Journal of Experimental Medicine最新文献_第3页

Dadaism catches up with DADA2. 达达主义赶上了DADA2。

IF 10.6 1区医学

Journal of Experimental Medicine Pub Date : 2025-11-03 Epub Date: 2025-08-27 DOI: 10.1084/jem.20251490

Dusan Bogunovic

引用次数: 0

A human-mouse atlas of intrarenal myeloid cells identifies conserved disease-associated macrophages in lupus nephritis. 人-小鼠肾内骨髓细胞图谱鉴定了狼疮肾炎中保守的疾病相关巨噬细胞。

IF 10.6 1区医学

Journal of Experimental Medicine Pub Date : 2025-11-03 Epub Date: 2025-09-03 DOI: 10.1084/jem.20241873

Paul J Hoover, Chirag Raparia, David J Lieb, Yochay Tzur, Joyce Kang, Arnon Arazi, Rollin Leavitt, Rakesh Mishra, Sujal I Shah, Daimon Simmons, Stephen Li, Michael Peters, Thomas Eisenhaure, Timothy J Few-Cooper, Saisram S Gurajala, Abraham Sonny, Jeffrey B Hodgin, Celine C Berthier, Joel M Guthridge, Andrea Fava, Robert M Clancy, Chaim Putterman, Peter M Izmirly, H Michael Belmont, Kenneth Kalunian, Diane Kamen, David Wofsy, Jill P Buyon, Judith A James, Michelle Petri, Betty Diamond, Soumya Raychaudhuri, Shai S Shen-Orr, Nir Hacohen, Anne Davidson

{"title":"A human-mouse atlas of intrarenal myeloid cells identifies conserved disease-associated macrophages in lupus nephritis.","authors":"Paul J Hoover, Chirag Raparia, David J Lieb, Yochay Tzur, Joyce Kang, Arnon Arazi, Rollin Leavitt, Rakesh Mishra, Sujal I Shah, Daimon Simmons, Stephen Li, Michael Peters, Thomas Eisenhaure, Timothy J Few-Cooper, Saisram S Gurajala, Abraham Sonny, Jeffrey B Hodgin, Celine C Berthier, Joel M Guthridge, Andrea Fava, Robert M Clancy, Chaim Putterman, Peter M Izmirly, H Michael Belmont, Kenneth Kalunian, Diane Kamen, David Wofsy, Jill P Buyon, Judith A James, Michelle Petri, Betty Diamond, Soumya Raychaudhuri, Shai S Shen-Orr, Nir Hacohen, Anne Davidson","doi":"10.1084/jem.20241873","DOIUrl":"10.1084/jem.20241873","url":null,"abstract":"Monocytes and macrophages in patients with lupus nephritis exhibit altered behavior compared with healthy kidneys. How to optimally use mouse models to develop treatments targeting these cells is poorly understood. This study compared intrarenal myeloid cells in four mouse models and 155 lupus nephritis patients using single-cell profiling, spatial transcriptomics, and functional studies. Across mouse models, monocyte and macrophage subsets consistently expanded or contracted in disease. A subset of murine classical monocytes expanded in disease; these cells expressed Cd9, Spp1, Ctsd, Cd63, Apoe, and Trem2, genes associated with tissue injury in other organs that play roles in inflammation, lipid metabolism, and tissue repair. Resident macrophages expressed similar genes in clinical disease. In humans, we identified analogous disease-associated monocytes and macrophages that were associated with kidney histological subtypes and disease progression, sharing gene expression and localizing to similar kidney microenvironments as in mice. This cross-species analysis supports the use of mouse functional studies for understanding human lupus nephritis.","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"222 11","pages":""},"PeriodicalIF":10.6,"publicationDate":"2025-11-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144956568","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}

引用次数: 0

A high-throughput zebrafish screen identifies novel candidate treatments for kaposiform lymphangiomatosis (KLA). 高通量斑马鱼筛选确定新的候选治疗卡西样淋巴管瘤病（KLA）。

IF 10.6 1区医学

Journal of Experimental Medicine Pub Date : 2025-11-03 Epub Date: 2025-08-21 DOI: 10.1084/jem.20240513

