The Role of Reactive Nitrogen and Oxygen Intermediates in Systemic Lupus Erythematosus

Systemic lupus erythematosus (SLE) is a complex autoimmune multiorgan disease. In SLE, the disruption of reactive intermediate homeostasis may lead to a break in immune tolerance, increased tissue damage, and altered enzyme function. This chapter reviews the latest evidence from both animal and human studies on the role of reactive intermediates (RIs) in the pathogenesis of SLE. RIs are short-lived molecules produced by normal cellular metabolism and aid in a multitude of physiological and pathological processes. Nitrogen-based reactive intermediates are known as reactive nitrogen intermediates (RNI), while those that are oxygen-based are known as reactive oxygen intermediates (ROIs). While iNOS activity can suppress parasitemia or tumor growth, its overexpression in the setting of lupus disease activity appears to lead to organ damage and an altered immune response. No study to date has used selective iNOS inhibitors to explore the pathogenic potential of iNOS in humans with lupus. However, several studies have demonstrated elevated markers of NO production in lupus patients compared to controls and a significant correlation between markers of systemic NO production and lupus disease activity. Conflicting results from murine studies using pharmacologic or genetic manipulation of NOS highlight the complex biology of reactive intermediates in lupus. Further studies should be directed toward investigating potential sources of RIs other than iNOS, defining the key reactive species that are dominant in lupus, and addressing how the interplay between RNIs and ROIs may lead to a break in tolerance and enhanced aggressiveness of lupus disease activity.