025-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145157017","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-09-06DOI: 10.1016/j.cellimm.2025.105025
Mohua Liu, Xiao Wang, Xiaoya Qu, Yao Wang, Xihui Shen, Lei Xu
Both trained immunity (TRIM) and endotoxin tolerance (ET) initiate similar metabolic reprogramming characterized by enhanced glycolysis following an initial stimulus. However, TRIM exhibited heightened immune activation upon restimulation, whereas ET showed suppressed innate immune response. This divergence is attributed to distinct metabolic intermediates accumulated after the initial stimulation. In TRIM, metabolites like fumarate and glutamine derivatives accumulate, reinforcing pro-inflammatory epigenetic modifications. Conversely, ET is characterized by increased itaconate and lactate levels, promoting anti-inflammatory epigenetic changes and metabolic paralysis. This review highlights metabolic intermediates as key regulators of innate immune fate decisions, presenting avenues for targeted immune modulation.
{"title":"Divergent metabolic rewiring shapes altered innate immunity","authors":"Mohua Liu, Xiao Wang, Xiaoya Qu, Yao Wang, Xihui Shen, Lei Xu","doi":"10.1016/j.cellimm.2025.105025","DOIUrl":"10.1016/j.cellimm.2025.105025","url":null,"abstract":"<div><div>Both trained immunity (TRIM) and endotoxin tolerance (ET) initiate similar metabolic reprogramming characterized by enhanced glycolysis following an initial stimulus. However, TRIM exhibited heightened immune activation upon restimulation, whereas ET showed suppressed innate immune response. This divergence is attributed to distinct metabolic intermediates accumulated after the initial stimulation. In TRIM, metabolites like fumarate and glutamine derivatives accumulate, reinforcing pro-inflammatory epigenetic modifications. Conversely, ET is characterized by increased itaconate and lactate levels, promoting anti-inflammatory epigenetic changes and metabolic paralysis. This review highlights metabolic intermediates as key regulators of innate immune fate decisions, presenting avenues for targeted immune modulation.</div></div>","PeriodicalId":9795,"journal":{"name":"Cellular immunology","volume":"417 ","pages":"Article 105025"},"PeriodicalIF":2.9,"publicationDate":"2025-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145019900","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-09-03DOI: 10.1016/j.cellimm.2025.105023
Xin Wang , Xu Sun , Xinmeng Yang , Guixia Xu , Yuan Wang , Mingming Jin , Chao Sun
Background
Sjögren's syndrome (SS) is an autoimmune disorder identified by a triad of sicca symptoms, pain, and fatigue. SS-induced skin injury seriously affects people's health but remains unsolved. Accumulating investigations have confirmed that exosomes (Exos) originating from bone marrow mesenchymal stem cells (BMSCs) can bolster the stressed microenvironment and tissue repair. Present study aimed to unravel therapeutic effects regarding BMSC Exos on SS-induced skin injury.
Methods
In this study, an SS mouse model was constructed, and exosomes from BMSCs (Exos) and hypoxic pretreated BMSCs (HExos) were isolated. The therapeutic effects of exosomes in SS were identified using ELISA, immunohistochemistry, and immunofluorescence. High-throughput sequencing (HTS) was utilized to characterize differentially expressed genes between Exos and HExos.
Results
The data showed that Exos, especially HExo treatments, affected the inhibition of SS-induced inflammatory factor expression, cell apoptosis, ROS deposition, and collagen loss. HTS and RT-qPCR detection showed PPARγ functioned importantly for HExo-mediated protective effects against SS-induced skin injury. The in vitro experiment using RAW confirmed that PPARγ expression inhibited LPS-induced M1-like macrophage activation, which was confirmed using the PPARγ antagonist T0070907. PPARγ upregulation improved therapeutic effects regarding Exos upon skin injury in SS mice by promoting M2-like macrophage activation.
Conclusion
Taken together, our study found that exosomes from hypoxic pretreated BMSCs attenuated primary Sjögren's syndrome-induced skin injury via PPARγ delivery and promoted M2-like macrophage activation.
