Journal of Experimental Medicine最新文献_第6页

A human STAT3 gain-of-function variant drives local Th17 dysregulation and skin inflammation in mice. 人类 STAT3 功能增益变体会导致小鼠局部 Th17 失调和皮肤炎症。

IF 12.6 1区医学

Journal of Experimental Medicine Pub Date : 2024-08-05 Epub Date: 2024-06-11 DOI: 10.1084/jem.20232091

Kelsey A Toth, Erica G Schmitt, Ana Kolicheski, Zev J Greenberg, Elizabeth Levendosky, Nermina Saucier, Kelsey Trammel, Vasileios Oikonomou, Michail S Lionakis, Eynav Klechevsky, Brian S Kim, Laura G Schuettpelz, Naresha Saligrama, Megan A Cooper

{"title":"A human STAT3 gain-of-function variant drives local Th17 dysregulation and skin inflammation in mice.","authors":"Kelsey A Toth, Erica G Schmitt, Ana Kolicheski, Zev J Greenberg, Elizabeth Levendosky, Nermina Saucier, Kelsey Trammel, Vasileios Oikonomou, Michail S Lionakis, Eynav Klechevsky, Brian S Kim, Laura G Schuettpelz, Naresha Saligrama, Megan A Cooper","doi":"10.1084/jem.20232091","DOIUrl":"10.1084/jem.20232091","url":null,"abstract":"Germline gain-of-function (GOF) variants in STAT3 cause an inborn error of immunity associated with early-onset poly-autoimmunity and immune dysregulation. To study tissue-specific immune dysregulation, we used a mouse model carrying a missense variant (p.G421R) that causes human disease. We observed spontaneous and imiquimod (IMQ)-induced skin inflammation associated with cell-intrinsic local Th17 responses in STAT3 GOF mice. CD4+ T cells were sufficient to drive skin inflammation and showed increased Il22 expression in expanded clones. Certain aspects of disease, including increased epidermal thickness, also required the presence of STAT3 GOF in epithelial cells. Treatment with a JAK inhibitor improved skin disease without affecting local Th17 recruitment and cytokine production. These findings collectively support the involvement of Th17 responses in the development of organ-specific immune dysregulation in STAT3 GOF and suggest that the presence of STAT3 GOF in tissues is important for disease and can be targeted with JAK inhibition.","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":null,"pages":null},"PeriodicalIF":12.6,"publicationDate":"2024-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11167377/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141300726","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

Five decades of natural killer cell discovery. 发现自然杀伤细胞的五十年

IF 15.3 1区医学

Journal of Experimental Medicine Pub Date : 2024-08-05 Epub Date: 2024-06-06 DOI: 10.1084/jem.20231222

Lewis L Lanier

引用次数: 0

Coxsackievirus A10 impairs nail regeneration and induces onychomadesis by mimicking DKK1 to attenuate Wnt signaling. 柯萨奇病毒 A10 通过模拟 DKK1 来削弱 Wnt 信号，从而损害指甲再生并诱发甲沟炎。

IF 15.3 1区医学

Journal of Experimental Medicine Pub Date : 2024-08-05 Epub Date: 2024-06-05 DOI: 10.1084/jem.20231512

Yingzi Cui, Qiaoni Shi, Pu Song, Jianyu Tong, Zhimin Cheng, Hangchuan Zhang, Xiaodan Wang, Yuxuan Zheng, Yao Wu, Meng Wan, Shihua Li, Xin Zhao, Zhou Tong, Zhengquan Yu, Shan Gao, Ye-Guang Chen, George Fu Gao

