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A1.08 CD141+ CLEC9A+ dendritic cells are enriched in an active state in the inflamedsynovium and contribute to synovial inflammation in rheumatoid arthritis
  1. M Canavan1,
  2. M O’Rourke2,
  3. C Orr2,
  4. S Basdeo3,
  5. J Fletcher3,
  6. DJ Veale2,
  7. U Fearon1
  1. 1Department of Molecular Rheumatology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Ireland
  2. 2Centre for Arthritis and Rheumatic Diseases, Dublin Academic Medical Centre, University College Dublin, Ireland
  3. 3School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Ireland

Abstract

Introduction Dendritic cells (DC) are a heterogeneous population of professional antigen presenting cells. Currently their classification within blood and skin has been well characterised however their identification within other tissues, in particular in the context of autoimmunity is limited. This work aims to identify DC within the inflamed synovium and elucidate how DC are altered by the microenvironment within the joint.

Methods DC immunophenotyping was assessed in whole blood (WB), synovial fluid (SF) and synovial tissue (ST) using 9 colour flow cytometry. CD141+ DC were isolated from SF, cultured overnight +/- TLR3 ligands and stained with a panel of antibodies. Monocyte derived DC were cultured in the presence of explant conditioned media (ECM) or SF. MoDC treated with SF were also cocultured with CD4+ T cells for 5 days, after which T cell proliferation and intracellular cytokines were examined.

Results RA patients have a significant decrease (p < 0.05) in mDC in WB compared to HC. CD11c+ HLADR+ myeloid cells are increased in the ST compared to WB, express higher levels of CD80/CD40 and express CD64, CD14 and CD16. These cells may represent a myeloid subset of cells unique to inflammatory tissues. DC in SF are more mature than PB DC (increased CD80/CD40; p < 0.05). SF is enriched in CD141+CLEC9A+DC compared to PB (p < 0.005). These cells are rare in WB and previously unidentified in SF. SF CD141+ DC express TREM1 while blood CD141+ DC do not. SF CD141+ DC express higher levels of CD80/CD86 and CD40 compared to blood CD141+ DC. To examine the effect of the synovial microenvironment on DC, MoDC were cultured in the presence of ECM or SF. Both induced a significant increase in the expression of CD80 (p < 0.05 and p < 0.0001). Finally DC treated with SF and subsequently cocultured with CD4+ T cells have enhanced IFNγ production and T cell proliferation.

Conclusion Unique DC subsets are found in both ST and SF within the joint. These cells display a more activated phenotype than DC in circulation and  the inflammatory nature of the joint contributes to this activation. These uniquely activated DC induce T cell proliferation and cytokine production.

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