Ivan Bassi, Amani Jabali, Lotan Levin, Giuseppina Lambiase, Noga Moshe, Naama Farag, Yaara Tevet, Gal Perlmoter, Shany Egozi, Gil S Leichner, Polina Geva, Aviv Barzilai, Camila Avivi, Jonathan Long, Jason J Otterstrom, Yael Paran, Haim Barr, Karina Yaniv, Shoshana Greenberger

{"title":"A high-throughput zebrafish screen identifies novel candidate treatments for kaposiform lymphangiomatosis (KLA).","authors":"Ivan Bassi, Amani Jabali, Lotan Levin, Giuseppina Lambiase, Noga Moshe, Naama Farag, Yaara Tevet, Gal Perlmoter, Shany Egozi, Gil S Leichner, Polina Geva, Aviv Barzilai, Camila Avivi, Jonathan Long, Jason J Otterstrom, Yael Paran, Haim Barr, Karina Yaniv, Shoshana Greenberger","doi":"10.1084/jem.20240513","DOIUrl":"https://doi.org/10.1084/jem.20240513","url":null,"abstract":"Kaposiform lymphangiomatosis (KLA) is a rare and aggressive disease caused by a somatic activating NRAS mutation (p.Q61R) in lymphatic endothelial cells (LECs). The development of new therapeutic avenues is hampered by the lack of animal models faithfully replicating the clinical manifestations of KLA. Here, we established a novel zebrafish model of KLA by conditionally expressing the human NRAS mutation in venous and lymphatic ECs. Mutant embryos recapitulate key clinical features of KLA, including dilated lymphatics and pericardial edema, which are reversed by trametinib, a MEK inhibitor used in KLA treatment. Leveraging this model in combination with an AI-based high-throughput drug screening platform, we identify cabozantinib, a tyrosine kinase inhibitor, and GSK690693, a competitive pan-Akt kinase inhibitor, as promising candidates for treating KLA. Notably, both drugs normalized sprouting and migration of cultured LECs from a KLA patient. Overall, our novel zebrafish model provides a powerful platform to dissect KLA pathogenesis and identify new therapeutic avenues.","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"222 11","pages":""},"PeriodicalIF":10.6,"publicationDate":"2025-11-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144956492","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}

引用次数: 0

Multi-omics uncovers transcriptional programs of gut-resident memory CD4+ T cells in Crohn's disease. 多组学揭示了克罗恩病中肠道常驻记忆CD4+ T细胞的转录程序。

IF 10.6 1区医学

Journal of Experimental Medicine Pub Date : 2025-11-03 Epub Date: 2025-09-04 DOI: 10.1084/jem.20242106

Mitsuru Arase, Mari Murakami, Takako Kihara, Ryuichi Kuwahara, Hironobu Toyota, Naoki Sumitani, Naohiko Kinoshita, Kelvin Y Chen, Takehito Yokoi, Daisuke Motooka, Daisuke Okuzaki, Yuhe Zhao, Hazuki Miyazaki, Takayuki Ogino, Seiichi Hirota, Hiroki Ikeuchi, Kiyoshi Takeda

{"title":"Multi-omics uncovers transcriptional programs of gut-resident memory CD4+ T cells in Crohn's disease.","authors":"Mitsuru Arase, Mari Murakami, Takako Kihara, Ryuichi Kuwahara, Hironobu Toyota, Naoki Sumitani, Naohiko Kinoshita, Kelvin Y Chen, Takehito Yokoi, Daisuke Motooka, Daisuke Okuzaki, Yuhe Zhao, Hazuki Miyazaki, Takayuki Ogino, Seiichi Hirota, Hiroki Ikeuchi, Kiyoshi Takeda","doi":"10.1084/jem.20242106","DOIUrl":"10.1084/jem.20242106","url":null,"abstract":"Tissue-resident memory T cells (TRM) remain in nonlymphatic barrier tissues for extended periods and are deeply involved in immune memory at the site of inflammation. Here, we employed multilayered single-cell analytic approaches including chromatin, gene, and protein profiling to characterize a unique CD4+ TRM subset present in the inflamed gut mucosa of Crohn's disease patients. We identified two key transcription factors, RUNX2 and BHLHE40, as regulators of pathologically relevant CD4+ TRM. These transcriptional regulators work together to induce distinct cellular properties of disease-specific TRM, such as cytotoxicity, T helper 1-effector activity, and tissue retention. Downregulation of RUNX2 and BHLHE40 in patient-derived gut CD4+ T cells resulted in the mitigation of the pathogenic phenotype of these cells. Conversely, the ectopic overexpression of both transcription factors in healthy donor-derived CD4+ T cells drove IFN-γ pathways and enhanced tissue residency. Our findings illuminate the transcriptional programs driving disease-specific T cell formation in Crohn's disease.","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"222 11","pages":""},"PeriodicalIF":10.6,"publicationDate":"2025-11-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12410336/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144992743","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}

