Background/Purpose: Ongoing production of type I interferons (IFN) is a key element in the pathogenesis of systemic lupus erythematosus (SLE). Type I IFNs trigger the over-expression of IFN-regulated genes, including galectin-3-binding protein (G3BP). G3BP serves as a scavenger receptor and is a potent immune stimulator. It mediates cellular adhesion and binding to the extracellular matrix of the basement membrane. Thus G3BP may serve as a measure of type I IFNs and has potentially important pathogenic roles in cell-cell interaction and immune complex trafficking in SLE. We here explore the relationship between type I IFN activity and plasma G3BP, compare plasma concentrations of G3BP in two cohorts of SLE patients to patients with systemic sclerosis (SSc) and healthy controls (HCs), and correlate G3BP concentrations with clinical and serological parameters.

 

Methods: Plasma and serum concentrations of G3BP were quantified using a commercially available ELISA. Type I IFN activity was assessed by an Mx1-driven luciferase reporter gene assay. Gene expression scores from 12 genes in peripheral blood mononuclear cells from 26 SLE patients and 10 HCs were compared to plasma concentrations of G3BP. Plasma and serum concentrations were compared in 4 SLE and 4 SSc patient samples. G3BP concentrations in 70 SLE patients were compared to HCs (n =51) and patients with systemic sclerosis (SSc, n =111). Additionally, G3BP levels were validated in an independent cohort of SLE patients (n =67) and HCs (n =50). Non-parametric correlation analyses were used to explore associations between G3BP concentrations and clinical and serological parameters in the two SLE cohorts. In 14 SLE patients consecutive serum samples (3 or 4 per patient, >6 months apart) were analysed and correlated to disease activity (SLEDAI).

 

Results: G3BP plasma concentrations correlated significantly with the Mx-1 driven luciferase reporter gene assay (r =0.56, p =0.0005) and INF-α gene expression scores (r =0.54, p =0.0002). No significant difference between serum and plasma levels of G3BP was observed (p =0.17). Plasma concentrations were similar in the two SLE cohorts (p =0.42) and highly significantly increased compared to HCs and SSc patients (p <0.0001 and 0.0009, both those with diffuse and limited cutaneous disease). Significant associations (p<0.05) with SLEDAI, cell counts, anti-dsDNA, and active nephritis could not be confirmed in the validation cohort. Temporal variations in serum concentrations were observed in the consecutive SLE-samples but were not associated with disease activity (SLEDAI).

 

Conclusion: The level of circulating G3BP is elevated in SLE patients compared with HCs and SSc patients. The SLE-specific elevated levels of G3BP correlated with type I IFN activity. G3BP could thus serve as an easy accessible measure of type I IFN gene activation. Additionally, this study highlights G3BP as an IFN-inducible effector molecule that may have a central role in SLE pathogenesis and thus putatively is a possible new target for therapeutic intervention.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/plasma-level-of-galectin-3-binding-protein-reflects-type-i-interferon-activity-and-is-highly-increased-in-patients-with-systemic-lupus-erythematosus/