Pullerits, R. | Search bioRxiv

bioRxiv2026

Neurostructural and molecular evidence of advanced brain aging in rheumatoid arthritis

Chronic systemic inflammation has been implicated in age-related neurodegeneration, but whether rheumatoid arthritis (RA) is associated with accelerated brain aging remains unclear. We combined structural magnetic resonance imaging (MRI), circulating neurodegeneration biomarkers, and peripheral monocyte transcriptomics to investigate brain aging in RA across two independent cohorts. A brain-age prediction model trained in healthy controls from the IXI imaging dataset was applied to RA patient cohorts from Gothenburg (n = 71) and Glasgow (n = 50). RA was associated with significantly elevated corrected brain-age gap relative to healthy controls (+6.5 years, 95% CI 4.2-8.8 years, p = 1.2 x 10-7), with substantially stronger effects in patients [≥]60 years. Older RA patients demonstrated a significant ventricular enlargement together with reduced frontal and parietal lobe volumes. Serum brain-derived tau and glial fibrillary acidic protein levels were elevated in RA. The increased brain-age gap was associated with altered myeloid transcriptional signatures. These findings demonstrate that RA is associated with age-related neurostructural alterations consistent with accelerated brain aging.

neuroscience↗

bioRxiv2025

Insulin exerts epigenetic control of joint-specific memory T cells in rheumatoid arthritis

BackgroundInsulin has epigenetic effect influencing gene expression. High peripheral insulin concentrations promote insulin resistance in autoimmunity. Oncoprotein survivin/BIRC5 modulates glucose metabolism through chromatin binding and propagates IFNg effects in CD4+ cells. In this study, we explored how insulin influences chromatin binding and metabolic activity in autoimmune CD4+ cells of patients with rheumatoid arthritis (RA). MethodsWe profiled the metabolic activity of CD4+ cell clusters using single-cell transcriptome analysis in blood, synovial fluid and synovial tissue of RA patients. Through chromatin immunoprecipitation and sequencing, we identified the genes controlled by deposition of survivin and acetylated lysine 27 on histone H3 (H3K27ac) in CD4+ cells. Treating CD4+ cells with insulin and histone deacetylase inhibitors (HDACi), we identified changes in H3K27ac, linked those to transcription of the H3K27-survivin-controlled genes and the pathogenic phenotype of CD4+ cells using flow cytometry. Finally, we explored if anti-diabetic and anti-rheumatic drugs affect the metabolic profile and memory phenotype of the metabolic active CD4+ cells. ResultsTranscription of survivin/BIRC5 and histone acetylation enzymes strongly correlate with active metabolism in blood CD4+ cells of RA patients. In RA synovial tissue, these BIRC5hi active T cell clusters are inflammatory, exhausted, and memory-like. Genome co-deposition of H3K27ac-survivin pinpointed the insulin-dependent genes in metabolic active CD4+ cells. These genes favored histone acetylation by suppressing methylating enzymes EZH2 and KMT2A, and T cell development by activating CD27, CD3G, and SCIMP. Inhibition of histone deacetylation reverted these transcriptional effects and supported cellular sensitivity to insulin. Insulin stimulation increased H3K27ac and together with HDACi, suppressed PDCD1 and IFNg transcription and production in CD4+CD27+CD45RO+ memory T cells. Immune modulation impacted metabolic activity and synergized with the effect of histone acetylation on insulin responsiveness in RA patients. ConclusionsRA synovia is enriched with the metabolic active BIRC5hiCD4+ T cell clusters. The metabolic activity of these cells is histone acetylation-dependent and mediates insulin effects through the H3K27ac-survivin epigenetic mechanism. Increasing plasma insulin levels when combined with insulin sensitivity, can be protective in RA dearmoring effector T cell function. Hence, increasing the insulin sensitivity by enabling histone acetylation presents a reasonable interventional goal to restore immune cell homeostasis in RA.

immunology↗