Science Translational Medicine最新文献

{"title":"Clinical, mechanistic, and therapeutic landscape of cutaneous fibrosis","authors":"Dayan J. Li,&nbsp;Charlotte E. Berry,&nbsp;Derrick C. Wan,&nbsp;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}

{"title":"B cells drive neuropathic pain–related behaviors in mice through IgG–Fc gamma receptor signaling","authors":"Michael J. Lacagnina,&nbsp;Kendal F. Willcox,&nbsp;Nabila Boukelmoune,&nbsp;Alexis Bavencoffe,&nbsp;Ishwarya Sankaranarayanan,&nbsp;Daniel T. Barratt,&nbsp;Younus A. Zuberi,&nbsp;Dorsa Dayani,&nbsp;Melissa V. Chavez,&nbsp;Jonathan T. Lu,&nbsp;Alex Bersellini Farinotti,&nbsp;Stephanie Shiers,&nbsp;Allison M. Barry,&nbsp;Juliet M. Mwirigi,&nbsp;Diana Tavares-Ferreira,&nbsp;Geoffrey A. Funk,&nbsp;Anna M. Cervantes,&nbsp;Camilla I. Svensson,&nbsp;Edgar T. Walters,&nbsp;Mark R. Hutchinson,&nbsp;Cobi J. Heijnen,&nbsp;Theodore J. Price,&nbsp;Nathan T. Fiore,&nbsp;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}

{"title":"Intratumoral radiation dose heterogeneity augments antitumor immunity in mice and primes responses to checkpoint blockade","authors":"Justin C. Jagodinsky,&nbsp;Jessica M. Vera,&nbsp;Won Jong Jin,&nbsp;Amanda G. Shea,&nbsp;Paul A. Clark,&nbsp;Raghava N. Sriramaneni,&nbsp;Thomas C. Havighurst,&nbsp;Ishan Chakravarthy,&nbsp;Raad H. Allawi,&nbsp;KyungMann Kim,&nbsp;Paul M. Harari,&nbsp;Paul M. Sondel,&nbsp;Michael A. Newton,&nbsp;Marka R. Crittenden,&nbsp;Michael J. Gough,&nbsp;Jessica R. Miller,&nbsp;Irene M. Ong,&nbsp;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}

{"title":"A deep intronic splice–altering AIRE variant causes APECED syndrome through antisense oligonucleotide-targetable pseudoexon inclusion","authors":"Sebastian Ochoa,&nbsp;Amy P. Hsu,&nbsp;Andrew J. Oler,&nbsp;Dhaneshwar Kumar,&nbsp;Daniel Chauss,&nbsp;Jan Piet van Hamburg,&nbsp;Gustaaf G. van Laar,&nbsp;Vasileios Oikonomou,&nbsp;Sundar Ganesan,&nbsp;Elise M. N. Ferré,&nbsp;Monica M. Schmitt,&nbsp;Tom DiMaggio,&nbsp;Princess Barber,&nbsp;Gregory M. Constantine,&nbsp;Lindsey B. Rosen,&nbsp;Paul G. Auwaerter,&nbsp;Bhumika Gandhi,&nbsp;Jennifer L. Miller,&nbsp;Rachel Eisenberg,&nbsp;Arye Rubinstein,&nbsp;Edith Schussler,&nbsp;Erjola Balliu,&nbsp;Vandana Shashi,&nbsp;Olaf Neth,&nbsp;Peter Olbrich,&nbsp;Kim My Le,&nbsp;Nanni Mamia,&nbsp;Saila Laakso,&nbsp;Pasi I. Nevalainen,&nbsp;Juha Grönholm,&nbsp;Mikko R. J. Seppänen,&nbsp;Louis Boon,&nbsp;Gulbu Uzel,&nbsp;Luis M. Franco,&nbsp;Theo Heller,&nbsp;Karen K. Winer,&nbsp;Rajarshi Ghosh,&nbsp;Bryce A. Seifert,&nbsp;Magdalena Walkiewicz,&nbsp;Luigi D. Notarangelo,&nbsp;Qing Zhou,&nbsp;Ivona Askentijevich,&nbsp;William Gahl,&nbsp;Cliffton L. Dalgard,&nbsp;Lalith Perera,&nbsp;Behdad Afzali,&nbsp;Sander W. Tas,&nbsp;Steven M. Holland,&nbsp;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&gt;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&gt;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&gt;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}

