Progression to rheumatoid arthritis in at-risk individuals is defined by systemic inflammation and by T and B cell dysregulation

IF 14.6 1区 医学 Q1 CELL BIOLOGY
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
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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.

Abstract Image

高危人群发展为类风湿关节炎是由全身性炎症和T细胞和B细胞失调决定的
类风湿关节炎(RA)发生前有一个危险的疾病阶段,可以通过抗纤氨酸化蛋白抗体(ACPAs)的存在来标记,但临床没有明显的滑膜炎(临床RA)。对高危人群进行先发制人的干预可以预防或延缓未来的组织损伤;然而,这一阶段的免疫生物学尚不清楚。使用综合多组学,我们对高危个体进行了纵向分析,其中三分之一的参与者在研究中发展为临床类风湿性关节炎。我们在高危个体的naïve T细胞和B细胞中发现了全身性炎症和激活的证据。在临床RA的发展过程中,非典型B细胞的促炎偏斜和记忆性CD4 T细胞的扩增,具有活化和B细胞帮助的特征,但循环ACPA滴度没有升高。naïve CD4 T细胞的表观遗传变化表明其倾向于分化为能够帮助B细胞的效应细胞。这些发现表征了ACPA+危险阶段的发病机制,并支持该疾病比临床RA早得多的概念。此外,开发了一个广泛的免疫资源,用于危险阶段和临床RA的进展,并使用交互式工具进行进一步调查。
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来源期刊
Science Translational Medicine
Science Translational Medicine CELL BIOLOGY-MEDICINE, RESEARCH & EXPERIMENTAL
CiteScore
26.70
自引率
1.20%
发文量
309
审稿时长
1.7 months
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.
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