Ziyuan He, Marla C. Glass, Pravina Venkatesan, Marie L. Feser, Leander Lazaro, Lauren Y. Okada, Nhung T. T. Tran, Yudong D. He, Samir Rachid Zaim, Christy E. Bennett, Padmapriyadarshini Ravisankar, Elisabeth M. Dornisch, Alexandra C. Ferrannini, Najeeb A. Arishi, Ashley G. Asamoah, Saman Barzideh, Lynne A. Becker, Elizabeth A. Bemis, Jane H. Buckner, Christopher E. Collora, Megan A. L. Criley, M. Kristen Demoruelle, Chelsie L. Fleischer, Jessica Garber, Palak C. Genge, Qiuyu Gong, Lucas T. Graybuck, Claire E. Gustafson, Brian C. Hattel, Veronica Hernandez, Alexander T. Heubeck, Erin K. Kawelo, Upaasana Krishnan, Emma L. Kuan, Kristine A. Kuhn, Christian M. LaFrance, Kevin J. Lee, Ruoxin Li, Cara Lord, Regina R. Mettey, Laura Moss, Blessing Musgrove, Katherine HY Nguyen, Andrea Ochoa, Vaishnavi Parthasarathy, Mark-Phillip Pebworth, Chong Pedrick, Tao Peng, Cole G. Phalen, Julian Reading, Charles R. Roll, Jennifer A. Seifert, Marguerite D. Siedschlag, Cate Speake, Christopher C. Striebich, Tyanna J. Stuckey, Elliott G. Swanson, Hideto Takada, Tylor Thai, Zachary J. Thomson, Nguyen Trieu, Vlad Tsaltskan, Wei Wang, Morgan D. A. Weiss, Amy Westermann, Fan Zhang, David L. Boyle, Ananda W. Goldrath, Thomas F. Bumol, Xiao-jun Li, V. Michael Holers, Peter J. Skene, Adam K. Savage, Gary S. Firestein, Kevin D. Deane, Troy R. Torgerson, Mark A. Gillespie
{"title":"Progression to rheumatoid arthritis in at-risk individuals is defined by systemic inflammation and by T and B cell dysregulation","authors":"Ziyuan He, Marla C. Glass, Pravina Venkatesan, Marie L. Feser, Leander Lazaro, Lauren Y. Okada, Nhung T. T. Tran, Yudong D. He, Samir Rachid Zaim, Christy E. Bennett, Padmapriyadarshini Ravisankar, Elisabeth M. Dornisch, Alexandra C. Ferrannini, Najeeb A. Arishi, Ashley G. Asamoah, Saman Barzideh, Lynne A. Becker, Elizabeth A. Bemis, Jane H. Buckner, Christopher E. Collora, Megan A. L. Criley, M. Kristen Demoruelle, Chelsie L. Fleischer, Jessica Garber, Palak C. Genge, Qiuyu Gong, Lucas T. Graybuck, Claire E. Gustafson, Brian C. Hattel, Veronica Hernandez, Alexander T. Heubeck, Erin K. Kawelo, Upaasana Krishnan, Emma L. Kuan, Kristine A. Kuhn, Christian M. LaFrance, Kevin J. Lee, Ruoxin Li, Cara Lord, Regina R. Mettey, Laura Moss, Blessing Musgrove, Katherine HY Nguyen, Andrea Ochoa, Vaishnavi Parthasarathy, Mark-Phillip Pebworth, Chong Pedrick, Tao Peng, Cole G. Phalen, Julian Reading, Charles R. Roll, Jennifer A. Seifert, Marguerite D. Siedschlag, Cate Speake, Christopher C. Striebich, Tyanna J. Stuckey, Elliott G. Swanson, Hideto Takada, Tylor Thai, Zachary J. Thomson, Nguyen Trieu, Vlad Tsaltskan, Wei Wang, Morgan D. A. Weiss, Amy Westermann, Fan Zhang, David L. Boyle, Ananda W. Goldrath, Thomas F. Bumol, Xiao-jun Li, V. Michael Holers, Peter J. Skene, Adam K. Savage, Gary S. Firestein, Kevin D. Deane, Troy R. Torgerson, Mark A. Gillespie","doi":"10.1126/scitranslmed.adt7214","DOIUrl":null,"url":null,"abstract":"<div >Rheumatoid arthritis (RA) is preceded by an at-risk stage of disease that can be marked by the presence of anticitrullinated protein antibodies (ACPAs) but the absence of clinically apparent synovitis (clinical RA). Preemptive intervention in at-risk individuals could prevent or delay future tissue damage; however, the immunobiology of this stage is unclear. Using integrative multiomics, we longitudinally profiled at-risk individuals, where one-third of participants developed clinical RA on study. We found evidence of systemic inflammation and signatures of activation in naïve T and B cells of at-risk individuals. During progression to clinical RA, proinflammatory skewing of atypical B cells and expansion of memory CD4 T cells with signatures of activation and B cell help were present without elevations in circulating ACPA titers. Epigenetic changes in naïve CD4 T cells suggested a predisposition to differentiate into effector cells capable of B cell help. These findings characterize pathogenesis of the ACPA<sup>+</sup> at-risk stage and support the concept that the disease begins much earlier than clinical RA. Additionally, an extensive immune resource of the at-risk stage and progression to clinical RA with interactive tools was developed to enable further investigation.