{"title":"Primary disorders of polyubiquitination: Dual roles in autoinflammation and immunodeficiency.","authors":"András N Spaan, Bertrand Boisson, Seth L Masters","doi":"10.1084/jem.20241047","DOIUrl":"https://doi.org/10.1084/jem.20241047","url":null,"abstract":"<p><p>The last decades have brought a rapid expansion of the number of primary disorders related to the polyubiquitination pathways in humans. Most of these disorders manifest with two seemingly contradictory clinical phenotypes: autoinflammation, immunodeficiency, or both. We provide an overview of the molecular pathogenesis of these disorders, and their role in inflammation and infection. By focusing on data from human genetic diseases, we explore the complexities of the polyubiquitination pathways and the corresponding clinical phenotypes of their deficiencies. We offer a road map for the discovery of new genetic etiologies. By considering the triggers that induce inflammation, we propose autoinflammation and immunodeficiency as continuous clinical phenotypes.</p>","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"222 5","pages":""},"PeriodicalIF":12.6,"publicationDate":"2025-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11998746/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144012242","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":"Splicing factor RBM10 loss fuels thyroid cancer metastasis.","authors":"Kevin Coughlin, Ledong Wan","doi":"10.1084/jem.20250050","DOIUrl":"10.1084/jem.20250050","url":null,"abstract":"<p><p>In this issue of JEM, Krishnamoorthy et al. (https://doi.org/10.1084/jem.20241029) identify the loss of the splicing factor RBM10 as a driver of metastasis in thyroid cancer through the regulation of RNA splicing. The synthetic lethal interaction between NF-κB and RBM10 loss reveals a potential therapeutic vulnerability.</p>","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"222 5","pages":""},"PeriodicalIF":12.6,"publicationDate":"2025-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11849749/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143483242","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}
Simon J Cleary, Longhui Qiu, Yurim Seo, Peter Baluk, Dan Liu, Nina K Serwas, Catherine A Taylor, Dongliang Zhang, Jason G Cyster, Donald M McDonald, Matthew F Krummel, Mark R Looney
{"title":"Intravital imaging of pulmonary lymphatics in inflammation and metastatic cancer.","authors":"Simon J Cleary, Longhui Qiu, Yurim Seo, Peter Baluk, Dan Liu, Nina K Serwas, Catherine A Taylor, Dongliang Zhang, Jason G Cyster, Donald M McDonald, Matthew F Krummel, Mark R Looney","doi":"10.1084/jem.20241359","DOIUrl":"10.1084/jem.20241359","url":null,"abstract":"<p><p>Intravital microscopy has enabled the study of immune dynamics in the pulmonary microvasculature, but many key events remain unseen because they occur in deeper lung regions. We therefore developed a technique for stabilized intravital imaging of bronchovascular cuffs and collecting lymphatics surrounding pulmonary veins in mice. Intravital imaging of pulmonary lymphatics revealed ventilation dependence of steady-state lung lymph flow and ventilation-independent lymph flow during inflammation. We imaged the rapid exodus of migratory dendritic cells through lung lymphatics following inflammation and measured effects of pharmacologic and genetic interventions targeting chemokine signaling. Intravital imaging also captured lymphatic immune surveillance of lung-metastatic cancers and lymphatic metastasis of cancer cells. To our knowledge, this is the first imaging of lymph flow and leukocyte migration through intact pulmonary lymphatics. This approach will enable studies of protective and maladaptive processes unfolding within the lungs and in other previously inaccessible locations.</p>","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"222 5","pages":""},"PeriodicalIF":12.6,"publicationDate":"2025-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11837973/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143449246","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":"Vaccinology: Getting our modernization act together.","authors":"Ofer Levy","doi":"10.1084/jem.20240961","DOIUrl":"https://doi.org/10.1084/jem.20240961","url":null,"abstract":"<p><p>Ofer Levy, Director, Precision Vaccines Program at Boston Children's Hospital, reflects on implications of the new FDA Modernization Act 2.0 on accelerating drug and vaccine discovery and development.</p>","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"222 5","pages":""},"PeriodicalIF":12.6,"publicationDate":"2025-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12013515/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143999638","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}
Zhangying Cai, Shoutang Wang, Siyan Cao, Yun Chen, Silvia Penati, Vincent Peng, Carla M Yuede, Wandy L Beatty, Kent Lin, Yiyang Zhu, Yingyue Zhou, Marco Colonna
