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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.
Perl A: Systems biology of lupus: mapping the impact of genomic and environmental factors on gene expression signatures, cellular signaling, metabolic pathways, hormonal and cytokine imbalance, and selecting targets for treatment. Autoimmunity. 2010, 43: 32-10.3109/08916930903374774.
Fernandez DR, Perl A: mTOR signaling: a central pathway to pathogenesis in systemic lupus erythematosus?. Discov Med. 2010, 9: 173-
Fernandez DR, Telarico T, Bonilla E, Li Q, Banerjee S, Middleton FA, Phillips PE, Crow MK, Oess S, Muller-Esterl W, Perl A: Activation of mTOR controls the loss of TCR in lupus T cells through HRES-1/Rab4-regulated lysosomal degradation. J Immunol. 2009, 182: 2063-10.4049/jimmunol.0803600.
Lai Z, Telarico T, Bartos A, Miklossy G, Hanczko R, Jimah J, Clair B, Tily H, Francis L, Garcia R, Phillips PE, Ramos I, Perl A: Reversal of CD3/CD4/CD25/Foxp3 Treg depletion in active SLE patients with rapamycin. Arthritis Rheum. 2010, 1196-doi: 10.1002/art.28951, Suppl 10
Francis L, Perl A: Pharmacotherapy of systemic lupus erythematosus. Expert Opin Pharmacother. 2009, 10: 1481-10.1517/14656560902971003.
Lai Z-W, Hanczko R, Bonilla E, Caza TN, Clair B, Bartos A, Miklossy G, Jimah J, Doherty E, Tily H, Francis L, Garcia R, Dawood M, Yu J, Ramos I, Coman I, Faraone SV, Phillips PE, Perl A: N-acetylcysteine reduces disease activity by blocking mTOR in T cells of lupus patients. Arthritis Rheum. 2012, doi: 10.1002/art.34502,
Fernandez D, Bonilla E, Mirza N, Perl A: Rapamycin reduces disease activity and normalizes T-cell activation-induced calcium fluxing in patients with systemic lupus erythematosus. Arthritis Rheum. 2006, 54: 2983-10.1002/art.22085.
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) doi:10.1186/ar3969
- Nitric Oxide
- Systemic Lupus Erythematosus
- Tyrosine Kinase
- Mitochondrial Dysfunction