Systemic inflammation and transcriptional reprogramming contribute to progression to active rheumatoid arthritis in ACPA+ individuals 4474
Abstract Description Some autoimmune diseases, including rheumatoid arthritis (RA), are preceded by a subclinical phase of disease activity. Proactive clinical management is hampered by a lack of biological understanding of this subclinical ‘at-risk’ state and the changes underlying disease development. In a cross-sectional and longitudinal multi-omics study of peripheral immunity in the autoantibody-positive at-risk for RA period, we identified 275 proteins that differentiated ACPA+ at-risk individuals (ARI) from ACPA- controls. A cluster of ACPA+ donors were found to have an inflammatory protein signature that included elevated IL-1B, VEGFA, CXCL3 and CCL4. This inflammatory signature was accompanied by transcriptional reprogramming across all major immune compartments of ARI, including naive, effector and memory T and B cells. By contrast, in longitudinal samples of ARI who developed clinical RA, the transcriptional response was restricted to naive and central memory (CM) CD4 T cells. We discovered a shared activation signature within naive and CM CD4 T cells during progression to clinical RA, highlighted by reduced expression of CD3 components together with elevated STAT5B, ICOS and AKT3. These progressive changes in naive and CM T cells were the same that were diminished in our independent analyses of a second study of RA patients who responded to CTLA4-Ig therapy. Our findings suggest pathogenesis begins prior to clinical symptoms and suggest approaches for proactive early intervention. Topic Categories Translational and Interventional Immunology (TI)
Authors
- Priya Ravisankar
- Kevin D. Deane (ORCID: https://orcid.org/0000-0003-2211-4861)
- 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)
- Christy Bennett (ORCID: https://orcid.org/0000-0003-2569-3803)
- Lauren Okada (ORCID: https://orcid.org/0000-0002-5691-3373)
- V. Michael Holers (ORCID: https://orcid.org/0000-0002-5634-7746)
- Leander Lazaro
- Adam K. Savage (ORCID: https://orcid.org/0000-0003-1913-5485)
- Nguyen Toan Tran (ORCID: https://orcid.org/0000-0001-7134-7878)
- M. Kristen Demoruelle (ORCID: https://orcid.org/0000-0002-2563-5155)
- 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)
- Kristine A. Kuhn (ORCID: https://orcid.org/0000-0002-6900-4195)
- Fan Zhang (ORCID: https://orcid.org/0000-0002-6102-2970)
- 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)
- Marie L. Feser (ORCID: https://orcid.org/0009-0003-0598-853X)
- Xiaojun Li (ORCID: https://orcid.org/0000-0003-0832-9479)
- Yudong D. He (ORCID: https://orcid.org/0000-0003-0818-605X)
Institutions
- University of California San Diego (US)
- Allen Institute for Immunology (US)
- University of Colorado Anschutz Medical Campus (US)
Publication Details
- Journal
- The Journal of Immunology
- Published
- 2025-11-01
- DOI
- https://doi.org/10.1093/jimmun/vkaf283.2153
- Primary Topic
- Rheumatoid Arthritis Research and Therapies
- Type
- article
- Field-Weighted Citation Impact
- 0.00