Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

A Novel Heterozygous STAT5B Loss-of-Function Variant Associated with Interleukin-17A-Responsive Systemic Juvenile Idiopathic Arthritis-like Disease

ABSTRACT: Objective. To define the cellular and molecular mechanisms of a novel heterozygous STAT5B loss-of-function variant in a child with systemic juvenile idiopathic arthritis-like disease and refractory arthritis. Methods. We integrated clinical genetics, immunoblotting and phospho-flow cytometry, synovial fluid immune profiling, and Xenium spatial transcriptomics of synovial tissue, comparing the patient with healthy blood and seronegative oligoarticular/polyarticular juvenile idiopathic arthritis (JIA) controls. Results. The patient carried a novel heterozygous STAT5B nonsense variant (p.Gln139Ter) associated with reduced STAT5B protein expression and impaired STAT5 phosphorylation. Synovial fluid CD4+ T cells showed markedly increased interleukin (IL)-17A production and reduced FOXP3 and CD25 expression in regulatory T cells (Tregs). Spatial transcriptomics revealed Th17 cells distributed diffusely throughout the patient's synovium, in contrast to JIA controls in which Th17 cells were largely restricted to tertiary lymphoid structures (TLS). The patient's severe arthritis, previously refractory to IL-1 and IL-6 blockade, improved markedly after interleukin-17A inhibition. Conclusion. STAT5B haploinsufficiency can present as an sJIA-like phenotype with Th17/IL-17 dysregulation and extra-TLS Th17 distribution. Integrated genetic, functional, and spatial tissue analyses can guide targeted therapy in refractory pediatric arthritis.

ORGANISM(S): Homo sapiens

PROVIDER: GSE338671 | GEO | 2026/09/22

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

RNA-seq analysis of IL-17A+/IFNy+ CD8+ and IL-17A+CD4+ T cells from Psoriatic Arthritis Synovial Fluid

Project description:Psoriatic arthritis is a seronegative polyarticular form of inflammatory arthritis . Genetic analysis implicates a role for both IL-17/23 axis and CD8+ T cells in disease susceptibility. Using RNA-seq we identified differential gene expression between synovial IL-17A+(IFNy+/-) CD8+ T cells compared to IL-17A-IFNy+ CD8+ T cells and IL-17A+CD4+ T cells from the synovial fluid of psoriatic arthritis patients. We find that IL-17A+CD8+ T cells have a transcriptional overlap with IL-17A+CD4+ T cells. Overall we show these IL-17A+ CD8+ T cells have a polyfunctional, pro-inflammatory capacity and are potentially derived from common precursors, shared with IL-17A-CD8+ T cells.

2020-04-17 | GSE137510 | GEO

Gene Expression Profiling of IL-17A-treated Synovial Fibroblasts from the Human Temporomandibular Joint

Project description:Synovial fibroblasts contribute to the inflammatory temporomandibular joint under pathogenic stimuli. Synovial fibroblasts and T cells participate in the perpetuation of joint inflammation in a mutual activation feedback, via secretion of cytokines and chemokines that stimulate each other. IL-17 is an inflammatory cytokine produced primarily by Th17 cells that plays critical roles in the pathogenesis of numerous autoimmune and inflammatory diseases. Here, we investigated the roles of IL-17A in temporomandibular joint disorders (TMD) by using genome-wide analysis of synovial fibroblasts isolated from patients with TMD. We analyzed the gene expression profiles of synovial fibroblasts that were treated with or without IL-17A. IL-17 induced gene expression in synovial fibroblasts from human temporomandibular joint was measured at 4 hours after treated with IL-17A (10 ng/ml) and untreated control samples. This experiment used one donor sample.

