Journal of Experimental Medicine最新文献

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The RNA binding protein Arid5a drives IL-17-dependent autoantibody-induced glomerulonephritis. RNA结合蛋白Arid5a驱动IL-17依赖性自身抗体诱导的肾小球肾炎。
IF 12.6 1区 医学
Journal of Experimental Medicine Pub Date : 2024-09-02 Epub Date: 2024-07-26 DOI: 10.1084/jem.20240656
Yang Li, Shachi P Vyas, Isha Mehta, Nariaki Asada, Ipsita Dey, Tiffany C Taylor, Rami Bechara, Nilesh Amatya, Felix E Y Aggor, Bianca M Coleman, De-Dong Li, Kenta Yamamoto, Ogechukwu Ezenwa, Yeque Sun, Esta Sterneck, C Joel McManus, Ulf Panzer, Partha S Biswas, Ram Savan, Jishnu Das, Sarah L Gaffen
{"title":"The RNA binding protein Arid5a drives IL-17-dependent autoantibody-induced glomerulonephritis.","authors":"Yang Li, Shachi P Vyas, Isha Mehta, Nariaki Asada, Ipsita Dey, Tiffany C Taylor, Rami Bechara, Nilesh Amatya, Felix E Y Aggor, Bianca M Coleman, De-Dong Li, Kenta Yamamoto, Ogechukwu Ezenwa, Yeque Sun, Esta Sterneck, C Joel McManus, Ulf Panzer, Partha S Biswas, Ram Savan, Jishnu Das, Sarah L Gaffen","doi":"10.1084/jem.20240656","DOIUrl":"10.1084/jem.20240656","url":null,"abstract":"<p><p>Autoantibody-mediated glomerulonephritis (AGN) arises from dysregulated renal inflammation, with urgent need for improved treatments. IL-17 is implicated in AGN and drives pathology in a kidney-intrinsic manner via renal tubular epithelial cells (RTECs). Nonetheless, downstream signaling mechanisms provoking kidney pathology are poorly understood. A noncanonical RNA binding protein (RBP), Arid5a, was upregulated in human and mouse AGN. Arid5a-/- mice were refractory to AGN, with attenuated myeloid infiltration and impaired expression of IL-17-dependent cytokines and transcription factors (C/EBPβ, C/EBPδ). Transcriptome-wide RIP-Seq revealed that Arid5a inducibly interacts with conventional IL-17 target mRNAs, including CEBPB and CEBPD. Unexpectedly, many Arid5a RNA targets corresponded to translational regulation and RNA processing pathways, including rRNAs. Indeed, global protein synthesis was repressed in Arid5a-deficient cells, and C/EBPs were controlled at the level of protein rather than RNA accumulation. IL-17 prompted Arid5a nuclear export and association with 18S rRNA, a 40S ribosome constituent. Accordingly, IL-17-dependent renal autoimmunity is driven by Arid5a at the level of ribosome interactions and translation.</p>","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"221 9","pages":""},"PeriodicalIF":12.6,"publicationDate":"2024-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11284280/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141759081","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
Dynamic Foxp3-chromatin interaction controls tunable Treg cell function. Foxp3与染色质的动态相互作用控制着可调的Treg细胞功能。
IF 12.6 1区 医学
Journal of Experimental Medicine Pub Date : 2024-09-02 Epub Date: 2024-06-27 DOI: 10.1084/jem.20232068
Minghong He, Xinying Zong, Beisi Xu, Wenjie Qi, Wenjun Huang, Mohamed Nadhir Djekidel, Yang Zhang, Vishwajeeth R Pagala, Jun Li, Xiaolei Hao, Clifford Guy, Lu Bai, Richard Cross, Chunliang Li, Junmin Peng, Yongqiang Feng
{"title":"Dynamic Foxp3-chromatin interaction controls tunable Treg cell function.","authors":"Minghong He, Xinying Zong, Beisi Xu, Wenjie Qi, Wenjun Huang, Mohamed Nadhir Djekidel, Yang Zhang, Vishwajeeth R Pagala, Jun Li, Xiaolei Hao, Clifford Guy, Lu Bai, Richard Cross, Chunliang Li, Junmin Peng, Yongqiang Feng","doi":"10.1084/jem.20232068","DOIUrl":"10.1084/jem.20232068","url":null,"abstract":"<p><p>Nuclear factor Foxp3 determines regulatory T (Treg) cell fate and function via mechanisms that remain unclear. Here, we investigate the nature of Foxp3-mediated gene regulation in suppressing autoimmunity and antitumor immune response. Contrasting with previous models, we find that Foxp3-chromatin binding is regulated by Treg activation states, tumor