Oxidative stress in the pathology and treatment of systemic lupus erythematosus

• Published in: Nature reviews. Rheumatology Vol. 9; no. 11; pp. 674 - 686
• Main Author: Perl, Andras
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.11.2013; Nature Publishing Group
• Subjects: 692/420/2780; 692/699/1670/122/1613; 692/699/1670/1613; Acetylcysteine; Animal models; Animals; Antigens; Antioxidants; Antioxidants - therapeutic use; Autoantigens; Autoimmunity - drug effects; Autoimmunity - physiology; Care and treatment; Comorbidity; Cytotoxicity; Drug therapy; Glutathione; Health aspects; Humans; Immune system; Kinases; Lupus; Lupus Erythematosus, Systemic - drug therapy; Lupus Erythematosus, Systemic - metabolism; Lupus Erythematosus, Systemic - pathology; Lymphocytes T; Medicine & Public Health; Oxidation; Oxidative stress; Oxidative Stress - physiology; Pathogenesis; Pathology; Patients; Physiological aspects; review-article; Rheumatology; Signal transduction; Systemic lupus erythematosus; T cells; Toxicity; United States
• ISSN: 1759-4790; 1759-4804; 1759-4804
• DOI: 10.1038/nrrheum.2013.147

Key Points Oxidative stress—generated through multiple mechanisms in a cell-type-specific manner—is a substantial contributor to disease pathogenesis, organ damage and comorbidities in patients with systemic lupus erythematosus (SLE) Pathways of oxidative pathogenesis, such as oxidative modification of self antigens and T-cell dysfunction, have been identified Organ systems in which the clinical importance of oxidative damage in SLE has been recognized include the cardiovascular and renal systems and the skin Biomarkers of oxidative stress correlate directly with disease activity in SLE Depletion of glutathione (reflecting oxidative stress) might have a pathogenic role; its reversal by N -acetylcysteine seems to have therapeutic benefit in mouse models and patients with SLE What is oxidative stress and how is it implicated in the pathogenesis of systemic lupus erythematosus (SLE)? Complex molecular pathways leading to and from redox imbalance in the context of SLE, including oxidative modification of autoantigens, are reviewed in this manuscript, alongside developmental approaches that aim to tackle and/or exploit oxidative stress in the clinical management of this disease. 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.