EBioMedicine最新文献

{"title":"Targeting B-cell subsets in type 1 diabetes: possible routes to therapy?","authors":"Noel G Morgan","doi":"10.1016/j.ebiom.2025.105610","DOIUrl":"10.1016/j.ebiom.2025.105610","url":null,"abstract":"","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"113 ","pages":"105610"},"PeriodicalIF":9.7,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11876756/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143457233","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":"TCL1A in naïve B cells as a therapeutic target for type 1 diabetes.","authors":"Siweier Luo, Lina Zhang, Chunfang Wei, Chipeng Guo, Zhe Meng, Honghui Zeng, Lele Hou, Le Wang, Zulin Liu, Yufei Du, Shiyu Tan, Yating Zhang, Xiaoding Xu, Liyang Liang, Yiming Zhou","doi":"10.1016/j.ebiom.2025.105593","DOIUrl":"10.1016/j.ebiom.2025.105593","url":null,"abstract":"<p><strong>Background: </strong>Type 1 diabetes (T1D) is an autoimmune disease characterised by the attack of pancreatic β cells by \"self\" immune cells. Although previous studies demonstrated that B cells contribute to T1D through antigen presentation and autoantibody production, the involvement of different populations of B cells, particularly in the early stages of T1D, has not been fully elucidated.</p><p><strong>Methods: </strong>In this study, we employed single-cell RNA sequencing (scRNA-seq) and flow cytometry to investigate immune cell populations in patients with newly diagnosed T1D, their relative controls and age-matched healthy controls. Phosphoprotein microarray analysis was employed to investigate changes in protein phosphorylation in B cells. Furthermore, we developed a siRNA-based nanomedicine and evaluated its therapeutic potential in the NOD mouse. The integration of scRNA-seq, flow cytometry, phosphoprotein microarrays, and functional assays established a robust framework for understanding and targeting B cell-mediated autoimmunity in T1D.</p><p><strong>Findings: </strong>Using single-cell RNA sequencing, we discovered that patients with T1D exhibited increased humoural immunity in the early stage of T1D. Specifically, the population of naïve B cells increased in patients with newly diagnosed T1D who expressed elevated levels of the AKT kinase coactivator TCL1A. Using a protein phosphorylation microarray, we confirmed that TCL1A knockdown specifically impaired AKT2 phosphorylation and affected B cell survival and proliferation. Notably, we discovered that the naïve B cell population increased and TCL1A expression was upregulated in NOD mice that developed T1D. Both the levels of naïve B cells and TCL1A were strongly associated with glucose intolerance in T1D mice. Importantly, treatment with a siRNA-based nanomedicine targeting Tcl1a mRNA effectively reduced the number of naïve B cells, prevented the loss of pancreatic β cells, and improved glucose intolerance in T1D mice.</p><p><strong>Interpretation: </strong>Using single-cell RNA-seq, we have not only uncovered a naïve B cell specific gene that may contribute to the pathogenesis of T1D but also highlighted the potential of siRNA-based nanomedicine for treating T1D. The clinical translation of these findings offers a new approach for the treatment of T1D.</p><p><strong>Funding: </strong>See Acknowledgements.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"113 ","pages":"105593"},"PeriodicalIF":9.7,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11872515/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143413534","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":"Blood N-glycomics reveals individuals at risk for cognitive decline and Alzheimer's disease.","authors":"Robin Ziyue Zhou, Stefan Gaunitz, Bjørn-Eivind Kirsebom, Britt Lundin, Marie Hellström, Alenka Jejcic, Anders Sköldunger, Anders Wimo, Bengt Winblad, Tormod Fladby, Sophia Schedin-Weiss, Lars O Tjernberg","doi":"10.1016/j.ebiom.2025.105598","DOIUrl":"10.1016/j.ebiom.2025.105598","url":null,"abstract":"<p><strong>Background: </strong>Blood biomarkers with prognostic accuracy for Alzheimer's disease (AD) are crucial for selecting at-risk individuals for interventions. Altered protein N-glycosylation has been implicated in several pathogenic pathways in AD and could be an early AD biomarker.