- Meeting abstract
- Open Access
Metabolic control of systemic lupus erythematosus: convergence of genetic and environmental factors on mitochondrial dysfunction and mTOR reveal treatment targets in lupus
- A Perl1
© Perl; licensee BioMed Central Ltd. 2012
- Published: 27 September 2012
- Nitric Oxide
- Systemic Lupus Erythematosus
- Tyrosine Kinase
- Mitochondrial Dysfunction
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.
This study was supported in part by NIH grants AI 048079, AI072648, AT004332 and the Alliance for Lupus Research.
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