Dataset Information

Single cell analysis of spondyloarthritis regulatory T cells identifies distinct synovial gene expression patterns and clonal fates.

ABSTRACT: Regulatory T cells (Tregs) play an important role in controlling inflammation and limiting autoimmunity, but their phenotypes at inflammatory sites in human disease are poorly understood. We here analyze the single-cell transcriptome of >16,000 Tregs obtained from peripheral blood and synovial fluid of two patients with HLA-B27+ ankylosing spondylitis and three patients with psoriatic arthritis, closely related forms of inflammatory spondyloarthritis. We identify multiple Treg clusters with distinct transcriptomic profiles, including, among others, a regulatory CD8⁺ subset expressing cytotoxic markers/genes, and a Th17-like RORC+ Treg subset characterized by IL-10 and LAG-3 expression. Synovial Tregs show upregulation of interferon signature and TNF receptor superfamily genes, and marked clonal expansion, consistent with tissue adaptation and antigen contact respectively. Individual synovial Treg clones map to different clusters indicating cell fate divergence. Finally, we demonstrate that LAG-3 directly inhibits IL-12/23 and TNF secretion by patient-derived monocytes, a mechanism with translational potential in SpA. Our detailed characterization of Tregs at an important inflammatory site illustrates the marked specialization of Treg subpopulations.

SUBMITTER: Simone D

PROVIDER: S-EPMC8671562 | biostudies-literature | 2021 Dec

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Single cell analysis of spondyloarthritis regulatory T cells identifies distinct synovial gene expression patterns and clonal fates.

Simone Davide D Penkava Frank F Ridley Anna A Sansom Stephen S Al-Mossawi M Hussein MH Bowness Paul P

Communications biology 20211214 1

Regulatory T cells (Tregs) play an important role in controlling inflammation and limiting autoimmunity, but their phenotypes at inflammatory sites in human disease are poorly understood. We here analyze the single-cell transcriptome of >16,000 Tregs obtained from peripheral blood and synovial fluid of two patients with HLA-B27+ ankylosing spondylitis and three patients with psoriatic arthritis, closely related forms of inflammatory spondyloarthritis. We identify multiple Treg clusters with dist ...[more]

PMID: 34907325

Similar Datasets

Project description:BackgroundSynovial fibroblasts (SFs) are specialized cells of the synovium that provide nutrients and lubricants for the proper function of diarthrodial joints. Recent evidence appreciates the contribution of SF heterogeneity in arthritic pathologies. However, the normal SF profiles and the molecular networks that govern the transition from homeostatic to arthritic SF heterogeneity remain poorly defined.MethodsWe applied a combined analysis of single-cell (sc) transcriptomes and epigenomes (scRNA-seq and scATAC-seq) to SFs derived from naïve and hTNFtg mice (mice that overexpress human TNF, a murine model for rheumatoid arthritis), by employing the Seurat and ArchR packages. To identify the cellular differentiation lineages, we conducted velocity and trajectory analysis by combining state-of-the-art algorithms including scVelo, Slingshot, and PAGA. We integrated the transcriptomic and epigenomic data to infer gene regulatory networks using ArchR and custom-implemented algorithms. We performed a canonical correlation analysis-based integration of murine data with publicly available datasets from SFs of rheumatoid arthritis patients and sought to identify conserved gene regulatory networks by utilizing the SCENIC algorithm in the human arthritic scRNA-seq atlas.ResultsBy comparing SFs from healthy and hTNFtg mice, we revealed seven homeostatic and two disease-specific subsets of SFs. In healthy synovium, SFs function towards chondro- and osteogenesis, tissue repair, and immune surveillance. The development of arthritis leads to shrinkage of homeostatic SFs and favors the emergence of SF profiles marked by Dkk3 and Lrrc15 expression, functioning towards enhanced inflammatory responses and matrix catabolic processes. Lineage inference analysis indicated that specific Thy1+ SFs at the root of trajectories lead to the intermediate Thy1+/Dkk3+/Lrrc15+ SF states and culminate in a destructive and inflammatory Thy1- SF identity. We further uncovered epigenetically primed gene programs driving the expansion of these arthritic SFs, regulated by NFkB and new candidates, such as Runx1. Cross-species analysis of human/mouse arthritic SF data determined conserved regulatory and transcriptional networks.ConclusionsWe revealed a dynamic SF landscape from health to arthritis providing a functional genomic blueprint to understand the joint pathophysiology and highlight the fibroblast-oriented therapeutic targets for combating chronic inflammatory and destructive arthritic disease.

Project description:BackgroundBoth vertebral bodies and posterior elements of the vertebrae (facet joints, FJ) can engage in bone formation in radiographic axial spondyloarthritis (r-axSpA). However, little is known about the specific structural lesions and progression patterns of FJs in r-axSpA.ObjectivesTo identify specific lesions related to r-axSpA and to investigate the distinct progression patterns by comparing the FJ changes of r-axSpA with that of diffuse idiopathic skeletal hyperostosis (DISH), osteoarthritis (OA), and control group (CG).DesignSingle-center, retrospective study. Longitudinal imaging data were retrieved and collected.MethodsAge- and sex-matched patients with complete thoracic and lumbar spine computed tomography (CT) data were included and their bilateral FJs were assessed. FJ changes were divided into erosions, ankylosis, joint-space narrowing, osteophytes, subchondral sclerosis, subchondral cysts, and vacuum phenomena. Average progressed year was defined as "number of changed vertebrae × interval years"/number of changed vertebrae.ResultsIn all, 50 patients in each group were included. Subchondral cysts and vacuum phenomena were not observed. Bilateral FJ ankylosis (FJA)/erosions in the thoracic and lumbar spine, and unilateral ankylosis/erosions in T1-4, T9-12 were significantly more common in r-axSpA. Joint-space narrowing/osteophytes/subchondral sclerosis were significantly more common in DISH and OA. FJ lesions progressed in 56.34% of vertebrae of r-axSpA. The most common pattern was "FJ normal advanced to ankylosis" (17.54%) which required 2.63 years. It was followed by "erosions advanced to ankylosis" (12.3%) which took 2.05 years, and by "normal FJ advanced to erosions" (11.04%) which took 2.29 years, respectively. Degenerative changes could also progress to FJ erosions/ankylosis (24.83%). The majority pattern in DISH/OA was "FJ changes advanced to subchondral sclerosis/osteophytes/joint-space narrowing."ConclusionBilateral FJA/erosions are r-axSpA-specific lesions. The specific progression pattern for r-axSpA was "FJ changes advanced to ankylosis/erosions." Repeated CT examination in intervals of at least 2 years will be more appropriate for monitoring FJ progression.

Dataset Information

Single cell analysis of spondyloarthritis regulatory T cells identifies distinct synovial gene expression patterns and clonal fates.

Publications

Single cell analysis of spondyloarthritis regulatory T cells identifies distinct synovial gene expression patterns and clonal fates.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets