Pub Date : 2024-09-25DOI: 10.1126/scitranslmed.adn7095
Qiang Li, Alfredo Sandoval, John Moth, Junkui Shang, Jia Yi Liew, Tiffany Dunn, Zhiyun Yang, Junfeng Su, Melissa Henwood, Philip Williams, Bo Chen
Spinal cord injury (SCI) results in acute damage and triggers secondary injury responses with sustained neuronal loss and dysfunction. However, the underlying mechanisms for these delayed neuronal pathologies are not entirely understood. SCI results in the swelling of spinal neurons, but the contribution of cell swelling to neuronal loss and functional deficits after SCI has not been systematically characterized. In this study, we devised a three-dimensional image analysis pipeline to evaluate spinal neurons, examining their types, quantities, volumes, and spatial distribution in a double-lateral hemisection SCI mouse model. We found that both excitatory and inhibitory neurons swell and are lost, albeit with distinct temporal patterns. Inhibitory neurons demonstrated marked swelling and decline in number on day 2 after SCI, which resolved by day 14. In contrast, excitatory neurons maintained persistent swelling and continued cell loss for at least 35 days after SCI in mice. Excitatory neurons exhibited sustained expression of the Na+-K+-Cl− cotransporter 1 (NKCC1), whereas inhibitory neurons down-regulated the protein by day 14 after SCI. Treatment with a Food and Drug Administration–approved NKCC1 inhibitor, bumetanide, mitigated swelling of excitatory neurons and reduced their loss in the secondary injury phase after SCI. The administration of bumetanide after SCI in mouse improved locomotor recovery, with functional benefits persisting for at least 4 weeks after treatment cessation. This study advances our understanding of SCI-related pathology and introduces bumetanide as a potential treatment to mitigate sustained neuronal swelling and enhance recovery after SCI.
{"title":"Reduction of prolonged excitatory neuron swelling after spinal cord injury improves locomotor recovery in mice","authors":"Qiang Li, Alfredo Sandoval, John Moth, Junkui Shang, Jia Yi Liew, Tiffany Dunn, Zhiyun Yang, Junfeng Su, Melissa Henwood, Philip Williams, Bo Chen","doi":"10.1126/scitranslmed.adn7095","DOIUrl":"10.1126/scitranslmed.adn7095","url":null,"abstract":"<div >Spinal cord injury (SCI) results in acute damage and triggers secondary injury responses with sustained neuronal loss and dysfunction. However, the underlying mechanisms for these delayed neuronal pathologies are not entirely understood. SCI results in the swelling of spinal neurons, but the contribution of cell swelling to neuronal loss and functional deficits after SCI has not been systematically characterized. In this study, we devised a three-dimensional image analysis pipeline to evaluate spinal neurons, examining their types, quantities, volumes, and spatial distribution in a double-lateral hemisection SCI mouse model. We found that both excitatory and inhibitory neurons swell and are lost, albeit with distinct temporal patterns. Inhibitory neurons demonstrated marked swelling and decline in number on day 2 after SCI, which resolved by day 14. In contrast, excitatory neurons maintained persistent swelling and continued cell loss for at least 35 days after SCI in mice. Excitatory neurons exhibited sustained expression of the Na<sup>+</sup>-K<sup>+</sup>-Cl<sup>−</sup> cotransporter 1 (NKCC1), whereas inhibitory neurons down-regulated the protein by day 14 after SCI. Treatment with a Food and Drug Administration–approved NKCC1 inhibitor, bumetanide, mitigated swelling of excitatory neurons and reduced their loss in the secondary injury phase after SCI. The administration of bumetanide after SCI in mouse improved locomotor recovery, with functional benefits persisting for at least 4 weeks after treatment cessation. This study advances our understanding of SCI-related pathology and introduces bumetanide as a potential treatment to mitigate sustained neuronal swelling and enhance recovery after SCI.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"16 766","pages":""},"PeriodicalIF":15.8,"publicationDate":"2024-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142320954","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}
Pub Date : 2024-09-25DOI: 10.1126/scitranslmed.adn1285
Vincent Rondeau, Jacob M. Berman, Tianyi Ling, Cristiana O’Brien, Rachel Culp-Hill, Julie A. Reisz, Mark Wunderlich, Yun Chueh, Karina E. Jiménez-Camacho, Christina Sexton, Katharine M. Carter, Cody Stillwell, Jonathan St-Germain, Duhan Yendi, Aarushi Gupta, Mary Shi, Aleksandra Bourdine, Vikram R. Paralkar, Soheil Jahangiri, Kristin J. Hope, Anastasia N. Tikhonova, Andrea Arruda, Mark D. Minden, Brian Raught, Angelo D’Alessandro, Courtney L. Jones
Acute myeloid leukemia (AML) is a devastating disease initiated and maintained by a rare subset of cells called leukemia stem cells (LSCs). LSCs are responsible for driving disease relapse, making the development of new therapeutic strategies to target LSCs urgently needed. The use of mass spectrometry–based metabolomics profiling has enabled the discovery of unique and targetable metabolic properties in LSCs. However, we do not have a comprehensive understanding of metabolite differences between LSCs and their normal counterparts, hematopoietic stem and progenitor cells (HSPCs). In this study, we used an unbiased mass spectrometry–based metabolomics analysis to define differences in metabolites between primary human LSCs and HSPCs, which revealed that LSCs have a distinct metabolome. Spermidine was the most enriched metabolite in LSCs compared with HSPCs. Pharmacological reduction of spermidine concentrations decreased LSC function but spared normal HSPCs. Polyamine depletion also decreased leukemic burden in patient-derived xenografts. Mechanistically, spermidine depletion induced LSC myeloid differentiation by decreasing eIF5A-dependent protein synthesis, resulting in reduced expression of a select subset of proteins. KAT7, a histone acetyltransferase, was one of the top candidates identified to be down-regulated by spermidine depletion. Overexpression of KAT7 partially rescued polyamine depletion–induced decreased colony-forming ability, demonstrating that loss of KAT7 is an essential part of the mechanism by which spermidine depletion targets AML clonogenic potential. Together, we identified and mechanistically dissected a metabolic vulnerability of LSCs that has the potential to be rapidly translated into clinical trials to improve outcomes for patients with AML.