</p><p><strong>Methods: </strong>We developed a mass spectrometry-based method to simultaneously quantify 62 blood N-glycan structures in individuals with biological or clinical AD and matched controls. We analysed N-glycan levels in a Swedish discovery cohort (n = 40) and validated our results in a Norwegian cohort (n = 60). Individuals were grouped according to N-glycan levels using unsupervised hierarchical clustering. Difference in disease progression between groups were modelled using linear mixed-effects models.</p><p><strong>Findings: </strong>A subgroup of individuals exhibited low blood N-glycosylation (32.4% of Swedish cohort, 37.9% of Norwegian cohort). In the Swedish cohort, low N-glycosylation was associated with AD and cognitive decline. In the Norwegian cohort, low blood N-glycosylation showed no correlation with amyloid/tau, but importantly, strongly predicted future cognitive decline. In total, fourteen N-glycan structures were significantly less abundant in the low N-glycosylation group compared to the rest of the individuals in both cohorts.</p><p><strong>Interpretation: </strong>Reduced blood N-glycan levels predict cognitive decline independent of amyloid or tau status. Blood N-glycome profiling could be used to identify individuals at risk for AD dementia.</p><p><strong>Funding: </strong>Stiftelsen för Gamla Tjänarinnor, Stockholm County Council-ALF, JPND, PMI-AD, Medical Diagnostics Karolinska, Helse-Nord, Gun och Bertil Stohnes stiftelse, Demensförbundet, Stiftelsen Dementia, Margaretha af Ugglas' foundation, Vinnova, the private initiative \"Innovative ways to fight Alzheimer's disease-Leif Lundblad Family and others\".</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"113 ","pages":"105598"},"PeriodicalIF":9.7,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11893330/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143472341","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":"A randomized, double-blind, Phase 1, single- and multiple-dose placebo-controlled study of the safety and pharmacokinetics of IN-006, an inhaled antibody treatment for COVID-19 in healthy volunteers.","authors":"Thomas R Moench, Lakshmi Botta, Brian Farrer, Jason D Lickliter, Hyunah Kang, Yoona Park, Cheolmin Kim, Marshall Hoke, Miles Brennan, Morgan D McSweeney, Zachary Richardson, John B Whelan, Jong Moon Cho, Soo Young Lee, Frances Faurot, Jeff Hutchins, Samuel K Lai","doi":"10.1016/j.ebiom.2025.105582","DOIUrl":"10.1016/j.ebiom.2025.105582","url":null,"abstract":"<p><strong>Background: </strong>Although COVID-19 is predominantly a respiratory tract infection, current antibody treatments are administered by systemic dosing. We hypothesize that inhaled delivery of a monoclonal antibody may be a more effective and convenient route. We investigated the safety, tolerability, and pharmacokinetics of IN-006, a reformulation of regdanvimab for nebulized delivery by a handheld nebulizer.</p><p><strong>Methods: </strong>A Phase 1 study was conducted in healthy volunteers aged 18-55 a Phase 1 unit in Melbourne, Australia (ACTRN12621001235897). Study staff and participants were blinded to treatment assignment, except for pharmacy staff preparing the study drug. The ratio of active:placebo randomization to each cohort was set at 3:1. The primary outcomes were safety and tolerability. Exploratory outcomes were pharmacokinetics of IN-006 in nasal fluid and serum.</p><p><strong>Findings: </strong>Twenty-three participants were enrolled and randomized across two single dose and one multiple dose cohorts (30 mg or 90 mg single nebulized dose, or seven daily 90 mg doses). There were no serious adverse events. All enrolled participants completed the study without treatment interruption or discontinuation. All treatment-emergent adverse events were transient, non-dose dependent, and graded mild to moderate in severity. Nebulization was well-tolerated and completed in an average of 6 min. Geometric mean nasal fluid concentrations of IN-006 in the multiple dose cohort were 739.8 μg/mL at 30 min after dosing and 1.2 μg/mL at 22 h. Geometric mean serum levels in the multiple dose cohort peaked at 0.51 μg/mL 3 days after the final dose.