Inflammatory consequences of inherited disorders affecting neutrophil function

Abstract

Primary immunodeficiencies affecting the function of neutrophils and other phagocytic leukocytes are notable for an increased susceptibility to bacterial and fungal infections as a result of impaired leukocyte recruitment, ingestion, and/or killing of microbes. The underlying molecular defects can also impact other innate immune responses to infectious and inflammatory stimuli, leading to inflammatory and autoimmune complications that are not always directly related to infection. This review will provide an update on congenital disorders affecting neutrophil function in which a combination of host defense and inflammatory complications are prominent, including nicotinamide dinucleotide phosphate oxidase defects in chronic granulomatous disease and β2 integrin defects in leukocyte adhesion deficiency.

Figure 1.

NADPH oxidase and genetic defects in CGD. The leukocyte NADPH oxidase enzyme complex is composed of membrane and cytosolic subunits that are referred to by their molecular mass (kDa) and the designation “phox,” for phagocyte oxidase. CYBB and CYBA refer to cytochrome b-245 β chain and cytochrome b-245 α chain, respectively, the large and small subunits of flavocytochrome b₅₅₈, whereas NCF refers to neutrophil cytosolic factor, used to designate the cytosolic regulatory subunits of the oxidase. Flavocytochrome b₅₅₈ is the electron transferase and is located in plasma, specific granules (in neutrophils), and phagosome and some endosome membranes. This heterodimer is composed of gp91^phox and p22^phox. The gp91^phox subunit is sometimes referred to as NOX2. CYBC1 (also known as EROS) is an endoplasmic reticulum protein important for expression of the flavocytochrome b₅₅₈ heterodimer. The soluble regulatory proteins p47^phox, p67^phox, and p40^phox form a complex in the cytosol; upon leukocyte activation, phosphorylation-induced conformational changes lead to their binding to flavocytochrome b₅₅₈. The small GTPase Rac is also essential for NADPH oxidase enzymatic activity, which, in its active GTP-bound state, becomes membrane bound and activates p67^phox. Together, these regulatory proteins activate the flavocytochrome b₅₅₈–mediated transfer of electrons from cytosolic NADPH across the membrane via FAD and heme redox centers to molecular oxygen, thereby forming superoxide in the extracellular space or within phagosomes or endosomes. Superoxide is converted into H₂O₂, which can diffuse across membranes, and other ROS. CGD results from inactivating recessive mutations in any 1 of the 5 phox subunits or CYBC1, as indicated with the approximate incidence, gene, and chromosomal location. Professional illustration by Patrick Lane, ScEYEnce Studios.

Figure 2.

NADPH oxidase–derived ROS have beneficial and deleterious effects. NADPH oxidase–derived ROS have damaging oxidative effects that are important for microbial killing but can damage host tissues. In addition, derivative ROS have immunoregulatory effects, which act to balance immune responses that otherwise promote inflammation and even autoimmunity. Likely factors contributing to abnormal inflammation in the absence of NADPH oxidase ROS include impaired digestion of microbes or debris, increased proinflammatory cytokine production reflecting changes in redox-regulated signals, delayed clearance of inflammatory neutrophils, and altered antigen presentation. Professional illustration by Patrick Lane, ScEYEnce Studios.

Figure 3.

NADPH oxidase–derived oxidants can influence multiple aspects of innate and adaptive immune responses. The phagocyte NADPH oxidase (red triangle) is assembled on the plasma membrane, phagosomes, and endocytic compartments. Superoxide is released inside membrane compartments or the extracellular space and is rapidly converted into derivative ROS. This includes dismutation to H₂O₂, which is membrane permeant and, thus, can diffuse into the cytosol. Oxidase-generated ROS can have many effects, depending on the site of ROS production, and, thus, can impact multiple pathways important for innate and adaptive immunity. See text for additional details. Professional illustration by Patrick Lane, ScEYEnce Studios.