{"title":"Exosomes from hypoxic pretreated BMSCs attenuate primary Sjögren's syndrome-induced skin injury via PPARγ-mediated M2-like macrophage activation","authors":"Xin Wang , Xu Sun , Xinmeng Yang , Guixia Xu , Yuan Wang , Mingming Jin , Chao Sun","doi":"10.1016/j.cellimm.2025.105023","DOIUrl":"10.1016/j.cellimm.2025.105023","url":null,"abstract":"<div><h3>Background</h3><div>Sjögren's syndrome (SS) is an autoimmune disorder identified by a triad of sicca symptoms, pain, and fatigue. SS-induced skin injury seriously affects people's health but remains unsolved. Accumulating investigations have confirmed that exosomes (Exos) originating from bone marrow mesenchymal stem cells (BMSCs) can bolster the stressed microenvironment and tissue repair. Present study aimed to unravel therapeutic effects regarding BMSC Exos on SS-induced skin injury.</div></div><div><h3>Methods</h3><div>In this study, an SS mouse model was constructed, and exosomes from BMSCs (Exos) and hypoxic pretreated BMSCs (HExos) were isolated. The therapeutic effects of exosomes in SS were identified using ELISA, immunohistochemistry, and immunofluorescence. High-throughput sequencing (HTS) was utilized to characterize differentially expressed genes between Exos and HExos.</div></div><div><h3>Results</h3><div>The data showed that Exos, especially HExo treatments, affected the inhibition of SS-induced inflammatory factor expression, cell apoptosis, ROS deposition, and collagen loss. HTS and RT-qPCR detection showed PPARγ functioned importantly for HExo-mediated protective effects against SS-induced skin injury. The in vitro experiment using RAW confirmed that PPARγ expression inhibited LPS-induced M1-like macrophage activation, which was confirmed using the PPARγ antagonist T0070907. PPARγ upregulation improved therapeutic effects regarding Exos upon skin injury in SS mice by promoting M2-like macrophage activation.</div></div><div><h3>Conclusion</h3><div>Taken together, our study found that exosomes from hypoxic pretreated BMSCs attenuated primary Sjögren's syndrome-induced skin injury via PPARγ delivery and promoted M2-like macrophage activation.</div></div>","PeriodicalId":9795,"journal":{"name":"Cellular immunology","volume":"418 ","pages":"Article 105023"},"PeriodicalIF":2.9,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145157462","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Human embryonic stem cell-derived NK (hESC-NK) cells or induced pluripotent stem cell derived NK cells have demonstrated efficacy and safety in clinical trials for cancer therapy and serve as a valuable tool for studying the mechanisms of human NK cell development and effector functions. We previously demonstrated that the methylase METTL3 was essential for the development and effector functions of murine NK cells, but its role in human NK cells remained unknown. Herein, we constructed an H1 ESC strain with reduced METTL3 expression using lentivirus-delivered short hairpin (sh) RNA and generated hESC-NK cells via a two-stage differentiation system. Our findings demonstrated that METTL3 knockdown in hESCs reduced the proportion of hematopoietic stem and progenitor cells (HSPCs, CD34+ cells) during embryoid bodies (EBs) formation, and impaired subsequent differentiation into mature NK cells. Moreover, ESC-NK cells derived from shMETTL3-ESC (called shMETTL3-ESC-NK) showed impaired anti-tumor activity, evidenced by downregulation of mRNA and protein levels of critical effectors (perforin, granzyme B and IFN-γ) and reduced cytotoxicity against target cells. Furthermore, both mRNA and protein levels of T-BET and EOMES were significantly down-regulated in shMETTL3-ESC-NK cells. These transcription factors are critical for NK cell development and cytotoxicity, and their downregulation may underlie the maturation defects of shMETTL3-ESC-NK cells. Collectively, our study elucidates that METTL3 promotes the development, maturation and cytotoxicity of hESC-NK cells, recapitulating previous reports in murine NK cells.
