Altered oxidative stress markers in relation to T cells, NK cells & killer immunoglobulin receptors that are associated with disease activity in SLE patients

Abstract

Systemic Lupus Erythematosus is an autoimmune disease with symptoms pervasive to all organ systems. It affects more females as compared to males (in the ratio 9:1). Oxidative stress plays a major role in the pathogenesis of SLE and other autoimmune diseases. In order to understand the relationship between cell specific oxidative stress and the severity of SLE, this research study involving the estimation of intracellular ROS accumulation in T and NK cell was conducted on SLE patients of North Indian Population. At the same time, to estimate anti-oxidant defense, Keap1 and Nrf2 levels were estimated in these cell types. The relationship between the expression of Killer immunoglobulin receptors i.e., KIR2DL4 & KIR3DL1 and oxidative stress was also evaluated as these receptors are imperative for the function and self-tolerance of NK cells. Oxidative stress was raised along with Keap1 and Nrf2 in T and NK cell subsets in SLE patients. The expression of KIR2DL4 was raised and that of KIR3DL1 was reduced in the NK cells of patients. The intensity of change in expression and its significance varied among the subsets. Nrf2 expression was raised in these species against oxidative stress as the antioxidant defense mechanism pertaining to Keap1-Nrf2 pathway, but the adequacy of response needs to be understood in further studies. The expression of KIR2DL4 and KIR3DL1 varied among the patient and healthy controls and the expression of the latter was found to have a significant positive relationship with plasma Glutathione(reduced) concentration.

The Potential of Nrf2 Activation as a Therapeutic Target in Systemic Lupus Erythematosus

“…They found a positive correlation between disease activity and protein expression of Nrf2 in CD3 + CD8 + T cells, but not with other cell types. SLE disease activity positively correlated with mRNA expression of Keap1 in CD4 + , CD8 + , and CD56 + cells and mRNA expression of Nrf2 in CD8 + cells [75]. The biologic effects of Keap1 and Nrf2 regulation in these cell subtypes during SLE remains to be determined.…”

“…Multiple studies have shown increased levels of oxidative stress in the blood, tissues, and immune cells of SLE patients [16,[73][74][75]. Furthermore, levels of oxidative stress correlate with disease activity.…”

“…Tandon et al evaluated oxidative stress, Keap1, and Nrf2 in T cell and Natural Killer (NK) cell subtypes isolated from SLE patients [75]. They found a positive correlation between SLE disease activity (as assessed by SLEDAI) and ROS in helper and cytotoxic T-cells.…”

Recent Advances in Understanding Nrf2 Agonism and Its Potential Clinical Application to Metabolic and Inflammatory Diseases

“…Aberrant IFN signaling, activation of the NLRP3 inflammasome, as well as B cells and Th17 cells, and even hyperactivation of cytototoxic CD8 + T cells is noted [ 162 , 163 , 164 , 165 ]. Also, T and natural killer cells from SLE patients show higher intracellular ROS levels of than B cells from healthy controls; at the same time, Keap1 and Nrf2 levels are elevated as an antioxidant defense mechanism [ 166 ]. Another study of patients with SLE shows that increased circulating plasmacytoid dendritic cells are associated with increased disease activity; in turn, disease activity is positively associated with increased levels of ROS in dendritic cells, due at least partially to reduction of Nrf2 expression.…”

Oxidative Stress in SLE T Cells, Is NRF2 Really the Target to Treat?

“…Nevertheless, there is mounting evidence for a defective redox clearance in SLE. Patients with highly active disease show impaired activity of oxidative stress regulating enzymes, such as superoxide dismutase (SOD) and gluthathione peroxidase (GPX) in serum and saliva while PBMCs of active SLE patients reveal higher intracellular ROS than those of healthy controls (6)(7)(8)(9). Increased oxygen intermediates have also been identified in macrophages of lupus mice (10).…”