microenvironment, and antigen and cytokine stimulations. Proteomics studies uncover dynamic proteins within Foxp3 proximity upon TCR or IL-2 receptor signaling in vitro, reflecting intricate interactions among Foxp3, signal transducers, and chromatin. Pharmacological inhibition and genetic knockdown experiments indicate that NFAT and AP-1 protein Batf are required for enhanced Foxp3-chromatin binding in activated Treg cells and tumor-infiltrating Treg cells to modulate target gene expression. Furthermore, mutations at the Foxp3 DNA-binding domain destabilize the Foxp3-chromatin association. These representative settings delineate context-dependent Foxp3-chromatin interaction, suggesting that Foxp3 associates with chromatin by hijacking DNA-binding proteins resulting from Treg activation or differentiation, which is stabilized by direct Foxp3-DNA binding, to dynamically regulate Treg cell function according to immunological contexts.</p>","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"221 9","pages":""},"PeriodicalIF":12.6,"publicationDate":"2024-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11211070/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141457370","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
Sarah Gaffen: I thrive on turning my vision for the lab into reality. 莎拉-格芬:我致力于将自己对实验室的设想变为现实。
IF 12.6 1区 医学
Journal of Experimental Medicine Pub Date : 2024-09-02 Epub Date: 2024-08-19 DOI: 10.1084/jem.20241418
Lucie Van Emmenis
{"title":"Sarah Gaffen: I thrive on turning my vision for the lab into reality.","authors":"Lucie Van Emmenis","doi":"10.1084/jem.20241418","DOIUrl":"10.1084/jem.20241418","url":null,"abstract":"<p><p>Sarah Gaffen, PhD, is a professor of medicine and rheumatology and holds the Gerald P. Rodnan endowed chair at the University of Pittsburgh. Her lab explores the biological function of IL-17 and its receptor in the context of fungal host defense and autoimmunity. We spoke to Sarah about where her interest in cytokines began, the importance of saying no in your career, and her interest in paleogenetics.</p>","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"221 9","pages":""},"PeriodicalIF":12.6,"publicationDate":"2024-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11334327/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142000073","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
Fetal MAVS and type I IFN signaling pathways control ZIKV infection in the placenta and maternal decidua. 胎儿 MAVS 和 I 型 IFN 信号通路控制 ZIKV 在胎盘和母体蜕膜中的感染。
IF 12.6 1区 医学
Journal of Experimental Medicine Pub Date : 2024-09-02 Epub Date: 2024-07-23 DOI: 10.1084/jem.20240694
Yael Alippe, Leran Wang, Reyan Coskun, Stéfanie P Muraro, Fang R Zhao, Michelle Elam-Noll, J Michael White, Daiana M Vota, Vanesa C Hauk, Jeffrey I Gordon, Scott A Handley, Michael S Diamond
{"title":"Fetal MAVS and type I IFN signaling pathways control ZIKV infection in the placenta and maternal decidua.","authors":"Yael Alippe, Leran Wang, Reyan Coskun, Stéfanie P Muraro, Fang R Zhao, Michelle Elam-Noll, J Michael White, Daiana M Vota, Vanesa C Hauk, Jeffrey I Gordon, Scott A Handley, Michael S Diamond","doi":"10.1084/jem.20240694","DOIUrl":"10.1084/jem.20240694","url":null,"abstract":"<p><p>The contribution of placental immune responses to congenital Zika virus (ZIKV) syndrome remains poorly understood. Here, we leveraged a mouse model of ZIKV infection to identify mechanisms of innate immune restriction exclusively in the fetal compartment of the placenta. ZIKV principally infected mononuclear trophoblasts in the junctional zone, which was limited by mitochondrial antiviral-signaling protein (MAVS) and type I interferon (IFN) signaling mechanisms. Single nuclear RNA sequencing revealed MAVS-dependent expression of IFN-stimulated genes (ISGs) in spongiotrophoblasts but not in other placental cells that use alternate pathways to induce ISGs. ZIKV infection of Ifnar1-/- or Mavs-/- placentas was associated with greater infection of the adjacent immunocompetent decidua, and heterozygous Mavs+/- or Ifnar1+/- dams carrying immunodeficient fetuses sustained greater maternal viremia and tissue infection than dams carrying wild-type fetuses. Thus, MAVS-IFN signaling in the fetus restricts ZIKV infection in junctional zone trophoblasts, which modulates dissemination and outcome for both the fetus and the pregnant mother.