{"title":"METTL3 positively regulates the development and cytotoxicity of human embryonic stem cells-derived NK cells.","authors":"Xiaofeng Yin, Zhaohui Zhang, Jiaxing Qiu, Yuxing Gong, Qinghua Bi, Meng Meng, Qiangqiang Lai, Hongchen Wang, Shaochang Zhou, Yuan Gao, Lingling Zhang, Wei Wu, Liang Song, Junping Wang, Fangjie Wang, Zhaoyang Zhong, Youcai Deng","doi":"10.1016/j.cellimm.2025.105011","DOIUrl":"10.1016/j.cellimm.2025.105011","url":null,"abstract":"<p><p>Human embryonic stem cell-derived NK (hESC-NK) cells or induced pluripotent stem cell derived NK cells have demonstrated efficacy and safety in clinical trials for cancer therapy and serve as a valuable tool for studying the mechanisms of human NK cell development and effector functions. We previously demonstrated that the methylase METTL3 was essential for the development and effector functions of murine NK cells, but its role in human NK cells remained unknown. Herein, we constructed an H1 ESC strain with reduced METTL3 expression using lentivirus-delivered short hairpin (sh) RNA and generated hESC-NK cells via a two-stage differentiation system. Our findings demonstrated that METTL3 knockdown in hESCs reduced the proportion of hematopoietic stem and progenitor cells (HSPCs, CD34<sup>+</sup> cells) during embryoid bodies (EBs) formation, and impaired subsequent differentiation into mature NK cells. Moreover, ESC-NK cells derived from shMETTL3-ESC (called shMETTL3-ESC-NK) showed impaired anti-tumor activity, evidenced by downregulation of mRNA and protein levels of critical effectors (perforin, granzyme B and IFN-γ) and reduced cytotoxicity against target cells. Furthermore, both mRNA and protein levels of T-BET and EOMES were significantly down-regulated in shMETTL3-ESC-NK cells. These transcription factors are critical for NK cell development and cytotoxicity, and their downregulation may underlie the maturation defects of shMETTL3-ESC-NK cells. Collectively, our study elucidates that METTL3 promotes the development, maturation and cytotoxicity of hESC-NK cells, recapitulating previous reports in murine NK cells.</p>","PeriodicalId":9795,"journal":{"name":"Cellular immunology","volume":"415-416 ","pages":"105011"},"PeriodicalIF":2.9,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144803699","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-08-27DOI: 10.1016/j.cellimm.2025.105015
Hao-Chien Hung , Tsui-Lien Mao , Ke-Hung Tsui , Ming-Huei Fan , Ainani Priza Minhalina , Chao-Lien Liu
Background
Ovarian cancer (OC) is a highly lethal gynecological malignancy, mainly due to chemoresistance and tumor recurrence. Cancer stem cells (CSCs) may be responsible for chemoresistance, and CSC has become a new target for treatment. In this study, we aimed to develop a three-dimensional (3D) OC model with well-recapitulated stemness in the tumor microenvironment (TME).
Results
We observed that the niche-like environment associated with CSC properties is characterized by the presence of CD133-positive cells during OC sphere induction. The cancer-associated fibroblast (CAF)-integrated 3D multicellular OC model recapitulates enhanced tumorigenicity and cytokine-mediated invasiveness more than the 2D monolayer culture. Chemoresistance of the 3D OC model is also acquired. In addition, the in vivo growth of an established xenograft model with a 3D CAF-integrated OC sphere exhibits proper stemness features and full cancer-associated markers for tumorigenesis.
After transduction of the CD133 gene into OC cells, gene ontology (GO) and KEGG pathway enrichment analyses reveal that cytokine-mediated endothelial mesenchymal transition (EMT) is possibly responsible for chemotherapy resistance and tumor progression, and enhanced PAR1, CXCR4, and PD-L1 expressions are also observed. In addition, we found that engineered chimeric antigen receptor (CAR)-T cells targeting PAR1 demonstrated significant in vitro cytotoxicity toward chemoresistant OC sphere with CD133 overexpression.
Conclusions
Taken together, our results show that a CD133-3D OC sphere recaptures TME that mimics a real late-stage OC condition, and it can act as a useful platform with mechanism-verifying in vitro and in vivo experiments in researching OC chemotherapy, immunotherapy, and cell therapy to discover new therapeutic approaches.
