Morten Aagaard Nielsen1, Thomas Andersen1, Anders Etzerodt1, Tue Wenzel Kragstrup1, Tue Kruse Rasmussen2, Kristian Stengaard-Pedersen3, Merete Lund Hetland4, Kim Hørslev-Petersen5, Peter Junker6, Mikkel Østergaard4, Malene Hvid7, Søren K Moestrup8, Bent Deleuran9. 1. Department of Biomedicine. 2. Department of Biomedicine, Department of Rheumatology. 3. Department of Rheumatology. Department of Clinical Medicine, Aarhus University, Aarhus. 4. Department of Rheumatology, Copenhagen University Hospital Glostrup, Glostrup, Denmark Center for Rheumatology and Spine Diseases, Glostrup Hospital. 5. Department of Rheumatology, King Christian 10th Hospital for the Rheumatic Diseases, Denmark Institute of Health Research, University of Southern Denmark, Gråsten, Denmark. 6. Department of Rheumatology, University of Southern Denmark. 7. Department of Biomedicine, Department of Clinical Medicine, Aarhus University, Aarhus. 8. Department of Clinical Biochemistry and Pharmacology, Odense University Hospital and Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark. 9. Department of Biomedicine, Department of Rheumatology. Department of Clinical Medicine, Aarhus University, Aarhus, bd@biomed.au.dk.
Abstract
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-naïve 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-α to cultured synovial mononuclear cells increased shedding of 4-1BB. 4-1BB ligand only increased TNF-α 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-α. 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.
RCT Entities:
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-naïve 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-α to cultured synovial mononuclear cells increased shedding of 4-1BB. 4-1BB ligand only increased TNF-α 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-α. 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.
Authors: Morten Aagaard Nielsen; Kristian Juul-Madsen; John Stegmayr; Chao Gao; Akul Y Mehta; Stinne Ravn Greisen; Tue Wenzel Kragstrup; Malene Hvid; Thomas Vorup-Jensen; Richard D Cummings; Hakon Leffler; Bent Winding Deleuran Journal: Front Immunol Date: 2022-06-24 Impact factor: 8.786