2015-11-05 | E-GEOD-74668 | biostudies-arrayexpress

A pathogenic Th17/CD38+ macrophage feedback loop drives inflammatory arthritis through TNFa

Project description:The pathobiology of rheumatoid inflammatory diseases, including rheumatoid arthritis (RA) and psoriatic arthritis (PsA), involves the interplay between innate and adaptive immune components and resident synoviocytes. Single-cell analyses of patient samples and relevant mouse models have characterized many cellular subsets in RA. However, the impact of interactions between cell types is not fully understood. Here, we temporally profiled murine arthritic synovial isolates at the single-cell level to identify perturbations like those found in human RA. Notably, murine macrophage subtypes like those in RA patients were expanded in arthritis and linked to promoting the function of Th17 cells in the joint. In vitro experiments identified a capacity for murine macrophages to maintain the functionality and expansion of Th17 cells. Reciprocally, murine Th17 cell-derived TNFa induced CD38+ macrophages that enhanced Th17 functionality. Murine synovial CD38+ macrophages were expanded during arthritis and their depletion or blockade via TNFa-neutralization alleviated disease while reducing IL-17A-producing cells. These findings identify a cellular feedback loop that promotes Th17 cell pathogenicity through TNFa to drive inflammatory arthritis.

2022-01-05 | GSE184609 | GEO

Proteome of neutrophils upon migration towards inflamed synovial fluid

Project description:Analysis of neutrophil proteomic alterations induced by migration towards inflamed joints in juvenile idiopathic arthritis (JIA). In this experiment neutrophil proteomes were investigated after migration towards JIA synovial fluid in an in vitro model of a synovial membrane, compared to neutrophils incubated in synovial fluid without migration. The migration model consisted of transwell inserts with human knee synoviocytes on the undersides and HMEC endothelial cells on the insides, placed in wells containing medium with 10 % JIA synovial fluid.

2022-02-15 | PXD029129 | Pride

Conversion of Th17 into exTh17 sustains rheumatoid-like IL-17-independent inflammatory arthritis [Xenium]

Project description:T helper 17 (Th17) cells are found in peripheral blood and synovial fluid of rheumatoid arthritis (RA) patients, however IL-17-targeted interventions have shown limited efficacy in established RA. While it is known that inflammation can induce Th17 transdifferentiation into Th1- or Tr1-like IL-17-negative exTh17 cells, the role of exTh17 in arthritis is not known. Here, we explore the premise that exTh17 cells promote joint inflammation in autoimmune arthritis. To assess the potential immunophenotypic dynamics and role of exTh17 in inflammatory arthritis, we performed Th17 lineage tracing studies in the SKG mouse model of RA. We show that in arthritic mice, synovial Th17 transdifferentiate into IFNγ- and IL-10- exTh17 which become the most prominent CD4+ population in chronic arthritis. SKG exTh17 cells are more arthritogenic than Th17, and able to sustain synovial inflammation that is IL-17-independent but enriched with IL-6 and TNF, two RA-promoting cytokines. Synovial exTh17 present a unique gene signature, including upregulation of CD44 and S1PR4. This gene signature has correlates in the profile of CD4+ T cells found in human RA synovium. We further demonstrate that crosstalk between Th17 and fibroblast-like synoviocytes via S1P signaling promote Th17-exTh17 conversion. Additionally, CD44 is necessary for the arthritogenic effect of exTh17. Our study suggests that the fibroblast-like synoviocyte expansion, which occurs during RA progression, can drive progressive conversion of Th17 into exTh17 which sustains inflammation with features of human established RA. The results offer new insights that could be potentially useful for future precision therapy approaches to RA.

