Oxidative stress in the pathology and treatment of systemic lupus erythematosus

Abstract

Oxidative stress is increased in systemic lupus erythematosus (SLE), and it contributes to immune system dysregulation, abnormal activation and processing of cell-death signals, autoantibody production and fatal comorbidities. Mitochondrial dysfunction in T cells promotes the release of highly diffusible inflammatory lipid hydroperoxides, which spread oxidative stress to other intracellular organelles and through the bloodstream. Oxidative modification of self antigens triggers autoimmunity, and the degree of such modification of serum proteins shows striking correlation with disease activity and organ damage in SLE. In T cells from patients with SLE and animal models of the disease, glutathione, the main intracellular antioxidant, is depleted and serine/threonine-protein kinase mTOR undergoes redox-dependent activation. In turn, reversal of glutathione depletion by application of its amino acid precursor, N-acetylcysteine, improves disease activity in lupus-prone mice; pilot studies in patients with SLE have yielded positive results that warrant further research. Blocking mTOR activation in T cells could conceivably provide a well-tolerated and inexpensive alternative approach to B-cell blockade and traditional immunosuppressive treatments. Nevertheless, compartmentalized oxidative stress in self-reactive T cells, B cells and phagocytic cells might serve to limit autoimmunity and its inhibition could be detrimental. Antioxidant therapy might also be useful in ameliorating damage caused by other treatments. This Review thus seeks to critically evaluate the complexity of oxidative stress and its relevance to the pathogenesis and treatment of SLE.

Oxidative Stress and Antioxidant Status in Immune Thrombocytopenia

“…SLE is an autoimmune inflammatory disease whose pathogenesis also refers to oxidative stress. Several studies have shown increased production of ROS or diminished levels of intracellular reduced glutathione in various blood components in SLE patients [11,12]. Several investigators suggested that restoration of the redox balance using antioxidant agents or diminishing effect of oxidative stress by intake of antioxidant nutrients, might attenuate the complication of SLE induced by oxidative stress [11].…”

“…Several studies have shown increased production of ROS or diminished levels of intracellular reduced glutathione in various blood components in SLE patients [11,12]. Several investigators suggested that restoration of the redox balance using antioxidant agents or diminishing effect of oxidative stress by intake of antioxidant nutrients, might attenuate the complication of SLE induced by oxidative stress [11]. Similarly, the deficiencies of SOD and peroxiredoxin inducing oxidative stress were considered to be an essential factor that might participate in the pathogenesis of another autoimmune disease autoimmune hemolytic anemia.…”

The relationship between oxidative stress and autoimmunity in Hashimoto's thyroiditis

“…For example, in systemic lupus erythematosus, which is an autoimmune disease, it has been proposed that oxidative stress may play a role in pathogenesis as well as increase in the course of the disease (11). Similarly, oxidative stress has also been demonstrated to be high in systemic sclerosis, another autoimmune disease (12).…”

Systemic Lupus Erythematosus-associated Neutrophil Cytosolic Factor 2 Mutation Affects the Structure of NADPH Oxidase Complex

“…Increased oxidative stress has been amply documented in SLE (41). To a large degree it is secondary to the chronic inflammation that occurs during the course of disease progression and/or during active disease.…”

“…Thus, diminished ROS production by phagocytic cells due to NADPH oxidase deficiency can cause impaired digestion of microbes or debris followed by increased Toll-like receptor stimulation (41) and/or altered redox status of cellular proteins resulting in increased proinflammatory cytokine production via the NFB pathway.…”