OP0256 ADAM17 And Galectin-9 are Critical Regulators of Local 4-1BB Activity and Disease Outcome in Rheumatoid Arthritis

BackgroundIn 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.ObjectivesTo determine the role of the interplay between 4-1BB, ADAM17 and Gal-9 in RA.Methods4-1BB 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.ResultsIn 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