卵巢癌（OC）是一种高致死率的妇科恶性肿瘤，主要原因是化疗耐药和肿瘤复发。肿瘤干细胞（Cancer stem cells, CSCs）可能与化疗耐药有关，已成为新的治疗靶点。在这项研究中，我们旨在建立一个肿瘤微环境（TME）中具有良好再现性的三维（3D） OC模型。结果我们观察到，在OC球诱导过程中，与CSC特性相关的小生境环境以cd133阳性细胞的存在为特征。与2D单层培养相比，癌症相关成纤维细胞（CAF）集成的3D多细胞OC模型更能再现增强的致瘤性和细胞因子介导的侵袭性。还获得了3D OC模型的化学耐药性。此外，具有3D ca -集成OC球的已建立的异种移植物模型的体内生长表现出适当的干性特征和肿瘤发生的全部癌症相关标志物。CD133基因转导至OC细胞后，基因本体（GO）和KEGG通路富集分析显示，细胞因子介导的内皮间充质转化（EMT）可能是化疗耐药和肿瘤进展的原因，PAR1、CXCR4和PD-L1表达也增强。此外，我们发现靶向PAR1的工程化嵌合抗原受体(CAR)-T细胞对CD133过表达的化疗耐药OC球具有显著的体外细胞毒性。综上所述，我们的研究结果表明，CD133-3D OC球重现了模拟真实的晚期OC病情的TME，可以作为体外和体内实验机制验证的有用平台，用于研究OC化疗、免疫治疗和细胞治疗，以发现新的治疗方法。
{"title":"A synergy of CD133 overexpression and TGF-β supplementation in tumorigenesis of ovarian cancer cell lines in a three-dimensional sphere forming model","authors":"Hao-Chien Hung , Tsui-Lien Mao , Ke-Hung Tsui , Ming-Huei Fan , Ainani Priza Minhalina , Chao-Lien Liu","doi":"10.1016/j.cellimm.2025.105015","DOIUrl":"10.1016/j.cellimm.2025.105015","url":null,"abstract":"<div><h3>Background</h3><div>Ovarian cancer (OC) is a highly lethal gynecological malignancy, mainly due to chemoresistance and tumor recurrence. Cancer stem cells (CSCs) may be responsible for chemoresistance, and CSC has become a new target for treatment. In this study, we aimed to develop a three-dimensional (3D) OC model with well-recapitulated stemness in the tumor microenvironment (TME).</div></div><div><h3>Results</h3><div>We observed that the niche-like environment associated with CSC properties is characterized by the presence of CD133-positive cells during OC sphere induction. The cancer-associated fibroblast (CAF)-integrated 3D multicellular OC model recapitulates enhanced tumorigenicity and cytokine-mediated invasiveness more than the 2D monolayer culture. Chemoresistance of the 3D OC model is also acquired. In addition, the in vivo growth of an established xenograft model with a 3D CAF-integrated OC sphere exhibits proper stemness features and full cancer-associated markers for tumorigenesis.</div><div>After transduction of the CD133 gene into OC cells, gene ontology (GO) and KEGG pathway enrichment analyses reveal that cytokine-mediated endothelial mesenchymal transition (EMT) is possibly responsible for chemotherapy resistance and tumor progression, and enhanced PAR1, CXCR4, and PD-L1 expressions are also observed. In addition, we found that engineered chimeric antigen receptor (CAR)-T cells targeting PAR1 demonstrated significant in vitro cytotoxicity toward chemoresistant OC sphere with CD133 overexpression.</div></div><div><h3>Conclusions</h3><div>Taken together, our results show that a CD133-3D OC sphere recaptures TME that mimics a real late-stage OC condition, and it can act as a useful platform with mechanism-verifying in vitro and in vivo experiments in researching OC chemotherapy, immunotherapy, and cell therapy to discover new therapeutic approaches.</div></div>","PeriodicalId":9795,"journal":{"name":"Cellular immunology","volume":"417 ","pages":"Article 105015"},"PeriodicalIF":2.9,"publicationDate":"2025-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144919967","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-08-25DOI: 10.1016/j.cellimm.2025.105014
Weixiang Liu , Jieming Ping , Ning Wu
Neutrophil extracellular traps (NETs) are web-like decondensed DNA filaments released by activated neutrophils, decorated with antimicrobial proteins such as myeloperoxidase (MPO) and elastase. Although several methods exist to evaluate NETs formation, including fluorescent microscopy or scanning electron microscopy (SEM), and flow cytometry, each has inherent limitations that restrict widespread application. Given the increasing relevance of NETs in various pathophysiological contexts, we sought to develop a simple, specific, objective and cost-effective flow cytometry-based method to assess NETs both in vitro and in vivo. Our approach leverages multi-parametric flow cytometry to simultaneously evaluate cell size, granularity, DNA decondensation, histone citrullination, and intracellular MPO. This method enables reliable detection of NETs in purified neutrophils as well as in tissue samples. Its performance was validated in parallel with conventional microscopy, confirming specificity and reproducibility. Notably, this FACS-based method is faster, more economical, and free from observer-bias, making it especially well-suited for both research and clinical sample analysis.