{"title":"Spermidine metabolism regulates leukemia stem and progenitor cell function through KAT7 expression in patient-derived mouse models","authors":"Vincent Rondeau, Jacob M. Berman, Tianyi Ling, Cristiana O’Brien, Rachel Culp-Hill, Julie A. Reisz, Mark Wunderlich, Yun Chueh, Karina E. Jiménez-Camacho, Christina Sexton, Katharine M. Carter, Cody Stillwell, Jonathan St-Germain, Duhan Yendi, Aarushi Gupta, Mary Shi, Aleksandra Bourdine, Vikram R. Paralkar, Soheil Jahangiri, Kristin J. Hope, Anastasia N. Tikhonova, Andrea Arruda, Mark D. Minden, Brian Raught, Angelo D’Alessandro, Courtney L. Jones","doi":"10.1126/scitranslmed.adn1285","DOIUrl":"10.1126/scitranslmed.adn1285","url":null,"abstract":"<div >Acute myeloid leukemia (AML) is a devastating disease initiated and maintained by a rare subset of cells called leukemia stem cells (LSCs). LSCs are responsible for driving disease relapse, making the development of new therapeutic strategies to target LSCs urgently needed. The use of mass spectrometry–based metabolomics profiling has enabled the discovery of unique and targetable metabolic properties in LSCs. However, we do not have a comprehensive understanding of metabolite differences between LSCs and their normal counterparts, hematopoietic stem and progenitor cells (HSPCs). In this study, we used an unbiased mass spectrometry–based metabolomics analysis to define differences in metabolites between primary human LSCs and HSPCs, which revealed that LSCs have a distinct metabolome. Spermidine was the most enriched metabolite in LSCs compared with HSPCs. Pharmacological reduction of spermidine concentrations decreased LSC function but spared normal HSPCs. Polyamine depletion also decreased leukemic burden in patient-derived xenografts. Mechanistically, spermidine depletion induced LSC myeloid differentiation by decreasing eIF5A-dependent protein synthesis, resulting in reduced expression of a select subset of proteins. KAT7, a histone acetyltransferase, was one of the top candidates identified to be down-regulated by spermidine depletion. Overexpression of KAT7 partially rescued polyamine depletion–induced decreased colony-forming ability, demonstrating that loss of KAT7 is an essential part of the mechanism by which spermidine depletion targets AML clonogenic potential. Together, we identified and mechanistically dissected a metabolic vulnerability of LSCs that has the potential to be rapidly translated into clinical trials to improve outcomes for patients with AML.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"16 766","pages":""},"PeriodicalIF":15.8,"publicationDate":"2024-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142320969","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}
Pub Date : 2024-09-25DOI: 10.1126/scitranslmed.adk8446
Hung-Chun Tung, Jong-Won Kim, Junjie Zhu, Sihan Li, Jiong Yan, Qing Liu, Imhoi Koo, Sergei A. Koshkin, Fuhua Hao, Guo Zhong, Meishu Xu, Zehua Wang, Jingyuan Wang, Yixian Huang, Yue Xi, Xinran Cai, Pengfei Xu, Songrong Ren, Takanobu Higashiyama, Frank J. Gonzalez, Song Li, Nina Isoherranen, Da Yang, Xiaochao Ma, Andrew D. Patterson, Wen Xie
Activation of extracellular matrix–producing hepatic stellate cells (HSCs) is a key event in liver fibrogenesis. We showed that the expression of the heme-thiolate monooxygenase cytochrome P450 1B1 (CYP1B1) was elevated in human and mouse fibrotic livers and activated HSCs. Systemic or HSC-specific ablation and pharmacological inhibition of CYP1B1 attenuated HSC activation and protected male but not female mice from thioacetamide (TAA)–, carbon tetrachloride (CCl4)–, or bile duct ligation (BDL)–induced liver fibrosis. Metabolomic analysis revealed an increase in the disaccharide trehalose in CYP1B1-deficient HSCs resulting from intestinal suppression of the trehalose-metabolizing enzyme trehalase, whose gene we found to be a target of RARα. Trehalose or its hydrolysis-resistant derivative lactotrehalose exhibited potent antifibrotic activity in vitro and in vivo by functioning as an HSC-specific autophagy inhibitor, which may account for the antifibrotic effect of CYP1B1 inhibition. Our study thus reveals an endobiotic function of CYP1B1 in liver fibrosis in males, mediated by liver-intestine cross-talk and trehalose. At the translational level, pharmacological inhibition of CYP1B1 or the use of trehalose/lactotrehalose may represent therapeutic strategies for liver fibrosis.
