Background/Purpose: Juvenile idiopathic arthritis (JIA) is the most common chronic inflammatory rheumatic disease of childhood, affecting 1:1,000 children worldwide. The hallmark of JIA is immune-mediated chronic inflammation in the synovium – clinically reflected by the presence of arthritis or a combination of joint pain, swelling, or limitation of joint movement. If inadequately treated, JIA can lead to profound lifelong joint deformity and disability. Thus, early diagnosis and treatment initiation is essential in the management of patients with JIA. Histological examination of synovium, although limited in scope, has identified immune cell infiltration of lymphocytes, plasma cells, macrophages as well as proliferation of fibroblast- and macrophage-like synoviocytes. To date, no comprehensive studies of JIA synovium have been performed as current best-practices do not routinely collect tissue biopsies for diagnosis or analysis. Recent single cell methodologies that assay open chromatin and transcriptome have made great strides in bridging this gap in adult rheumatic conditions by directly examining the synovium. The objective of this study is to leverage novel multiomic single cell strategies to characterize cell heterogeneity in the synovium of children with JIA.

Methods: Ultrasound guided synovial biopsies were performed in two children to isolate synovium. Tissue was enzymatically digested, sorted for viability, nuclei isolated, and single cell libraries generated with the 10X multiome (RNA + ATAC) pipeline. A PBMC sample from a JIA patient was also included to define tissue enrichment. Data was aligned with cellranger and processed with custom analysis pipelines.

Results: We obtain high quality data from three samples for single cell RNA and ATAC sequencing with a median of 1350 genes and 6233 ATAC peaks from 5771 cells. Integration of gene expression and open chromatin data, harmonization by donor, and clustering identifies 11 broad populations including T, B and fibroblasts cells. Comparison between tissue and blood sample identifies an enrichment of activated/memory CD4 and CD8 T cells and a decrease in monocytes populations specific to the synovium. Pathogenic HLA-DR+ fibroblasts are exclusively identified in synovium. Fine-grained analysis of T cells with our recently developed T cell annotation program (TCAT) identifies evidence of proliferation in Tfh/Tph and T regulatory cells.

Conclusion: To our knowledge, this is the first multiomic single cell study of JIA synovium that simultaneously captures gene expression and open chromatin. We implement a high-quality processing pipeline and identify cell heterogeneity specific to the synovium. In particular, we find evidence of immune cell activation and proliferation in Tfh/Tph and T regulatory cells from synovium.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/multiomic-investigation-of-juvenile-idiopathic-arthritis-synovium-reveals-immune-cell-heterogeneity/