</p>","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"221 9","pages":""},"PeriodicalIF":12.6,"publicationDate":"2024-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11270594/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141748320","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
Transcription of HIV-1 at sites of intact latent provirus integration. 完整潜伏前病毒整合点的 HIV-1 转录。
IF 12.6 1区 医学
Journal of Experimental Medicine Pub Date : 2024-09-02 Epub Date: 2024-08-14 DOI: 10.1084/jem.20240391
Ana Rafaela Teixeira, Cintia Bittar, Gabriela S Silva Santos, Thiago Y Oliveira, Amy S Huang, Noemi Linden, Isabella A T M Ferreira, Tetyana Murdza, Frauke Muecksch, R Brad Jones, Marina Caskey, Mila Jankovic, Michel C Nussenzweig
{"title":"Transcription of HIV-1 at sites of intact latent provirus integration.","authors":"Ana Rafaela Teixeira, Cintia Bittar, Gabriela S Silva Santos, Thiago Y Oliveira, Amy S Huang, Noemi Linden, Isabella A T M Ferreira, Tetyana Murdza, Frauke Muecksch, R Brad Jones, Marina Caskey, Mila Jankovic, Michel C Nussenzweig","doi":"10.1084/jem.20240391","DOIUrl":"10.1084/jem.20240391","url":null,"abstract":"<p><p>HIV-1 antiretroviral therapy is highly effective but fails to eliminate a reservoir of latent proviruses, leading to a requirement for life-long treatment. How the site of integration of authentic intact latent proviruses might impact their own or neighboring gene expression or reservoir dynamics is poorly understood. Here, we report on proviral and neighboring gene transcription at sites of intact latent HIV-1 integration in cultured T cells obtained directly from people living with HIV, as well as engineered primary T cells and cell lines. Proviral gene expression was correlated to the level of endogenous gene expression under resting but not activated conditions. Notably, latent proviral promoters were 100-10,000× less active than in productively infected cells and had little or no measurable impact on neighboring gene expression under resting or activated conditions. Thus, the site of integration has a dominant effect on the transcriptional activity of intact HIV-1 proviruses in the latent reservoir, thereby influencing cytopathic effects and proviral immune evasion.</p>","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"221 9","pages":""},"PeriodicalIF":12.6,"publicationDate":"2024-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11323366/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141975773","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
FOXP3 snatches transcription factors depending on the context. FOXP3 可根据上下文情况抢夺转录因子。
IF 12.6 1区 医学
Journal of Experimental Medicine Pub Date : 2024-09-02 Epub Date: 2024-07-01 DOI: 10.1084/jem.20240940
Lisa Schmidleithner, Philipp Stüve, Markus Feuerer
{"title":"FOXP3 snatches transcription factors depending on the context.","authors":"Lisa Schmidleithner, Philipp Stüve, Markus Feuerer","doi":"10.1084/jem.20240940","DOIUrl":"10.1084/jem.20240940","url":null,"abstract":"<p><p>FOXP3 hijacks DNA-binding proteins to regulate gene expression. In this issue of JEM, He et al. (https://doi.org/10.1084/jem.20232068) propose a dynamic model in which FOXP3 associates with DNA-binding proteins to regulate Treg cell function in response to environmental cues.</p>","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"221 9","pages":""},"PeriodicalIF":12.6,"publicationDate":"2024-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11215522/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141468424","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