{"title":"Inhibition of heme-thiolate monooxygenase CYP1B1 prevents hepatic stellate cell activation and liver fibrosis by accumulating trehalose","authors":"Hung-Chun Tung, Jong-Won Kim, Junjie Zhu, Sihan Li, Jiong Yan, Qing Liu, Imhoi Koo, Sergei A. Koshkin, Fuhua Hao, Guo Zhong, Meishu Xu, Zehua Wang, Jingyuan Wang, Yixian Huang, Yue Xi, Xinran Cai, Pengfei Xu, Songrong Ren, Takanobu Higashiyama, Frank J. Gonzalez, Song Li, Nina Isoherranen, Da Yang, Xiaochao Ma, Andrew D. Patterson, Wen Xie","doi":"10.1126/scitranslmed.adk8446","DOIUrl":"10.1126/scitranslmed.adk8446","url":null,"abstract":"<div >Activation of extracellular matrix–producing hepatic stellate cells (HSCs) is a key event in liver fibrogenesis. We showed that the expression of the heme-thiolate monooxygenase cytochrome P450 1B1 (CYP1B1) was elevated in human and mouse fibrotic livers and activated HSCs. Systemic or HSC-specific ablation and pharmacological inhibition of CYP1B1 attenuated HSC activation and protected male but not female mice from thioacetamide (TAA)–, carbon tetrachloride (CCl<sub>4</sub>)–, or bile duct ligation (BDL)–induced liver fibrosis. Metabolomic analysis revealed an increase in the disaccharide trehalose in CYP1B1-deficient HSCs resulting from intestinal suppression of the trehalose-metabolizing enzyme trehalase, whose gene we found to be a target of RARα. Trehalose or its hydrolysis-resistant derivative lactotrehalose exhibited potent antifibrotic activity in vitro and in vivo by functioning as an HSC-specific autophagy inhibitor, which may account for the antifibrotic effect of CYP1B1 inhibition. Our study thus reveals an endobiotic function of CYP1B1 in liver fibrosis in males, mediated by liver-intestine cross-talk and trehalose. At the translational level, pharmacological inhibition of CYP1B1 or the use of trehalose/lactotrehalose may represent therapeutic strategies for liver fibrosis.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"16 766","pages":""},"PeriodicalIF":15.8,"publicationDate":"2024-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142320968","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}
Pub Date : 2024-09-25DOI: 10.1126/scitranslmed.adn7871
Dayan J. Li, Charlotte E. Berry, Derrick C. Wan, Michael T. Longaker
When dysregulated, skin fibrosis can lead to a multitude of pathologies. We provide a framework for understanding the wide clinical spectrum, mechanisms, and management of cutaneous fibrosis encompassing a variety of matrix disorders, fibrohistiocytic neoplasms, injury-induced scarring, and autoimmune scleroses. Underlying such entities are common mechanistic pathways that leverage morphogenic signaling, immune activation, and mechanotransduction to modulate fibroblast function. In light of the limited array of available treatments for cutaneous fibrosis, scientific insights have opened new therapeutic and investigative avenues for conditions that still lack effective interventions.
{"title":"Clinical, mechanistic, and therapeutic landscape of cutaneous fibrosis","authors":"Dayan J. Li, Charlotte E. Berry, Derrick C. Wan, Michael T. Longaker","doi":"10.1126/scitranslmed.adn7871","DOIUrl":"10.1126/scitranslmed.adn7871","url":null,"abstract":"<div >When dysregulated, skin fibrosis can lead to a multitude of pathologies. We provide a framework for understanding the wide clinical spectrum, mechanisms, and management of cutaneous fibrosis encompassing a variety of matrix disorders, fibrohistiocytic neoplasms, injury-induced scarring, and autoimmune scleroses. Underlying such entities are common mechanistic pathways that leverage morphogenic signaling, immune activation, and mechanotransduction to modulate fibroblast function. In light of the limited array of available treatments for cutaneous fibrosis, scientific insights have opened new therapeutic and investigative avenues for conditions that still lack effective interventions.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"16 766","pages":""},"PeriodicalIF":15.8,"publicationDate":"2024-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142320961","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}
Pub Date : 2024-09-25DOI: 10.1126/scitranslmed.adj1277
Michael J. Lacagnina, Kendal F. Willcox, Nabila Boukelmoune, Alexis Bavencoffe, Ishwarya Sankaranarayanan, Daniel T. Barratt, Younus A. Zuberi, Dorsa Dayani, Melissa V. Chavez, Jonathan T. Lu, Alex Bersellini Farinotti, Stephanie Shiers, Allison M. Barry, Juliet M. Mwirigi, Diana Tavares-Ferreira, Geoffrey A. Funk, Anna M. Cervantes, Camilla I. Svensson, Edgar T. Walters, Mark R. Hutchinson, Cobi J. Heijnen, Theodore J. Price, Nathan T. Fiore, Peter M. Grace
Neuroimmune interactions are essential for the development of neuropathic pain, yet the contributions of distinct immune cell populations have not been fully unraveled. Here, we demonstrate the critical role of B cells in promoting mechanical hypersensitivity (allodynia) after peripheral nerve injury in male and female mice. Depletion of B cells with a single injection of anti-CD20 monoclonal antibody at the time of injury prevented the development of allodynia. B cell–deficient (muMT) mice were similarly spared from allodynia. Nerve injury was associated with increased immunoglobulin G (IgG) accumulation in ipsilateral lumbar dorsal root ganglia (DRGs) and dorsal spinal cords. IgG was colocalized with sensory neurons and macrophages in DRGs and microglia in spinal cords. IgG also accumulated in DRG samples from human donors with chronic pain, colocalizing with a marker for macrophages and satellite glia. RNA sequencing revealed a B cell population in naive mouse and human DRGs. A B cell transcriptional signature was enriched in DRGs from human donors with neuropathic pain. Passive transfer of IgG from injured mice induced allodynia in injured muMT recipient mice. The pronociceptive effects of IgG are likely mediated through immune complexes interacting with Fc gamma receptors (FcγRs) expressed by sensory neurons, microglia, and macrophages, given that both mechanical allodynia and hyperexcitability of dissociated DRG neurons were abolished in nerve-injured FcγR-deficient mice. Consistently, the pronociceptive effects of IgG passive transfer were lost in FcγR-deficient mice. These data reveal that a B cell–IgG–FcγR axis is required for the development of neuropathic pain in mice.
