Synovial tissue myeloid dendritic cell subsets exhibit distinct tissue-niche localization and function in health and rheumatoid arthritis
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<sup>+</sup> 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<sup>+</sup> 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.
Authors
- Simon Milling (ORCID: https://orcid.org/0000-0003-4384-5516)
- Maria Rita Gigante (ORCID: https://orcid.org/0000-0001-9509-1977)
- Stefano Alivernini (ORCID: https://orcid.org/0000-0002-7383-4212)
- Kenneth F. Baker (ORCID: https://orcid.org/0000-0002-6735-2911)
- Thomas D. Otto (ORCID: https://orcid.org/0000-0002-1246-7404)
- Dario Bruno (ORCID: https://orcid.org/0000-0002-6647-9208)
- Theodoros Simakou (ORCID: https://orcid.org/0000-0002-0839-6383)
- David McDonald (ORCID: https://orcid.org/0000-0002-2410-9364)
- Roberta Benvenuto (ORCID: https://orcid.org/0009-0000-4048-9101)
- Andrew Filby (ORCID: https://orcid.org/0000-0001-9078-4360)
- Lavinia Agra Coletto (ORCID: https://orcid.org/0000-0001-6613-9468)
- Aziza Elmesmari (ORCID: https://orcid.org/0000-0001-7755-6283)
- Clara Di Mario (ORCID: https://orcid.org/0000-0001-9459-3326)
- Roopa Madhu (ORCID: https://orcid.org/0000-0001-6226-160X)
- John D. Isaacs (ORCID: https://orcid.org/0000-0002-6103-7056)
- Barbara Tolusso (ORCID: https://orcid.org/0000-0002-9108-6609)
- Simone Perniola (ORCID: https://orcid.org/0000-0001-6918-4731)
- Ilya Korsunsky (ORCID: https://orcid.org/0000-0003-4848-3948)
- Kevin Wei (ORCID: https://orcid.org/0000-0002-1821-167X)
- Mariola Kurowska‐Stolarska (ORCID: https://orcid.org/0000-0003-2124-7777)
- Domenico Somma (ORCID: https://orcid.org/0000-0003-2486-7250)
- Neal L. Millar (ORCID: https://orcid.org/0000-0001-9251-9907)
- Luca Petricca (ORCID: https://orcid.org/0000-0003-3544-3162)
- Jack Frew (ORCID: https://orcid.org/0000-0003-0816-3325)
- Jasmine P X Sim
- Audrey Paoletti (ORCID: https://orcid.org/0000-0001-8979-385X)
- Olympia M Hardy (ORCID: https://orcid.org/0009-0007-5145-8571)
- Iain B. McInnes (ORCID: https://orcid.org/0000-0002-6462-4280)
- Nigel B. Jamieson (ORCID: https://orcid.org/0000-0002-9552-4725)
- Marco Gessi
- Lucy MacDonald (ORCID: https://orcid.org/0000-0001-7727-3873)
- Elisa Gremese (ORCID: https://orcid.org/0000-0002-2248-1058)
- Maria Antonietta D’Agostino (ORCID: https://orcid.org/0000-0002-5347-0060)
- Charles McSharry (ORCID: https://orcid.org/0000-0003-4758-9038)
- Denise Campobasso
- Karen Affleck
Institutions
- Brigham and Women's Hospital (US)
- Harvard University (US)
- Age UK (GB)
- Agostino Gemelli University Polyclinic (IT)
- Istituti di Ricovero e Cura a Carattere Scientifico (IT)
- University of Glasgow (GB)
- Newcastle University (GB)
Publication Details
- Journal
- Immunity
- Published
- 2024-11-27
- DOI
- https://doi.org/10.1016/j.immuni.2024.11.004
- Citations
- 44
- Primary Topic
- Immunotherapy and Immune Responses
- Type
- article
- Field-Weighted Citation Impact
- 10.58
Funders
- Medical Research Council