A primary example of genetic immunodeficiency that af-fects oxygen-dependent killing mechanisms is chronic granulomatous disease (CGD). In this inherited disor-der of neutrophils and other phagocytic cells, one of the components of the NADPH oxidase complex (phox system) has mutated or is absent. As a result, neutrophils cannot produce reactive oxygen intermediates (ROIs). The NADPH oxidase complex consists of five molecules. Two of them, glycoprotein 91 (gp91) and protein 22 (p22), are part of a membrane-bound cytochrome called cy-tochrom B558 (see Fig. 10.8). Three other cytosolic com-ponents—protein 47 (p47), protein 67 (p67), and protein 40 (p40)—are components of Rac-2 GTPase, which is required for oxidase activity. Neutrophil activation and stimulation from phagocytosis cause cytosolic pro-teins to translocate to the plasma membrane of the phagolysosome to assemble the active NADPH oxidase complex. The assembled enzyme transports electrons from cytosolic NADPH across the membrane to molecular O2 residing inside the phagolysosome, generating bactericidal superoxide anions (O2 –) and other ROIs. Approximately 50% to 70% of all CGD cases are caused by a mutation in the CYBB (cytochrome B, b subunit) gene located on the X chromosome. This gene encodes glycoprotein 91 (gp91), which is necessary for proper function of the NADPH oxidase complex. Since gp91 deficiency is an X-linked disease, CGD caused by this mutation is often re-ferred as X91 disease. Another 20% to 40% of those with CGD have mutations in the NCF1 gene on chromo-some 7 that codes for protein 47. Mutations in gene NCF2 (which encodes protein 67) and CYBA (which encodes protein 22) are rare, accounting for fewer than 10% of all cases of CGD. Mutations in the NCF1, NCF2, and CYBA genes produce autosomal recessive forms of CGD. CGD decreases the ability of neutrophils to kill certain types of bacteria and fungi. Individuals with this disease are frequently affected by recurrent life-threatening bacte-rial and fungal infections and chronic inflammatory condi-tions. The most common pathologic changes occur in tissues and organs that form barriers against the entry of microorganisms from the external environment. They in-clude skin (skin infections), gingiva (swollen inflamed gums), lungs (pneumonia), lymph nodes (lymphoadenitis), gastrointestinal tract (enteritis, diarrhea), liver, and spleen. Another characteristic feature of CGD is the development of enlarged, tumorlike masses called granulomas. The presence of granulomas may cause serious problems in the gastrointestinal tract by obstructing the passage of food and in the genitourinary tract by blocking the flow of urine from the kidneys and bladder.