神经免疫相互作用对神经病理性疼痛的发展至关重要，但不同免疫细胞群的贡献尚未完全阐明。在这里，我们证明了 B 细胞在促进雄性和雌性小鼠周围神经损伤后机械过敏（异动症）中的关键作用。在损伤时注射一次抗 CD20 单克隆抗体以消耗 B 细胞，可防止异感症的发生。B细胞缺失（muMT）小鼠同样不会出现异感症。神经损伤与同侧腰椎背根神经节（DRGs）和脊髓背侧的免疫球蛋白 G（IgG）积累增加有关。IgG 与感觉神经元、DRG 中的巨噬细胞和脊髓中的小胶质细胞共定位。在患有慢性疼痛的人类供体的DRG样本中也有IgG聚集，并与巨噬细胞和卫星胶质细胞的标记物共定位。RNA 测序揭示了天真小鼠和人类 DRG 中的 B 细胞群。B细胞转录特征在患有神经性疼痛的人类供体的DRG中富集。受伤小鼠的 IgG 被动转移会诱发受伤的 muMT 受体小鼠的异动症。IgG的代痛觉效应可能是通过免疫复合物与感觉神经元、小胶质细胞和巨噬细胞表达的Fcγ受体（FcγRs）相互作用而介导的，因为在神经损伤的FcγR缺陷小鼠中，机械异感和离体DRG神经元的过度兴奋都被取消了。同样，在 FcγR 缺失的小鼠中，IgG 被动转移的代痛觉效应也消失了。这些数据揭示了小鼠神经病理性疼痛的发生需要B细胞-IgG-FcγR轴。
{"title":"B cells drive neuropathic pain–related behaviors in mice through IgG–Fc gamma receptor signaling","authors":"Michael J. Lacagnina, Kendal F. Willcox, Nabila Boukelmoune, Alexis Bavencoffe, Ishwarya Sankaranarayanan, Daniel T. Barratt, Younus A. Zuberi, Dorsa Dayani, Melissa V. Chavez, Jonathan T. Lu, Alex Bersellini Farinotti, Stephanie Shiers, Allison M. Barry, Juliet M. Mwirigi, Diana Tavares-Ferreira, Geoffrey A. Funk, Anna M. Cervantes, Camilla I. Svensson, Edgar T. Walters, Mark R. Hutchinson, Cobi J. Heijnen, Theodore J. Price, Nathan T. Fiore, Peter M. Grace","doi":"10.1126/scitranslmed.adj1277","DOIUrl":"10.1126/scitranslmed.adj1277","url":null,"abstract":"<div >Neuroimmune interactions are essential for the development of neuropathic pain, yet the contributions of distinct immune cell populations have not been fully unraveled. Here, we demonstrate the critical role of B cells in promoting mechanical hypersensitivity (allodynia) after peripheral nerve injury in male and female mice. Depletion of B cells with a single injection of anti-CD20 monoclonal antibody at the time of injury prevented the development of allodynia. B cell–deficient (muMT) mice were similarly spared from allodynia. Nerve injury was associated with increased immunoglobulin G (IgG) accumulation in ipsilateral lumbar dorsal root ganglia (DRGs) and dorsal spinal cords. IgG was colocalized with sensory neurons and macrophages in DRGs and microglia in spinal cords. IgG also accumulated in DRG samples from human donors with chronic pain, colocalizing with a marker for macrophages and satellite glia. RNA sequencing revealed a B cell population in naive mouse and human DRGs. A B cell transcriptional signature was enriched in DRGs from human donors with neuropathic pain. Passive transfer of IgG from injured mice induced allodynia in injured muMT recipient mice. The pronociceptive effects of IgG are likely mediated through immune complexes interacting with Fc gamma receptors (FcγRs) expressed by sensory neurons, microglia, and macrophages, given that both mechanical allodynia and hyperexcitability of dissociated DRG neurons were abolished in nerve-injured FcγR-deficient mice. Consistently, the pronociceptive effects of IgG passive transfer were lost in FcγR-deficient mice. These data reveal that a B cell–IgG–FcγR axis is required for the development of neuropathic pain in mice.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"16 766","pages":""},"PeriodicalIF":15.8,"publicationDate":"2024-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/scitranslmed.adj1277","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142320970","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}
Pub Date : 2024-09-18DOI: 10.1126/scitranslmed.adk0642
Justin C. Jagodinsky, Jessica M. Vera, Won Jong Jin, Amanda G. Shea, Paul A. Clark, Raghava N. Sriramaneni, Thomas C. Havighurst, Ishan Chakravarthy, Raad H. Allawi, KyungMann Kim, Paul M. Harari, Paul M. Sondel, Michael A. Newton, Marka R. Crittenden, Michael J. Gough, Jessica R. Miller, Irene M. Ong, Zachary S. Morris
Radiation therapy (RT) activates multiple immunologic effects in the tumor microenvironment (TME), with diverse dose-response relationships observed. We hypothesized that, in contrast with homogeneous RT, a heterogeneous RT dose would simultaneously optimize activation of multiple immunogenic effects in a single TME, resulting in a more effective antitumor immune response. Using high-dose-rate brachytherapy, we treated mice bearing syngeneic tumors with a single fraction of heterogeneous RT at a dose ranging from 2 to 30 gray. When combined with dual immune checkpoint inhibition in murine models, heterogeneous RT generated more potent antitumor responses in distant, nonirradiated tumors compared with any homogeneous dose. The antitumor effect after heterogeneous RT required CD4 and CD8 T cells and low-dose RT to a portion of the tumor. At the 3-day post-RT time point, dose heterogeneity imprinted the targeted TME with spatial differences in immune-related gene expression, antigen presentation, and susceptibility of tumor cells to immune-mediated destruction. At a later 10-day post-RT time point, high-, moderate-, or low-RT-dose regions demonstrated distinct infiltrating immune cell populations. This was associated with an increase in the expression of effector-associated cytokines in circulating CD8 T cells. Consistent with enhanced adaptive immune priming, heterogeneous RT promoted clonal expansion of effector CD8 T cells. These findings illuminate the breadth of dose-dependent effects of RT on the TME and the capacity of heterogeneous RT to promote antitumor immunity when combined with immune checkpoint inhibitors.
