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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.

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  • Authors+Show Affiliations

    Departments of Medicine, Microbiology and Immunology, Biochemistry and Molecular Biology, Division of Rheumatology, State University of New York, 750 East Adams Street, Syracuse, NY 13210, USA.

    Source

    Nature reviews. Rheumatology 9:11 2013 Nov pg 674-86

    MeSH

    Animals
    Antioxidants
    Autoimmunity
    Humans
    Lupus Erythematosus, Systemic
    Oxidative Stress

    Pub Type(s)

    Journal Article
    Research Support, N.I.H., Extramural
    Research Support, Non-U.S. Gov't
    Review

    Language

    eng

    PubMed ID

    24100461

    Citation

    Perl, Andras. "Oxidative Stress in the Pathology and Treatment of Systemic Lupus Erythematosus." Nature Reviews. Rheumatology, vol. 9, no. 11, 2013, pp. 674-86.
    Perl A. Oxidative stress in the pathology and treatment of systemic lupus erythematosus. Nat Rev Rheumatol. 2013;9(11):674-86.
    Perl, A. (2013). Oxidative stress in the pathology and treatment of systemic lupus erythematosus. Nature Reviews. Rheumatology, 9(11), pp. 674-86. doi:10.1038/nrrheum.2013.147.
    Perl A. Oxidative Stress in the Pathology and Treatment of Systemic Lupus Erythematosus. Nat Rev Rheumatol. 2013;9(11):674-86. PubMed PMID: 24100461.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - Oxidative stress in the pathology and treatment of systemic lupus erythematosus. A1 - Perl,Andras, Y1 - 2013/10/08/ PY - 2013/10/9/entrez PY - 2013/10/9/pubmed PY - 2014/6/19/medline SP - 674 EP - 86 JF - Nature reviews. Rheumatology JO - Nat Rev Rheumatol VL - 9 IS - 11 N2 - 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. SN - 1759-4804 UR - https://www.unboundmedicine.com/medline/citation/24100461/full_citation L2 - http://dx.doi.org/10.1038/nrrheum.2013.147 DB - PRIME DP - Unbound Medicine ER -