引用次数: 0

Salmonella-superspreader hosts require gut regulatory T cells to maintain a disease-tolerant state. 沙门氏菌超级传播者宿主需要肠道调节性T细胞来维持疾病耐受状态。

IF 10.6 1区医学

Journal of Experimental Medicine Pub Date : 2025-11-03 Epub Date: 2025-09-09 DOI: 10.1084/jem.20242431

Blanda Di Luccia, Liliana M Massis, Daniel S C Butler, Ramya Narasimhan, Sarah J Ruddle, Trung H M Pham, José G Vilches-Moure, Denise M Monack

{"title":"Salmonella-superspreader hosts require gut regulatory T cells to maintain a disease-tolerant state.","authors":"Blanda Di Luccia, Liliana M Massis, Daniel S C Butler, Ramya Narasimhan, Sarah J Ruddle, Trung H M Pham, José G Vilches-Moure, Denise M Monack","doi":"10.1084/jem.20242431","DOIUrl":"10.1084/jem.20242431","url":null,"abstract":"Host-pathogen interactions involve two critical strategies: resistance, whereby hosts clear invading microbes, and tolerance, whereby hosts carry high pathogen burden asymptomatically. Here, we investigate mechanisms by which Salmonella-superspreader (SSP) hosts maintain an asymptomatic state during chronic infection. We found that regulatory T cells (Tregs) are essential for this disease-tolerant state, limiting intestinal immunopathology and enabling SSP hosts to thrive, while facilitating Salmonella transmission. Treg depletion in SSP mice resulted in decreased survival, heightened gut inflammation, and impairment of the intestinal barrier, without affecting Salmonella persistence. Colonic Tregs from SSP mice exhibited a unique transcriptomic profile characterized by the upregulation of type 1 inflammatory genes, including the transcription factor T-bet. In the absence of Tregs, we observed robust expansion of cytotoxic CD4+ T cells, with CD4+ T cell depletion restoring homeostasis. These results uncover a critical host strategy to establish disease tolerance during chronic enteric infection, providing novel insights into mucosal responses to persistent pathogens and chronic intestinal inflammation.","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"222 11","pages":""},"PeriodicalIF":10.6,"publicationDate":"2025-11-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12419162/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145023451","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}

引用次数: 0

ALK2/3 recruitment to the immunological synapse is required for T cell activation and death. 免疫突触对ALK2/3的募集是T细胞激活和死亡所必需的。

IF 10.6 1区医学

Journal of Experimental Medicine Pub Date : 2025-10-06 Epub Date: 2025-07-30 DOI: 10.1084/jem.20250121

Jun-Ge Shi, Zhen-Wu Ma, Zi-Lun Ruan, Ye Xu, Wen-Hao Hang, Rui Liu, Yong Xiong, Hong-Bing Shu, Shu Li