放射治疗（RT）会激活肿瘤微环境（TME）中的多种免疫效应，并观察到不同的剂量-反应关系。我们假设，与均质 RT 相比，异质 RT 剂量能同时优化激活单一 TME 中的多种免疫效应，从而产生更有效的抗肿瘤免疫反应。我们利用高剂量率近距离放射疗法，对携带合成肿瘤的小鼠进行单剂量异质RT治疗，剂量范围为2至30灰。当在小鼠模型中结合双重免疫检查点抑制时，与任何均质剂量相比，异质RT能在远处未照射的肿瘤中产生更强的抗肿瘤反应。异质 RT 后的抗肿瘤效果需要 CD4 和 CD8 T 细胞以及对部分肿瘤的低剂量 RT。在RT后3天的时间点，剂量异质性使靶向TME在免疫相关基因表达、抗原呈递和肿瘤细胞对免疫介导的破坏敏感性方面存在空间差异。在 RT 后 10 天的时间点上，高、中、低 RT 剂量区域显示出不同的浸润免疫细胞群。这与循环 CD8 T 细胞中效应相关细胞因子表达的增加有关。与增强的适应性免疫启动相一致，异质性 RT 促进了效应 CD8 T 细胞的克隆扩增。这些发现阐明了RT对TME的剂量依赖性效应的广度，以及异质RT与免疫检查点抑制剂联合使用时促进抗肿瘤免疫的能力。
{"title":"Intratumoral radiation dose heterogeneity augments antitumor immunity in mice and primes responses to checkpoint blockade","authors":"Justin C. Jagodinsky, Jessica M. Vera, Won Jong Jin, Amanda G. Shea, Paul A. Clark, Raghava N. Sriramaneni, Thomas C. Havighurst, Ishan Chakravarthy, Raad H. Allawi, KyungMann Kim, Paul M. Harari, Paul M. Sondel, Michael A. Newton, Marka R. Crittenden, Michael J. Gough, Jessica R. Miller, Irene M. Ong, Zachary S. Morris","doi":"10.1126/scitranslmed.adk0642","DOIUrl":"10.1126/scitranslmed.adk0642","url":null,"abstract":"<div >Radiation therapy (RT) activates multiple immunologic effects in the tumor microenvironment (TME), with diverse dose-response relationships observed. We hypothesized that, in contrast with homogeneous RT, a heterogeneous RT dose would simultaneously optimize activation of multiple immunogenic effects in a single TME, resulting in a more effective antitumor immune response. Using high-dose-rate brachytherapy, we treated mice bearing syngeneic tumors with a single fraction of heterogeneous RT at a dose ranging from 2 to 30 gray. When combined with dual immune checkpoint inhibition in murine models, heterogeneous RT generated more potent antitumor responses in distant, nonirradiated tumors compared with any homogeneous dose. The antitumor effect after heterogeneous RT required CD4 and CD8 T cells and low-dose RT to a portion of the tumor. At the 3-day post-RT time point, dose heterogeneity imprinted the targeted TME with spatial differences in immune-related gene expression, antigen presentation, and susceptibility of tumor cells to immune-mediated destruction. At a later 10-day post-RT time point, high-, moderate-, or low-RT-dose regions demonstrated distinct infiltrating immune cell populations. This was associated with an increase in the expression of effector-associated cytokines in circulating CD8 T cells. Consistent with enhanced adaptive immune priming, heterogeneous RT promoted clonal expansion of effector CD8 T cells. These findings illuminate the breadth of dose-dependent effects of RT on the TME and the capacity of heterogeneous RT to promote antitumor immunity when combined with immune checkpoint inhibitors.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"16 765","pages":""},"PeriodicalIF":15.8,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142245135","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}
Pub Date : 2024-09-18DOI: 10.1126/scitranslmed.adk0845
Sebastian Ochoa, Amy P. Hsu, Andrew J. Oler, Dhaneshwar Kumar, Daniel Chauss, Jan Piet van Hamburg, Gustaaf G. van Laar, Vasileios Oikonomou, Sundar Ganesan, Elise M. N. Ferré, Monica M. Schmitt, Tom DiMaggio, Princess Barber, Gregory M. Constantine, Lindsey B. Rosen, Paul G. Auwaerter, Bhumika Gandhi, Jennifer L. Miller, Rachel Eisenberg, Arye Rubinstein, Edith Schussler, Erjola Balliu, Vandana Shashi, Olaf Neth, Peter Olbrich, Kim My Le, Nanni Mamia, Saila Laakso, Pasi I. Nevalainen, Juha Grönholm, Mikko R. J. Seppänen, Louis Boon, Gulbu Uzel, Luis M. Franco, Theo Heller, Karen K. Winer, Rajarshi Ghosh, Bryce A. Seifert, Magdalena Walkiewicz, Luigi D. Notarangelo, Qing Zhou, Ivona Askentijevich, William Gahl, Cliffton L. Dalgard, Lalith Perera, Behdad Afzali, Sander W. Tas, Steven M. Holland, Michail S. Lionakis
Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is a life-threatening monogenic autoimmune disorder primarily caused by biallelic deleterious variants in the autoimmune regulator (AIRE) gene. We prospectively evaluated 104 patients with clinically diagnosed APECED syndrome and identified 17 patients (16%) from 14 kindreds lacking biallelic AIRE variants in exons or flanking intronic regions; 15 had Puerto Rican ancestry. Through whole-genome sequencing, we identified a deep intronic AIRE variant (c.1504-818 G>A) cosegregating with the disease in all 17 patients. We developed a culture system of AIRE-expressing primary patient monocyte-derived dendric cells and demonstrated that c.1504-818 G>A creates a cryptic splice site and activates inclusion of a 109–base pair frame-shifting pseudoexon. We also found low-level AIRE expression in patient-derived lymphoblastoid cell lines (LCLs) and confirmed pseudoexon inclusion in independent extrathymic AIRE–expressing cell lines. Through protein modeling and transcriptomic analyses of AIRE-transfected human embryonic kidney 293 and thymic epithelial cell 4D6 cells, we showed that this variant alters the carboxyl terminus of the AIRE protein, abrogating its function. Last, we developed an antisense oligonucleotide (ASO) that reversed pseudoexon inclusion and restored the normal AIRE transcript sequence in LCLs. Thus, our findings revealed c.1504-818 G>A as a founder APECED-causing AIRE variant in the Puerto Rican population and uncovered pseudoexon inclusion as an ASO-reversible genetic mechanism underlying APECED.
