RMD open · 2026
Early features of cellular ageing impair differentiation capacity in human lymph node fibroblasts prior to rheumatoid arthritis onset.
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Jiménez-Martínez Marina, De Jong Tineke A, Houtman Miranda, Semmelink Johanna F, Zelcer Noam, van de Sande Marleen G H, Dankers Wendy, van Baarsen Lisa G M
Аннотация
OBJECTIVE: Cellular ageing of the immune system has been suggested to play a role in the pathogenesis of rheumatoid arthritis (RA). RA onset is preceded by a preclinical phase of systemic autoimmunity without overt tissue inflammation, allowing the investigation of predisease cellular dysfunction in at-risk individuals. Lymph nodes (LNs) are crucial for (auto)antibody development, with LN fibroblasts playing a key role in regulating immune homeostasis. Here, we investigated age-associated alterations in LN fibroblast differentiation capacity during the at-risk and established stages of RA.
METHODS: Primary LN fibroblasts were isolated from inguinal LN core biopsies obtained from healthy controls, at-risk individuals and patients with RA. Adipogenic differentiation assays served as a functional readout of cellular plasticity and bulk RNA sequencing was used to evaluate ageing-related transcriptional changes.
RESULTS: LN fibroblasts from at-risk individuals and patients with RA exhibited reduced adipogenic capacity, reflected by fewer lipid droplet-positive cells on differentiation. Transcriptomic analysis revealed downregulation of cell cycle, DNA repair and differentiation pathways. These fibroblasts also failed to upregulate the cell cycle switch G0S2 on stimulation.
CONCLUSION: Together, these findings indicate a disrupted coordination between cell cycle processes and differentiation in at-risk and RA LN fibroblasts, consistent with features of cellular ageing. Notably, these alterations were already present in at-risk individuals prior to clinical disease onset, suggesting that reduced fibroblast fitness may contribute to impaired LN tissue homeostasis in disease-prone individuals.
METHODS: Primary LN fibroblasts were isolated from inguinal LN core biopsies obtained from healthy controls, at-risk individuals and patients with RA. Adipogenic differentiation assays served as a functional readout of cellular plasticity and bulk RNA sequencing was used to evaluate ageing-related transcriptional changes.
RESULTS: LN fibroblasts from at-risk individuals and patients with RA exhibited reduced adipogenic capacity, reflected by fewer lipid droplet-positive cells on differentiation. Transcriptomic analysis revealed downregulation of cell cycle, DNA repair and differentiation pathways. These fibroblasts also failed to upregulate the cell cycle switch G0S2 on stimulation.
CONCLUSION: Together, these findings indicate a disrupted coordination between cell cycle processes and differentiation in at-risk and RA LN fibroblasts, consistent with features of cellular ageing. Notably, these alterations were already present in at-risk individuals prior to clinical disease onset, suggesting that reduced fibroblast fitness may contribute to impaired LN tissue homeostasis in disease-prone individuals.