T-cell and B-cell signaling biomarkers and treatment targets in lupus

Abstract

Purpose of review Systemic lupus erythematosus is characterized by the production of antinuclear autoantibodies and dysfunction of T-cells, B-cells, and dendritic cells. Here, we review newly recognized genetic factors and mechanisms that underlie abnormal intracellular signal processing and intercellular communication within the immune system in systemic lupus erythematosus. Recent findings Activation of the mammalian target of rapamycin plays a pivotal role in abnormal activation of T and B-cells in systemic lupus erythematosus. In T-cells, increased production of nitric oxide and mitochondrial hyperpolarization were identified as metabolic checkpoints upstream of mammalian target of rapamycin activation. Mammalian target of rapamycin controls the expression T-cell receptor-associated signaling proteins CD4 and CD3ζ through increased expression of the endosome recycling regulator HRES-1/Rab4 gene, mediates enhanced Ca2+ fluxing and skews the expression of tyrosine kinases both in T and B-cells, and blocks the expression of Foxp3 and the expansion of regulatory T-cells. Mitochondrial hyperpolarization and the resultant ATP depletion predispose T-cells to necrosis, thus promoting the dendritic cell activation, antinuclear autoantibody production, and inflammation. Summary Mitochondrial hyperpolarization, increased activity of mammalian target of rapamycin and Syk kinases, enhanced receptor recycling and Ca2+ flux have emerged as common T and B-cell biomarkers and targets for treatment in systemic lupus erythematosus.

IL-21 in the pathogenesis and treatment of skin diseases

“…Signaling through the phosphatidylinositol 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) pathways may also be relevant in certain physiologic or pathologic conditions. disease and that cytokines are key mediators of this interplay [20]. IL-21 is most likely involved in the pathogenesis of SLE.…”

Animal Models of Molecular Pathology

“…Abnormalities in signaling components have been found in SLE patients. 78 The immune system is dysregulated by changes in cell signaling thresholds as well as by defects in inhibitory molecules, resulting in a breakdown of tolerance, and the production of autoreactive B and T cells.…”

T cell metabolism in autoimmune diseases

“…An increase in Akt activation has been demonstrated in the peripheral blood from SLE patients, concurrently with an up-regulation of the phosphorylation of one of its downstream targets, GSK3 [95], known as a negative regulator of cell cycle progression [96]. An abnormal activation of mTOR has been demonstrated in human SLE [97], and promising results in the treatment of the disease have been obtained with rapamycin, which could act by facilitating the differentiation of Treg cells and promoting the expansion of other subsets able to limit the T cell stimulation of auto-reactive B cells [98]. Beyond Akt and mTOR, a dysregulation in leptin expression has also been found in SLE patients [99; 100], but further studies are required to unlock the mechanisms that control its secretion.…”