{"title":"Perfusion imaging metrics after acute traumatic spinal cord injury are associated with injury severity in rats and humans","authors":"Zin Z. Khaing,&nbsp;Jannik Leyendecker,&nbsp;Jennifer N. Harmon,&nbsp;Sananthan Sivakanthan,&nbsp;Lindsay N. Cates,&nbsp;Jeffrey E. Hyde,&nbsp;Melissa Krueger,&nbsp;Robb W. Glenny,&nbsp;Matthew Bruce,&nbsp;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}

{"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,&nbsp;Julien Oury,&nbsp;Bernhardt Vankerckhoven,&nbsp;Christophe Steyaert,&nbsp;Stine Marie Jensen,&nbsp;Dana L. E. Vergoossen,&nbsp;Christa Kneip,&nbsp;Leah Santana,&nbsp;Jamie L. Lim,&nbsp;Jaap J. Plomp,&nbsp;Roy Augustinus,&nbsp;Shohei Koide,&nbsp;Christophe Blanchetot,&nbsp;Peter Ulrichts,&nbsp;Maartje G. Huijbers,&nbsp;Karen Silence,&nbsp;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}

{"title":"Deep humoral profiling coupled to interpretable machine learning unveils diagnostic markers and pathophysiology of schistosomiasis","authors":"Anushka Saha,&nbsp;Trirupa Chakraborty,&nbsp;Javad Rahimikollu,&nbsp;Hanxi Xiao,&nbsp;Lorena B. Pereira de Oliveira,&nbsp;Timothy W. Hand,&nbsp;Sukwan Handali,&nbsp;W. Evan Secor,&nbsp;Lucia A. O. Fraga,&nbsp;Jessica K. Fairley,&nbsp;Jishnu Das,&nbsp;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}

{"title":"Preschool-age children maintain a distinct memory CD4+ T cell and memory B cell response after SARS-CoV-2 infection","authors":"Benoît Manfroi,&nbsp;Bui Thi Cuc,&nbsp;Aurélien Sokal,&nbsp;Alexis Vandenberghe,&nbsp;Sarah Temmam,&nbsp;Mikaël Attia,&nbsp;Mohamed El Behi,&nbsp;Francesco Camaglia,&nbsp;Ngan Thu Nguyen,&nbsp;Jelka Pohar,&nbsp;Layale Salem-Wehbe,&nbsp;Valentine Pottez-Jouatte,&nbsp;Sibyline Borzakian,&nbsp;Narcisse Elenga,&nbsp;Caroline Galeotti,&nbsp;Guillaume Morelle,&nbsp;Camille de truchis de Lays,&nbsp;Michaela Semeraro,&nbsp;Anne-Sophie Romain,&nbsp;Mélodie Aubart,&nbsp;Naim Ouldali,&nbsp;Florence Mahuteau-Betzer,&nbsp;Claire Beauvineau,&nbsp;Elsa Amouyal,&nbsp;Romain Berthaud,&nbsp;Célia Crétolle,&nbsp;Marc Duval Arnould,&nbsp;Albert Faye,&nbsp;Mathie Lorrot,&nbsp;Grégoire Benoist,&nbsp;Nelly Briand,&nbsp;Marie Courbebaisse,&nbsp;Roland Martin,&nbsp;Peter Van Endert,&nbsp;Jean-Sébastien Hulot,&nbsp;Anne Blanchard,&nbsp;Eric Tartour,&nbsp;Maria Leite-de-Moraes,&nbsp;Guillaume Lezmi,&nbsp;Mickael Ménager,&nbsp;Marine Luka,&nbsp;Claude-Agnès Reynaud,&nbsp;Jean-Claude Weill,&nbsp;Laetitia Languille,&nbsp;Marc Michel,&nbsp;Pascal Chappert,&nbsp;Thierry Mora,&nbsp;Aleksandra M. Walczak,&nbsp;Marc Eloit,&nbsp;Petra Bacher,&nbsp;Alexander Scheffold,&nbsp;Matthieu Mahévas,&nbsp;Isabelle Sermet-Gaudelus,&nbsp;Simon Fillatreau","doi":"10.1126/scitranslmed.adl1997","DOIUrl":"10.1126/scitranslmed.adl1997","url":null,"abstract":"<div >The development of the human immune system lasts for several years after birth. The impact of this maturation phase on the quality of adaptive immunity and the acquisition of immunological memory after infection at a young age remains incompletely defined. Here, using an antigen-reactive T cell (ARTE) assay and multidimensional flow cytometry, we profiled circulating severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)–reactive CD3⁺CD4⁺CD154⁺ T cells in children and adults before infection, during infection, and 11 months after infection, stratifying children into separate age groups and adults according to disease severity. During SARS-CoV-2 infection, children younger than 5 years old displayed a lower antiviral CD4⁺ T cell response, whereas children older than 5 years and adults with mild disease had, quantitatively and phenotypically, comparable virus-reactive CD4⁺ T cell responses. Adults with severe disease mounted a response characterized by higher frequencies of virus-reactive proinflammatory and cytotoxic T cells. After SARS-CoV-2 infection, preschool-age children not only maintained neutralizing SARS-CoV-2–reactive antibodies postinfection comparable to adults but also had phenotypically distinct memory T cells displaying high inflammatory features and properties associated with migration toward inflamed sites. Moreover, preschool-age children had markedly fewer circulating virus-reactive memory B cells compared with the other cohorts. Collectively, our results reveal unique facets of antiviral immunity in humans at a young age and indicate that the maturation of adaptive responses against SARS-CoV-2 toward an adult-like profile occurs in a progressive manner.</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":"142245170","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}