</p><p><strong>Interpretation: </strong>IN-006 was well-tolerated and achieved concentrations in the respiratory tract orders of magnitude above the IC₅₀ range typical of antiviral mAbs. These data support further development of nebulized delivery of antiviral mAbs for respiratory infectious disease.</p><p><strong>Funding: </strong>This work was funded by the U.S. Army Medical Research and Development Command (W81XWH-15-9-0001) and regdanvimab was provided by Celltrion, Inc.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"113 ","pages":"105582"},"PeriodicalIF":9.7,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11849668/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143381856","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":"Intranasal recombinant protein subunit vaccine targeting TLR3 induces respiratory tract IgA and CD8 T cell responses and protects against respiratory virus infection.","authors":"Katharina Wørzner, Signe Tandrup Schmidt, Julie Zimmermann, Ahmad Tami, Charlotta Polacek, Carlota Fernandez-Antunez, Katrine Top Hartmann, Rune Fledelius Jensen, Julia Sid Hansen, Kristin Illigen, Louise Krag Isling, Gitte Erbs, Gregers Jungersen, Ida Rosenkrands, Anna Offersgaard, Judith Gottwein, Kenn Holmbeck, Henrik Elvang Jensen, Santseharay Ramirez, Frank Follmann, Jens Bukh, Gabriel Kristian Pedersen","doi":"10.1016/j.ebiom.2025.105615","DOIUrl":"10.1016/j.ebiom.2025.105615","url":null,"abstract":"<p><strong>Background: </strong>Intranasal vaccines against respiratory viruses are desired due to ease of administration and potential to protect against virus infection of the upper respiratory tract.</p><p><strong>Methods: </strong>We tested a cationic liposomal adjuvant delivering the TLR3 agonist Poly (I:C) (CAF®09b) for intranasal administration, by formulating this with SARS-CoV-2 spike trimeric protein and assessing airway mucosal immune responses in mice. The vaccine was further evaluated in SARS-CoV-2 virus challenge models, using mice expressing the human ACE2 receptor and Syrian hamsters.</p><p><strong>Findings: </strong>The intranasal vaccine elicited both serum neutralising antibody responses and IgA responses in the upper respiratory tract. Uniquely, it also elicited high-magnitude CD4 and CD8 T cell responses in the lung parenchyma and nasal-associated lymphoid tissue. In contrast, parenteral administration of the same vaccine, or the mRNA-1273 (Spikevax®) vaccine, led to systemic antibody responses and vaccine-induced CD4 T cells were mainly found in circulation. The intranasal vaccine protected against homologous SARS-CoV-2 (Wuhan-Hu-1) challenge in K18-hACE2 mice, preventing weight loss and virus infection in the upper and lower airways. In Syrian hamsters, the vaccine prevented weight loss and significantly reduced virus load after challenge with the homologous strain and Omicron BA.5.</p><p><strong>Interpretation: </strong>This study demonstrates that intranasal subunit vaccines containing TLR3-stimulating cationic liposomes effectively induce airway IgA and T cell responses, which could be utilised in future viral pandemics.</p><p><strong>Funding: </strong>This work was primarily supported by the European Union Horizon 2020 research and innovation program under grant agreement no. 101003653.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"113 ","pages":"105615"},"PeriodicalIF":9.7,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11893338/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143472344","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":"An LNP-mRNA vaccine modulates innate cell trafficking and promotes polyfunctional Th1 CD4⁺ T cell responses to enhance BCG-induced protective immunity against Mycobacterium tuberculosis.","authors":"Hannah Lukeman, Hareth Al-Wassiti, Stewart A Fabb, Leonard Lim, Trixie Wang, Warwick J Britton, Megan Steain, Colin W Pouton, James A Triccas, Claudio Counoupas","doi":"10.1016/j.ebiom.2025.105599","DOIUrl":"10.1016/j.ebiom.2025.105599","url":null,"abstract":"<p><strong>Background: </strong>Mycobacterium tuberculosis remains the largest infectious cause of mortality worldwide, even with over a century of widespread administration of the only licenced tuberculosis (TB) vaccine, Bacillus Calmette-Guérin (BCG). mRNA technology remains an underexplored approach for combating chronic bacterial infections such as TB.