title: TAM receptor ligands in lupus: protein S but not Gas6 levels reflect disease activity in systemic lupus erythematosus.
abstract: BACKGROUND
  The 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.
  
  
  METHODS
  107 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).
  
  
  RESULTS
  Overall, 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.
  
  
  CONCLUSIONS
  In 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.
authors.affiliation: Department of Medicine, Temple University School of Medicine, Philadelphia, PA 19140, USA. chsuh@ajou.ac.kr
authors.forename: Chang-Hee
authors.initials: CH
authors.lastname: Suh
authors.forename: Brendan
authors.initials: B
authors.lastname: Hilliard
authors.forename: Sophia
authors.initials: S
authors.lastname: Li
authors.forename: Joan T
authors.initials: JT
authors.lastname: Merrill
authors.forename: Philip L
authors.initials: PL
authors.lastname: Cohen
mesh_terms: D000328:Adult; D017209:Apoptosis / Q000276:immunology; D015415:Biomarkers / Q000097:blood; D003176:Complement C3 / Q000378:metabolism; D003181:Complement C4 / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000097:blood*; D008024:Ligands; D008180:Lupus Erythematosus, Systemic / Q000276:immunology / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D017293:Protein S / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000276:immunology / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000276:immunology / Q000378:metabolism*; D012720:Severity of Illness Index; D055815:Young Adult; D000076202:c-Mer Tyrosine Kinase; D000094963:Axl Receptor Tyrosine Kinase; D000099255:Growth Arrest-Specific Protein 6
chemical_list: D015415:Biomarkers; D003176:Complement C3; D003181:Complement C4; D036341:Intercellular Signaling Peptides and Proteins; D008024:Ligands; D017293:Protein S; D011518:Proto-Oncogene Proteins; D020794:Receptor Protein-Tyrosine Kinases; D000076202:c-Mer Tyrosine Kinase; D000094963:Axl Receptor Tyrosine Kinase; D000099255:Growth Arrest-Specific Protein 6; C097072:MERTK protein, human; C084944:TYRO3 protein, human; C000722289:AXL protein, human