Recarte-Pelz Pedro, Tàssies Dolors, Espinosa Gerard, Hurtado Begoña, Sala Núria, Cervera Ricard, Reverter Joan Carles, de Frutos Pablo García
Arthritis Res Ther. 2013 Mar 12;15(2):R41. doi: 10.1186/ar4199.
Growth arrest-specific gene 6 protein (GAS6) and protein S (ProS) are vitamin K-dependent proteins present in plasma with important regulatory functions in systems of response and repair to damage. They interact with receptor tyrosine kinases of the Tyro3, Axl and MerTK receptor tyrosine kinase (TAM) family, involved in apoptotic cell clearance (efferocytosis) and regulation of the innate immunity. TAM-deficient mice show spontaneous lupus-like symptoms. Here we tested the genetic profile and plasma levels of components of the system in patients with systemic lupus erythematosus (SLE), and compare them with a control healthy population.
Fifty SLE patients and 50 healthy controls with matched age, gender and from the same geographic area were compared. Genetic analysis was performed in GAS6 and the TAM receptor genes on SNPs previously identified. The concentrations of GAS6, total and free ProS, and the soluble forms of the three TAM receptors (sAxl, sMerTK and sTyro3) were measured in plasma from these samples.
Plasma concentrations of GAS6 were higher and, total and free ProS were lower in the SLE patients compared to controls, even when patients on oral anticoagulant treatment were discarded. Those parameters correlated with SLE disease activity index (SLEDAI) score, GAS6 being higher in the most severe cases, while free and total ProS were lower. All 3 soluble receptors increased its concentration in plasma of lupus patients.
The present study highlights that the GAS6/ProS-TAM system correlates in several ways with disease activity in SLE. We show here that this correlation is affected by common polymorphisms in the genes of the system. These findings underscore the importance of mechanism of regulatory control of innate immunity in the pathology of SLE.
生长停滞特异性基因6蛋白（GAS6）和蛋白S（ProS）是血浆中维生素K依赖蛋白，在损伤应答和修复系统中具有重要调节功能。它们与Tyro3、Axl和MerTK受体酪氨酸激酶（TAM）家族的受体酪氨酸激酶相互作用，参与凋亡细胞清除（胞葬作用）和固有免疫调节。TAM缺陷小鼠表现出自发性狼疮样症状。在此，我们检测了系统性红斑狼疮（SLE）患者该系统各组分的基因谱和血浆水平，并将其与健康对照人群进行比较。
比较50例SLE患者和50例年龄、性别匹配且来自同一地理区域的健康对照者。对先前鉴定的单核苷酸多态性（SNP）在GAS6和TAM受体基因上进行遗传分析。测定这些样本血浆中GAS6、总ProS和游离ProS以及三种TAM受体（sAxl、sMerTK和sTyro3）的可溶性形式的浓度。
与对照组相比，SLE患者血浆中GAS6浓度较高，总ProS和游离ProS浓度较低，即使排除接受口服抗凝治疗的患者也是如此。这些参数与SLE疾病活动指数（SLEDAI）评分相关，在最严重的病例中GAS6较高，而游离ProS和总ProS较低。狼疮患者血浆中所有3种可溶性受体的浓度均升高。
本研究强调GAS6/ProS - TAM系统在多个方面与SLE疾病活动相关。我们在此表明，这种相关性受该系统基因常见多态性的影响。这些发现强调了固有免疫调节机制在SLE病理中的重要性。