</p><p><strong>Methods: </strong>We have developed a lipid nanoparticle (LNP)-mRNA vaccine, termed mRNA^CV2, encoding for the M. tuberculosis CysVac2 fusion protein, which we have previously formulated as an adjuvanted subunit vaccine. This LNP-mRNA vaccine was administered intramuscularly to female C57BL/6 mice as a standalone vaccine or as booster to BCG to assess immunogenicity and efficacy of the construct.</p><p><strong>Findings: </strong>Vaccination with mRNA^CV2 induced high frequencies of polyfunctional, antigen-specific Th1 CD4⁺ T cells in the blood and lungs, which was associated with the rapid recruitment of both innate and adaptive immune cells to lymph nodes draining the site of immunisation. mRNA^CV2 vaccination also provided significant pulmonary protection in M. tuberculosis-infected mice, reducing bacterial load and inflammatory infiltration in the lungs. Importantly, mRNA^CV2 enhanced immune responses and long-term protection when used to boost BCG-primed mice.</p><p><strong>Interpretation: </strong>These findings of a protective LNP-mRNA vaccine for TB highlight the potential of the LNP-mRNA platform for TB control and support further research to facilitate translation to humans.</p><p><strong>Funding: </strong>This work was supported by the NHMRC Centre of Research Excellence in Tuberculosis Control to JAT and WJB (APP1153493), and MRFF mRNA Clinical Trial Enabling Infrastructure grant to CWP and HAW (MRFCTI000006).</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"113 ","pages":"105599"},"PeriodicalIF":9.7,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11871481/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143432487","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":"Overall survival according to time-of-day of combined immuno-chemotherapy for advanced non-small cell lung cancer: a bicentric bicontinental study.","authors":"Zhe Huang, Abdoulaye Karaboué, Liang Zeng, Adrien Lecoeuvre, Lemeng Zhang, Xiao-Mei Li, Haoyue Qin, Gabrielle Danino, Feng Yang, Marie-Sara Malin, Li Deng, Marte Rigal, Hong Liu, Xiang Chen, Qinqin Xu, Lamiae Grimaldi, Thierry Collon, Jing Wang, René Adam, Nong Yang, Boris Duchemann, Yongchang Zhang, Francis Lévi","doi":"10.1016/j.ebiom.2025.105607","DOIUrl":"10.1016/j.ebiom.2025.105607","url":null,"abstract":"<p><strong>Background: </strong>Circadian rhythms regulate immune cell activity, influencing responses to vaccines, and immune checkpoint inhibitors (ICIs). Early time-of-day administration (ToDA) of singe-agent ICIs has been associated with improved overall survival (OS) in patients with metastatic \"immunotherapy sensitive\" cancers. However, the impact of ToDA on OS in patients receiving combination therapy with ICIs and chemotherapy for advanced non-small cell lung cancer (NSCLC) remains unclear.</p><p><strong>Methods: </strong>This retrospective study included patients from oncology units in Paris, France (Cohort 1) and Hunan, China (Cohort 2) who received first-line immuno-chemotherapy for stage IIIC or IV NSCLC between January 2018 and October 2023. The primary outcome was OS. The median ToDA of the initial four ICI infusions was computed for each patient. Hazard ratio (HR) for death or progression were determined using cut-off times ranging from 10:30 to 13:00. Kaplan Meier and Cox models were used to estimate OS and progression-free survival (PFS) adjusting for main patient characteristics.