{"title":"A deep intronic splice–altering AIRE variant causes APECED syndrome through antisense oligonucleotide-targetable pseudoexon inclusion","authors":"Sebastian Ochoa, Amy P. Hsu, Andrew J. Oler, Dhaneshwar Kumar, Daniel Chauss, Jan Piet van Hamburg, Gustaaf G. van Laar, Vasileios Oikonomou, Sundar Ganesan, Elise M. N. Ferré, Monica M. Schmitt, Tom DiMaggio, Princess Barber, Gregory M. Constantine, Lindsey B. Rosen, Paul G. Auwaerter, Bhumika Gandhi, Jennifer L. Miller, Rachel Eisenberg, Arye Rubinstein, Edith Schussler, Erjola Balliu, Vandana Shashi, Olaf Neth, Peter Olbrich, Kim My Le, Nanni Mamia, Saila Laakso, Pasi I. Nevalainen, Juha Grönholm, Mikko R. J. Seppänen, Louis Boon, Gulbu Uzel, Luis M. Franco, Theo Heller, Karen K. Winer, Rajarshi Ghosh, Bryce A. Seifert, Magdalena Walkiewicz, Luigi D. Notarangelo, Qing Zhou, Ivona Askentijevich, William Gahl, Cliffton L. Dalgard, Lalith Perera, Behdad Afzali, Sander W. Tas, Steven M. Holland, Michail S. Lionakis","doi":"10.1126/scitranslmed.adk0845","DOIUrl":"10.1126/scitranslmed.adk0845","url":null,"abstract":"<div >Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is a life-threatening monogenic autoimmune disorder primarily caused by biallelic deleterious variants in the autoimmune regulator (<i>AIRE</i>) gene. We prospectively evaluated 104 patients with clinically diagnosed APECED syndrome and identified 17 patients (16%) from 14 kindreds lacking biallelic <i>AIRE</i> variants in exons or flanking intronic regions; 15 had Puerto Rican ancestry. Through whole-genome sequencing, we identified a deep intronic <i>AIRE</i> variant (c.1504-818 G>A) cosegregating with the disease in all 17 patients. We developed a culture system of <i>AIRE</i>-expressing primary patient monocyte-derived dendric cells and demonstrated that c.1504-818 G>A creates a cryptic splice site and activates inclusion of a 109–base pair frame-shifting pseudoexon. We also found low-level <i>AIRE</i> expression in patient-derived lymphoblastoid cell lines (LCLs) and confirmed pseudoexon inclusion in independent extrathymic <i>AIRE</i>–expressing cell lines. Through protein modeling and transcriptomic analyses of <i>AIRE</i>-transfected human embryonic kidney 293 and thymic epithelial cell 4D6 cells, we showed that this variant alters the carboxyl terminus of the AIRE protein, abrogating its function. Last, we developed an antisense oligonucleotide (ASO) that reversed pseudoexon inclusion and restored the normal <i>AIRE</i> transcript sequence in LCLs. Thus, our findings revealed c.1504-818 G>A as a founder APECED-causing <i>AIRE</i> variant in the Puerto Rican population and uncovered pseudoexon inclusion as an ASO-reversible genetic mechanism underlying APECED.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"16 765","pages":""},"PeriodicalIF":15.8,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142245149","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}
Pub Date : 2024-09-18DOI: 10.1126/scitranslmed.adn4970
Zin Z. Khaing, Jannik Leyendecker, Jennifer N. Harmon, Sananthan Sivakanthan, Lindsay N. Cates, Jeffrey E. Hyde, Melissa Krueger, Robb W. Glenny, Matthew Bruce, Christoph P. Hofstetter
Traumatic spinal cord injury (tSCI) causes an immediate loss of neurological function, and the prediction of recovery is difficult in the acute phase. In this study, we used contrast-enhanced ultrasound imaging to quantify intraspinal vascular disruption acutely after tSCI. In a rodent thoracic tSCI model, contrast-enhanced ultrasound revealed a perfusion area deficit that was positively correlated with injury severity and negatively correlated with hindlimb locomotor function at 8 weeks after injury. The spinal perfusion index was calculated by normalizing the contrast inflow at the injury center to the contrast inflow in the injury periphery. The spinal perfusion index decreased with increasing injury severity and positively correlated with hindlimb locomotor function at 8 weeks after injury. The feasibility of intraoperative contrast-enhanced ultrasound imaging was further tested in a cohort of 27 patients with acute tSCI of varying severity and including both motor-complete and motor-incomplete tSCIs. Both the perfusion area deficit and spinal perfusion index were different between motor-complete and motor-incomplete patients. Moreover, the perfusion area deficit and spinal perfusion index correlated with the injury severity at intake and exhibited a correlation with extent of functional recovery at 6 months. Our data suggest that intraoperative contrast-enhanced, ultrasound-derived metrics are correlated with injury severity and chronic functional outcome after tSCI. Larger clinical studies are required to better assess the reliability of the proposed contrast-enhanced ultrasound biomarkers and their prognostic capacity.
