The B cell compartment exhibits a pro-inflammatory skewing during progression to Rheumatoid Arthritis 4776
Abstract Description Rheumatoid arthritis (RA) is an autoimmune disease characterized by joint inflammation and bone destruction. RA is preceded by a subclinical phase that is defined by elevated levels of RA-associated autoantibodies, most preeminently anti-citrullinated protein antibodies (ACPA). Nonetheless, we have an incomplete understanding of the changes in the B cell compartment that contribute to the breaking of tolerance that underlies risk of RA development. Here, we performed a longitudinal, multi-omics study of peripheral B cells from ACPA+ at-risk individuals (ARI). We captured single-cell RNA and flow cytometry data for 2.1 million and 200 million peripheral blood mononuclear cells, respectively, from 45 ARI. Our results indicate proinflammatory-skewed naive and memory B cell subsets among ARI, coinciding with systemic inflammation. Naive B cells display transcriptional signatures of increased B cell receptor (BCR) signaling and antigen presentation and are primed for IgG3 class-switching and elevated proinflammatory cytokine and RANKL secretion. Further, we identified a subset of CD27- ITGAX+ effector memory B cells that increase in abundance during progression to clinical RA. This population has transcriptional features of chronic BCR engagement and a gene program associated with long-lived humoral immunity. These data suggest that in addition to ACPA production, ongoing B cell activation is a feature of progression to clinical RA. Funding Sources Paul G. Allen Family Foundation Topic Categories Basic Autoimmunity (BA)
Authors
- Vaishnavi Parthasarathy
- Kevin D. Deane (ORCID: https://orcid.org/0000-0003-2211-4861)
- Veronica Hernandez (ORCID: https://orcid.org/0000-0003-2568-2565)
- Thomas F. Bumol
- David Boyle (ORCID: https://orcid.org/0000-0001-6919-7137)
- Gary S. Firestein (ORCID: https://orcid.org/0000-0003-3495-960X)
- Qiuyu Gong (ORCID: https://orcid.org/0009-0006-3885-0862)
- Claire E. Gustafson (ORCID: https://orcid.org/0000-0002-1437-6709)
- Padmapriyadarshini Ravisankar (ORCID: https://orcid.org/0000-0002-7061-9875)
- Christy Bennett (ORCID: https://orcid.org/0000-0003-2569-3803)
- Lauren Okada (ORCID: https://orcid.org/0000-0002-5691-3373)
- Palak C. Genge (ORCID: https://orcid.org/0000-0002-0851-6445)
- Adam K. Savage (ORCID: https://orcid.org/0000-0003-1913-5485)
- Marla C. Glass (ORCID: https://orcid.org/0000-0003-3763-0842)
- Pravina Venkatesan
- Ziyuan He (ORCID: https://orcid.org/0000-0003-3556-8248)
- Ananda W. Goldrath (ORCID: https://orcid.org/0000-0002-5900-508X)
- Alex Heubeck
- Upaasana Krishnan (ORCID: https://orcid.org/0000-0001-8589-7061)
- Troy R. Torgerson (ORCID: https://orcid.org/0000-0003-3489-5036)
- Peter J. Skene (ORCID: https://orcid.org/0000-0001-8965-5326)
- Julian Reading (ORCID: https://orcid.org/0000-0002-8533-3992)
- Lucas T. Graybuck (ORCID: https://orcid.org/0000-0002-8814-6818)
- Samir Rachid Zaim (ORCID: https://orcid.org/0009-0007-9256-2324)
- Mark A. Gillespie (ORCID: https://orcid.org/0000-0001-7820-8598)
- Elisabeth M. Dornisch (ORCID: https://orcid.org/0009-0009-6969-8690)
- Cole Phalen (ORCID: https://orcid.org/0000-0002-0196-2805)
- Jessica Garber (ORCID: https://orcid.org/0009-0007-8773-9754)
- Tyanna Stuckey (ORCID: https://orcid.org/0009-0003-3262-8441)
- Xiaojun Li (ORCID: https://orcid.org/0000-0003-0832-9479)
- Fan Zhang (ORCID: https://orcid.org/0000-0001-6798-2422)
- Yudong D. He (ORCID: https://orcid.org/0000-0003-0818-605X)
- Michael Holers
- Erin K. Kawelo (ORCID: https://orcid.org/0009-0004-0329-9914)
- Blessing Musgrove
Institutions
- Allen Institute for Immunology (US)
Publication Details
- Journal
- The Journal of Immunology
- Published
- 2025-11-01
- DOI
- https://doi.org/10.1093/jimmun/vkaf283.2401
- Primary Topic
- Rheumatoid Arthritis Research and Therapies
- Type
- article
- Field-Weighted Citation Impact
- 0.00