Deep immunophenotyping reveals circulating activated lymphocytes in individuals at risk for rheumatoid arthritis
Inamo, Jun Keegan, Joshua Griffith, Alec Ghosh, Tusharkanti Horisberger, Alice Howard, Kaitlyn Pulford, John F Murzin, Ekaterina Hancock, Brandon Dominguez, Salina T
Inamo, Jun
Keegan, Joshua
Griffith, Alec
Ghosh, Tusharkanti
Horisberger, Alice
Howard, Kaitlyn
Pulford, John F
Murzin, Ekaterina
Hancock, Brandon
Dominguez, Salina T
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Publication date
2025-03-17
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Abstract
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.
Citation
Inamo J, Keegan J, Griffith A, Ghosh T, Horisberger A, Howard K, Pulford JF, Murzin E, Hancock B, Dominguez ST, Gurra MG, Gurajala S, Jonsson AH, Seifert JA, Feser ML, Norris JM, Cao Y, Apruzzese W, Bridges SL, Bykerk VP, Goodman S, Donlin LT, Firestein GS, Bathon JM, Hughes LB, Filer A, Pitzalis C, Anolik JH, Moreland L, Hacohen N, Guthridge JM, James JA, Cuda CM, Perlman H, Brenner MB, Raychaudhuri S, Sparks JA; Accelerating Medicines Partnership RA/SLE Network; Holers VM, Deane KD, Lederer J, Rao DA, Zhang F. Deep immunophenotyping reveals circulating activated lymphocytes in individuals at risk for rheumatoid arthritis. J Clin Invest. 2025 Mar 17;135(6):e185217. doi: 10.1172/JCI185217.
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Journal Article