Arthritis & Rheumatology最新文献

Objective: Ankylosing spondylitis (AS) and enthesitis-related arthritis (ERA) are autoimmune bone diseases characterized by prominent heterotopic ossification and both have poor prognoses. The pathologic mechanisms of these diseases remain poorly understood.

Methods: After single-cell RNA-sequencing and T cell receptor (TCR) profiling, we used flow cytometry and multiplex immunofluorescence to quantify and map specific immune-cell subsets within lesions of early rheumatoid arthritis and AS, analyzing a total of 33 patient specimens. Furthermore, we identified a peptide from versican, a chondroitin sulfate proteoglycan of ligament, to establish an AS mouse model. In the novel model, immune-cell quantification, spatial mapping, and targeted therapies were applied to elucidate the pathogenic roles of key cellular subpopulations.

Results: Conventional Type 1 dendritic cells (cDC1s) were enriched in the joints of patients with ERA and exhibited a high level of major histocompatibility complex (MHC) I antigen presentation, which robustly interact with CD8⁺ T cells. Moreover, cDC1s, harboring the molecular of MHC I antigen presentation, were detected in spinal ligament tissue of patients with AS. In mice, versican-derived peptide combined with Type II collagen stably and efficiently elicits a model exhibiting hallmark enthesitis and heterotopic ossification. In this model, cDC1s and IL-17A⁺CD8⁺ T cells were highly enriched in the ligamentous synovial tissues. Blocking the recruitment of cDC1s through XCL1-neutralizing antibody alleviates arthritis symptoms in vivo.

Conclusion: Thus, cDC1s promote autoimmune reactions and osteoarticular lesions through IL-17A⁺CD8⁺ T cells. Targeting cDC1 represents a novel therapeutic target for bone remodeling arthritis.

Objective: Little is known about the pathogenesis of rheumatoid arthritis-related interstitial lung disease (RA-ILD). This study aimed to clarify the cellular and transcriptomic landscape of epithelial and immune cells in RA-ILD.

Methods: We performed single-cell RNA sequencing on fluorescence-activated cell sorted epithelial cells and immune cells from lung explants of four controls, three patients with non-RA connective tissue disease (CTD)-ILD, and five patients with RA-ILD. For T cell subclusters, we performed an integrative analysis with publicly available synovial T cell data. We performed immunofluorescence staining on lung sections from four controls, nine patients with RA-ILD, eight patients with non-RA CTD-ILD, and six patients with idiopathic pulmonary fibrosis.

Results: We profiled 184,814 cells in total and identified 18 distinct cell clusters. We found fewer alveolar type II cells with reciprocally higher frequencies of other epithelial cell types (basal cells and ciliated cells) and fewer FCN1⁺ CD14⁺ monocytes in RA-ILD lungs. In T cell subset analysis, peripheral helper T (Tph) cells were exclusively observed in RA-ILD lungs. Compared with synovial Tph cells, lung Tph cells had elevated expression profiles of activation and lower cytotoxic and exhausted signatures. From gene ontology analysis, genes associated with the small GTPase-mediated signal transduction were enriched in lung Tph cells. On confirmatory immunofluorescence staining, Tph cells were specifically present in RA-ILD lungs.

Conclusion: We report a detailed transcriptomic analysis of the epithelial and immune cells in RA-ILD lungs and include a cross-tissue comparison that demonstrates organ-specific variations in the characteristics of Tph cells.

Objective: Giant 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.

Methods: DNA 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 differentially methylated regions (DMRs). Lastly, we compared our findings with previous transcriptomics and epigenomics studies on GCA-affected arteries.

Results: EWAS identified 3,644 DMPs (P_adj < 0.05, |Δβ| > 0.3), indicating a profound alteration within GCA-affected arterial tissue. These DMPs were annotated to 1,517 potentially dysregulated genes. A total of 282 additional genes were identified by annotation of significant DMRs. Pathway enrichment analysis revealed a significant alteration of inflammatory mechanisms, such as interleukin-2 and interleukin-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.

Conclusion: Our 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.