2026-03-25 | GSE293970 | GEO

CD4+ tissue resident memory Th17 cells drive IL-17A-mediated joint pathology in Spondyloarthritis

Project description:Interleukin (IL)-17A plays a central role in driving joint pathology in Spondyloarthritis (SpA). In this study, synovial tissues from patients with Axial SpA and Psoriatic arthritis were analyzed using single-cell RNA sequencing and spatial RNA profiling to pinpoint the cellular source of IL-17A. The results revealed that IL-17A expression is exclusively localized to CD4⁺CXCR6⁺ tissue resident memory Th17 (TRM17) cells, which interact with activated CLEC10A⁺ dendritic cells within the joint. These interactions coincide with an enhanced IL-17A response signature in both sublining and lining fibroblasts. Furthermore, in vitro-generated TRM17-like cells from blood memory CD4⁺ T cells recapitulated the in situ characteristics by producing IL-17A in response to T cell receptor stimulation, while IL-23 selectively amplified TCR-mediated IL-17F and IFN-γ production. Importantly, perturbation of the epigenetic regulator BRD1 impaired the generation of TRM17-like cells. These findings underscore the predominant role of TRM17 cells as the source of IL-17A in SpA and suggest that targeting BRD1 or depleting TRM17 cells may offer promising therapeutic strategies for achieving long-term disease remission.

2025-05-29 | GSE290921 | GEO

Interleukin-17A causes osteoarthritis-like transcriptional changes in human osteoarthritis-derived chondrocytes and synovial fibroblasts in vitro

Project description:Increased interleukin (IL)-17A has been identified in joints affected by osteoarthritis (OA), but it is unclear how IL-17A, and its family members IL-17AF and IL-17F, can contribute to human OA pathophysiology. Therefore, we aimed to evaluate the gene expression and signalling pathway activation effects of the different IL-17 family members in chondrocytes and fibroblasts derived from cartilage and synovium of patients with end-stage knee OA. Chondrocytes and synovial fibroblasts derived from end-stage OA patients were treated with IL-17A, IL-17AF, or IL-17F, and gene expression was assessed with bulk RNA-Seq. Hallmark pathway analysis showed that IL-17 cytokines regulated several OA pathophysiology-related pathways including immune-, angiogenesis-, and complement-pathways in both chondrocytes and synovial fibroblasts derived from end-stage OA patients. While overall IL-17A induced the strongest transcriptional response, followed by IL-17AF and IL-17F, not all genes followed this pattern. Disease-Gene Network analysis revealed that IL-17A-related changes in gene expression in these cells are associated with experimental arthritis, knee arthritis, and musculoskeletal disease gene-sets. In conclusion, the association of IL-17-induced transcriptional changes with arthritic gene-sets supports a role for IL-17A in OA pathophysiology.

2021-06-02 | GSE171952 | GEO

Gene Expression Profiling of IL-17A-treated Synovial Fibroblasts from the Human Temporomandibular Joint

2015-11-05 | GSE74668 | GEO

TH17 cells converted into exTH17 cells sustain rheumatoid-like IL-17–independent inflammatory arthritis

Project description:T helper 17 (TH17) cells are found in the periphery and synovium of patients with rheumatoid arthritis (RA); however, IL-17–targeted interventions have limited efficacy in established RA. Inflammation can induce TH17 cell transdifferentiation into IL-17–negative exTH17 cells, but the role of exTH17 cells in arthritis is unknown. We performed TH17 cell lineage tracing in the SKG mouse model of RA. In arthritic mice, synovial TH17 cells transdifferentiate into CD44+ exTH17 cells, which are more arthritogenic and sustain inflammation that is IL-17 independent. The exTH17 cell gene signature includes up-regulation of CD44 and sphingosine-1-phosphate receptor 4 (S1PR4) and correlates with the profile of human RA synovial CD4+ T cells. We demonstrate that cross-talk between TH17 cells and fibroblast-like synoviocytes (FLSs) via S1P promotes TH17-exTH17 cell conversion. CD44 is necessary for exTH17 cell–mediated arthritis. Our study suggests that FLS expansion during RA progression promotes TH17-exTH17 cell conversion. These results could potentially enable RA precision therapy.

2025-09-19 | GSE234597 | GEO

TH17 cells converted into exTH17 cells sustain rheumatoid-like IL-17–independent inflammatory arthritis

2025-09-19 | GSE234596 | GEO