Arthritis & Rheumatology最新文献

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.

Objective: Patients with juvenile idiopathic arthritis (JIA) frequently exhibit antinuclear antibodies (ANAs), but the specific antigen target recognized by them and the presence of additional autoantibody specificities in patients with JIA remains elusive.

Methods: Plasma samples from 110 untreated patients with active JIA, as well as from 14 children with unspecified arthritis and 151 age- and sex-matched healthy children, were analyzed with multiple modern clinical-grade autoantibody assays, including automated indirect immunofluorescence to screen for ANAs with HEp-2 cells, and specific immune assays to detect reactivity to individual autoantigens. In addition, a HuProt proteome microarray was used to screen for novel autoantibody targets in plasma samples from five patients with ANA-positive JIA and four ANA-negative healthy controls.

Results: Homogeneous nuclear ANA staining, indicating reactivity toward chromatin, was detected in most (61.8%) patients with JIA but rarely in healthy controls (2.6%; P < 0.0001). No antibody reactivity to specific nuclear antigens or other autoantigens associated with connective tissue diseases was detected. However, 20% of patients with JIA harbored antibodies against double-stranded DNA (dsDNA)-nucleosome complexes (compared with 2.6% of controls, P < 0.0001). Finally, the proteome microarray revealed core histone H2A variant H2AFY, part of the nucleosome, to be the most widely recognized human protein by autoantibodies of patients with JIA.

Conclusion: Autoantibody reactivity in JIA primarily targets chromatin, but the epitopes targeted are likely either posttranslationally modified or multimolecule epitopes, such as dsDNA-nucleosome complexes, rather than epitopes on individual native proteins or purified dsDNA.