Abstract
IntroductionThe TAM (tyro 3, axl, mer) kinases are key regulators of innate immunity and are important in the phagocytosis of apoptotic cells. Gas6 and protein S are ligands for these TAM kinases and bind to phosphatidyl serine residues exposed during apoptosis. In animal models, absence of TAM kinases is associated with lupus-like disease. To test whether human systemic lupus erythematosus (SLE) patients might have deficient levels of TAM ligands, we measured Gas 6 and protein S levels in SLE.Methods107 SLE patients were recruited. Of these, 45 SLE patients were matched age, gender and ethnicity with normal controls (NC). Gas6 and free protein S were measured with sandwich enzyme linked immunosorbent assays (ELISAs).ResultsOverall, the plasma concentrations of Gas6 and free protein S were not different between 45 SLE patients and 45 NC. In SLE patients, the levels of free protein S were positively correlated with age (r = 0.2405, P = 0.0126), however those of Gas6 were not. There was no correlation between the concentrations of Gas6 and free protein S in individuals. Levels of free protein S were significantly lower in SLE patients with a history of serositis, neurologic disorder, hematologic disorder and immunologic disorder. Gas6 levels were elevated in patients with a history of neurologic disorder. The SLE patients with anti-Sm or anti-cardiolipin IgG showed lower free protein S levels. Circulating free protein S was positively correlated with complement component 3 (C3) (r = 0.3858, P < 0.0001) and complement component 4 (C4) (r = 0.4275, P < 0.0001). In the patients with active BILAG hematologic involvement, the levels of free protein S were lower and those of Gas6 were higher.ConclusionsIn SLE, free protein S was decreased in patients with certain types of clinical history and disease activity. Levels of free protein S were strongly correlated with C3 and C4 levels. Gas6 levels in SLE patients differed little from levels in NC, but they were elevated in the small numbers of patients with a history of neurological disease. The correlation of decreased protein S levels with lupus disease activity is consistent with a role for the TAM receptors in scavenging apoptotic cells and controlling inflammation. Protein S appears more important functionally in SLE patients than Gas6 in this regard.
Highlights
The TAM kinases are key regulators of innate immunity and are important in the phagocytosis of apoptotic cells
growth arrest-specific 6 (Gas6) levels in systemic lupus erythematosus (SLE) patients differed little from levels in normal controls (NC), but they were elevated in the small numbers of patients with a history of neurological disease
In examining the levels of free protein S in all 107 SLE patients, free protein S was positively correlated with age (r = 0.2405, P = 0.0126), but Gas6 levels did not increase with age (Figure 2)
Summary
The TAM (tyro 3, axl, mer) kinases are key regulators of innate immunity and are important in the phagocytosis of apoptotic cells. Gas and protein S are ligands for these TAM kinases and bind to phosphatidyl serine residues exposed during apoptosis. To test whether human systemic lupus erythematosus (SLE) patients might have deficient levels of TAM ligands, we measured Gas 6 and protein S levels in SLE. Systemic lupus erythematosus (SLE) is a chronic autoimmune disease with diverse presentations. Apoptotic cells are engulfed by macrophages in the early phase of cell death without inducing inflammation or the immune response. In SLE, the clearance of apoptotic cells by macrophages is impaired, which may allow apoptotic cells to serve as immunogens for the induction of autoreactive T and B cells and drive the production of autoantibodies [4]
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