Distinct tissue-niche localization and function of synovial tissue myeloid DC subsets in health, and in active and remission Rheumatoid Arthritis

MacDonald, L.; Elmesmari, A.; Somma, D.; Frew, J.; Di Mario, C.; Madhu, R.; Paoletti, A.; Simakou, T.; Hardy, O. M.; Tolusso, B.; Campobasso, D.; Perniola, S.; Gessi, M.; Gigante, M. R.; Petricca, L.; Bruno, D.; Coletto, L. A.; Benvenuto, R.; Isaacs, J. D.; Filby, A.; McDonald, D.; Sim, J. P. X.; Jamieson, N.; D'Agostino, M. A.; Wei, K.; Millar, N. L.; Milling, S.; McSharry, C.; Gremese, E.; Affleck, K.; Baker, K. F.; McInnes, I. B.; Otto, T. D.; Korsunsky, I.; Alivernini, S.; Kurowska-Stolarska, M.

doi:10.1101/2024.07.17.600758

Home/Archive/bioRxiv

bioRxiv · 10.1101/2024.07.17.600758

Distinct tissue-niche localization and function of synovial tissue myeloid DC subsets in health, and in active and remission Rheumatoid Arthritis

View original source ↗Export metadata ↓

Abstract

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 AXLpos 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 CCL5pos TEM and CCL5posCXCL13pos TPH, promoting synovitis. In the sublining lymphoid niche, CCR7pos DC2 mReg specifically interact with naive-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 AXLpos 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 AXLpos DC2, may restore immune homeostasis in RA. In briefDeconstruction 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. HighlightsO_LIHuman RA synovium exhibits condition and niche specific myeloid DC clusters that vary in their tissue differentiation trajectories and functions. C_LIO_LIST-CD14pos DC3 (iDC3) support inflammatory CCL5pos TEM and CCL5pos TPH cell activation in the hyperplastic lining layer. C_LIO_LIST-CCR7pos DC2 (mReg), driven by MIR155, interact with naive-T-cells in sublining lymphoid niches. C_LIO_LIA specific inflammatory signature of blood predecessors of ST-DC3s predict flare in RA. C_LI Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=199 HEIGHT=200 SRC="FIGDIR/small/600758v1_ufig1.gif" ALT="Figure 1"> View larger version (74K): org.highwire.dtl.DTLVardef@27ab01org.highwire.dtl.DTLVardef@4be238org.highwire.dtl.DTLVardef@1f10734org.highwire.dtl.DTLVardef@1102056_HPS_FORMAT_FIGEXP M_FIG C_FIG

Explore related subjects

immunology Preprint

Keep this discovery

Explore connections, maps & timelines

BibTeX RIS

MacDonald, L., Elmesmari, A., Somma, D., Frew, J., Di Mario, C., Madhu, R., Paoletti, A., Simakou, T., Hardy, O. M., Tolusso, B., Campobasso, D., Perniola, S., Gessi, M., Gigante, M. R., Petricca, L., Bruno, D., Coletto, L. A., Benvenuto, R., Isaacs, J. D., Filby, A., McDonald, D., Sim, J. P. X., Jamieson, N., D'Agostino, M. A., Wei, K., Millar, N. L., Milling, S., McSharry, C., Gremese, E., Affleck, K., Baker, K. F., McInnes, I. B., Otto, T. D., Korsunsky, I., Alivernini, S., Kurowska-Stolarska, M.. 2024-07-19. Distinct tissue-niche localization and function of synovial tissue myeloid DC subsets in health, and in active and remission Rheumatoid Arthritis. https://doi.org/10.1101/2024.07.17.600758

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

Exploratory positional differences in observed CDRH2 lineage-state transitions following HIV-1 germline-targeting vaccination