{"title":"Establishment of a multi-parameter flow cytometry method to identify and characterize neutrophil extracellular traps","authors":"Weixiang Liu , Jieming Ping , Ning Wu","doi":"10.1016/j.cellimm.2025.105014","DOIUrl":"10.1016/j.cellimm.2025.105014","url":null,"abstract":"<div><div>Neutrophil extracellular traps (NETs) are web-like decondensed DNA filaments released by activated neutrophils, decorated with antimicrobial proteins such as myeloperoxidase (MPO) and elastase. Although several methods exist to evaluate NETs formation, including fluorescent microscopy or scanning electron microscopy (SEM), and flow cytometry, each has inherent limitations that restrict widespread application. Given the increasing relevance of NETs in various pathophysiological contexts, we sought to develop a simple, specific, objective and cost-effective flow cytometry-based method to assess NETs both <em>in vitro</em> and <em>in vivo</em>. Our approach leverages multi-parametric flow cytometry to simultaneously evaluate cell size, granularity, DNA decondensation, histone citrullination, and intracellular MPO. This method enables reliable detection of NETs in purified neutrophils as well as in tissue samples. Its performance was validated in parallel with conventional microscopy, confirming specificity and reproducibility. Notably, this FACS-based method is faster, more economical, and free from observer-bias, making it especially well-suited for both research and clinical sample analysis.</div></div>","PeriodicalId":9795,"journal":{"name":"Cellular immunology","volume":"417 ","pages":"Article 105014"},"PeriodicalIF":2.9,"publicationDate":"2025-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144895389","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-08-16DOI: 10.1016/j.cellimm.2025.105012
Xuebi Wang , Wei Wang , Yabin Liu , Peng Wang , Qin Huang , Di Tian , Yixin Liao , Zhigang Yi , Feng Li , Yuanjia Tang , Chen Zhao , Xiaohong Fan , Yun Ling
Objectives
Neurosyphilis (NS) can cause a range of central nervous system (CNS) damage, from asymptomatic states to severe mental disorders. While lumbar puncture is a reliable diagnostic method for NS, it is often poorly accepted due to its invasive nature, particularly by patients with mild symptoms. This study aims to develop a prediction model for the early diagnosis of NS that without requiring lumbar puncture.
Methods
Clinical data, including imaging, routine blood tests, immune markers, HIV status and cerebrospinal fluid (CSF) examination, were collected from the Shanghai Public Health Clinical Center from 2021 to 2023,. The dataset was randomly split into training and validation sets in an 8:2 ratio. Univariate analysis, the least absolute shrinkage and selection operator (LASSO) and multivariate logistic regression were used to identify significant predictors.
Results
Out of 1078 suspected patients, 702 confirmed syphilis patients with positive Treponema pallidum specific antibody (anti-TP) and positive Treponema Pallidum Particle Agglutination (TRUST) in serum were selected. Among them, 246 patients were diagnosed as NS based on the positive anti-TP in CSF, while 456 patients were classified as non-neurosyphilis (NNS). In the NS group, cerebral ischemia/infarction, ataxia, decreased vision, mental/behavioral disorders, memory impairment, high levels of anti-TP and TRUST (>1:16), elevated red blood cell (RBC) and platelet (PLT) counts, and shorter prothrombin time (PT) were identified. A nomogram was established based on independent prognostic factors. The receiver operating characteristic (ROC) curves and calibration curves showed high predictive accuracy, and clinical decision curve analysis (DCA) indicated good clinical applicability.
Conclusions
The developed nomogram offers a reliable and non-invasive method for early identification of NS in syphilis patients, regardless of their HIV or immune status.
{"title":"Establishing a clinical prediction model of neurosyphilis via a lumbar-puncture-free nomogram","authors":"Xuebi Wang , Wei Wang , Yabin Liu , Peng Wang , Qin Huang , Di Tian , Yixin Liao , Zhigang Yi , Feng Li , Yuanjia Tang , Chen Zhao , Xiaohong Fan , Yun Ling","doi":"10.1016/j.cellimm.2025.105012","DOIUrl":"10.1016/j.cellimm.2025.105012","url":null,"abstract":"<div><h3>Objectives</h3><div>Neurosyphilis (NS) can cause a range of central nervous system (CNS) damage, from asymptomatic states to severe mental disorders. While lumbar puncture is a reliable diagnostic method for NS, it is often poorly accepted due to its invasive nature, particularly by patients with mild symptoms. This study aims to develop a prediction model for the early diagnosis of NS that without requiring lumbar puncture.