{"title":"Loss of ATG7 in microglia impairs UPR, triggers ferroptosis, and weakens amyloid pathology control.","authors":"Zhangying Cai, Shoutang Wang, Siyan Cao, Yun Chen, Silvia Penati, Vincent Peng, Carla M Yuede, Wandy L Beatty, Kent Lin, Yiyang Zhu, Yingyue Zhou, Marco Colonna","doi":"10.1084/jem.20230173","DOIUrl":"10.1084/jem.20230173","url":null,"abstract":"<p><p>Microglia impact brain development, homeostasis, and pathology. One important microglial function in Alzheimer's disease (AD) is to contain proteotoxic amyloid-β (Aβ) plaques. Recent studies reported the involvement of autophagy-related (ATG) proteins in this process. Here, we found that microglia-specific deletion of Atg7 in an AD mouse model impaired microglia coverage of Aβ plaques, increasing plaque diffusion and neurotoxicity. Single-cell RNA sequencing, biochemical, and immunofluorescence analyses revealed that Atg7 deficiency reduces unfolded protein response (UPR) while increasing oxidative stress. Cellular assays demonstrated that these changes lead to lipoperoxidation and ferroptosis of microglia. In aged mice without Aβ buildup, UPR reduction and increased oxidative damage induced by Atg7 deletion did not impact microglia numbers. We conclude that reduced UPR and increased oxidative stress in Atg7-deficient microglia lead to ferroptosis when exposed to proteotoxic stress from Aβ plaques. However, these microglia can still manage misfolded protein accumulation and oxidative stress as they age.</p>","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"222 4","pages":""},"PeriodicalIF":12.6,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11823820/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143407703","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}
Chehyun Nam, Guowei Huang, Yueyuan Zheng, Hua Zhao, Yuhao Pan, Boyan Hu, Talia Wenger, Hieu T Van, Li-Yan Xu, En-Min Li, H Phillip Koeffler, Kai Ge, Yali Dou, Uttam K Sinha, Young Min Park, De-Chen Lin
{"title":"The MLL3/GRHL2 complex regulates malignant transformation and anti-tumor immunity in squamous cancer.","authors":"Chehyun Nam, Guowei Huang, Yueyuan Zheng, Hua Zhao, Yuhao Pan, Boyan Hu, Talia Wenger, Hieu T Van, Li-Yan Xu, En-Min Li, H Phillip Koeffler, Kai Ge, Yali Dou, Uttam K Sinha, Young Min Park, De-Chen Lin","doi":"10.1084/jem.20240758","DOIUrl":"10.1084/jem.20240758","url":null,"abstract":"<p><p>Upper aerodigestive squamous cell carcinoma (UASCC) presents significant challenges in clinical management due to its aggressive nature. Here, we elucidate the role of MLL3 mutations as early, clonal genomic events in UASCC tumorigenesis, highlighting their role as foundational drivers of cancer development. Utilizing CRISPR-edited, cross-species organoid modeling, we demonstrate that loss of MLL3 contributes to early squamous neoplastic evolution. Furthermore, we identify an MLL3/GRHL2 protein complex that regulates the UASCC epigenome, particularly impacting immune response pathways. Notably, a novel MLL3/GRHL2-IRF1 axis promotes the expression of Th1 chemokines, enhancing anti-tumor immunity by facilitating T cell infiltration into the tumor microenvironment. Consequently, MLL3 regulates the in vivo efficacy of immune checkpoint blockade (ICB) therapy, corroborated by the strong association between MLL3 expression and human patients' clinical response to ICB therapy. Our work underscores the significance of MLL3 in UASCC pathogenesis and highlights the interplay between MLL3/GRHL2 and immune response pathways as potential therapeutic targets for UASCC treatment.</p>","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"222 4","pages":""},"PeriodicalIF":12.6,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11834937/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143441087","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}
Hannah Peckham, Anna Radziszewska, Justyna Sikora, Nina M de Gruijter, Restuadi Restuadi, Melissa Kartawinata, Lucia Martin-Gutierrez, George A Robinson, Claire T Deakin, Lucy R Wedderburn, Elizabeth C Jury, Gary Butler, Emma S Chambers, Elizabeth C Rosser, Coziana Ciurtin
{"title":"Estrogen influences class-switched memory B cell frequency only in humans with two X chromosomes.","authors":"Hannah Peckham, Anna Radziszewska, Justyna Sikora, Nina M de Gruijter, Restuadi Restuadi, Melissa Kartawinata, Lucia Martin-Gutierrez, George A Robinson, Claire T Deakin, Lucy R Wedderburn, Elizabeth C Jury, Gary Butler, Emma S Chambers, Elizabeth C Rosser, Coziana Ciurtin","doi":"10.1084/jem.20241253","DOIUrl":"10.1084/jem.20241253","url":null,"abstract":"<p><p>Sex differences in immunity are well-documented, though mechanisms underpinning these differences remain ill-defined. Here, in a human-only ex vivo study, we demonstrate that postpubertal cisgender females have higher levels of CD19+CD27+IgD- class-switched memory B cells compared with age-matched cisgender males. This increase is only observed after puberty and before menopause, suggesting a strong influence for sex hormones. Accordingly, B cells express high levels of estrogen receptor 2 (ESR2), and class-switch-regulating genes are enriched for ESR2-binding sites. In a gender-diverse cohort, blockade of natal estrogen in transgender males (XX karyotype) reduced class-switched memory B cell frequency, while gender-affirming estradiol treatment in transgender females (XY karyotype) did not increase these levels. In postmenopausal cis-females, class-switched memory B cells were increased in those taking hormone replacement therapy (HRT) compared with those who were not. These data demonstrate that sex hormones and chromosomes work in tandem to impact immune responses, with estrogen only influencing the frequency of class-switched memory B cells in individuals with an XX chromosomal background.</p>","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"222 4","pages":""},"PeriodicalIF":12.6,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11893172/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143572916","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}