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 817","pages":""},"PeriodicalIF":14.6000,"publicationDate":"2025-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/scitranslmed.adt7214","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Science Translational Medicine","FirstCategoryId":"3","ListUrlMain":"https://www.science.org/doi/10.1126/scitranslmed.adt7214","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CELL BIOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
Rheumatoid arthritis (RA) is preceded by an at-risk stage of disease that can be marked by the presence of anticitrullinated protein antibodies (ACPAs) but the absence of clinically apparent synovitis (clinical RA). Preemptive intervention in at-risk individuals could prevent or delay future tissue damage; however, the immunobiology of this stage is unclear. Using integrative multiomics, we longitudinally profiled at-risk individuals, where one-third of participants developed clinical RA on study. We found evidence of systemic inflammation and signatures of activation in naïve T and B cells of at-risk individuals. During progression to clinical RA, proinflammatory skewing of atypical B cells and expansion of memory CD4 T cells with signatures of activation and B cell help were present without elevations in circulating ACPA titers. Epigenetic changes in naïve CD4 T cells suggested a predisposition to differentiate into effector cells capable of B cell help. These findings characterize pathogenesis of the ACPA+ at-risk stage and support the concept that the disease begins much earlier than clinical RA. Additionally, an extensive immune resource of the at-risk stage and progression to clinical RA with interactive tools was developed to enable further investigation.
期刊介绍:
Science Translational Medicine is an online journal that focuses on publishing research at the intersection of science, engineering, and medicine. The goal of the journal is to promote human health by providing a platform for researchers from various disciplines to communicate their latest advancements in biomedical, translational, and clinical research.
The journal aims to address the slow translation of scientific knowledge into effective treatments and health measures. It publishes articles that fill the knowledge gaps between preclinical research and medical applications, with a focus on accelerating the translation of knowledge into new ways of preventing, diagnosing, and treating human diseases.
The scope of Science Translational Medicine includes various areas such as cardiovascular disease, immunology/vaccines, metabolism/diabetes/obesity, neuroscience/neurology/psychiatry, cancer, infectious diseases, policy, behavior, bioengineering, chemical genomics/drug discovery, imaging, applied physical sciences, medical nanotechnology, drug delivery, biomarkers, gene therapy/regenerative medicine, toxicology and pharmacokinetics, data mining, cell culture, animal and human studies, medical informatics, and other interdisciplinary approaches to medicine.
The target audience of the journal includes researchers and management in academia, government, and the biotechnology and pharmaceutical industries. It is also relevant to physician scientists, regulators, policy makers, investors, business developers, and funding agencies.