</div></div><div><h3>Methods</h3><div>Clinical data, including imaging, routine blood tests, immune markers, HIV status and cerebrospinal fluid (CSF) examination, were collected from the Shanghai Public Health Clinical Center from 2021 to 2023,. The dataset was randomly split into training and validation sets in an 8:2 ratio. Univariate analysis, the least absolute shrinkage and selection operator (LASSO) and multivariate logistic regression were used to identify significant predictors.</div></div><div><h3>Results</h3><div>Out of 1078 suspected patients, 702 confirmed syphilis patients with positive <em>Treponema pallidum</em> specific antibody (anti-TP) and positive <em>Treponema Pallidum</em> Particle Agglutination (TRUST) in serum were selected. Among them, 246 patients were diagnosed as NS based on the positive anti-TP in CSF, while 456 patients were classified as non-neurosyphilis (NNS). In the NS group, cerebral ischemia/infarction, ataxia, decreased vision, mental/behavioral disorders, memory impairment, high levels of anti-TP and TRUST (>1:16), elevated red blood cell (RBC) and platelet (PLT) counts, and shorter prothrombin time (PT) were identified. A nomogram was established based on independent prognostic factors. The receiver operating characteristic (ROC) curves and calibration curves showed high predictive accuracy, and clinical decision curve analysis (DCA) indicated good clinical applicability.</div></div><div><h3>Conclusions</h3><div>The developed nomogram offers a reliable and non-invasive method for early identification of NS in syphilis patients, regardless of their HIV or immune status.</div></div>","PeriodicalId":9795,"journal":{"name":"Cellular immunology","volume":"415 ","pages":"Article 105012"},"PeriodicalIF":2.9,"publicationDate":"2025-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144865995","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-08-08DOI: 10.1016/j.cellimm.2025.105013
Yiqi Wang , Xiuhua Zhang , Jiannan Zhang , Mingbo Zhao, Yang Chong, Quankuan Gu, Xianglin Meng, Mingyan Zhao
Acute lung injury (ALI) is a respiratory disease induced by uncontrolled inflammatory responses in the lungs. The pathological features of ALI include alveolar structural damage and pulmonary edema, which ultimately leads to pulmonary dysfunction. ANAPC5 (Anaphase-promoting complex subunit 5) is an E3 ubiquitin ligase known for its anti-inflammatory properties. This study aims to investigate the effects of ANAPC5 on ALI and its underlying molecular mechanism. In the lung tissue of an ALI mouse model induced by lipopolysaccharide (LPS) administration, we observed downregulation of ANAPC5. Through both in vivo and in vitro experiments, we assessed the effect of ANAPC5 on lung injury by conducting pathological analysis and molecular biological detection. ANAPC5 overexpression alleviated inflammatory cell infiltration, reduced alveolar wall thickening, suppressed pulmonary inflammation, and decreased the levels of inflammatory cytokines in bronchoalveolar lavage fluid (BALF) and lung tissue of the ALI model. Moreover, ANAPC5 inhibited M1 polarization and promoted M2 polarization of macrophages both in vitro and in vivo. We also found that ANAPC5 significantly suppressed the activation and expression of the epidermal growth factor receptor (EGFR) through inducing its ubiquitination in macrophages. In LPS-induced M1 macrophages, the presence of EGFR significantly decreased CD24 expression, followed by reversing the inhibitory effects of ANAPC5 on inflammatory responses and macrophage polarization. Collectively, our findings suggest that ANAPC5 serves as a therapeutic molecular target that mitigates ALI through regulating macrophage M1/M2 polarization via the EGFR/CD24 axis.
{"title":"ANAPC5 mitigates acute lung injury through regulating macrophage M1/M2 polarization via the EGFR/CD24 axis","authors":"Yiqi Wang , Xiuhua Zhang , Jiannan Zhang , Mingbo Zhao, Yang Chong, Quankuan Gu, Xianglin Meng, Mingyan Zhao","doi":"10.1016/j.cellimm.2025.105013","DOIUrl":"10.1016/j.cellimm.2025.105013","url":null,"abstract":"<div><div>Acute lung injury (ALI) is a respiratory disease induced by uncontrolled inflammatory responses in the lungs. The pathological features of ALI include alveolar structural damage and pulmonary edema, which ultimately leads to pulmonary dysfunction. ANAPC5 (Anaphase-promoting complex subunit 5) is an E3 ubiquitin ligase known for its anti-inflammatory properties. This study aims to investigate the effects of ANAPC5 on ALI and its underlying molecular mechanism. In the lung tissue of an ALI mouse model induced by lipopolysaccharide (LPS) administration, we observed downregulation of ANAPC5. Through both <em>in vivo</em> and <em>in vitro</em> experiments, we assessed the effect of ANAPC5 on lung