{"title":"Coxsackievirus A10 impairs nail regeneration and induces onychomadesis by mimicking DKK1 to attenuate Wnt signaling.","authors":"Yingzi Cui, Qiaoni Shi, Pu Song, Jianyu Tong, Zhimin Cheng, Hangchuan Zhang, Xiaodan Wang, Yuxuan Zheng, Yao Wu, Meng Wan, Shihua Li, Xin Zhao, Zhou Tong, Zhengquan Yu, Shan Gao, Ye-Guang Chen, George Fu Gao","doi":"10.1084/jem.20231512","DOIUrl":"10.1084/jem.20231512","url":null,"abstract":"Coxsackievirus A10 (CV-A10) infection, a prominent cause of childhood hand-foot-and-mouth disease (HFMD), frequently manifests with the intriguing phenomenon of onychomadesis, characterized by nail shedding. However, the underlying mechanism is elusive. Here, we found that CV-A10 infection in mice could suppress Wnt/β-catenin signaling by restraining LDL receptor-related protein 6 (LRP6) phosphorylation and β-catenin accumulation and lead to onychomadesis. Mechanistically, CV-A10 mimics Dickkopf-related protein 1 (DKK1) to interact with Kringle-containing transmembrane protein 1 (KRM1), the CV-A10 cellular receptor. We further found that Wnt agonist (GSK3β inhibitor) CHIR99021 can restore nail stem cell differentiation and protect against nail shedding. These findings provide novel insights into the pathogenesis of CV-A10 and related viruses in onychomadesis and guide prognosis assessment and clinical treatment of the disease.","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":null,"pages":null},"PeriodicalIF":15.3,"publicationDate":"2024-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11153773/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141248186","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

Maturation of germinal center B cells after influenza virus vaccination in humans. 人类接种流感病毒疫苗后生殖中心 B 细胞的成熟。

IF 12.6 1区医学

Journal of Experimental Medicine Pub Date : 2024-08-05 Epub Date: 2024-06-27 DOI: 10.1084/jem.20240668

Katherine M McIntire, Hailong Meng, Ting-Hui Lin, Wooseob Kim, Nina E Moore, Julianna Han, Meagan McMahon, Meng Wang, Sameer Kumar Malladi, Bassem M Mohammed, Julian Q Zhou, Aaron J Schmitz, Kenneth B Hoehn, Juan Manuel Carreño, Temima Yellin, Teresa Suessen, William D Middleton, Sharlene A Teefey, Rachel M Presti, Florian Krammer, Jackson S Turner, Andrew B Ward, Ian A Wilson, Steven H Kleinstein, Ali H Ellebedy

{"title":"Maturation of germinal center B cells after influenza virus vaccination in humans.","authors":"Katherine M McIntire, Hailong Meng, Ting-Hui Lin, Wooseob Kim, Nina E Moore, Julianna Han, Meagan McMahon, Meng Wang, Sameer Kumar Malladi, Bassem M Mohammed, Julian Q Zhou, Aaron J Schmitz, Kenneth B Hoehn, Juan Manuel Carreño, Temima Yellin, Teresa Suessen, William D Middleton, Sharlene A Teefey, Rachel M Presti, Florian Krammer, Jackson S Turner, Andrew B Ward, Ian A Wilson, Steven H Kleinstein, Ali H Ellebedy","doi":"10.1084/jem.20240668","DOIUrl":"10.1084/jem.20240668","url":null,"abstract":"Germinal centers (GC) are microanatomical lymphoid structures where affinity-matured memory B cells and long-lived bone marrow plasma cells are primarily generated. It is unclear how the maturation of B cells within the GC impacts the breadth and durability of B cell responses to influenza vaccination in humans. We used fine needle aspiration of draining lymph nodes to longitudinally track antigen-specific GC B cell responses to seasonal influenza vaccination. Antigen-specific GC B cells persisted for at least 13 wk after vaccination in two out of seven individuals. Monoclonal antibodies (mAbs) derived from persisting GC B cell clones exhibit enhanced binding affinity and breadth to influenza hemagglutinin (HA) antigens compared with related GC clonotypes isolated earlier in the response. Structural studies of early and late GC-derived mAbs from one clonal lineage in complex with H1 and H5 HAs revealed an altered binding footprint. Our study shows that inducing sustained GC reactions after influenza vaccination in humans supports the maturation of responding B cells.","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":null,"pages":null},"PeriodicalIF":12.6,"publicationDate":"2024-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11211068/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141457369","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

Human CD127 negative ILC2s show immunological memory. 人类 CD127 阴性 ILC2 显示出免疫记忆。

IF 12.6 1区医学

Journal of Experimental Medicine Pub Date : 2024-08-05 Epub Date: 2024-06-18 DOI: 10.1084/jem.20231827