</p><p><strong>Findings: </strong>The study included 713 patients (Cohort 1, n = 165; Cohort 2, n = 548). Pembrolizumab was the most common ICI (51%), which was used with either pemetrexed-carboplatin/cisplatin (49%) or paclitaxel-carboplatin (51%). The optimal ToDA cut-off was 11:30, with patients receiving immuno-chemotherapy before 11:30 showing significantly improved OS (33.0 months [95% CI, 27.5-41.0] vs 19.5 months [18.0-22.5]; p < 0.0001). Multivariable analysis confirmed that earlier ToDA was associated with better OS (adjusted HR = 0.47 [95% CI, 0.37-0.60]). ToDA significantly impacted OS in each cohort and for PFS and response rates in each cohort and the pooled data.</p><p><strong>Interpretation: </strong>This sizeable bi-continental study provided real-world evidence that morning administration of standard first-line immuno-chemotherapy was associated with improved clinical outcomes compared to afternoon dosing in patients with NSCLC. Randomised trials are required to validate this finding and inform recommendations for clinical practice.</p><p><strong>Funding: </strong>National Natural Science Foundation of China (82222048, 82003206, 82173338, and 82102747).</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"113 ","pages":"105607"},"PeriodicalIF":9.7,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11893323/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143472346","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":"Corrigendum to \"Correlation between systemic allergen desensitisation and long-term asthma protection in mice following intravenous administration of the live tuberculosis vaccine MTBVAC\" [EBioMedicine 107(2024)105272] DOI: https://doi.org/10.1016/j.ebiom.2024.105272.","authors":"Silvia Calvo, Jose Manuel Rodrigo-Muñoz, Raquel Tarancón, Santiago Uranga, Carlos Martín, Victoria Del Pozo, Nacho Aguiló","doi":"10.1016/j.ebiom.2025.105637","DOIUrl":"10.1016/j.ebiom.2025.105637","url":null,"abstract":"","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"113 ","pages":"105637"},"PeriodicalIF":9.7,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11905857/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143522904","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":"Bi-allelic LAMP3 variants in childhood interstitial lung disease: a surfactant-related disease.","authors":"Camille Louvrier, Tifenn Desroziers, Yohan Soreze, Martha Delgado Rodriguez, Lucie Thomas, Valérie Nau, Florence Dastot-Le Moal, Jonathan A Bernstein, F Sessions Cole, Markus Damme, Anthony Fischer, Matthias Griese, Daniel Hinds, Laura Keehan, Carlos Milla, Hadhud Mohammad, Jonathan Rips, Jennifer A Wambach, Daniel J Wegner, Serge Amselem, Marie Legendre, Irina Giurgea, Sonia Athina Karabina, Oded Breuer, Aurore Coulomb l'Herminé, Nadia Nathan","doi":"10.1016/j.ebiom.2025.105626","DOIUrl":"10.1016/j.ebiom.2025.105626","url":null,"abstract":"<p><strong>Background: </strong>LAMP3 encodes a lysosomal membrane protein associated with lamellar bodies and has recently been proposed as a candidate gene for childhood interstitial lung diseases (chILD). Here, we identified two LAMP3 variants in a proband with chILD and performed functional validation of these variants as well as the previously reported variants to demonstrate the role of LAMP3 in pathology.</p><p><strong>Methods: </strong>LAMP3 variants were identified by exome sequencing. Ex vivo studies included mRNA analysis from nasal brushing and lung tissue and immunohistochemistry from lung biopsy. In vitro functional analyses in the A549 cell line included immunofluorescence staining and expression analysis of LAMP3. Interactions between LAMP3 and the surfactant protein (SP)-B and SP-C were evaluated by co-immunoprecipitation.</p><p><strong>Findings: </strong>Two heterozygous LAMP3 variants (Y302Qfs∗2 and T268M) were identified in a 15 year old boy with chILD. LAMP3 mRNA revealed that the frameshift variant resulted in nonsense-mediated mRNA decay. Reduced LAMP3 expression was confirmed in the patient's lung tissue. Functional studies of the T268M and the previously reported G288R variant revealed reduced levels of the mutant proteins. In addition, impaired N-glycosylation and protein instability were demonstrated with the T268M variant. Finally, we provided evidence for an interaction between LAMP3 and SP-B and SP-C, revealing a direct link between LAMP3 and surfactant metabolism.