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Abstract
Even though systemic lupus erythematosus (SLE) is associated with high morbidity and mortality rates among young and middle-aged women, the molecular mechanisms of disease pathogenesis are not fully understood. Previous studies from our laboratory suggested an association between oxidative stress and SLE disease activity (SLEDAI). To further assess the role of reactive oxygen species (ROS) in SLE, we examined the contribution of lipid-derived reactive aldehydes (LDRAs)-specific immune complexes in SLE. Sera from 60 SLE patients with varying SLEDAI and 32 age- and gender- matched healthy controls were analyzed for oxidative stress and related markers. Patients were divided into two groups based on their SLEDAI scores (<6 and ≥ 6). Both SLEDAI groups showed higher serum 4-hydroxynonenal (HNE)-/malondialdehyde (MDA)-protein adducts and their specific immune complexes (HNE-/MDA-specific ICs) together with IL-17 than the controls, but the levels were significantly greater in the high SLEDAI (≥ 6) group. Moreover, the serum levels of anti-oxidant enzymes Cu/Zn superoxide dismutase (SOD) and catalase (CAT) were significantly reduced in both patient groups compared to controls. Remarkably, for the first time, our data show that increased HNE-/MDA-specific ICs are positively associated with SLEDAI and elevated circulating immune complexes (CICs), suggesting a possible causal relationship among oxidative stress, LDRA-specific ICs and the development of SLE. Our findings, apart from providing firm support to an association between oxidative stress and SLE, also suggest that these oxidative stress markers, especially the HNE-/MDA-specific ICs, may be useful in evaluating the prognosis of SLE as well as in elucidating the mechanisms of disease pathogenesis.
Highlights
Autoimmune diseases (ADs) include approximately 80 different disorders affecting ~ 5% of the population [1, 2]
To evaluate the involvement of lipid-derived reactive aldehydes (LDRAs) in the pathogenesis of Systemic lupus erythematosus (SLE), we first determined the formation of HNE-/MDA-protein adducts in the sera of SLE patients vs. age- and gendermatched controls, because HNE and MDA are two major LDRAs and generally accepted biomarkers of oxidative stress/lipid peroxidation [6, 8, 15, 16, 18, 20, 27]
In an attempt to provide novel evidence and validate our central hypothesis that initiation of autoimmunity may be mediated by increased formation of HNE-/MDA-modified proteins following excessive reactive oxygen species (ROS) generation and oxidative stress, oxidative stress markers and related indexes were quantitated in the sera of SLE patients vs. age- and gender-matched control subjects
Summary
Autoimmune diseases (ADs) include approximately 80 different disorders affecting ~ 5% of the population [1, 2]. Excessive oxidative stress and decreased antioxidant levels are reported in various ADs, SLE [6, 7, 9, 10], and the enhanced oxidative stress has been linked to disease induction, progression and severity of SLE [6, 11,12,13]. Antioxidants such as N-acetylcysteine (NAC) can improve autoimmune response and reduce SLE disease activity by decreasing oxidative stress, further supporting the significance of oxidative stress in disease pathogenesis [9, 10, 14, 15]
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