Distinct tissue-niche localization and function of synovial tissue myeloid DC subsets in health, and in active and remission Rheumatoid Arthritis
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Current rheumatoid arthritis (RA) treatments do not restore immune tolerance. Investigating dendritic cell (DC) populations in human synovial tissue (ST) may reveal pathways to re-instate tolerance in RA. With single-cell and spatial-transcriptomics of synovial tissue biopsies, validated by micro co-culture systems, we identified condition and niche-specific myeloid DC clusters with distinct differentiation trajectories and functions. Healthy synovium contains a unique tolerogenic AXL pos DC2 cluster in the superficial sublining layer. In active RA, a macrophage-rich lining-layer niche becomes populated with inflammatory DC3 clusters that specifically activate memory CCL5 pos TEM and CCL5 pos CXCL13 pos TPH, promoting synovitis. In the sublining lymphoid niche, CCR7 pos DC2 mReg specifically interact with naïve-T-cells, potentially driving the local expansion of new effector T-cells. Sustained remission sees the resolution of these niches but lacks the recovery of tolerogenic AXL pos DC2, indicating latent potential for disease flare. A human RA disease-flare model showed that the activation of blood predecessor of ST-DC3 clusters precedes the onset of inflammation in joints. Therapeutic strategies targeting pathogenic ST-DC3 clusters, or reinstating tolerogenic AXL pos DC2, may restore immune homeostasis in RA.
In brief
Deconstruction of human RA synovium, using single-cell spatial transcriptomics and micro-culture systems, reveals distinct neighbourhoods within the synovial architecture across health, and RA patients with active disease or sustained remission. Discrete niches are identified that contain distinct myeloid DC clusters that differ in frequency, differentiation trajectories, and effector functions.
Highlights
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Human RA synovium exhibits condition and niche specific myeloid DC clusters that vary in their tissue differentiation trajectories and functions.
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ST-CD14 pos DC3 (iDC3) support inflammatory CCL5 pos TEM and CCL5 pos TPH cell activation in the hyperplastic lining layer.
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ST-CCR7 pos DC2 (mReg), driven by MIR155, interact with naïve-T-cells in sublining lymphoid niches.
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A specific inflammatory signature of blood predecessors of ST-DC3s predict flare in RA.