Borrego-Yaniz, G. | bioRxiv Science

bioRxiv2026

Single-Cell RNA Sequencing Reveals Impaired Regulatory T Cell Function and a Pro-inflammatory Th17 Profile in Systemic Sclerosis

ObjectiveThis resource deeply characterizes the CD4+ T cell subpopulations populations in SSc patients, with a novel single-cell RNA sequencing (scRNA-seq) approach, offering unprecedented insights into the cellular and molecular underpinnings of the disease. MethodsWe performed scRNA-seq to analyze over 80,000 CD4+ T cells from 8 SSc patients and 8 healthy controls, integrating abundance, transcriptional, and TCR repertoire analysis, to define CD4+ T cell subtype-specific signatures associated with SSc. ResultsSSc CD4+ T cells displayed a global interferon-driven activation signature and significantly reduced TNF signaling. Key transcriptomic alterations included the downregulation of SOX4 and CD83, alongside an expansion of Th2 and proinflammatory, steroid-resistant Th17 cells. Furthermore, Tregs exhibited a destabilized state characterized by high FCRL3 and reduced FOXP3 expression. Finally, TCR repertoire analysis identified increased clonal expansion specifically within the central memory (Tcm) compartment. ConclusionTogether, this data revealed SSc-associated cell population states in CD4+ T cells with unique transcriptomic signatures and provided a publicly accessible interactive platform to facilitate exploration of this dataset by the research community.

genetics↗

bioRxiv2025

Genome-wide DNA methylation study reveals specific signatures in the affected arterial tissue of giant cell arteritis patients

ObjectivesGiant cell arteritis (GCA) is a large-vessel vasculitis, potentially causing complications such as blindness and strokes. This study aims to gain insights into the pathogenesis of GCA by identifying specific DNA methylation signatures in the arterial tissue of patients with this vasculitis. MethodsDNA methylation profiling was analyzed in 79 temporal artery biopsy samples (69 patients with GCA and 10 controls) by performing an epigenome-wide association study (EWAS). Differential analysis was performed to identify differentially methylated positions (DMPs) and regions (DMRs). Lastly, we compared our findings with previous transcriptomics and epigenomics studies on GCA-affected arteries. ResultsEWAS identified 3,644 DMPs (FDR < 0.05, |{Delta}{beta}| > 0.3), indicating a profound alteration within GCA-affected arterial tissue. These DMPs were annotated to 1,517 potentially dysregulated genes. 282 additional genes were identified by annotation of significant DMRs. Pathway enrichment analysis revealed a significant alteration of inflammatory mechanisms, such as interleukins 2 and 7, as well as pathways related to vascular remodeling. Omics study comparison revealed 37 genes consistently affected across datasets, many of them linked to immune signaling and T cell regulation. Notably, markers of exhausted T cells, including SLAMF6 and HAVCR2, were present among them. ConclusionsOur study identified GCA-specific DNA methylation signatures in arterial tissue, revealing disrupted inflammatory and vascular pathways, and suggesting the involvement of exhausted T cells in this condition. These findings offer new insights into GCA pathogenesis and provide new potential targets for the treatment of this debilitating disease. Key messagesO_ST_ABSWhat is already known on this topicC_ST_ABS{square} Affected arteries by giant cell arteritis (GCA) exhibit unique epigenetic signatures, reflecting significant disruptions in gene regulation. However, small sample sizes have constrained the clinical translation and broader interpretation of these findings, leaving key gaps in understanding GCA pathogenesis and identifying therapeutic targets. What this study adds{square} This study provides the largest-to-date epigenome-wide DNA methylation profiling in GCA-affected arteries, uncovering thousands of epigenetic changes and revealing profound disruptions in inflammatory and vascular pathways, including IL-2, IL-7, and CXCR4 signaling. {square}We compiled 37 genes consistently affected across different omics datasets in GCA-affected arteries, providing a robust list of candidates for further research into GCA pathogenesis and treatment. {square}Our findings provide evidence of T cell exhaustion in GCA-affected arteries, supported by consistent changes in key markers such as SLAMF6 and HAVCR2 (TIM-3), suggesting a novel mechanism of immune dysregulation in GCA. How this study might affect research, practice or policy{square} This study nominates exhausted T cells, the NLRP3 inflammasome, and CXCR4 signaling as novel contributors in GCA pathogenesis, suggesting new therapeutic targets for further research in the treatment of this disease.

immunology↗