We investigated the cytokine production induced by 2-Glycoprotein I in activated T cells that infiltratein vivoatherosclerotic lesions of lupus-antiphospholipid syndrome patients

We investigated the cytokine production induced by 2-Glycoprotein I in activated T cells that infiltratein vivoatherosclerotic lesions of lupus-antiphospholipid syndrome patients. and Fas/FasLigand-mediated-cytotoxicity. Altogether, our results indicate that 2-Glycoprotein I is able to elicit a local Interleukin-17/Interleukin-21 and Interferon- inflammation in lupus-antiphospholipid syndrome patients that might lead, if unabated, to plaque instability and subsequent arterial thrombosis, suggesting that this T helper 17/T helper 1 pathway may represent a novel target for the prevention and treatment of the disease. == Introduction == Systemic lupus erythematosus (SLE) is usually a systemic autoimmune disease that is frequently associated with antiphospholipid syndrome (APS) characterized by recurrent vascular thrombosis and pregnancy morbidities associated with the persistent presence of autoantibodies against phospholipid-binding proteins, namely antiphospholipid antibodies (aPL), such as 2-glycoprotein I (2GPI).1Besides its role in the acquired pro-coagulant diathesis, GZD824 aPL have been also associated with accelerated atherosclerosis to explain cardiovascular manifestations of the syndrome.24An accelerated atherosclerosis in SLE was first demonstrated in 1975 by Bulkleyet al.5in a necroscopic study, that was further confirmed by Urowitzet al. 6 Many studies showed that SLE is usually associated with coronary heart disease and atherosclerosis;79an important prospective study demonstrated that SLE patients have an accelerated progression of carotid plaque formations compared to non-lupus controls.10SLE patients have a reduced life expectancy mainly due to the increased prevalence of cardiovascular diseases. Incidence of major cardiovascular events is usually 2.5 times higher in SLE patients compared to the general population. Compared to healthy subjects, SLE women, aged 35-44 years, have a 50 times increased risk of myocardial infarction and accelerated atherosclerosis, that is a well recognized comorbidity in SLE.11,12 Atherosclerosis is a multifactorial disease for which a number of different pathogenic mechanisms have been proposed. In addition to classical risk factors, in the last two decades, attention has been focused on inflammatory processes.13,14Observations in humans and animals suggest that atherosclerotic plaques derive from specific cellular and molecular mechanisms that can be ascribed to an inflammatory disease of the arterial wall, the lesions of which consist of activated macrophages and T lymphocytes. If inflammation continues unabated, it results in an increased number of plaque-infiltrating macrophages and T cells, which contribute to the remodeling of the arterial GZD824 wall, eventually favoring plaque instability and rupture.15Within the T-cell population infiltrating the plaque, most cells are activated CD4+T helper (Th) 1 and Th17 cells expressing HLA-DR and the interleukin (IL)-2 receptor (CD25).16,17 Current evidence indicates that autoimmunity can be detected within the atherosclerotic lesions.18Accordingly, self-phospholipids, such as oxidized low-density lipoprotein (oxLDL) and human heat shock proteins, drive T-cell inflammation in atherosclerotic patients.19,20However, the multifactorial nature of atherosclerosis suggests that a larger number of autoantigens might be involved. It has been hypothesized that this development of an anti-2GPI-specific response in the target organ may con tribute to atherothrombosis in SLE-APS patients. This hypothesis is largely based on the 2GPI presence in human atherosclerotic plaques21,22and around the enhanced fatty streak formation in transgenic atherosclerosis-prone mice immunized with 2GPI.23,24Moreover, 2GPI-reactive T cells SRSF2 have also been found to promote early atherosclerosis in LDL receptor deficient mice.25 In this study, we demonstrate that, in SLE-APS patients, both IL-17 and IFN- are secreted by atherosclerotic plaques infiltrating Th cells in response to 2GPI, and suggest that 2GPI drives a local Th17/Th1 inflammatory response, which can be responsible for plaque instability and rupture, leading to atherothrombosis. == Methods == A detailed description of the methods is available in theOnline Supplementary Appendix. == Reagents == Human 2GPI was purified as described.26We ruled out the presence of contaminants by a limulus test. The human 2GPI used was with a limulus test and resulted negative throughout the whole study. GZD824 == Patients == Upon approval of the.