Willis R, Smikle M, DeCeulaer K, Romay-Penabad Z, Papalardo E, Jajoria P, Harper B, Murthy V, Petri M, Gonzalez E B
1 University of Texas Medical Branch, Galveston, TX, USA.
2 University of the West Indies, Mona Campus, Kingston, Jamaica.
Lupus. 2017 Dec;26(14):1517-1527. doi: 10.1177/0961203317706557. Epub 2017 May 3.
Background The abnormal biological activity of cytokines plays an important role in the pathophysiology of both systemic lupus erythematosus (SLE) and antiphospholipid syndrome (APS). Several studies have highlighted the association of vitamin D and certain pro-inflammatory cytokines with disease activity in SLE. However, there are limited data on the association of vitamin D and antiphospholipid antibodies (aPL) with various proinflammatory biomarkers in these patients and their relative impact on clinical outcomes. Methods The serum levels of several aPL, 25-hydroxy-vitamin D, pro-inflammatory cytokines including IFNα, IL-1β, IL-6, IL-8, IP10, sCD40L, TNFα and VEGF were measured in 312 SLE patients from the Jamaican ( n = 45) and Hopkins ( n = 267) lupus cohorts using commercial Milliplex and ELISA assays. Oxidized LDL/β2glycoprotein antigenic complexes (oxLβ2Ag) and their associated antibodies were also measured in the Jamaican cohort. Healthy controls for oxidative marker and cytokine testing were used. Results Abnormally low vitamin D levels were present in 61.4% and 73.3% of Hopkins and Jamaican SLE patients, respectively. Median concentrations of IP10, TNFα, sCD40L and VEGF were elevated in both cohorts, oxLβ2Ag and IL-6 were elevated in the Jamaican cohort, and IFNα, IL-1β and IL-8 were the same or lower in both cohorts compared to controls. IP10 and VEGF were independent predictors of disease activity, aPL, IP10 and IL-6 were independent predictors of thrombosis and IL-8, and low vitamin D were independent predictors of pregnancy morbidity despite there being no association of vitamin D with pro-inflammatory cytokines. Conclusions Our results indicate that aPL-mediated pro-inflammatory cytokine production is likely a major mechanism of thrombus development in SLE patients. We provide presumptive evidence of the role IL-8 and hypovitaminosis D play in obstetric pathology in SLE but further studies are required to characterize the subtle complexities of vitamin D's relationship with cytokine production and disease activity in these patients.
背景 细胞因子的异常生物学活性在系统性红斑狼疮（SLE）和抗磷脂综合征（APS）的病理生理学中起重要作用。多项研究强调了维生素D和某些促炎细胞因子与SLE疾病活动的关联。然而，关于维生素D和抗磷脂抗体（aPL）与这些患者各种促炎生物标志物的关联及其对临床结局的相对影响的数据有限。方法 使用商业多重检测和酶联免疫吸附测定法，对来自牙买加（n = 45）和霍普金斯（n = 267）狼疮队列的312例SLE患者的几种aPL、25-羟基维生素D、促炎细胞因子（包括IFNα、IL-1β、IL-6、IL-8、IP10、sCD40L、TNFα和VEGF）的血清水平进行了测量。在牙买加队列中还测量了氧化型低密度脂蛋白/β2糖蛋白抗原复合物（oxLβ2Ag）及其相关抗体。使用了健康对照进行氧化标志物和细胞因子检测。结果 霍普金斯和牙买加SLE患者中，维生素D水平异常低的分别占61.4%和73.3%。两个队列中IP10、TNFα、sCD40L和VEGF的中位数浓度均升高，牙买加队列中oxLβ2Ag和IL-6升高，与对照组相比，两个队列中IFNα、IL-1β和IL-8相同或更低。IP10和VEGF是疾病活动的独立预测因子，aPL、IP10和IL-6是血栓形成的独立预测因子，IL-8和低维生素D是妊娠并发症的独立预测因子，尽管维生素D与促炎细胞因子无关联。结论 我们的结果表明，aPL介导的促炎细胞因子产生可能是SLE患者血栓形成的主要机制。我们提供了IL-8和维生素D缺乏在SLE产科病理中作用的推测性证据，但需要进一步研究来阐明这些患者中维生素D与细胞因子产生及疾病活动关系的细微复杂性。
