Systemic Lupus Erythematosus: Pathogenesis at the Functional Limit of Redox Homeostasis

Abstract

Systemic lupus erythematosus (SLE) is a disease characterized by the production of autoreactive antibodies and cytokines, which are thought to have a major role in disease activity and progression. Immune system exposure to excessive amounts of autoantigens that are not efficiently removed is reported to play a significant role in the generation of autoantibodies and the pathogenesis of SLE. While several mechanisms of cell death-based autoantigenic exposure and compromised autoantigen removal have been described in relation to disease onset, a significant association with the development of SLE can be attributed to increased apoptosis and impaired phagocytosis of apoptotic cells. Both apoptosis and impaired phagocytosis can be caused by hydrogen peroxide whose cellular production is enhanced by exposure to endogenous hormones or environmental chemicals, which have been implicated in the pathogenesis of SLE. Hydrogen peroxide can cause lymphocyte apoptosis and glutathione depletion, both of which are associated with the severity of SLE. The cellular accumulation of hydrogen peroxide is facilitated by the myriad of stimuli causing increased cellular bioenergetic activity that enhances metabolic production of this toxic oxidizing agent such as emotional stress and infection, which are recognized SLE exacerbating factors. When combined with impaired cellular hydrogen peroxide removal caused by xenobiotics and genetically compromised hydrogen peroxide elimination due to enzymatic polymorphic variation, a mechanism for cellular accumulation of hydrogen peroxide emerges, leading to hydrogen peroxide-induced apoptosis and impaired phagocytosis, enhanced autoantigen exposure, formation of autoantibodies, and development of SLE.

Neutrophils in the Pathogenesis of Rheumatoid Arthritis and Systemic Lupus Erythematosus: Same Foe Different M.O.

“…Increased mitochondrial ROS production and higher levels of O 2 - , H 2 O 2 , and HO • in SLE neutrophils ( 76 , 77 ) are met by a decreased redox capacity compared to healthy controls ( 68 , 251 , 254 ). This is due to lower concentrations of glutathione which is critical for adequate redox capacity ( 255 , 256 ). Neutrophils have a large capacity to keep glutathione in the reduced form via the activity of glutathione reductase (GRs) ( 257 ).…”

Molecular Aspects of Systemic Lupus Erythematosus

“…The SLE susceptibility genes that have been identified to date affect activation of autoimmune responses, resulting in aggregation of immune complexes [5]. Research also has found increased apoptosis and impaired phagocytosis in blood mononuclear cells of SLE patients [6,7].…”

Hydrogen peroxide in dermatology

“…All these factors are implicated in the pathogenesis of systemic lupus erythematosus. 3 Patients with systemic sclerosis express high levels of exhaled hydrogen peroxide which may indicate oxidative stress in the airways. 4 Vitiligo and halo nevus Elevated hydrogen peroxide was found in both serum and lesional skin of vitiligo patients.…”