Current Concepts of Hyperinflammation in Chronic Granulomatous Disease

Chronic granulomatous disease (CGD) is the most common inherited
disorder of phagocytic functions, caused by genetic defects in the
leukocyte nicotinamide dinucleotide phosphate (NADPH) oxidase.
Consequently, CGD phagocytes are impaired in destroying
phagocytosed microorganisms, rendering the patients susceptible to
bacterial and fungal infections. Besides this immunodeficiency, CGD
patients suffer from various autoinflammatory symptoms, such as
granuloma formation in the skin or urinary tract and Crohn-like
colitis. Owing to improved antimicrobial treatment strategies, the
majority of CGD patients reaches adulthood, yet the
autoinflammatory manifestations become more prominent by lack of
causative treatment options. The underlying pathomechanisms driving
hyperinflammatory reactions in CGD are poorly understood, but
recent studies implicate reduced neutrophil apoptosis and
efferocytosis, dysbalanced innate immune receptors, altered T-cell
surface redox levels, induction of Th17 cells, the enzyme
indolamine-2,3-dioxygenase (IDO), impaired Nrf2 activity, and
inflammasome activation. Here we discuss immunological mechanisms
of hyperinflammation and their potential therapeutic implications
in CGD.