Type I interferon as a novel risk factor for endothelial progenitor cell depletion and endothelial dysfunction in systemic lupus erythematosus

Abstract

Objective. The premature atherosclerosis seen in patients with systemic lupus erythematosus (SLE) is not explained by traditional risk factors. SLE disease activity, such as renal involvement and presence of autoantibodies, is associated with elevated serum levels of type I interferon (IFN-I), a family of cytokines with potent antiviral and antiproliferative effects. This study was undertaken to test the hypothesis that elevated IFN-I levels could lead to endothelial dysfunction, a surrogate for cardiovascular disease, by causing a reduction in the number of endothelial progenitor cells (EPCs), bone marrow-derived cells that participate in endothelial repair.Methods. EPCs were enumerated in the peripheral blood of SLE patients (n ‫؍‬ 70) and healthy controls (n ‫؍‬ 31), using a colony-forming assay. Serum IFN-I levels were quantified by real-time polymerase chain reaction measurement of the expression of the IFN-I-inducible gene MX1. Endothelial function was determined by peripheral arterial plethysmography.Results. SLE patients had markedly reduced levels of EPC colony-forming units compared with controls (median 5.7/ml peripheral blood [interquartile range 1.9-12.8] versus 28.5/ml peripheral blood [14.7-47.3]; P < 0.0001), and the depletion of EPCs was more dramatic in patients with elevated levels of IFN-I.Stepwise multiple regression analysis showed that MX1 expression and serum levels of C-reactive protein were independently associated with the reduction of EPCs. Importantly, high IFN-I levels were associated with impaired endothelial function in patients with SLE. Conclusion. These data support the novel hypothesis that depletion of EPCs caused by excessive IFN-I may be linked to endothelial dysfunction and increased cardiovascular risk in SLE.It has been firmly established that patients with systemic lupus erythematosus (SLE) are at increased risk of cardiovascular mortality and morbidity (1,2). However, the premature atherosclerosis and endothelial dysfunction in SLE are not solely attributable to traditional cardiovascular risk factors (3,4). Indeed, the risk of developing coronary heart disease remains increased 8-10-fold even after adjustment for risk factors identified in the Framingham Heart Study (3). SLE itself has been determined to be an independent risk factor for endothelial dysfunction, and as many as 40% of patients with lupus exhibit subclinical atherosclerosis (5,6). The cause of the additional risk remains unclear, and factors related to the disease process itself have been implicated.A number of recent studies indicate that type I interferons (IFN-I) are integral to the pathogenesis of SLE (7). Originally characterized with regard to their antiviral properties, the type I IFNs IFN␣ and IFN␤ play important roles in a multitude of immune functions. They exert potent antiproliferative and antiangiogenic effects and are commonly used in cancer treatment (8,9). Antinuclear antibodies, anti-double-stranded

Microparticles (CD146) and Arterial Stiffness Versus Carotid Intima Media Thickness as an Early Predictors of Vascular Affection in Systemic Lupus Patients

“…Our results showed a statistically significant difference in CD146 level between SLE patients and controls with a mean of 4.2±1.1, 2.2±0.7, respectively, and this in agreement with results of Robak et al 14 In contrast to our data, two other reports showed significant deficiency of circulating endothelial cell count in their SLE patients. 15,16 An explanation for these discrepancies may be the fact that our study included Egyptians only, whereas their studies involved Africans, Americans, whites, and others. Our results showed no statistically significant correlation between CD146 and patients age or the disease duration, and this was consistent with findings of Elshal et al 17 and Abdelaziz et al, 18 who demonstrated that CD146 level was independent of the age of SLE patients and/or the duration of the disease.…”

Endothelial progenitor cells: Are they displaying a function in autoimmune disorders?

“…Although modulation of EPC numbers has been identified in the course of cardiovascular disease or vascular trauma (which appears to be predictive of clinical coronary events in the general population), there is still much controversy regarding their true identity and role. In SLE, while most of the studies demonstrated low percentages of circulating EPC (Lee et al, 2007;Moonen et al, 2007;Westerweel et al, 2007;Robak et al, 2009), results are inconsistent, most likely due to different protocols adopted for identifying EPC (Hooks et al, 1979). Nevertheless, whether the number of circulating EPC can predict cardiovascular events in patients with SLE remains to be answered by prospective studies.…”

Modulation of Autoimmunity and Atherosclerosis – Common Targets and Promising Translational Approaches Against Disease –

“…78 SLE patients with high type I IFN activity in the serum display substantial endothelial dysfunction, which has been proposed as a mechanism of the increased risk for CVD in SLE patients. 79 Type I IFN signaling is upregulated in ruptured human atherosclerotic plaques, and accelerates disease in hypercholesterolemic mice, suggesting a deleterious function of this cytokine in atherosclerotic CVD. 80 Anti-IFNα therapy is under investigation in the "low" type I IFN subgroup of SLE patients, in whom it has been associated with clinical improvements.…”