Deep immunophenotyping reveals circulating activated lymphocytes in individuals at risk for rheumatoid arthritis
Rheumatoid arthritis (RA) is a systemic autoimmune disease currently with no universally highly effective prevention strategies. Identifying pathogenic immune phenotypes in at-risk populations prior to clinical onset is crucial to establishing effective prevention strategies. Here, we applied multimodal single-cell technologies (mass cytometry and CITE-Seq) to characterize the immunophenotypes in blood from at-risk individuals (ARIs) identified through the presence of serum antibodies against citrullinated protein antigens (ACPAs) and/or first-degree relative (FDR) status, as compared with patients with established RA and people in a healthy control group. We identified significant cell expansions in ARIs compared with controls, including CCR2+CD4+ T cells, T peripheral helper (Tph) cells, type 1 T helper cells, and CXCR5+CD8+ T cells. We also found that CD15+ classical monocytes were specifically expanded in ACPA-negative FDRs, and an activated PAX5lo naive B cell population was expanded in ACPA-positive FDRs. Further, we uncovered the molecular phenotype of the CCR2+CD4+ T cells, expressing high levels of Th17- and Th22-related signature transcripts including CCR6, IL23R, KLRB1, CD96, and IL22. Our integrated study provides a promising approach to identify targets to improve prevention strategy development for RA.
Authors
- Tusharkanti Ghosh (ORCID: https://orcid.org/0000-0002-7537-6374)
- Michael B. Brenner (ORCID: https://orcid.org/0000-0001-6202-8445)
- Kevin D. Deane (ORCID: https://orcid.org/0000-0003-2211-4861)
- Jill M. Norris (ORCID: https://orcid.org/0000-0001-8674-2598)
- Carla M. Cuda (ORCID: https://orcid.org/0000-0002-2022-8171)
- Alec Griffith (ORCID: https://orcid.org/0000-0002-4289-3017)
- Laura T. Donlin (ORCID: https://orcid.org/0000-0002-1428-090X)
- Justin Pulford (ORCID: https://orcid.org/0000-0003-4756-8480)
- Jeffrey A. Sparks (ORCID: https://orcid.org/0000-0002-5556-4618)
- Gary S. Firestein (ORCID: https://orcid.org/0000-0003-3495-960X)
- Jennifer H. Anolik (ORCID: https://orcid.org/0000-0002-1450-1549)
- Susan M. Goodman (ORCID: https://orcid.org/0000-0003-1197-7864)
- Harris Perlman (ORCID: https://orcid.org/0000-0003-4174-608X)
- Joel M. Guthridge (ORCID: https://orcid.org/0000-0002-9308-237X)
- James A. Lederer (ORCID: https://orcid.org/0000-0002-6445-252X)
- V. Michael Holers (ORCID: https://orcid.org/0000-0002-5634-7746)
- Joan M. Bathon (ORCID: https://orcid.org/0000-0001-6811-8986)
- Vivian P. Bykerk (ORCID: https://orcid.org/0000-0002-1219-3845)
- Andrew D. Filer (ORCID: https://orcid.org/0000-0001-8164-6249)
- Nir Hacohen (ORCID: https://orcid.org/0000-0002-2349-2656)
- Miranda G. Gurra (ORCID: https://orcid.org/0000-0002-1879-6575)
- Costantino Pitzalis (ORCID: https://orcid.org/0000-0003-1326-5051)
- Jun Inamo (ORCID: https://orcid.org/0000-0002-9927-7936)
- Alice Horisberger (ORCID: https://orcid.org/0000-0002-3732-8662)
- Brandon L. Hancock
- Fan Zhang (ORCID: https://orcid.org/0000-0002-6102-2970)
- Larry W. Moreland (ORCID: https://orcid.org/0000-0003-4483-0359)
- Salina Dominguez (ORCID: https://orcid.org/0009-0002-2659-7610)
- Siddarth Gurajala
- Kaitlyn Howard (ORCID: https://orcid.org/0000-0002-9398-6176)
- Anna Helena Jonsson (ORCID: https://orcid.org/0000-0002-9558-2474)
- Soumya Raychaudhuri (ORCID: https://orcid.org/0000-0002-1901-8265)
- Marie L. Feser (ORCID: https://orcid.org/0009-0003-0598-853X)
- Deepak A. Rao (ORCID: https://orcid.org/0000-0001-9672-7746)
- Judith A. James (ORCID: https://orcid.org/0000-0002-9574-7355)
- S. Louis Bridges (ORCID: https://orcid.org/0000-0003-3785-1389)
- Jennifer Seifert (ORCID: https://orcid.org/0000-0001-5851-7246)
- Ekaterina Murzin
- Ye Cao (ORCID: https://orcid.org/0000-0002-1654-9060)
- Laura B. Hughes
- Joshua Keegan
- William Apruzzese
Institutions
- Broad Institute (US)
- Northwestern University (US)
- Hospital for Special Surgery (US)
- Brigham and Women's Hospital (US)
- La Jolla Institute for Immunology (US)
- Humanitas University (IT)
- Harvard University (US)
- Colorado School of Public Health (US)
- Queen Mary University of London (GB)
- Cornell University (US)
- University of Rochester Medical Center (US)
- Oklahoma Medical Research Foundation (US)
- University of Alabama at Birmingham (US)
- Arthritis Society (CA)
- Northwestern Medicine (US)
- William Harvey Research Institute (GB)
- Center for Rheumatology (US)
- NIHR Birmingham Biomedical Research Centre (GB)
- Columbia University (US)
- University of Birmingham (GB)
- University of Colorado Denver (US)
- University of Lausanne (CH)
Publication Details
- Journal
- Journal of Clinical Investigation
- Published
- 2025-03-16
- DOI
- https://doi.org/10.1172/jci185217
- Citations
- 22
- Primary Topic
- Systemic Lupus Erythematosus Research
- Type
- article
- Field-Weighted Citation Impact
- 36.70
Funders
- National Institutes of Health
- National Institute of Arthritis and Musculoskeletal and Skin Diseases