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

Abstract

Systemic lupus erythematosus (SLE) is characterized by the dysfunction of T cells, B cells, and dendritic cells, the release of pro-inflammatory nuclear materials from necrotic cells, and the formation of antinuclear antibodies (ANA) and immune complexes of ANA with DNA, RNA, and nuclear proteins. Activation of the mammalian target of rapamycin (mTOR) has recently emerged as a key factor in abnormal activation of T 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 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 and B cell biomarkers and targets for treatment in SLE.

Keywords::

• Lupus
• mitochondria
• nitric oxide
• glutathione
• mammalian target of rapamycin
• Syk

Declaration of interest: This work was supported in part by grants AI 048079, AI 061066, and AI 072648 from the National Institutes of Health, the Alliance for Lupus Research, and the Central New York Community Foundation. The author reports no conflicts of interest. The author alone is responsible for the content and writing of the paper.