Human inborn errors of the phagocyte respiratory burst: Chronic granulomatous disease and beyond

The phagocyte respiratory burst is an effector mechanism of immunity by which granulocytes, monocytes, and other myeloid cells generate reactive oxygen species (ROS). Inborn errors of core phagocyte NADPH oxidase components (gp91phox, p22phox, p47phox, and p67phox) underlie most cases of chronic granulomatous disease, characterized by severe, recurrent bacterial and fungal infections. An expanding spectrum of inborn errors of immunity (IEIs) has been identified that affect molecules that trigger (IFN-γ, TNF, and their signaling pathways) or control NADPH oxidase assembly and activation (EROS, p40phox, PKCδ, RAC2, and DOCK2), thereby impairing ROS production. Studies of these genetic disorders, which include infection, autoinflammation, and autoimmunity, have identified crucial pathways governing the induction, regulation, assembly, priming, activation, and function of the phagocyte NADPH oxidase complex. We review here the diverse IEIs affecting phagocyte ROS production, highlighting disorders in which ROS generation is absent, reduced, or subset-specific, and the corresponding cellular, immunological, and clinical phenotypes.