Kids' noses resist COVID-19. 孩子们的鼻子能抵抗 COVID-19。
IF 12.6 1区 医学
Journal of Experimental Medicine Pub Date : 2024-09-02 Epub Date: 2024-07-01 DOI: 10.1084/jem.20241027
Ivan Zanoni
{"title":"Kids' noses resist COVID-19.","authors":"Ivan Zanoni","doi":"10.1084/jem.20241027","DOIUrl":"10.1084/jem.20241027","url":null,"abstract":"<p><p>Children resist COVID-19, and previous studies reported increased innate immunity in their upper airways. A new paper by Watkins et al. (https://doi.org/10.1084/jem.20230911) shows that the nasal mucosa of children is characterized by often asymptomatic viral and/or bacterial infections that dynamically regulate distinct innate immune programs.</p>","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"221 9","pages":""},"PeriodicalIF":12.6,"publicationDate":"2024-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11215540/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141468426","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
Immature B cell homing shapes human lymphoid tissue structure and function. 未成熟 B 细胞归巢塑造了人类淋巴组织的结构和功能。
IF 12.6 1区 医学
Journal of Experimental Medicine Pub Date : 2024-09-02 Epub Date: 2024-08-02 DOI: 10.1084/jem.20240085
Jo Spencer, Chiara Dionisi
{"title":"Immature B cell homing shapes human lymphoid tissue structure and function.","authors":"Jo Spencer, Chiara Dionisi","doi":"10.1084/jem.20240085","DOIUrl":"10.1084/jem.20240085","url":null,"abstract":"<p><p>Shortly after the emergence of newly formed human B cells from bone marrow as transitional cells, they diverge along two developmental pathways that can be distinguished by the level of IgM they express and migratory biases. Here, we propose that differential tissue homing of immature B cell subsets contributes to human lymphoid tissue structure and function.</p>","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"221 9","pages":""},"PeriodicalIF":12.6,"publicationDate":"2024-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11296955/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141874992","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
Loss of tolerance precedes triggering and lifelong persistence of pathogenic type I interferon autoantibodies. 在致病性 I 型干扰素自身抗体触发并终生存在之前,耐受性会丧失。
IF 12.6 1区 医学
Journal of Experimental Medicine Pub Date : 2024-09-02 Epub Date: 2024-07-17 DOI: 10.1084/jem.20240365
Sonja Fernbach, Nina K Mair, Irene A Abela, Kevin Groen, Roger Kuratli, Marie Lork, Christian W Thorball, Enos Bernasconi, Paraskevas Filippidis, Karoline Leuzinger, Julia Notter, Andri Rauch, Hans H Hirsch, Michael Huber, Huldrych F Günthard, Jacques Fellay, Roger D Kouyos, Benjamin G Hale
{"title":"Loss of tolerance precedes triggering and lifelong persistence of pathogenic type I interferon autoantibodies.","authors":"Sonja Fernbach, Nina K Mair, Irene A Abela, Kevin Groen, Roger Kuratli, Marie Lork, Christian W Thorball, Enos Bernasconi, Paraskevas Filippidis, Karoline Leuzinger, Julia Notter, Andri Rauch, Hans H Hirsch, Michael Huber, Huldrych F Günthard, Jacques Fellay, Roger D Kouyos, Benjamin G Hale","doi":"10.1084/jem.20240365","DOIUrl":"10.1084/jem.20240365","url":null,"abstract":"<p><p>Autoantibodies neutralizing type I interferons (IFN-Is) can underlie infection severity. Here, we trace the development of these autoantibodies at high-resolution using longitudinal samples from 1,876 well-treated individuals living with HIV over a 35-year period. Similar to general populations, ∼1.9% of individuals acquired anti-IFN-I autoantibodies as they aged (median onset ∼63 years). Once detected, anti-IFN-I autoantibodies persisted lifelong, and titers increased over decades. Individuals developed