</p><p><strong>Interpretation: </strong>LAMP3 bi-allelic variants leading to LAMP3 dysfunction emerges as a cause of chILD associated with a heterogeneous phenotype that remains to be further defined. The close links between LAMP3 and surfactant metabolism could explain the pathophysiology of this genetic disease.</p><p><strong>Funding: </strong>No specific funding.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"113 ","pages":"105626"},"PeriodicalIF":9.7,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11914748/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143536899","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":"Dynamic forecasting module for chronic graft-versus-host disease progression based on a disease-associated subpopulation of B cells: a multicenter prospective study.","authors":"Yuanchen Ma, Jieying Chen, Zhiping Fan, Jiahao Shi, Gang Li, Xiaobo Li, Tao Wang, Na Xu, Jialing Liu, Zhishan Li, Heshe Li, Xiaoran Zhang, Dongjun Lin, Wu Song, Qifa Liu, Weijun Huang, Xiaoyong Chen, Andy Peng Xiang","doi":"10.1016/j.ebiom.2025.105587","DOIUrl":"10.1016/j.ebiom.2025.105587","url":null,"abstract":"<p><strong>Background: </strong>Predicting chronic graft-versus-host disease (cGVHD) progression has been challenging due to its dynamic nature and the lack of reliable real-time monitoring tools, necessitating substantial investments of time and financial resources for effective management. Consequently, identifying appropriate immune cell subsets or molecules as prognostic or predictive biomarkers for cGVHD is essential.</p><p><strong>Methods: </strong>Building on the pivotal role of B-cell homeostasis in cGVHD progression, we integrated spectral flow cytometry with advanced machine learning algorithms to systematically analyze the relationship between B cells and cGVHD progression. Leveraging the identification of a distinct B-cell subpopulation, we developed cGPS (cGVHD Progress Score), a user-friendly tool based on marker distribution. To validate cGPS, we conducted both retrospective and prospective multi-center studies involving 91 patients (25 non-GVHD and 66 cGVHD cases).</p><p><strong>Findings: </strong>We identified a distinct B-cell subpopulation characterized by CD27⁺CD86⁺CD20^-, which can precisely distinguish cGVHD. Leveraging this discovery, we developed cGPS. The retrospective study highlighted the predictive power of cGPS, achieving an impressive area under the curve (AUC) of 0.98 for identifying non-GVHD patients prone to cGVHD and 0.88 for predicting disease progression in cGVHD patients. Notably, the prospective study highlighted cGPS's effectiveness, as it accurately predicted all instances of cGVHD development or progression within an average of three-month observation window.</p><p><strong>Interpretation: </strong>These findings validate cGPS as a highly effective and dynamic B cell-based tool for monitoring cGVHD progression, offering a crucial solution for prognosis and prediction of treatment effectiveness. The multicenter approach applied to both retrospective and prospective studies strengthen the reliability and adaptability of our findings. We are confident that cGPS is a highly competitive tool with great potential for clinical application.</p><p><strong>Funding: </strong>This work was supported by grants from the National Key Research and Development Program of China, Stem Cell and Translational Research (2022YFA1105000, 2022YFA1104100); the National Natural Science Foundation of China (82430050, 32130046, 82270230, 81970109); Key Research and Development Program of Guangdong Province (2023B1111050006); Guangdong Basic and Applied Basic Research Foundation (2023B1515020119); Key Scientific and Technological Program of Guangzhou City (2023B01J1002); Pioneering talents project of Guangzhou Development Zone (2021-L029); the Shenzhen Science and Technology Program (KJZD20230923114504008).</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"113 ","pages":"105587"},"PeriodicalIF":9.7,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11872411/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143413529","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}