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Metabolic control of systemic lupus erythematosus: convergence of genetic and environmental factors on mitochondrial dysfunction and mTOR reveal treatment targets in lupus
Arthritis Research & Therapy volume 14, Article number: A35 (2012)
Systemic lupus erythematosus (SLE) is characterized by the dysfunction of T cells, B cells, and dendritic cells, the release of proinflammatory nuclear materials from necrotic cells and the formation of antinuclear antibodies (ANA) and immune complexes of ANA with DNA, RNA, and nuclear proteins . Oxidative stress and inflammation lead to parenchymal and vascular tissue damage, the latter resulting in accelerated atherosclerosis that is a major cause of mortality in SLE. Activation of the mammalian target of rapamycin (mTOR) has recently emerged as a key factor in abnormal activation of T cells and B cells in SLE . In T cells, increased production of nitric oxide and mitochondrial hyperpolarization (MHP) were identified as metabolic checkpoints upstream of mTOR activation. mTOR controls the expression T-cell receptor-associated signaling proteins CD4 and CD3ζ through increased expression of the endosome recycling regulator Rab5 and HRES-1/Rab4 genes , enhances Ca2+ fluxing and skews the expression of tyrosine kinases both in T cells and B cells, and blocks the expression of Foxp3 and the generation of regulatory T cells . MHP, increased activity of mTOR, Rab GTPases, and Syk kinases, and enhanced Ca2+ flux have emerged as common T-cell and B-cell biomarkers and targets for treatment in SLE . While inactivation and depletion of B cells have shown success in both animal models and patients, blockade of oxidative stress , mTOR , tyrosine kinases and T-cell-B-cell interaction are also being evaluated as targets for treatment in SLE.
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This study was supported in part by NIH grants AI 048079, AI072648, AT004332 and the Alliance for Lupus Research.
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Perl, A. Metabolic control of systemic lupus erythematosus: convergence of genetic and environmental factors on mitochondrial dysfunction and mTOR reveal treatment targets in lupus. Arthritis Res Ther 14, A35 (2012). https://doi.org/10.1186/ar3969
- Nitric Oxide
- Systemic Lupus Erythematosus
- Tyrosine Kinase
- Mitochondrial Dysfunction