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

摘要

Purpose of reviewSystemic 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 findingsActivation 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 CD3?through increased expression of the endosome recycling regulator HRES-1/Rab4 gene, mediates enhanced Ca~(2+) 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. SummaryMitochondrial hyperpolarization, increased activity of mammalian target of rapamycin and Syk kinases, enhanced receptor recycling and Ca~(2+) flux have emerged as common T and B-cell biomarkers and targets for treatment in systemic lupus erythematosus.