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Oxidative stress and vascular disease in patients with Systemic Lupus Erythematosus and prima Antiphospholipid Syndrome

Alves, José António Pereira Delgado; (2004) Oxidative stress and vascular disease in patients with Systemic Lupus Erythematosus and prima Antiphospholipid Syndrome. Doctoral thesis (Ph.D), UCL (University College London). Green open access

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Systemic Lupus Erythematosus (SLE) and the Antiphospholipid Syndrome (APS) are related autoimmune diseases, characterised by a broad spectrum of clinical features associated with autoantibodies directed towards nuclear and phospholipid / protein antigens, respectively. Accelerated atherosclerosis has been recognized as a major feature of both conditions, however the mechanisms by which it occurs are not clear. Oxidative stress is an important factor in atherosclerosis and the presence of an increased oxidative state has been recognized in SLE and APS. The overall aim of this thesis is to identify possible factors that contribute to this oxidative stress and to evaluate the mechanisms involved. Two different animal models were used to study the effects of anti-CL antibodies on nitric oxide (NO) synthesis. In a short term functional rat model (4 hours), a human anti-CL IgG monoclonal antibody (IS4) increased NO production through induction of iNOS, whilst in a long term mouse model (30 days), IS4 was associated with a pro-oxidant status with a decrease in paraoxonase activity (an anti-oxidant enzyme present in HDL) and nitric oxide levels, resulting in a decrease in total anti-oxidant capacity of plasma. Nitrotyrosine levels were increased suggesting a previous increased NO production, confirming the findings of the short-term model. In a clinical study, serum from patients with APS, presented an inverse correlation between anti-phospholipid antibodies and paraoxonase activity, confirming the results reported in the animal models. In patients with SLE, anti-HDL antibodies were identified and inversely correlated with paraoxonase activity and with total anti-oxidant capacity of plasma. These antibodies were shown to be a heterogeneous group, represented by antibodies cross-reacting with cardiolipin and antibodies directed against a different antigen, probably apolipoprotein A-I. In another clinical setting, infertile women submitted to in vitro fertilization, positive for anti-cardiolipin antibodies but without the Antiphospholipid Antibody Syndrome, presented with similar pro-oxidant changes in their serum, suggesting that these can be a direct consequence of the antibodies rather than an independent characteristic of the syndrome. In conclusion, anti-phospholipid antibodies may induce oxidative stress in patients with SLE and APS through a short-term up-regulation of nitric oxide synthesis, associated with an inhibition of the anti-oxidant activity of paraoxonase. In long-term, these effects combine to create a pro-oxidant environment, which can explain the enhance atherogenesis and thrombogenesis found in these patients.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: Oxidative stress and vascular disease in patients with Systemic Lupus Erythematosus and prima Antiphospholipid Syndrome
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Thesis digitised by ProQuest.
Keywords: Health and environmental sciences; Autoimmune diseases
URI: https://discovery.ucl.ac.uk/id/eprint/10104506
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