Chronic granulomatous disease (CGD) is caused by mutations in components of the phagocyte oxidase (phox) enzyme complex. It is a rare disease, estimated to affect about 1 in 1 million individuals in the United States. About two thirds of cases show an X-linked recessive pattern of inheritance, and the remainder are autosomal recessive. The most common X-linked form of the disease is caused by a mutation in the gene encoding the 91-kD a subunit of cytochrome b558, an integral membrane protein also known as phox-91. This mutation results in defective production of superoxide anion, one of several reactive oxygen species, which constitute a major microbicidal mechanism of phagocytes (see Chapter 4). Mutations in other components of the phox complex contribute to autosomal recessive variants of CGD. Defective production of reactive oxygen species results in a failure to kill phagocytosed microbes. The disease is characterized by recurrent infections with catalase-producing intracel-lular bacteria and fungi, usually from early childhood. Many of the organisms that are particularly troublesome in CGD patients produce catalase, which destroys the microbicidal hydrogen peroxide that may be produced by host cells from the residual reactive oxygen radical superoxide. Because the infections are not controlled by phagocytes, they stimulate chronic cell-mediated immune responses, resulting in T cell-mediated macrophage activation and the formation of granulomas composed of activated macrophages. Presumably, these activated macrophages try to limit or to eliminate the microbes despite defective production of reactive oxygen species. This his-tologic appearance is the basis for the name of the disorder. The disease is often fatal, even with aggressive antibiotic therapy.
The cytokine interferon-y (IFN-y) enhances transcription of the gene encoding phox-91 and also stimulates other components of the phagocyte oxidase enzyme complex. Therefore, IFN-y stimulates the production of superoxide by normal neutrophils as well as by CGD neutrophils, especially in cases in which the coding portion of the phox-91 gene is intact but its transcription is reduced. Once neutrophil superoxide production is restored to about 10% of normal levels, resistance to infection is greatly improved. IFN-y therapy is now commonly used for the treatment of X-linked CGD.
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