{"title":"ALK2/3 recruitment to the immunological synapse is required for T cell activation and death.","authors":"Jun-Ge Shi, Zhen-Wu Ma, Zi-Lun Ruan, Ye Xu, Wen-Hao Hang, Rui Liu, Yong Xiong, Hong-Bing Shu, Shu Li","doi":"10.1084/jem.20250121","DOIUrl":"https://doi.org/10.1084/jem.20250121","url":null,"abstract":"Antigen recognition by TCR triggers T cell activation and activation-induced cell death (AICD). We identified that the BMP receptors ALK2 and ALK3 were interdependently required for induction of a subset of effector genes and AICD in activated T cells, independent of their BMP ligands. Upon T cell activation, ALK2/3 were recruited to the immunological synapse and phosphorylated by PKC-θ at the conserved T203, resulting in their enhanced kinase activities. The activated ALK2/3, in the absence of BMP, phosphorylated SMAD1/5 at S57, which is reciprocally antagonistic to BMP-induced phosphorylation of SMAD1/5 at S463/465. The S57-phosphorylated SMAD1/5 associated with c-Fos to induce effector genes upon T cell activation. Disruption of Alk2 in T cells attenuated T cell-mediated immunity to Listeria, whereas blocking BMPs enhanced host defense to Listeria in WT but not Alk2-deficient mice. Our findings suggest that the BMP-independent ALK2/3-SMAD1/5 axis plays essential roles in T cell activation and AICD, which is reciprocally antagonistic with BMP-triggered inhibition of T cell-mediated immunity.","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"222 10","pages":""},"PeriodicalIF":10.6,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144742246","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}

引用次数: 0

Women in STEM becoming independent: Asking for help creates opportunities for connections and kindness. STEM领域的女性变得独立：寻求帮助创造了建立联系和友善的机会。

IF 10.6 1区医学

Journal of Experimental Medicine Pub Date : 2025-10-06 Epub Date: 2025-09-17 DOI: 10.1084/jem.20251668

Michela Frascoli, Dequina Nicholas, Ada Weinstock, Chia-Lin Hsu, Anushka Dongre, Jessica A Osterhout, Anna-Maria Globig, Deepshika Ramanan, Martine Therrien, Alexandra McCubbrey

引用次数: 0

Targeting infection-specific peptides in immunopeptidomics studies for vaccine target discovery. 免疫肽组学研究中针对感染特异性肽的疫苗靶点发现。

IF 12.6 1区医学

Journal of Experimental Medicine Pub Date : 2025-10-06 Epub Date: 2025-07-21 DOI: 10.1084/jem.20250444

Owen Leddy, Yuko Yuki, Mary Carrington, Bryan D Bryson, Forest M White

{"title":"Targeting infection-specific peptides in immunopeptidomics studies for vaccine target discovery.","authors":"Owen Leddy, Yuko Yuki, Mary Carrington, Bryan D Bryson, Forest M White","doi":"10.1084/jem.20250444","DOIUrl":"10.1084/jem.20250444","url":null,"abstract":"Vaccine-elicited T cell responses can contribute to immune protection against emerging infectious disease risks such as antimicrobial-resistant (AMR) microbial pathogens and viruses with pandemic potential, but rapidly identifying appropriate targets for T cell priming vaccines remains challenging. Mass spectrometry (MS) analysis of peptides presented on MHCs can identify potential targets for protective T cell responses in a proteome-wide manner. However, pathogen-derived peptides are outnumbered by self-peptides in the MHC repertoire and may be missed in untargeted MS analyses. Here, we present a novel approach, termed PathMHC, that uses computational analysis of untargeted MS data followed by targeted MS to discover novel pathogen-derived MHC peptides more efficiently than untargeted methods alone. We applied this workflow to identify MHC peptides derived from multiple microbes, including potential vaccine targets presented on MHC-I by human dendritic cells infected with Mycobacterium tuberculosis (Mtb), finding that all Mtb peptides detected in the MHC-I repertoire derived from proteins exported by type VII secretion systems. PathMHC will facilitate antigen discovery campaigns for vaccine development.","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"222 10","pages":""},"PeriodicalIF":12.6,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12279011/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144674939","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}

引用次数: 0

ASXL1 deficiency causes epigenetic dysfunction, combined immunodeficiency, and EBV-associated lymphoma. ASXL1缺失导致表观遗传功能障碍、联合免疫缺陷和ebv相关淋巴瘤。