Laura Mathä, Lisette Krabbendam, Sergio Martinez Høyer, Balthasar A Heesters, Korneliusz Golebski, Chantal Kradolfer, Maryam Ghaedi, Junjie Ma, Ralph Stadhouders, Claus Bachert, Lars-Olaf Cardell, Nan Zhang, Gabriele Holtappels, Sietze Reitsma, Leanne Carijn Helgers, Teunis B H Geijtenbeek, Jonathan M Coquet, Fumio Takei, Hergen Spits, Itziar Martinez-Gonzalez

{"title":"Human CD127 negative ILC2s show immunological memory.","authors":"Laura Mathä, Lisette Krabbendam, Sergio Martinez Høyer, Balthasar A Heesters, Korneliusz Golebski, Chantal Kradolfer, Maryam Ghaedi, Junjie Ma, Ralph Stadhouders, Claus Bachert, Lars-Olaf Cardell, Nan Zhang, Gabriele Holtappels, Sietze Reitsma, Leanne Carijn Helgers, Teunis B H Geijtenbeek, Jonathan M Coquet, Fumio Takei, Hergen Spits, Itziar Martinez-Gonzalez","doi":"10.1084/jem.20231827","DOIUrl":"10.1084/jem.20231827","url":null,"abstract":"ILC2s are key players in type 2 immunity and contribute to maintaining homeostasis. ILC2s are also implicated in the development of type 2 inflammation-mediated chronic disorders like asthma. While memory ILC2s have been identified in mouse, it is unknown whether human ILC2s can acquire immunological memory. Here, we demonstrate the persistence of CD45RO, a marker previously linked to inflammatory ILC2s, in resting ILC2s that have undergone prior activation. A high proportion of these cells concurrently reduce the expression of the canonical ILC marker CD127 in a tissue-specific manner. Upon isolation and in vitro stimulation of CD127-CD45RO+ ILC2s, we observed an augmented ability to proliferate and produce cytokines. CD127-CD45RO+ ILC2s are found in both healthy and inflamed tissues and display a gene signature of cell activation. Similarly, mouse memory ILC2s show reduced expression of CD127. Our findings suggest that human ILC2s can acquire innate immune memory and warrant a revision of the current strategies to identify human ILC2s.","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":null,"pages":null},"PeriodicalIF":12.6,"publicationDate":"2024-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11187981/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141419414","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

Changing behind the scenes. 幕后的变化

IF 12.6 1区医学

Journal of Experimental Medicine Pub Date : 2024-08-05 Epub Date: 2024-07-17 DOI: 10.1084/jem.20240840

Mandy J McGeachy

引用次数: 0

Women in STEM becoming independent: Our shared motivation and enthusiasm are our driving force. 科技、工程和数学领域的女性正在独立：我们共同的动力和热情是我们前进的动力。

IF 12.6 1区医学

Journal of Experimental Medicine Pub Date : 2024-08-05 Epub Date: 2024-06-24 DOI: 10.1084/jem.20240971

Liudmila Andreeva, Lidia Bosurgi, Shu Zhen Chong, Coco Chu, Yejing Ge, Esther Hoste, Kellie A Jurado, Jette Lengefeld, Archita Mishra, Stefanie Wculek, Arabella Young

引用次数: 0

Traffic on the TLR expressway. TLR 高速公路上的交通。

IF 12.6 1区医学

Journal of Experimental Medicine Pub Date : 2024-08-05 Epub Date: 2024-06-13 DOI: 10.1084/jem.20240841

Justin Taft, Dusan Bogunovic

引用次数: 0

A viral E3 ubiquitin ligase produced by herpes simplex virus 1 inhibits the NLRP1 inflammasome. 由单纯疱疹病毒1产生的病毒E3泛素连接酶抑制NLRP1炎症小体。

IF 12.6 1区医学

Journal of Experimental Medicine Pub Date : 2024-08-05 Epub Date: 2024-06-11 DOI: 10.1084/jem.20231518

Pooja Parameswaran, Laurellee Payne, Jennifer Powers, Mehdi Rashighi, Megan H Orzalli

