Synovial fibroblast gene expression is associated with sensory nerve growth and pain in rheumatoid arthritis

Science Translational Medicine, Год журнала: 2024, Номер 16(742)

Опубликована: Апрель 10, 2024

It has been presumed that rheumatoid arthritis (RA) joint pain is related to inflammation in the synovium; however, recent studies reveal scores patients do not correlate with synovial inflammation. We developed a machine-learning approach (graph-based gene expression module identification or GbGMI) identify an 815-gene associated biopsy samples from established RA who had limited at arthroplasty. then validated this finding independent cohort of early untreated little Single-cell RNA sequencing analyses indicated most these 815 genes were robustly expressed by lining layer fibroblasts. Receptor-ligand interaction analysis predicted cross-talk between human fibroblasts and dorsal root ganglion neurons expressing calcitonin gene–related peptide (CGRP + ). Both fibroblast culture supernatant netrin-4, which abundantly was within GbGMI-identified pain-associated module, increased branching pain-sensitive murine CGRP vitro. Imaging solvent-cleared tissue humans revealed pain-sensing encasing blood vessels growing into hypertrophic papilla. Together, findings support model whereby express enhance growth regions hypertrophy RA.

Язык: Английский

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Interferon subverts an AHR–JUN axis to promote CXCL13+ T cells in lupus

Nature, Год журнала: 2024, Номер 631(8022), С. 857 - 866

Опубликована: Июль 10, 2024

Язык: Английский

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Contextual AI models for single-cell protein biology

Nature Methods, Год журнала: 2024, Номер 21(8), С. 1546 - 1557

Опубликована: Июль 22, 2024

Understanding protein function and developing molecular therapies require deciphering the cell types in which proteins act as well interactions between proteins. However, modeling across biological contexts remains challenging for existing algorithms. Here we introduce PINNACLE, a geometric deep learning approach that generates context-aware representations. Leveraging multiorgan single-cell atlas, PINNACLE learns on contextualized interaction networks to produce 394,760 representations from 156 type 24 tissues. PINNACLE's embedding space reflects cellular tissue organization, enabling zero-shot retrieval of hierarchy. Pretrained can be adapted downstream tasks: enhancing 3D structure-based resolving immuno-oncological interactions, investigating drugs' effects types. outperforms state-of-the-art models nominating therapeutic targets rheumatoid arthritis inflammatory bowel diseases pinpoints with higher predictive capability than context-free models. ability adjust its outputs basis context it operates paves way large-scale context-specific predictions biology.

Язык: Английский

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T Cell Dysregulation in Rheumatoid Arthritis: from Genetic Susceptibility to Established Disease

Current Rheumatology Reports, Год журнала: 2025, Номер 27(1)

Опубликована: Янв. 25, 2025

Abstract Purpose of Review Rheumatoid arthritis (RA) is a complex autoimmune disease characterized by chronic inflammation the synovial tissue, where T cells play central role in pathogenesis. Recent research has identified peripheral helper (Tph) as critical mediators local B cell activation inflamed tissues. This review synthesizes latest advancements our understanding RA, from initiation to established disease. Findings We explore recent advances regarding genetic and epigenetic factors that predispose individuals mechanisms differentiation, interactions between other immune stromal within microenvironment. The emergence Tph key drivers RA pathobiology highlighted, along with their potential therapeutic targets. also discuss heterogeneity responses interplay cells, while addressing gaps such recruitment plasticity phenotypes. Summary A deeper dynamics will provide valuable insights for developing targeted therapies modulate cell-mediated improve patient outcomes.

Язык: Английский

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Clonal associations between lymphocyte subsets and functional states in rheumatoid arthritis synovium

Nature Communications, Год журнала: 2024, Номер 15(1)

Опубликована: Июнь 11, 2024

Abstract Rheumatoid arthritis (RA) is an autoimmune disease involving antigen-specific T and B cells. Here, we perform single-cell RNA repertoire sequencing on paired synovial tissue blood samples from 12 seropositive RA patients. We identify clonally expanded CD4 + cells, including CCL5+ cells peripheral helper (Tph) which show a prominent transcriptomic signature of recent activation effector function. CD8 higher oligoclonality than with the largest clones enriched in GZMK+ possibly virus-reactive TCRs are distributed across clusters. In cell compartment, NR4A1+ activated plasma synovium demonstrate substantial clonal expansion. that share BCRs ABC, memory, Receptor-ligand analysis predicted IFNG TNFRSF members as mediators Tph-B interactions. Together, these results reveal relationships between functionally distinct lymphocyte populations infiltrate patients RA.

