Abstract
SLE is a multifactorial, heterogeneous group of disease which is potentially fatal and can be characterized by anti-nuclear autoantibody production and consequent organ, especially kidney failure [1]. Therapy is still restricted and limited to general immunosuppressants and cytotoxic drugs with many side effects. Therefore, the understanding of the fine molecular mechanisms of disease pathogenesis is crucial to develop new therapeutic approaches. The complex interaction of the innate dendritic cells and adaptive immune T and B cells significantly contribute to disease pathogenesis. Both T and B cells are hyperactive in SLE. T cells exhibit aberrant signaling profile upon antigen receptor activation and changes in proximal signaling molecules and adaptor proteins which together shape the pathogenic lupus T cell phenotype. Lupus T cells exhibit a metabolically dysregulated status, including persistent mitochondrial hyperpolarization (MHP) [2,3], increased mitochondrial mass, oxidative stress and depleted intracellular glutathione levels [4,5]. Lupus T cells also show increased cytoplasmic and mitochondrial calcium levels and signaling profile. A significant inducer of MHP is nitric oxide, which is produced mainly by monocytes in SLE. MHP leads to subsequent necrosis releasing necrotic material from T cells, which triggers dendritic cells and B cells. Closely related to MHP, T cells show altered metabolic gene expression signature, including the overexpression of the mitochondrial outer membrane protein VDAC (voltage dependent anion channel) and SOD2 (superoxide dismutase). Transaldolase, an enzyme of the pentose-phosphate pathway which is responsible for the production of nucleotides and maintenance of reducing environment [6] is also overexpressed in lupus T cells and it has been previously shown that overexpression of this enzyme results in MHP [7]. Consistent with altered metabolism, lupus T cells show enhanced activation of the mTOR (mammalian target of rapamycin) pathway.
Highlights
MTOR regulates the differentiation of CD8+ memory T cells by regulating the expression of the transcription factors eomesodermin and T-bet [11]
A recent report is about mTOR activation and downstream signaling component HIF 1-alpha governed transcriptional regulation is required for the proper differentiation of Th17 cells suggesting that overactivation of mTOR in these cells might contribute to the development and maintenance of the autoimmunity [16]
As in other autoimmune diseases, Th17 cells are over-represented in lupus [17]
Summary
MTOR regulates the differentiation of CD8+ memory T cells by regulating the expression of the transcription factors eomesodermin and T-bet [11]. A recent report is about mTOR activation and downstream signaling component HIF (hypoxia-inducible factor) 1-alpha governed transcriptional regulation is required for the proper differentiation of Th17 cells suggesting that overactivation of mTOR in these cells might contribute to the development and maintenance of the autoimmunity [16]. Following activation of the HIF1α, Th17 cells exhibit more active glycolytic transcriptional program than Treg cells.
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