Defects in Bacterial Killing
The best example of an immunodeficiency characterized by failure of phagocyte-mediated bacterial killing is chronic granulomatous disease (CGD). In normal neutrophils (and monocytes), bacterial phagocytosis results in the activation of the nicotinamide adenine dinucleotide phos-phate (NADPH) oxidase complex, which produces superoxide and generates a mi-lieu within the phagosome that activate
the proteolytic enzymes, cathepsin, and elastase. The activity of the proteolytic enzymes is bactericidal. The NADPH oxi-dase complex comprises two membrane-associated proteins, p91phox and p22phox (also called the α and β units of cytochrome B558, respectively), complexed with three cytosolic cofactors, p47phox, p40phox, and p67phox. Mutations have been identified in four out of five components (p91phox, p22phox, p47phox, p67phox), resulting in defective NADPH oxidase activity, leading to impairment of bacterial kill-ing by phagocytic cells. The result is a clinical syndrome, called CGD, character-ized by failure of bacterial degradation in vivo, resulting in the persistence of tissue inflammation with granuloma formation in a variety of organs. CGD due to p91phox deficiency is X-linked, while the other vari-ants of CGD are inherited in an autosomal recessive manner.
In CGD, the bacterial killing mecha-nisms that depend on the phagocyte oxidase system are inoperative, but the nonoxidative killing mechanisms are still intact. Therefore, patients with CGD are not troubled by the broad range of microbes that a neutropenic patient would be susceptible to. Instead, CGD patients get infections with a restricted range of micro-organisms, which are only susceptible to the bactericidal mechanisms initiated by NADPH oxidase activation. The spectrum of microorganisms that causes infections in CGD include S. aureus, Gram-negative bacteria (Burkholderia cepacea, Salmonella, Serratia), and fungi (Aspergillus spp.). Characteristic sites of infection include subcutaneous tissue, lymph nodes, lungs, and liver. Oral and perioral ulceration are common.
The formation of chronic granulomata in various tissues is a typical feature of CGD. In critical locations, chronic granu-loma formation may cause pathology. Granulomatous obstruction of the gastro-intestinal or genitourinary tract may be a consequence. Hepatosplenomegaly may occur due to granulomatous infiltration of these organs. A granulomatous colitis, resembling Crohn’s disease, occurs in about 15 percent of CGD patients, highlighting the importance of normal phagocyte func-tion for preventing harmful inflammation in the large intestine.
Diagnosis of CGD is based on the abil-ity of stimulated neutrophils from these patients to oxidize dyes to give a colored product or a fluorescent product, detect-able by flow cytometry. Prophylactic treat-ment with IFN-γ substantially reduces the incidence of bacterial and fungal infections in CGD patients, for reasons that are not fully understood.
The cytosolic GTPase Rac2 is required for the normal actin polymerization and optimal function of the phagocyte oxidase system. Rac2 deficiency results in impaired neutrophil mobility and poor superoxide responses to some stimuli. A single affected patient identified to date had a clinical presentation similar to that seen in LAD.