Язык: Английский

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Distinct mucosal endotypes as initiators and drivers of rheumatoid arthritis

Nature Reviews Rheumatology, Год журнала: 2024, Номер 20(10), С. 601 - 613

Опубликована: Сен. 9, 2024

Язык: Английский

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The chromatin landscape of pathogenic transcriptional cell states in rheumatoid arthritis

Nature Communications, Год журнала: 2024, Номер 15(1)

Опубликована: Май 31, 2024

Abstract Synovial tissue inflammation is a hallmark of rheumatoid arthritis (RA). Recent work has identified prominent pathogenic cell states in inflamed RA synovial tissue, such as T peripheral helper cells; however, the epigenetic regulation these yet to be defined. Here, we examine genome-wide open chromatin at single-cell resolution 30 samples, including 12 samples with transcriptional data multimodal experiments. We identify 24 classes and predict their associated transcription factors, CD8 + GZMK class EOMES lining fibroblast AP-1. By integrating an atlas, propose that represent ‘superstates’ corresponding multiple states. Finally, demonstrate utility this atlas through associations between disease phenotypes abundance, well nomination mediating effects putatively causal genetic variants.

Язык: Английский

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The therapeutic potential of immunoengineering for systemic autoimmunity

Nature Reviews Rheumatology, Год журнала: 2024, Номер 20(4), С. 203 - 215

Опубликована: Фев. 21, 2024

Язык: Английский

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Interferons and epigenetic mechanisms in training, priming and tolerance of monocytes and hematopoietic progenitors

Immunological Reviews, Год журнала: 2024, Номер 323(1), С. 257 - 275

Опубликована: Апрель 3, 2024

Training and priming of innate immune cells involve preconditioning by PAMPs, DAMPs, and/or cytokines that elicits stronger induction inflammatory genes upon secondary challenge. Previous models distinguish training based whether activation returns to baseline prior Tolerance is a protective mechanism whereby potent stimuli induce refractoriness are important for memory responses protect against infection, efficacy vaccines, maintaining in state readiness; tolerance prevents toxicity from excessive activation. Dysregulation these processes can contribute pathogenesis autoimmune/inflammatory conditions, post-COVID-19 hyperinflammatory states, or sepsis-associated immunoparalysis. Training, priming, regulate similar "signature" such as TNF, IL6, IL1B utilize overlapping epigenetic mechanisms. We review how interferons (IFNs), best known activating JAK-STAT signaling interferon-stimulated genes, also play key role regulating training, via chromatin-mediated present new data on monocyte-to-macrophage differentiation modulates IFN-γ-mediated affects regulation AP-1 CEBP activity, attenuates superinduction genes. "training-priming continuum" model integrates IFN-mediated into current concepts about proposes central STAT1 IRF1.

Язык: Английский

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Inhibition of macrophage polarization and pyroptosis in collagen-induced arthritis through MSC-exo and ginsenoside Rh2

Arthritis Research & Therapy, Год журнала: 2025, Номер 27(1)

Опубликована: Янв. 9, 2025

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by joint inflammation, tissue damage, and fibrosis, significantly affecting the quality of life. While there are currently some effective treatments available, they often come with side effects. There an urgent need to find new that can further improve therapeutic outcomes reduce Our study investigates role Mesenchymal Stem Cell exosomes (MSC-exo) combined Ginsenoside Rh2 (Rh2) in treatment RA. We specifically focus on how this strategy influences macrophage polarization pyroptosis. This research utilized collagen-induced rat model. The findings reveal combination MSC-exo inhibit M1 macrophages, increase proportion M2-like suppress M1-like pyroptosis via NLRP3/Caspase11/GSDMD-N pathway. In model, showed synergistic contributes deeper understanding RA's pathogenesis presents potential targeted interventions. application offers promising insights for future innovative strategies RA treatment, paving way more management disease.

Язык: Английский

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