Article Text

OP0256 ADAM17 And Galectin-9 are Critical Regulators of Local 4-1BB Activity and Disease Outcome in Rheumatoid Arthritis
  1. M.A. Nielsen1,
  2. T. Andersen1,
  3. A. Etzerodt1,
  4. T. Kragstrup1,
  5. T. Rasmussen1,
  6. K. Stengaard-Pedersen1,
  7. M. Hetland2,
  8. K. Hørslev-Petersen3,
  9. M. Østergaard4,
  10. M. Hvid1,
  11. S. Moestrup3,
  12. B. Deleuran1
  1. 1Aarhus University (AU), Aarhus
  2. 2Rigshospitalet, Copenhagen
  3. 3University of Southern Denmark, Odense
  4. 4Glostrup Hospital, Glostrup, Denmark


Background In rheumatoid arthritis (RA) 4-1BB (TNFSFR9) is believed to be involved in the continued T cell activation within the inflamed joint. 4-1BB binds to 4-1BB ligand (4-1BBL) generating local clonal expansion and accumulation of antigen-specific effector-type T cells.

Galectin-9 (Gal-9) is upregulated at site of inflammation and has recently been suggested to be a restricting factor for the inflammatory signal of 4-1BB.

ADAM17 (TACE) has previously been linked to RA and inflammation. It is a sheddase with a broad substrate specificity although it is best know for its involvement in TNFα release by being the main sheddase of proTNFα.

Objectives To determine the role of the interplay between 4-1BB, ADAM17 and Gal-9 in RA.

Methods 4-1BB and Gal-9 expression was studied in paired peripheral blood mononuclear cells (PBMC) and synovial fluid mononuclear cells (SFMCs) by flow cytometry in chronic RA (cRA), and in PBMCs from healthy volunteers (HV). 4-1BBL, Gal-9, and TNFα were used to stimulate SFMCs. Surface plasmon resonance analysis was performed with human recombinant proteins 4-1BB, 4-1BBL, and Gal-9. Transfected HEK293 cells expressing 4-1BB were established to investigate potential sheddases of 4-1BB.

Soluble 4-1BB was measured by ELISA in plasma from treatment naïve early RA (eRA) patients obtained at treatment initiation (the OPERA regimen, n=96)1.

Results In chronic RA (cRA), the percentage of T cells expressing 4-1BB was significantly higher in SFMCs compared with PBMCs and in cRA PBMCs compared with HV PBMCs (both p<0.01). After TNFα stimulation of SFMCs the percentage of 4-1BB-positive T cells doubled (p<0.05). Stimulation of RA SFMC cultures with 4-1BBL only increased the TNFα production when combined with Gal-9, confirming that Gal-9 is pivotal for the function of 4-1BB in RA (p<0.05). When HEK293 cells expressing 4-1BB were incubated with PMA, the level of s4-1BB doublet (p<0.05). The role of ADAM17 in this process, was confirmed by RNAi mediated ADAM17 knockdown, which decreased the shedding of 4-1BB to the level of control and mock-transfected cells (p<0.05). The plasma concentration of s4-1BB was significantly elevated in eRA patients at baseline compared with HV (P<0.01). Baseline s4-1BB associated with baseline SJ40 and DAS28CRP at 24 months (both p<0.05)). Furthermore, the ability to sustain high s4-1BB plasma levels correlated with progression in TSS after 12 month (ρ =0.25, p=0.02).

Conclusions ADAM17 induces 4-1BB shedding in RA and is connected to TNFα metabolism. Gal-9 is pivotal for the local function of 4-1BB in RA. Furthermore, high plasma levels of s4-1BB are associated with number of swollen joints, but also with a good prognosis measured by DAS28CRP and TSS. 4-1BB metabolism thereby plays a central role in the delicate network of pro- and anti-inflammatory factors in RA.


  1. Hørslev-Petersen et al. Ann rheum Dis. 2013

Disclosure of Interest None declared

Statistics from

Request permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.