{"title":"Erratum for the Research Article “Adjuvantation of a SARS-CoV-2 mRNA vaccine with controlled tissue-specific expression of an mRNA encoding IL-12p70” by B. Brook et al.","authors":"","doi":"10.1126/scitranslmed.ads5741","DOIUrl":"10.1126/scitranslmed.ads5741","url":null,"abstract":"","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"16 764","pages":""},"PeriodicalIF":15.8,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142170414","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}

{"title":"Targeted partial reprogramming of age-associated cell states improves markers of health in mouse models of aging","authors":"Sanjeeb Kumar Sahu,&nbsp;Pradeep Reddy,&nbsp;Jinlong Lu,&nbsp;Yanjiao Shao,&nbsp;Chao Wang,&nbsp;Mako Tsuji,&nbsp;Estrella Nuñez Delicado,&nbsp;Concepcion Rodriguez Esteban,&nbsp;Juan Carlos Izpisua Belmonte","doi":"10.1126/scitranslmed.adg1777","DOIUrl":"10.1126/scitranslmed.adg1777","url":null,"abstract":"<div >Aging is a complex multifactorial process associated with epigenome dysregulation, increased cellular senescence, and decreased rejuvenation capacity. Short-term cyclic expression of <i>octamer-binding transcription factor 4</i> (<i>Oct4</i>), <i>sex-determining region Y-box 2</i> (<i>Sox2</i>), <i>Kruppel-like factor 4</i> (<i>Klf4</i>), and <i>cellular myelocytomatosis oncogene</i> (<i>cMyc</i>) (<i>OSKM</i>) in wild-type mice improves health but fails to distinguish cell states, posing risks to healthy cells. Here, we delivered a single dose of adeno-associated viruses (AAVs) harboring <i>OSK</i> under the control of the <i>cyclin-dependent kinase inhibitor 2a</i> (<i>Cdkn2a</i>) promoter to specifically partially reprogram aged and stressed cells in a mouse model of Hutchinson-Gilford progeria syndrome (HGPS). Mice showed reduced expression of proinflammatory cytokines and extended life spans upon aged cell–specific <i>OSK</i> expression. The bone marrow and spleen, in particular, showed pronounced gene expression changes, and partial reprogramming in aged HGPS mice led to a shift in the cellular composition of the hematopoietic stem cell compartment toward that of young mice. Administration of AAVs carrying <i>Cdkn2a-OSK</i> to naturally aged wild-type mice also delayed aging phenotypes and extended life spans without altering the incidence of tumor development. Furthermore, intradermal injection of AAVs carrying <i>Cdkn2a</i>-<i><i>OSK</i></i> led to improved wound healing in aged wild-type mice. Expression of <i>CDKN2A</i>-<i>OSK</i> in aging or stressed human primary fibroblasts led to reduced expression of inflammation-related genes but did not alter the expression of cell cycle–related genes. This targeted partial reprogramming approach may therefore facilitate the development of strategies to improve health and life span and enhance resilience in the elderly.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"16 764","pages":""},"PeriodicalIF":15.8,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142170434","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}