Innate immune cell subsets are enriched in synovial fluid of ACPA-negative rheumatoid arthritis and characterized by distinct type I IFN gene signatures.
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Argyriou A, Wadsworth MH, Fienman J, Gonzalez-Sanchez AC, Ghannoum S, Krishna C, Gerstner C, Horuluoglu B, Sijbranda M, Rönnblom L, Eloranta ML, Wahren-Herlenius M, Hensvold A, Turcinov S, Winkler A, Malmström V, Chemin K
Ann. Rheum. Dis. - (-) - [2025-10-03; online 2025-10-03]
Around 30% of patients with rheumatoid arthritis (RA) lack rheumatoid factor and anti-citrullinated protein antibodies (ACPA) complicating diagnosis and potentially delaying treatment. We hypothesised that innate immune mechanisms might be more prominent in ACPA- RA. We performed single-cell RNA sequencing of mononuclear cells from peripheral blood (PBMC) and synovial fluid (SFMC) of patients with ACPA- and ACPA+ RA (n = 4 per group: discovery cohort; n = 8 per group: validation cohort). Dendritic cells and proinflammatory cytokine production were analysed by flow cytometry on SFMC from patients with ACPA- RA, ACPA+ RA, and psoriatic arthritis. Interferon (IFN) levels in synovial fluid (SF) and serum were measured in these groups. Several macrophage subsets and cDC2 were enriched in ACPA- RA SF whereas the frequency of Tph and B cells was increased in ACPA+ RA SF. Type I IFN-stimulated genes were detected in SFMC, but not PBMC, of patients with ACPA- RA. A type I IFN signature was also observed in synovial tissue from two patients with ACPA- RA in an independent dataset. IFN levels were higher in SF than serum but IFN-α/β production did not differ between ACPA+ and ACPA- RA. This study identifies a distinct innate cell composition and type I IFN gene response in synovial joints, but not in peripheral blood, of patients with ACPA- RA. Similar IFN levels across groups suggest the IFN signature may have been primed before the cells entered the joints. These findings provide a foundation for future research on type I IFN responses in ACPA- RA.
NGI Stockholm (Genomics Applications) [Service]
NGI Stockholm (Genomics Production) [Service]
National Genomics Infrastructure [Service]
PubMed 41046204
DOI 10.1016/j.ard.2025.07.029
Crossref 10.1016/j.ard.2025.07.029
pii: S0003-4967(25)04299-2