Chapter 061. Disorders of Granulocytes and Monocytes (Part 9) Chronic Granulomatous Disease Chronic

Chronic Granulomatous Disease Chronic granulomatous disease (CGD) is a group of disorders of granulocyte and monocyte oxidative metabolism. Although CGD is rare, with an incidence of 1 in 200,000 individuals, it is an important model of defective neutrophil oxidative metabolism. Most often CGD is inherited as an X-linked recessive trait; 30% of patients inherit the disease in an autosomal recessive pattern. Mutations in the genes for the four proteins that assemble at the plasma membrane account for all patients with CGD. Two proteins (a 91-kDa protein, abnormal in X-linked CGD, and a 22-kDa protein, absent in one form of...
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Chapter 061. Disorders of Granulocytes and Monocytes (Part 9) Chronic Granulomatous Disease Chronic Chapter 061. Disorders of Granulocytes and Monocytes (Part 9) Chronic Granulomatous Disease Chronic granulomatous disease (CGD) is a group of disorders ofgranulocyte and monocyte oxidative metabolism. Although CGD is rare, with anincidence of 1 in 200,000 individuals, it is an important model of defectiveneutrophil oxidative metabolism. Most often CGD is inherited as an X-linkedrecessive trait; 30% of patients inherit the disease in an autosomal recessivepattern. Mutations in the genes for the four proteins that assemble at the plasmamembrane account for all patients with CGD. Two proteins (a 91-kDa protein,abnormal in X-linked CGD, and a 22-kDa protein, absent in one form ofautosomal recessive CGD) form the heterodimer cytochrome b-558 in the plasmamembrane. Two other proteins (47 and 67 kDa, abnormal in the other autosomalrecessive forms of CGD) are cytoplasmic in origin and interact with thecytochrome after cell activation to form NADPH oxidase, required for hydrogenperoxide production. Leukocytes from patients with CGD have severelydiminished hydrogen peroxide production. The genes involved in each of thedefects have been cloned and sequenced and the chromosome locations identified.Patients with CGD characteristically have increased numbers of infections due tocatalase-positive microorganisms (organisms that destroy their own hydrogenperoxide). When patients with CGD become infected, they often have extensiveinflammatory reactions, and lymph node suppuration is common despite theadministration of appropriate antibiotics. Aphthous ulcers and chronicinflammation of the nares are often present. Granulomas are frequent and canobstruct the gastrointestinal or genitourinary tracts. The excessive inflammationprobably reflects failure to inhibit the synthesis or degradation of chemoattractantsand antigens, leading to persistent neutrophil accumulation. Impaired killing ofintracellular microorganisms by macrophages may lead to persistent cell-mediatedimmune activation and granuloma formation. Autoimmune complications such asimmune thrombocytopenic purpura and juvenile rheumatoid arthritis are alsoincreased in CGD. In addition, discoid lupus is more common in X-linked carriers. Disorders of Phagocyte Activation Phagocytes depend on cell-surface stimulation to induce signals that evokemultiple levels of the inflammatory response, including cytokine synthesis,chemotaxis, and antigen presentation. Mutations affecting the major pathway thatsignals through NF-κB have been noted in patients with a variety of infectionsusceptibility syndromes. If the defects are at a very late stage of signaltransduction, in the protein critical for NF-κB activation known as the NF-κBessential modulator (NEMO), then affected males develop ectodermal dysplasiaand severe immune deficiency with susceptibility to bacteria, fungi, mycobacteria,and viruses. If the defect in NF-κB activation is closer to the signaling source, inthe IL-1 receptor–associated kinase 4 (IRAK4), then children have a markedsusceptibility to pyogenic infections early in life but develop resistance toinfection later. Mononuclear Phagocytes The mononuclear phagocyte system is composed of monoblasts,promonocytes, and monocytes, in addition to the structurally diverse tissuemacrophages that make up what was previously referred to as thereticuloendothelial system. Macrophages are long-lived phagocytic cells capableof many of the functions of neutrophils. They are also secretory cells thatparticipate in many immunologic and inflammatory processes distinct fromneutrophils. Monocytes leave the circulation by diapedesis more slowly thanneutrophils and have a half-life in the blood of 12–24 h. After blood monocytes arrive in the tissues, they differentiate intomacrophages (big eaters) with specialized functions suited for specific anatomiclocations. Macrophages are particularly abundant in capillary walls of the lung,spleen, liver, and bone marrow, where they function to remove microorganismsand other noxious elements from the blood. Alveolar macrophages, liver Kupffercells, splenic macrophages, peritoneal macrophages, bone marrow macrophages,lymphatic macrophages, brain microglial cells, and dendritic macrophages all havespecialized functions. Macrophage-secreted products include lysozyme, neutralproteases, acid hydrolases, arginase, complement components, enzyme inhibitors(plasmin, α2-macroglobulin), binding proteins (transferrin, fibronectin,transcobalamin II), nucleosides, and cytokines (TNF-α; IL-1, -8, -12, -18). IL-1(Chaps. 17 and 308) has many functions, including initiatin ...