{"title":"Perfusion imaging metrics after acute traumatic spinal cord injury are associated with injury severity in rats and humans","authors":"Zin Z. Khaing, Jannik Leyendecker, Jennifer N. Harmon, Sananthan Sivakanthan, Lindsay N. Cates, Jeffrey E. Hyde, Melissa Krueger, Robb W. Glenny, Matthew Bruce, Christoph P. Hofstetter","doi":"10.1126/scitranslmed.adn4970","DOIUrl":"10.1126/scitranslmed.adn4970","url":null,"abstract":"<div >Traumatic spinal cord injury (tSCI) causes an immediate loss of neurological function, and the prediction of recovery is difficult in the acute phase. In this study, we used contrast-enhanced ultrasound imaging to quantify intraspinal vascular disruption acutely after tSCI. In a rodent thoracic tSCI model, contrast-enhanced ultrasound revealed a perfusion area deficit that was positively correlated with injury severity and negatively correlated with hindlimb locomotor function at 8 weeks after injury. The spinal perfusion index was calculated by normalizing the contrast inflow at the injury center to the contrast inflow in the injury periphery. The spinal perfusion index decreased with increasing injury severity and positively correlated with hindlimb locomotor function at 8 weeks after injury. The feasibility of intraoperative contrast-enhanced ultrasound imaging was further tested in a cohort of 27 patients with acute tSCI of varying severity and including both motor-complete and motor-incomplete tSCIs. Both the perfusion area deficit and spinal perfusion index were different between motor-complete and motor-incomplete patients. Moreover, the perfusion area deficit and spinal perfusion index correlated with the injury severity at intake and exhibited a correlation with extent of functional recovery at 6 months. Our data suggest that intraoperative contrast-enhanced, ultrasound-derived metrics are correlated with injury severity and chronic functional outcome after tSCI. Larger clinical studies are required to better assess the reliability of the proposed contrast-enhanced ultrasound biomarkers and their prognostic capacity.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"16 765","pages":""},"PeriodicalIF":15.8,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142245166","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}
Pub Date : 2024-09-18DOI: 10.1126/scitranslmed.ado7189
Roeland Vanhauwaert, Julien Oury, Bernhardt Vankerckhoven, Christophe Steyaert, Stine Marie Jensen, Dana L. E. Vergoossen, Christa Kneip, Leah Santana, Jamie L. Lim, Jaap J. Plomp, Roy Augustinus, Shohei Koide, Christophe Blanchetot, Peter Ulrichts, Maartje G. Huijbers, Karen Silence, Steven J. Burden
Muscle-specific kinase (MuSK) is essential for the formation, function, and preservation of neuromuscular synapses. Activation of MuSK by a MuSK agonist antibody may stabilize or improve the function of the neuromuscular junction (NMJ) in patients with disorders of the NMJ, such as congenital myasthenia (CM). Here, we generated and characterized ARGX-119, a first-in-class humanized agonist monoclonal antibody specific for MuSK, that is being developed for treatment of patients with neuromuscular diseases. We performed in vitro ligand-binding assays to show that ARGX-119 binds with high affinity to the Frizzled-like domain of human, nonhuman primate, rat, and mouse MuSK, without off-target binding, making it suitable for clinical development. Within the Fc region, ARGX-119 harbors L234A and L235A mutations to diminish potential immune-activating effector functions. Its mode of action is to activate MuSK, without interfering with its natural ligand neural Agrin, and cluster acetylcholine receptors in a dose-dependent manner, thereby stabilizing neuromuscular function. In a mouse model of DOK7 CM, ARGX-119 prevented early postnatal lethality and reversed disease relapse in adult Dok7 CM mice by restoring neuromuscular function and reducing muscle weakness and fatigability in a dose-dependent manner. Pharmacokinetic studies in nonhuman primates, rats, and mice revealed a nonlinear PK behavior of ARGX-119, indicative of target-mediated drug disposition and in vivo target engagement. On the basis of this proof-of-concept study, ARGX-119 has the potential to alleviate neuromuscular diseases hallmarked by impaired neuromuscular synaptic function, warranting further clinical development.
