Abstract
Reactive oxygen species (ROS) occupy a paradoxical position in autoimmune disease: excessive or dysregulated ROS contribute to oxidative injury and inflammatory amplification, whereas physiological ROS function as spatially and temporally regulated signals required for immune homeostasis. This duality suggests that redox dysregulation may involve not only excessive ROS but also failure of physiologically required ROS signaling. We define this latter state as oxidative deficiency: a functionally defined state in which an inadequate physiological ROS signal impairs a specific redox-dependent biological process, rather than simply reflecting low total ROS or increased antioxidant capacity. Genetic and experimental studies of NADPH oxidase (NOX) pathways demonstrate that impaired NOX-dependent ROS generation can modify immune regulation and autoimmune susceptibility in selected contexts, with particularly strong support in systemic lupus erythematosus and experimental arthritis. However, divergent findings in experimental autoimmune encephalomyelitis and protection from autoimmune diabetes following reduced NOX2 activity demonstrate substantial disease- and function-specific effects. We therefore propose that oxidative deficiency and pathological oxidative stress represent distinct, independently testable dimensions of autoimmune-associated redox dysregulation whose relationship may be sequential, concurrent, or absent depending on disease context. In selected settings, oxidative deficiency may precede and later coexist with pathological oxidative stress, although direct temporal evidence for this trajectory in human autoimmune disease remains limited. The framework is experimentally falsifiable: evidence for oxidative deficiency requires demonstration of an inadequate physiological ROS signal, impairment of the corresponding biological function, and, where feasible, functional rescue following selective restoration of the deficient signal. This framework extends established redox concepts by distinguishing failure of physiological ROS signaling from pathological oxidant excess and provides testable criteria for defining their roles in autoimmune disease.