Session Title: Rheumatoid Arthritis – Etiology and Pathogenesis Poster III
Session Type: ACR Poster Session C
Session Time: 9:00AM-11:00AM
Galectin-3 (Gal-3) and the co-stimulatory T cell receptor and glycoprotein 4-1BB are both considered important in inflammation and immune responses. This had led to the investigation of Gal-3 inhibitors in fibrotic diseases and agonistic anti-4-1BB antibodies in cancer treatment. We and others have previously shown that galectins are capable of binding to receptors of the TNF superfamily thereby modulating inflammatory signals1.
Purpose: To investigate the interplay between 4-1BB and Gal-3 in rheumatoid arthritis (RA).
Gal-3 was measured in plasma samples from newly diagnosed, active and treatment-naïve RA (eRA) patients at baseline and after 3 months of aggressive treatment (the OPERA trial, n=97)2 and plasma and synovial fluid samples from chronic RA (cRA) patients (n=17) by ELISA. The 28-joint disease activity score with CRP (DAS28CRP) and radiographic damage (i.e. total Sharp score (TSS)) were used to evaluate treatment outcomes over a 2-year period. Plasma samples from age and gender matched healthy controls (HC) (n=48) were also included.
Fluorescence polarization analyses were used to evaluate the binding between 4-1BB and Gal-3. Synovial fluid mononuclear cells (SFMCs) from patients with chronic RA (n=8) were cultured for 24 hours, co-incubated with either 4-1BB, 4-1BB ligand, Gal-3, or a combination hereof.
Plasma levels of Gal-3 were increased in eRA (mean: 8.1 ng/ml (CI: 7.6-8.6))compared to HC (mean: 6.4 ng/ml (5.9-6.9)) (p < 0.0001). Gal-3 correlated with DAS28CRP at baseline (ρ = 0.27) (p < 0.05). A decrease in Gal-3 levels from baseline to 3 months were significantly correlated with high disease activity after 2 years of treatment evaluated by DAS28CRP (ρ = 0.23)and radiographic damage evaluated by DTSS (0-24 months) (ρ =0.26) both (p < 0.05). After 3 months of intensive treatment, the plasma levels of Gal-3 were still elevated (mean: 8.3 ng/ml (7.8-8.7)) compared with HC (p < 0.0001). In cRA, Gal-3 levels in synovial fluid were tripled (mean: 30.9 ng/ml (18.3-43.5)) compared with levels found in plasma (mean: 9.1 ng/ml (7.8-10.4)) (p< 0.01). Gal-3 was capable of binding 4-1BB (Kd=1.43 mM (1-1.86 mM)). A mutant Gal-3 (Gal-3 R186S) with severely reduced affinity for endogenous glycans,did not bind to 4-1BB, thus excluding that the 4-1BB and Gal-3 binding is influenced by a protein-protein interaction. Shedding of 4-1BB was increased by addition of Gal-3 (p < 0.05). When SFMC cultures were stimulated with a combination of 4-1BBL and Gal-3, the level of MCP-1 decreased by 50% compared to MCP-1 production from untreated cultures and cultures stimulated with either 4-1BBL or Gal-3 separately (p < 0.05).
In early RA patients, persistent high plasma levels of Gal-3 during the first 3 months of treatment were associated with lower disease activity and less radiographic progression after 2 years of treatment. Explaining some of these associations, Gal-3 was found to be a new binding partner to 4-1BB, modulating both shedding and function of this receptor in RA. These observations support that Gal-3 is implicated in RA disease pathology at least partly by interacting with the 4-1BB receptor.
- Nielsen MA et al. Rheumatology. 2016
- Hørslev-Petersen K et al. Ann rheum Dis. 2013
To cite this abstract in AMA style:Nielsen MA, Kragstrup TW, Stengaard-Pedersen K, Hørslev-Petersen K, Hetland ML, Østergaard M, Junker P, Hvid M, Nilsson U, Stegmayr J, Leffler H, Deleuran B. Galectin-3 Is a Regulator of 4-1BB/CD137 Activity and Associates with Outcome in Rheumatoid Arthritis. [abstract]. Arthritis Rheumatol. 2018; 70 (suppl 10). https://acrabstracts.org/abstract/galectin-3-is-a-regulator-of-4-1bb-cd137-activity-and-associates-with-outcome-in-rheumatoid-arthritis/. Accessed April 17, 2021.
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