distinct neutralizing and non-neutralizing autoantibody repertoires at discrete times that selectively targeted combinations of IFNα, IFNβ, and IFNω. Emergence of neutralizing anti-IFNα autoantibodies correlated with reduced baseline IFN-stimulated gene levels and was associated with subsequent susceptibility to severe COVID-19 several years later. Retrospective measurements revealed enrichment of pre-existing autoreactivity against other autoantigens in individuals who later developed anti-IFN-I autoantibodies, and there was evidence for prior viral infections or increased IFN at the time of anti-IFN-I autoantibody triggering. These analyses suggest that age-related loss of self-tolerance prior to IFN-I immune-triggering poses a risk of developing lifelong functional IFN-I deficiency.</p>","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"221 9","pages":""},"PeriodicalIF":12.6,"publicationDate":"2024-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11253716/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141626910","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
Haploinsufficiency in PTPN2 leads to early-onset systemic autoimmunity from Evans syndrome to lupus. PTPN2单倍体缺陷导致从埃文斯综合征到狼疮的早发性系统性自身免疫。
IF 12.6 1区 医学
Journal of Experimental Medicine Pub Date : 2024-09-02 Epub Date: 2024-07-19 DOI: 10.1084/jem.20232337
Marie Jeanpierre, Jade Cognard, Maud Tusseau, Quentin Riller, Linh-Chi Bui, Jérémy Berthelet, Audrey Laurent, Etienne Crickx, Marianna Parlato, Marie-Claude Stolzenberg, Felipe Suarez, Guy Leverger, Nathalie Aladjidi, Sophie Collardeau-Frachon, Christine Pietrement, Marion Malphettes, Antoine Froissart, Christine Bole-Feysot, Nicolas Cagnard, Fernando Rodrigues Lima, Thierry Walzer, Frédéric Rieux-Laucat, Alexandre Belot, Anne-Laure Mathieu
{"title":"Haploinsufficiency in PTPN2 leads to early-onset systemic autoimmunity from Evans syndrome to lupus.","authors":"Marie Jeanpierre, Jade Cognard, Maud Tusseau, Quentin Riller, Linh-Chi Bui, Jérémy Berthelet, Audrey Laurent, Etienne Crickx, Marianna Parlato, Marie-Claude Stolzenberg, Felipe Suarez, Guy Leverger, Nathalie Aladjidi, Sophie Collardeau-Frachon, Christine Pietrement, Marion Malphettes, Antoine Froissart, Christine Bole-Feysot, Nicolas Cagnard, Fernando Rodrigues Lima, Thierry Walzer, Frédéric Rieux-Laucat, Alexandre Belot, Anne-Laure Mathieu","doi":"10.1084/jem.20232337","DOIUrl":"10.1084/jem.20232337","url":null,"abstract":"<p><p>An exome sequencing strategy employed to identify pathogenic variants in patients with pediatric-onset systemic lupus or Evans syndrome resulted in the discovery of six novel monoallelic mutations in PTPN2. PTPN2 is a phosphatase that acts as an essential negative regulator of the JAK/STAT pathways. All mutations led to a loss of PTPN2 regulatory function as evidenced by in vitro assays and by hyperproliferation of patients' T cells. Furthermore, patients exhibited high serum levels of inflammatory cytokines, mimicking the profile observed in individuals with gain-of-function mutations in STAT factors. Flow cytometry analysis of patients' blood cells revealed typical alterations associated with autoimmunity and all patients presented with autoantibodies. These findings further supported the notion that a loss of function in negative regulators of cytokine pathways can lead to a broad spectrum of autoimmune manifestations and that PTPN2 along with SOCS1 haploinsufficiency constitute a new group of monogenic autoimmune diseases that can benefit from targeted therapy.</p>","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"221 9","pages":""},"PeriodicalIF":12.6,"publicationDate":"2024-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11259789/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141727260","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
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