Shan-Shan Wang, Jia Yuan, Xinyu Thomas Tang, Xiujuan Yin, Ke Fang, Lin Veronica Chen, Zhenggang Ren, Bo O Zhou
{"title":"Periductal fibroblasts participate in liver homeostasis, fibrosis, and tumorigenesis.","authors":"Shan-Shan Wang, Jia Yuan, Xinyu Thomas Tang, Xiujuan Yin, Ke Fang, Lin Veronica Chen, Zhenggang Ren, Bo O Zhou","doi":"10.1084/jem.20232123","DOIUrl":"10.1084/jem.20232123","url":null,"abstract":"<p><p>Hepatic fibroblasts comprise groups of stromal cells in the liver that are phenotypically distinct from hepatic stellate cells. However, their physiology is poorly understood. By single-cell RNA sequencing, we identified Cd34 and Dpt as hepatic fibroblast-specific genes. Cd34-CreER labeled periportal-venous and periductal fibroblasts, but few pericentral-venous fibroblasts. Cd34+ fibroblasts generated ∼25% of myofibroblasts in periportal fibrosis and ∼40% of cancer-associated fibroblasts (CAFs) in intrahepatic cholangiocarcinoma (ICC). Myofibroblast formation by Cd34+ fibroblasts required Tgfbr2. Depletion of Cd34+ fibroblasts increased the frequency of the ductal epithelial cells under homeostasis and accelerated the progression of ICC. Dpt-CreER labeled periportal- and pericentral-venous fibroblasts, but much less periductal fibroblasts. Dpt+ cells generated ∼15% of myofibroblasts in periportal fibrosis, but few myofibroblasts in pericentral fibrosis or CAFs in ICC. Thus, an orthogonal combination of Cd34-CreER and Dpt-CreER dissected the fates of periductal, periportal-venous, and pericentral-venous fibroblasts. Both periductal and periportal-venous fibroblasts contribute to liver fibrosis. Periductal fibroblasts also contribute to ductal homeostasis and ICC progression.</p>","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"222 4","pages":""},"PeriodicalIF":12.6,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11784584/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143064604","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}
Kerry L Hilligan, Patricia A Darrah, Robert A Seder, Alan Sher
{"title":"Deconvoluting the interplay of innate and adaptive immunity in BCG-induced nonspecific and TB-specific host resistance.","authors":"Kerry L Hilligan, Patricia A Darrah, Robert A Seder, Alan Sher","doi":"10.1084/jem.20240496","DOIUrl":"10.1084/jem.20240496","url":null,"abstract":"<p><p>BCG is the oldest vaccine in continuous use. While current intradermal vaccination regimens confer limited protection outside the context of pediatric extrapulmonary tuberculosis (TB), promising new data indicate that when administered mucosally or intravenously at a higher dose, BCG can induce sterilizing immunity against pulmonary TB in nonhuman primates. BCG is also known to promote nonspecific host resistance against a variety of unrelated infections and is a standard immunotherapy for bladder cancer, suggesting that this innate immune function may contribute to its protective role against TB. Here, we propose that both the mycobacterial-specific and off-target effects of BCG depend on the interplay of adaptive and innate cells and the cytokines they produce, and that the elucidation of this interaction should be a major strategy in the development of more effective BCG-based vaccines and immunotherapies.</p>","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"222 4","pages":""},"PeriodicalIF":12.6,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11917170/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143657473","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}
Benjamin Israelow, Eric Song, Tianyang Mao, Peiwen Lu, Amit Meir, Feimei Liu, Mia Madel Alfajaro, Jin Wei, Huiping Dong, Robert J Homer, Aaron Ring, Craig B Wilen, Akiko Iwasaki
{"title":"Correction: Mouse model of SARS-CoV-2 reveals inflammatory role of type I interferon signaling.","authors":"Benjamin Israelow, Eric Song, Tianyang Mao, Peiwen Lu, Amit Meir, Feimei Liu, Mia Madel Alfajaro, Jin Wei, Huiping Dong, Robert J Homer, Aaron Ring, Craig B Wilen, Akiko Iwasaki","doi":"10.1084/jem.2020124102192025c","DOIUrl":"10.1084/jem.2020124102192025c","url":null,"abstract":"","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"222 4","pages":""},"PeriodicalIF":12.6,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11864074/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143501909","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}