{"title":"ARGX-119 is an agonist antibody for human MuSK that reverses disease relapse in a mouse model of congenital myasthenic syndrome","authors":"Roeland Vanhauwaert, Julien Oury, Bernhardt Vankerckhoven, Christophe Steyaert, Stine Marie Jensen, Dana L. E. Vergoossen, Christa Kneip, Leah Santana, Jamie L. Lim, Jaap J. Plomp, Roy Augustinus, Shohei Koide, Christophe Blanchetot, Peter Ulrichts, Maartje G. Huijbers, Karen Silence, Steven J. Burden","doi":"10.1126/scitranslmed.ado7189","DOIUrl":"10.1126/scitranslmed.ado7189","url":null,"abstract":"<div >Muscle-specific kinase (MuSK) is essential for the formation, function, and preservation of neuromuscular synapses. Activation of MuSK by a MuSK agonist antibody may stabilize or improve the function of the neuromuscular junction (NMJ) in patients with disorders of the NMJ, such as congenital myasthenia (CM). Here, we generated and characterized ARGX-119, a first-in-class humanized agonist monoclonal antibody specific for MuSK, that is being developed for treatment of patients with neuromuscular diseases. We performed in vitro ligand-binding assays to show that ARGX-119 binds with high affinity to the Frizzled-like domain of human, nonhuman primate, rat, and mouse MuSK, without off-target binding, making it suitable for clinical development. Within the Fc region, ARGX-119 harbors L234A and L235A mutations to diminish potential immune-activating effector functions. Its mode of action is to activate MuSK, without interfering with its natural ligand neural Agrin, and cluster acetylcholine receptors in a dose-dependent manner, thereby stabilizing neuromuscular function. In a mouse model of <i>DOK7</i> CM, ARGX-119 prevented early postnatal lethality and reversed disease relapse in adult <i>Dok7</i> CM mice by restoring neuromuscular function and reducing muscle weakness and fatigability in a dose-dependent manner. Pharmacokinetic studies in nonhuman primates, rats, and mice revealed a nonlinear PK behavior of ARGX-119, indicative of target-mediated drug disposition and in vivo target engagement. On the basis of this proof-of-concept study, ARGX-119 has the potential to alleviate neuromuscular diseases hallmarked by impaired neuromuscular synaptic function, warranting further clinical development.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"16 765","pages":""},"PeriodicalIF":15.8,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/scitranslmed.ado7189","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142245155","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}
Pub Date : 2024-09-18DOI: 10.1126/scitranslmed.adk7832
Anushka Saha, Trirupa Chakraborty, Javad Rahimikollu, Hanxi Xiao, Lorena B. Pereira de Oliveira, Timothy W. Hand, Sukwan Handali, W. Evan Secor, Lucia A. O. Fraga, Jessica K. Fairley, Jishnu Das, Aniruddh Sarkar
Schistosomiasis, a highly prevalent parasitic disease, affects more than 200 million people worldwide. Current diagnostics based on parasite egg detection in stool detect infection only at a late stage, and current antibody-based tests cannot distinguish past from current infection. Here, we developed and used a multiplexed antibody profiling platform to obtain a comprehensive repertoire of antihelminth humoral profiles including isotype, subclass, Fc receptor (FcR) binding, and glycosylation profiles of antigen-specific antibodies. Using Essential Regression (ER) and SLIDE, interpretable machine learning methods, we identified latent factors (context-specific groups) that move beyond biomarkers and provide insights into the pathophysiology of different stages of schistosome infection. By comparing profiles of infected and healthy individuals, we identified modules with unique humoral signatures of active disease, including hallmark signatures of parasitic infection such as elevated immunoglobulin G4 (IgG4). However, we also captured previously uncharacterized humoral responses including elevated FcR binding and specific antibody glycoforms in patients with active infection, helping distinguish them from those without active infection but with equivalent antibody titers. This signature was validated in an independent cohort. Our approach also uncovered two distinct endotypes, nonpatent infection and prior infection, in those who were not actively infected. Higher amounts of IgG1 and FcR1/FcR3A binding were also found to be likely protective of the transition from nonpatent to active infection. Overall, we unveiled markers for antibody-based diagnostics and latent factors underlying the pathogenesis of schistosome infection. Our results suggest that selective antigen targeting could be useful in early detection, thus controlling infection severity.
{"title":"Deep humoral profiling coupled to interpretable machine learning unveils diagnostic markers and pathophysiology of schistosomiasis","authors":"Anushka Saha, Trirupa Chakraborty, Javad Rahimikollu, Hanxi Xiao, Lorena B. Pereira de Oliveira, Timothy W. Hand, Sukwan Handali, W. Evan Secor, Lucia A. O. Fraga, Jessica K. Fairley, Jishnu Das, Aniruddh Sarkar","doi":"10.1126/scitranslmed.adk7832","DOIUrl":"10.1126/scitranslmed.adk7832","url":null,"abstract":"<div >Schistosomiasis, a highly prevalent parasitic disease, affects more than 200 million people worldwide. Current diagnostics based on parasite egg detection in stool detect infection only at a late stage, and current antibody-based tests cannot distinguish past from current infection. Here, we developed and used a multiplexed antibody profiling platform to obtain a comprehensive repertoire of antihelminth humoral profiles including isotype, subclass, Fc receptor (FcR) binding, and glycosylation profiles of antigen-specific antibodies. Using Essential Regression (ER) and SLIDE, interpretable machine learning methods, we identified latent factors (context-specific groups) that move beyond biomarkers and provide insights into the pathophysiology of different stages of schistosome infection. By comparing profiles of infected and healthy individuals, we identified modules with unique humoral signatures of active disease, including hallmark signatures of parasitic infection such as elevated immunoglobulin G4 (IgG4). However, we also captured previously uncharacterized humoral responses including elevated FcR binding and specific antibody glycoforms in patients with active infection, helping distinguish them from those without active infection but with equivalent antibody titers. This signature was validated in an independent cohort. Our approach also uncovered two distinct endotypes, nonpatent infection and prior infection, in those who were not actively infected. Higher amounts of IgG1 and FcR1/FcR3A binding were also found to be likely protective of the transition from nonpatent to active infection. Overall, we unveiled markers for antibody-based diagnostics and latent factors underlying the pathogenesis of schistosome infection. Our results suggest that selective antigen targeting could be useful in early detection, thus controlling infection severity.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"16 765","pages":""},"PeriodicalIF":15.8,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142245167","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}
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