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Lookup NU author(s): Dr Domenico Somma, Professor John IsaacsORCiD, Professor Andrew FilbyORCiD, Dr David McDonald, Dr JASMINE Sim, Dr Ken BakerORCiD, Professor Iain McInnes
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© 2024 The Author(s). Current rheumatoid arthritis (RA) treatments do not restore immune tolerance. Investigating dendritic cell (DC) populations in human synovial tissue (ST) may reveal pathways to reinstate tolerance in RA. Using single-cell and spatial transcriptomics of ST biopsies, as well as co-culture systems, we identified condition- and niche-specific DC clusters with distinct functions. Healthy tissue contained tolerogenic AXL+ DC2s in the lining niche. In active RA, the hyperplasic lining niche was populated with inflammatory DC3s that activated CCL5-positive effector memory T cells, promoting synovitis. Lymphoid niches that emerged in the sublining layer were enriched with CCR7+ DC2s, which interacted with naive T cells, potentially driving the local expansion of new effector T cells. Remission saw the resolution of these pathogenic niches but lacked recovery of tolerogenic DC2s and exhibited activation of blood precursors of ST-DC3 clusters prior to flare-ups. Targeting pathogenic DC3s or restoring tolerogenic DC2s may help restore immune homeostasis in RA joints.
Author(s): MacDonald L, Elmesmari A, Somma D, Frew J, Di Mario C, Madhu R, Paoletti A, Simakou T, Hardy OM, Tolusso B, Campobasso D, Perniola S, Gessi M, Gigante MR, Petricca L, Bruno D, Coletto LA, Benvenuto R, Isaacs JD, Filby A, McDonald D, Sim JPX, Jamieson N, Wei K, D'Agostino MA, Millar NL, Milling S, McSharry C, Gremese E, Affleck K, Baker KF, McInnes IB, Otto TD, Korsunsky I, Alivernini S, Kurowska-Stolarska M
Publication type: Article
Publication status: Published
Journal: Immunity
Year: 2024
Volume: 57
Issue: 12
Pages: 2843-2862.e12
Print publication date: 10/12/2024
Online publication date: 27/11/2024
Acceptance date: 05/11/2024
Date deposited: 17/12/2024
ISSN (print): 1074-7613
ISSN (electronic): 1097-4180
Publisher: Cell Press
URL: https://doi.org/10.1016/j.immuni.2024.11.004
DOI: 10.1016/j.immuni.2024.11.004
Data Access Statement: All scRNA-seq and spatial data raw files are available from ArrayExpress under accession numbers E-MTAB-14191 (Co-Culture scRNA-seq), E-MTAB-14169 (BioRRA scRNA-seq), E-MTAB-14192 (Paired PB/ST scRNA-seq), E-MTAB-14213 (healthy, active RA and remission ST scRNA-seq/CITE-seq), E-MTAB-14198 (Sort-seq), S-BSST1483 (CosMx Spatial Transcriptomics). Scripts for analysis of scRNA-seq and published bulk RNA-seq datasets are available at https://doi.org/10.5281/zenodo.13866418. All raw microscopy pictures are available at BioImage Archive under accession number S-BIAD1388. More details are provided in the key resources table. All original code (Spatial Transcriptomic Data Analysis) has been deposited at Zenodo repository and is publicly available at https://doi.org/10.5281/zenodo.13869471 as of date of publication. Any additional information required to re-analyze the data reported in this paper is available from the lead contact upon request.
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