injury by conducting pathological analysis and molecular biological detection. ANAPC5 overexpression alleviated inflammatory cell infiltration, reduced alveolar wall thickening, suppressed pulmonary inflammation, and decreased the levels of inflammatory cytokines in bronchoalveolar lavage fluid (BALF) and lung tissue of the ALI model. Moreover, ANAPC5 inhibited M1 polarization and promoted M2 polarization of macrophages both <em>in vitro</em> and <em>in vivo</em>. We also found that ANAPC5 significantly suppressed the activation and expression of the epidermal growth factor receptor (EGFR) through inducing its ubiquitination in macrophages. In LPS-induced M1 macrophages, the presence of EGFR significantly decreased CD24 expression, followed by reversing the inhibitory effects of ANAPC5 on inflammatory responses and macrophage polarization. Collectively, our findings suggest that ANAPC5 serves as a therapeutic molecular target that mitigates ALI through regulating macrophage M1/M2 polarization <em>via</em> the EGFR/CD24 axis.</div></div>","PeriodicalId":9795,"journal":{"name":"Cellular immunology","volume":"415 ","pages":"Article 105013"},"PeriodicalIF":2.9,"publicationDate":"2025-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144865996","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-07-17DOI: 10.1016/j.cellimm.2025.105010
Yonghai Li , Yue Shao , Xianfen Ma , Yaning Li , Yijia Yang , Fengyuan Wang , Yushan Yan , Xiaoxi Hu , Yujie Dai , Meng Li , Max Löhning , Ping Shen , Juntang Lin
Objectives
Chloroquine (CQ) has been used to treat rheumatoid arthritis and systemic lupus erythematosus, but its use in multiple sclerosis (MS) is limited by side effects and insufficient efficacy. To enhance treatment outcomes, understanding CQ's therapeutic mechanisms in MS is crucial. Thus, we administered CQ to mice with experimental autoimmune encephalomyelitis (EAE) and investigated its disease-ameliorating effects and underlying cellular mechanisms.
Methods
CQ was applied intraperitoneally six days after EAE induction, immune responses, with a focus on inflammatory and regulatory T cells, as well as dendritic cells in blood, lymph nodes, spleen, and bone marrow were analyzed by flow cytometry.
Results
CQ treatment significantly reduced cumulative disease score and maximal disease score in CQ-treated group. Immunohistochemical analysis of the spinal cords confirmed the reduced demyelination after CQ treatment, which is accompanied by significantly decreased infiltration of T cells, B cells, and macrophages, and less activated microglia cells. Flow cytometry analysis of peripheral lymphoid organs revealed a significant decrease of inflammatory Th17 cells, which is associated with reduced pDC and their IFN-α expression, as well as Treg cells in CQ-treated mice. Indeed, depletion of pDC alone or simultaneously with CQ treatment significantly reduced EAE severity.
Conclusion
Our results demonstrated that CQ treatment inhibits the development of EAE disease on one hand by enhancing the expansion of Treg in dLN and spleen, and on the other hand by inhibiting the accumulation of pDC and their IFN-α expression in the spleen and bone marrow. This joint effort restricts the level of inflammation in peripheral and later in CNS. Furthermore, developing a pDC-targeted CQ treatment will not only increase the treatment efficiency, but also largely decrease side effects.
{"title":"Chloroquine treatment ameliorates experimental autoimmune encephalomyelitis by inhibiting T cell differentiation and pDC accumulation","authors":"Yonghai Li , Yue Shao , Xianfen Ma , Yaning Li , Yijia Yang , Fengyuan Wang , Yushan Yan , Xiaoxi Hu , Yujie Dai , Meng Li , Max Löhning , Ping Shen , Juntang Lin","doi":"10.1016/j.cellimm.2025.105010","DOIUrl":"10.1016/j.cellimm.2025.105010","url":null,"abstract":"<div><h3>Objectives</h3><div>Chloroquine (CQ) has been used to treat rheumatoid arthritis and systemic lupus erythematosus, but its use in multiple sclerosis (MS) is limited by side effects and insufficient efficacy. To enhance treatment outcomes, understanding CQ's therapeutic mechanisms in MS is crucial. Thus, we administered CQ to mice with experimental autoimmune encephalomyelitis (EAE) and investigated its disease-ameliorating effects and underlying cellular mechanisms.</div></div><div><h3>Methods</h3><div>CQ was applied intraperitoneally six days after EAE induction, immune responses, with a focus on inflammatory and regulatory T cells, as well as dendritic cells in blood, lymph nodes, spleen, and bone marrow were analyzed by flow cytometry.