Background: Germline-targeting HIV-1 vaccination recruits VRC01-class B-cell precursors, but the positional patterns of observed longitudinal B-cell receptor lineage-state changes remain incompletely described. We compared CDRH2 profiles between homologous and heterologous boosting regimens using published IAVI G002 data. Methods: Participant-specific Week-8 lineages were prospectively matched to Week-24 observations. Germline-to-nongermline changes in sampled lineage-modal residues were evaluated at seven IGHV1-2*02 CDRH2 positions using participant-balanced, mean-centered profiles and exact participant-label permutation inference. Sampling-depth and sorting-probe sensitivity analyses assessed observability. A separate participant-held-out benchmark evaluated antibody-language-model representations for predicting observed Week-24 lineage detection. Results: The CDRH2 analysis included 332 lineages, 15 participants, 2,179 eligible lineage-position observations, and 241 observed state changes. The regional profile statistic was 0.027066 (exact p = 0.001709; six-region adjusted q = 0.010256), with descriptive differences at V-relative positions 51, 54, and 55. Most eligible longitudinal observations had one assessable cell per visit. In seven Group-1 participants, Week-24 dual-probe sampling recovered 181 baseline lineages with eOD-GT8 and 143 with Cg28v2, including 60 detected by both probes. In a separate cohort of 2,739 lineages from 17 participants, IgBERT and AbLang-2 representations did not improve participant-balanced average precision over a four-feature biological baseline. Conclusions: Observed CDRH2 lineage-modal-state profiles differed between regimens in this exploratory secondary analysis. Sparse sampling, potentially probe-related ascertainment, and absent linked functional validation preclude inference about mutation timing, functional improvement, or causal booster effects.

immunology↗

bioRxiv2026

Multivalent mRNA tuberculosis vaccines protect against mycobacterial infection in zebrafish, mice and guinea pigs

Despite a century of BCG use, tuberculosis remains a leading cause of death from infectious diseases and more effective vaccines are urgently needed. Here we combined antigen discovery in zebrafish with mRNA vaccine technology to generate multivalent vaccine candidates, TUmRNA4, TUmRNA6 and TUmRNA9, encoding four, six, or nine Mycobacterium tuberculosis antigens, respectively. The vaccines were well tolerated, and induced robust antigen-specific cellular immune responses, including IFN{gamma} production and expansion of memory T-cell populations. In mice, TUmRNA4 and TUmRNA6 reduced pulmonary M. tuberculosis burden and lung pathology to levels comparable to BCG vaccination and TUmRNA6 enhanced BCG-mediated protection when used as a booster vaccine. In guinea pigs, TUmRNA9 reduced bacterial burden in the lungs, spleen, and lymph nodes and decreased pulmonary lesions. These findings demonstrate that protective antigens identified in zebrafish can be translated into effective multivalent mRNA vaccines and establish a framework for tuberculosis vaccine development across multiple preclinical models.

immunology↗

bioRxiv2026

AlphaScreen profiling of extracellular vesicle-associated platelet, immune, and vascular markers reveals disease-specific signatures in ME/CFS, fibromyalgia, and long COVID

Introduction: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), fibromyalgia (FM), and long COVID (LC-19) are chronic diseases with overlapping clinical features and poorly understood pathophysiology. Increasing evidence suggests the involvement of immune dysregulation, endothelial dysfunction, and altered vascular physiology. Extracellular vesicles (EVs) are key mediators of intercellular communication and are envisioned as sensors of homeostasis and disease. The aim of this study was to determine whether EV marker profiling could provide a basis for the differential diagnosis of ME/CFS, FM and LC-19 and/or patient stratification. Methods: EV-enriched plasma from ME/CFS, FM, cases co-diagnosed with ME/CFS and FM, LC-19 patients, and matched healthy controls (n = 10 per study group) were analyzed. EV concentration and size distribution were assessed by nanoparticle tracking analysis, followed by targeted profiling of EV-associated surface markers via AlphaScreen, including tetraspanins CD9 and CD63, platelet- (CD41/CD61), myeloid- (CD13), immune- (CD74 and CX3CR1), and renin-angiotensin system- associated ACE1 (also known as CD143), and ACE2 surface markers. Results: The studied disease groups presented distinct EV signatures. LC-19 samples exhibited the most pronounced and coordinated alterations, characterized by increased levels of CD9/CD74, CD9/CX3CR1, and CD9/ACE1-positive EVs, along with reduced overall particle concentrations. Notably, platelet-derived CD9/CD41/CD61-positive EVs were significantly elevated in both LC-19 and ME/CFS, as compared to healthy controls, indicating enhanced platelet activation. Immune-associated markers revealed differential pathway activation in LC-19, with CD74-positive EVs reflecting antigen presentation and inflammatory signaling, and CX3CR1-positive EVs indicating altered leukocyte trafficking and vascular interaction. Increased ACE1-positive EVs in LC-19 further suggested a shift toward pro-inflammatory renin-angiotensin signaling. Conclusion: Collectively, these findings support a disease-specific dysregulation of platelet, immune, and vascular pathways. The integrated EV signatures distinguish LC-19 from the related chronic conditions ME/CFS and FM, highlighting the potential of EV-based profiling for differential diagnosis. Our results provide a systems-level perspective on the differential pathophysiology of these disorders and identify EV-associated markers as candidate biomarkers with clinical value.

immunology↗