The role of nitric oxide in abnormal T cell signal transduction in systemic lupus erythematosus

Abstract

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by production of antinuclear autoantibodies and diverse array of clinical manifestations. T cells from patients with SLE have been shown to be activated in vivo and provide help to autoreactive B cells. Lupus T cells exhibit enhanced spontaneous and diminished activation-induced apoptosis and predisposition to necrosis. Persistent mitochondrial hyperpolarization and ATP depletion - associated with significantly increased mitochondrial mass - characterize T lymphocyte dysfunction in SLE. In addition to cell death abnormalities, mitochondrial dysfunction is associated with altered signal transduction through the T cell receptor and Ca2+ fluxing. Exposure of normal T cell to nitric oxide induces mitochondrial hyperpolarization and biogenesis and regenerates the Ca2+ signaling profile of lupus T cells. This article reviews a novel understanding of the role of nitric oxide in signal transduction and cell death abnormalities in SLE.

Fig. 1

Schematic diagram of intercellular signals underlying mitochondrial dysfunction of lupus T cells. Increased NO production by monocytes generates mitochondrial biogenesis in T cells, leading enhanced mitochondrial Ca²⁺ content and altering Ca²⁺ signaling profile of lupus T cells. NO induces mitochondrial hyperpolarization and ATP depletion thus contributing to relative resistance to apoptotic stimuli and increased necrosis. Necrotic T cells release factors such as calreticulin and high mobility group protein (HMGP1) that promote expansion and differentiation of dendritic cells. Dendritic cells (DC) produce increased amounts of IFN that, in turn, enhances monocyte iNOS activity and NO production. Positive feed back between necrosis-prone T cells, NO-producing monocytes, and enhanced IFN production by dendritic cells create a vicious cycle and lead to persistent inflammation in SLE.