</div></div><div><h3>Results</h3><div>CQ treatment significantly reduced cumulative disease score and maximal disease score in CQ-treated group. Immunohistochemical analysis of the spinal cords confirmed the reduced demyelination after CQ treatment, which is accompanied by significantly decreased infiltration of T cells, B cells, and macrophages, and less activated microglia cells. Flow cytometry analysis of peripheral lymphoid organs revealed a significant decrease of inflammatory Th17 cells, which is associated with reduced pDC and their IFN-α expression, as well as Treg cells in CQ-treated mice. Indeed, depletion of pDC alone or simultaneously with CQ treatment significantly reduced EAE severity.</div></div><div><h3>Conclusion</h3><div>Our results demonstrated that CQ treatment inhibits the development of EAE disease on one hand by enhancing the expansion of Treg in dLN and spleen, and on the other hand by inhibiting the accumulation of pDC and their IFN-α expression in the spleen and bone marrow. This joint effort restricts the level of inflammation in peripheral and later in CNS. Furthermore, developing a pDC-targeted CQ treatment will not only increase the treatment efficiency, but also largely decrease side effects.</div></div>","PeriodicalId":9795,"journal":{"name":"Cellular immunology","volume":"415 ","pages":"Article 105010"},"PeriodicalIF":3.7,"publicationDate":"2025-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144679089","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-07-14DOI: 10.1016/j.cellimm.2025.105001
Kai Yan, Zhongdang Xiao
Chimeric antigen receptor (CAR)-T cell therapy has revolutionized the treatment of hematologic malignancies, but its long-term efficacy is hindered by antigen escape, T-cell exhaustion, and the immunosuppressive tumor microenvironment (TME). Programmed death ligand 1 (PD-L1) expression in the TME inhibits CAR-T cell function, limiting persistence and cytotoxic capacity. To address this, we engineered CD19/BCMA-targeted CAR-T cells co-expressing a PD1IL7R chimeric switch receptor (CSR). This novel receptor converts PD-L1-mediated inhibitory signals into IL7R-driven pro-survival and proliferative pathways, enhancing CAR-T cell expansion, persistence, and cytotoxicity in a PD-L1–dependent but antigen-specific manner. In vitro, CD19/BCMA-PD1IL7R CAR-T cells exhibit improved central memory T-cell formation, increased cytokine secretion, and superior antitumor activity compared to conventional CAR-T cells. Notably, these functional enhancements were evident even at low levels of PD-L1 expression on target cells, and no off-target effects were observed. Our findings suggest that incorporating the PD1-IL7R switch receptor into CAR-T cells effectively overcomes PD-L1–mediated immunosuppression, enhancing both their persistence and antitumor efficacy. This approach offers a versatile strategy for improving CAR-T therapy in the treatment of both hematologic and solid tumors.
{"title":"Enhancing the antitumor activity of CD19/BCMA CAR-T cells in vitro with a PD1IL7R chimeric switch receptor","authors":"Kai Yan, Zhongdang Xiao","doi":"10.1016/j.cellimm.2025.105001","DOIUrl":"10.1016/j.cellimm.2025.105001","url":null,"abstract":"<div><div>Chimeric antigen receptor (CAR)-T cell therapy has revolutionized the treatment of hematologic malignancies, but its long-term efficacy is hindered by antigen escape, T-cell exhaustion, and the immunosuppressive tumor microenvironment (TME). Programmed death ligand 1 (PD-L1) expression in the TME inhibits CAR-T cell function, limiting persistence and cytotoxic capacity. To address this, we engineered CD19/BCMA-targeted CAR-T cells co-expressing a PD1IL7R chimeric switch receptor (CSR). This novel receptor converts PD-L1-mediated inhibitory signals into IL7R-driven pro-survival and proliferative pathways, enhancing CAR-T cell expansion, persistence, and cytotoxicity in a PD-L1–dependent but antigen-specific manner. In vitro, CD19/BCMA-PD1IL7R CAR-T cells exhibit improved central memory T-cell formation, increased cytokine secretion, and superior antitumor activity compared to conventional CAR-T cells. Notably, these functional enhancements were evident even at low levels of PD-L1 expression on target cells, and no off-target effects were observed. Our findings suggest that incorporating the PD1-IL7R switch receptor into CAR-T cells effectively overcomes PD-L1–mediated immunosuppression, enhancing both their persistence and antitumor efficacy. This approach offers a versatile strategy for improving CAR-T therapy in the treatment of both hematologic and solid tumors.</div></div>","PeriodicalId":9795,"journal":{"name":"Cellular immunology","volume":"415 ","pages":"Article 105001"},"PeriodicalIF":3.7,"publicationDate":"2025-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144614817","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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