Recent topics and advanced therapies in chronic granulomatous disease.

ABSTRACT

Chronic granulomatous disease (CGD) is a primary immunodeficiency characterized by the inability of phagocytes to produce reactive oxygen species (ROS) owing to a defect in any of the five components (CYBB/gp91phox, CYBA/p22phox, NCF1/p47phox, NCF2/p67phox, and NCF4/p40phox) and a concomitant regulatory component of Rac1/2 and CYBC1/Eros of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex. Patients with CGD are at an increased risk of life-threatening infections caused by catalase-positive bacteria and fungi and of inflammatory complications such as CGD colitis. Antimicrobial and azole antifungal prophylaxes have considerably reduced the incidence and severity of bacterial and improved fungal infections and overall survival. CGD studies have revealed the precise epidemiology and role of NADPH oxidase in innate immunity which has led to a new understanding of the importance of phagocyte oxygen metabolism in various host-defense systems and the fields leading to cell death processes. Moreover, ROS plays central roles in the determination of cell fate as secondary messengers and by modifying of various signaling molecules. According to this increasing knowledge about the effects of ROS on the inflammasomal system, immunomodulatory treatments, such as IFN-γ and anti-IL-1 antibodies, have been established. This review covers the current topics in CGD and the relationship between ROS and ROS-mediated pathophysiological phenomena. In addition to the shirt summary of hematopoietic stem cell transplantation and gene therapy, we introduce a novel ROS-producing enzyme replacement therapy using PEG-fDAO to compensate for NADPH oxidase deficiency.