Chapter 189

Abstract

Abstract

1. Phagocytic cells are an essential component of the innate immune system that provides a first line of defense against microbial infection. This protective capacity is based on both oxygen-dependent and oxygen-independent killing mechanisms. The latter include the release of hydrolytic and cytotoxic proteins from cytoplasmic granules into the phagolysosome. Oxygen-dependent microbial killing by activated phagocytes relies on the generation of toxic oxygen products from molecular oxygen through a series of electron transfers. This process is mediated by a multicomponent nicotinamide adenine dinucleotide phosphate (NADPH) oxidase that assembles in the plasma membrane during ingestion of microorganisms. Granules also release myeloperoxidase into the phagolysosome, and the enzyme catalyzes production of the microbicidal agent hypochlorous acid. These oxygen-dependent events do not occur normally in phagocytes from patients with chronic granulomatous disease, myeloperoxidase deficiency, or deficiency of the enzymes glucose 6-phosphate dehydrogenase (G-6-PD), glutathione synthetase, or glutathione reductase.

2. Congenital absence or structural mutation of any one of the four major components of the NADPH oxidase complex in phagocytes results in the clinical syndrome of chronic granulomatous disease, characterized by recurrent pyogenic infections of the skin, soft tissues, liver, spleen, lymph nodes, and respiratory tract. Catalase-positive bacteria and fungi are the common pathogens. Phagocytes from these patients ingest organisms normally but display impaired microbial killing, which is the basis of the clinical syndrome. Chronic granulomatous disease is a heterogeneous disorder with regard to mode of inheritance because the four major oxidase components are encoded at different chromosomal locations (1q25, 7q11.23, 16p23, and Xp21.1); see Table 189-5 for MIM and GenBank data. The disease is also heterogeneous with regard to severity of clinical presentation because the mutations in the gene encoding the most commonly affected component (the major subunit of flavocytochrome b 558, encoded on the X chromosome) can lead to different degrees of residual function and, consequently, variability in the capacity to kill ingested microorganisms.

3. Severe G-6-PD deficiency in neutrophils, which leads to impaired hexose monophosphate shunt activity, can mimic chronic granulomatous disease. Affected neutrophils are unable to generate the NADPH required to sustain activity of the respiratory burst oxidase and as a result display a defect in intracellular killing.

4. Myeloperoxidase, present in the azurophilic granules of mature neutrophils, catalyzes the formation of hypochlorous acid from chloride ion and H2O2 generated by the respiratory burst. The partial or complete absence of myeloperoxidase affects about 1 in 2,000 apparently healthy individuals. Myeloperoxidase deficiency is usually not associated with clinically significant infections, with the exception of invasive fungal disease in individuals with concomitant diabetes mellitus. Several cardiovascular and neurologic diseases associated with underlying inflammation have been linked to abnormal levels of myeloperoxidase, suggesting that the consequences of inherited myeloperoxidase deficiency may be subtle and exhibit a phenotype unrelated to infection or host defense.

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