IF 10.6 1区医学

Journal of Experimental Medicine Pub Date : 2025-10-06 Epub Date: 2025-07-31 DOI: 10.1084/jem.20240945

Maggie P Fu, Mehul Sharma, Pariya Yousefi, Sarah M Merrill, Ryan Tan, Simran Samra, Audi Setiadi, Liam Golding, Bhavi P Modi, Kate L Del Bel, Rebecca J Deyell, Jacob Rozmus, Wingfield Rehmus, Kyla J Hildebrand, Elliot James, Géraldine Blanchard-Rohner, Susan Lin, Kevin E Shopsowitz, Jefferson Terry, Anna F Lee, Britt I Drögemöller, Allison Matthews, Maja Tarailo-Graovac, Laura Sauvé, Hana Mitchell, Julie S Prendiville, Julia L MacIsaac, Kristy Dever, David T S Lin, Mandy Meijer, Colin J D Ross, Simon R M Dobson, Suzanne M Vercauteren, Wyeth W Wasserman, Clara D M van Karnebeek, Margaret L McKinnon, Michael S Kobor, Stuart E Turvey, Catherine M Biggs

{"title":"ASXL1 deficiency causes epigenetic dysfunction, combined immunodeficiency, and EBV-associated lymphoma.","authors":"Maggie P Fu, Mehul Sharma, Pariya Yousefi, Sarah M Merrill, Ryan Tan, Simran Samra, Audi Setiadi, Liam Golding, Bhavi P Modi, Kate L Del Bel, Rebecca J Deyell, Jacob Rozmus, Wingfield Rehmus, Kyla J Hildebrand, Elliot James, Géraldine Blanchard-Rohner, Susan Lin, Kevin E Shopsowitz, Jefferson Terry, Anna F Lee, Britt I Drögemöller, Allison Matthews, Maja Tarailo-Graovac, Laura Sauvé, Hana Mitchell, Julie S Prendiville, Julia L MacIsaac, Kristy Dever, David T S Lin, Mandy Meijer, Colin J D Ross, Simon R M Dobson, Suzanne M Vercauteren, Wyeth W Wasserman, Clara D M van Karnebeek, Margaret L McKinnon, Michael S Kobor, Stuart E Turvey, Catherine M Biggs","doi":"10.1084/jem.20240945","DOIUrl":"10.1084/jem.20240945","url":null,"abstract":"Inborn errors of immunity (IEIs) are caused by deleterious variants in immune-related genes. ASXL1 is an epigenetic modifier not previously linked to an IEI. Clonal hematopoiesis and hematologic neoplasms often feature somatic ASXL1 variants, and Bohring-Opitz syndrome, a neurodevelopmental disorder, is caused by heterozygous truncating ASXL1 variants. We present an IEI caused by biallelic germline missense variants in ASXL1. The patient had a history of hematologic abnormalities and viral-associated complications, including chronic macrocytosis, persistent vaccine-strain rubella granulomas, and EBV-associated Hodgkin lymphoma. Immunophenotyping revealed loss of B cells, hypogammaglobulinemia, and impairments in cytotoxic T and NK cell populations. T cells exhibited skewing toward an exhausted memory phenotype, global DNA methylation loss, and increased epigenetic aging. These aberrations were ameliorated by wild-type ASXL1 transduction, confirming the patient variants' pathogenicity. This study defines a novel human IEI caused by ASXL1 deficiency, a diagnosis that should be considered in individuals with chronic viral infections, viral-associated malignancies, and combined immune deficiency.","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"222 10","pages":""},"PeriodicalIF":10.6,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144753534","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}

引用次数: 0

ApoE-calypse tau: ApoE-tau synergy in Alzheimer's disease. ApoE-calypse tau: ApoE-tau在阿尔茨海默病中的协同作用。

IF 10.6 1区医学

Journal of Experimental Medicine Pub Date : 2025-10-06 Epub Date: 2025-08-26 DOI: 10.1084/jem.20250965

Matthew Paul Lennol, Chiara Bordier, Léana Kamelher, Jason D Ulrich, David M Holtzman, Maud Gratuze

引用次数: 0