{"title":"A viral E3 ubiquitin ligase produced by herpes simplex virus 1 inhibits the NLRP1 inflammasome.","authors":"Pooja Parameswaran, Laurellee Payne, Jennifer Powers, Mehdi Rashighi, Megan H Orzalli","doi":"10.1084/jem.20231518","DOIUrl":"10.1084/jem.20231518","url":null,"abstract":"Guard proteins initiate defense mechanisms upon sensing pathogen-encoded virulence factors. Successful viral pathogens likely inhibit guard protein activity, but these interactions have been largely undefined. Here, we demonstrate that the human pathogen herpes simplex virus 1 (HSV-1) stimulates and inhibits an antiviral pathway initiated by NLRP1, a guard protein that induces inflammasome formation and pyroptotic cell death when activated. Notably, HSV-1 infection of human keratinocytes promotes posttranslational modifications to NLRP1, consistent with MAPK-dependent NLRP1 activation, but does not result in downstream inflammasome formation. We identify infected cell protein 0 (ICP0) as the critical HSV-1 protein that is necessary and sufficient for inhibition of the NLRP1 pathway. Mechanistically, ICP0's cytoplasmic localization and function as an E3 ubiquitin ligase prevents proteasomal degradation of the auto-inhibitory NT-NLRP1 fragment, thereby preventing inflammasome formation. Further, we demonstrate that inhibiting this inflammasome is important for promoting HSV-1 replication. Thus, we have established a mechanism by which HSV-1 overcomes a guard-mediated antiviral defense strategy in humans.","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":null,"pages":null},"PeriodicalIF":12.6,"publicationDate":"2024-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11167375/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141306092","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

Large-scale mutational analysis identifies UNC93B1 variants that drive TLR-mediated autoimmunity in mice and humans. 大规模突变分析确定了驱动小鼠和人类 TLR 介导的自身免疫的 UNC93B1 变体。

IF 12.6 1区医学

Journal of Experimental Medicine Pub Date : 2024-08-05 Epub Date: 2024-05-23 DOI: 10.1084/jem.20232005

Victoria E Rael, Julian A Yano, John P Huizar, Leianna C Slayden, Madeleine A Weiss, Elizabeth A Turcotte, Jacob M Terry, Wenqi Zuo, Isabelle Thiffault, Tomi Pastinen, Emily G Farrow, Janda L Jenkins, Mara L Becker, Stephen C Wong, Anne M Stevens, Catherine Otten, Eric J Allenspach, Devon E Bonner, Jonathan A Bernstein, Matthew T Wheeler, Robert A Saxton, Bo Liu, Olivia Majer, Gregory M Barton

{"title":"Large-scale mutational analysis identifies UNC93B1 variants that drive TLR-mediated autoimmunity in mice and humans.","authors":"Victoria E Rael, Julian A Yano, John P Huizar, Leianna C Slayden, Madeleine A Weiss, Elizabeth A Turcotte, Jacob M Terry, Wenqi Zuo, Isabelle Thiffault, Tomi Pastinen, Emily G Farrow, Janda L Jenkins, Mara L Becker, Stephen C Wong, Anne M Stevens, Catherine Otten, Eric J Allenspach, Devon E Bonner, Jonathan A Bernstein, Matthew T Wheeler, Robert A Saxton, Bo Liu, Olivia Majer, Gregory M Barton","doi":"10.1084/jem.20232005","DOIUrl":"10.1084/jem.20232005","url":null,"abstract":"Nucleic acid-sensing Toll-like receptors (TLR) 3, 7/8, and 9 are key innate immune sensors whose activities must be tightly regulated to prevent systemic autoimmune or autoinflammatory disease or virus-associated immunopathology. Here, we report a systematic scanning-alanine mutagenesis screen of all cytosolic and luminal residues of the TLR chaperone protein UNC93B1, which identified both negative and positive regulatory regions affecting TLR3, TLR7, and TLR9 responses. We subsequently identified two families harboring heterozygous coding mutations in UNC93B1, UNC93B1+/T93I and UNC93B1+/R336C, both in key negative regulatory regions identified in our screen. These patients presented with cutaneous tumid lupus and juvenile idiopathic arthritis plus neuroinflammatory disease, respectively. Disruption of UNC93B1-mediated regulation by these mutations led to enhanced TLR7/8 responses, and both variants resulted in systemic autoimmune or inflammatory disease when introduced into mice via genome editing. Altogether, our results implicate the UNC93B1-TLR7/8 axis in human monogenic autoimmune diseases and provide a functional resource to assess the impact of yet-to-be-reported UNC93B1 mutations.","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":null,"pages":null},"PeriodicalIF":12.6,"publicationDate":"2024-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11116816/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141081727","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