Abstract
Objective: T cell immunoglobulin and mucin-domain-containing molecule 3 (TIM-3) is implicated in the development of various autoimmune diseases. We aimed to investigate the levels of soluble TIM-3 (sTIM-3) and their associations between clinical parameters in patients with systemic lupus erythematosus (SLE). Methods: Serum samples were collected from 65 patients with SLE and 35 age-matched healthy controls (HCs). The SLE Disease Activity Index 2000 (SLEDAI-2K) and the Systemic Lupus International Collaborating Clinics (SLICC) damage index (SDI) were used to assess SLE disease activity and SLE-related organ damage. British Isles Lupus Assessment Group (BILAG)-2004 index was also used to assess SLE disease activity. Soluble TIM-3 (sTIM-3) in sera from patients with SLE and HCs were evaluated by enzyme-linked immunosorbent assay (ELISA). The results were compared with the clinical parameters of SLE including SLE disease activity. Results: Serum sTIM-3 levels in patients with SLE (median 2123 pg/mL (interquartile range (IQR), 229–7235)) were significantly higher than those in HCs (1363 pg/mL; IQR, 1097–1673; p = 0.0015). Serum levels of sTIM-3 were correlated with disease activity of SLE using the SLEDAI-2K score (p < 0.001, r = 0.53). The serum sTIM-3 levels in SLE patients with active renal disease (BILAG renal index A-B) were significantly higher than those without the active renal disease (BILAG renal index C–E). However, no significant difference was observed in serum sTIM-3 levels between SLE patients with and without active involvement in other organs (BILAG index). Serum sTIM-3 levels were significantly elevated in SLE patients with organ damage (2710 pg/mL; IQR, 256–7235) compared to those without organ damage (1532 pg/mL; IQR, 228–5274), as assessed by the SDI (p = 0.0102). Conclusions: Circulating sTIM-3 levels are elevated in SLE patients, and serum sTIM-3 levels are associated with SLE disease activity and SLE-related organ damage. The data indicate a possible link between the TIM-3/Gal-9 pathway and SLE clinical phenotypes, and further investigation of the TIM-3 pathway in SLE pathophysiology is warranted.
Highlights
Immune checkpoint receptors of co-inhibitory or co-stimulatory molecules are major components of the immune system [1]
In Systemic lupus erythematosus (SLE) patients, the T cell immunoglobulin and mucin-domain-containing molecule 3 (TIM-3) ligand, galectin 9 (Gal-9), is upregulated and correlates with interferon-signature gene expression [11]. These findings indicate that the TIM-3/Gal-9 pathway plays an important role in Th1 and Th17 immune response and blockage of the TIM-3/Gal-9 interaction results in exacerbated autoimmune diseases [12]
TIM-3 can be shed from the cell surface by a-disintegrin-like and metalloproteinase with thrombospondin type 1 motifs (ADAM) 10 or ADAM17-mediated cleavage within the TIM-3 stalk region, resulting in a soluble form of TIM-3 [14], which is elevated in the sera of patients with autoimmune diseases [15]
Summary
Immune checkpoint receptors of co-inhibitory or co-stimulatory molecules are major components of the immune system [1]. As a negative checkpoint receptor, T cell immunoglobulin and mucin-domain-containing molecule 3 (TIM-3) and its ligand galectin 9 (Gal-9) are thought to be involved with the pathogenesis of autoimmune diseases [2]. In SLE patients, the TIM-3 ligand, Gal-9, is upregulated and correlates with interferon-signature gene expression [11]. These findings indicate that the TIM-3/Gal-9 pathway plays an important role in Th1 and Th17 immune response and blockage of the TIM-3/Gal-9 interaction results in exacerbated autoimmune diseases [12]. Expression of TIM-3 on peripheral blood mononuclear cells (PBMCs) isolated from SLE patients is associated with SLE disease activity [13]. We investigated the associations between circulating sTIM-3 and clinical parameters of SLE, including disease activity
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