A disintegrin and metalloprotease 17 and galectin 9 are important regulators of local 4 1BB activity and disease outcome in rheumatoid arthritis.
OBJECTIVE Co stimulatory T cell cytokines are important in the progression of RA. This study investigates the interplay between 4 1BB, a disintegrin and metalloprotease 17 (ADAM17) and galectin 9 (Gal 9) in RA. METHODS Stimulated mononuclear cells from patients with chronic RA (n 12) were co incubated with tissue inhibitor of metalloproteinase, 4 1BB ligand and Gal 9. Plasma samples were examined for soluble 4 1BB (s4 1BB) in newly diagnosed, treatment naive patients with RA (n 97) The 28 joint DAS with CRP (28DAS CRP) total Sharp score, erosion score and joint space narrowing were used to evaluate treatment outcome serially over a 2 year period. RESULTS RA CD4( and CD8( synovial T cells express high levels of 4 1BB. The addition of TNF a to cultured synovial mononuclear cells increased shedding of 4 1BB. 4 1BB ligand only increased TNF a shedding in combination with Gal 9. RNA interference mediated knockdown of ADAM17 or the addition of an ADAM17 inhibitor reduced the 4 1BB shedding. Shedding of 4 1BB was not influenced by Gal 9. Plasma levels of s4 1BB were increased in early RA and correlated with the number of swollen joints at baseline. After 3 months of treatment, the plasma levels of s4 1BB were equal to those of the controls. Baseline plasma levels of s4 1BB were inversely correlated with DAS28 CRP after 2 years of treatment, but not with total Sharp score, erosion score or joint space narrowing. CONCLUSION ADAM17 induces 4 1BB shedding in RA. Gal 9 is pivotal for the function of 4 1BB and induction of TNF a. Furthermore, high plasma levels of s4 1BB were associated with the number of swollen joints, but also with a low DAS28 CRP after 2 years treatment in early RA.
Rheumatology