Immunology

Question 1

What is CGD? Mode(s) of inheritance? How common is it? Genes mutated? Pathogenesis? Treatment?

Answer 1

CGD is a rare X-linked or autosomal recessive chronic granulomatous disease that results from abnormal leucocyte oxidative metabolism. There is an abnormality affecting different elements of the respiratory burst oxidase or its activating mechanism. The patients have recurring infections, usually bacterial but sometimes fungal, which present in infancy or early childhood in most cases.

• Which genes are mutated in CGD? CGD is caused by mutations in components of the phagocyte oxidase (phox) enzyme complex.
• Estimated to affect about 1 in 1 million individuals in the US.
• 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 α 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. Mutations in other components of the phox complex contribute to autosomal recessive variants of CGD.
• Pathogenesis: Defective production of ROS results in a failure to kill phagocytosed microbes. The disease is characterized by recurrent infections with catalase-producing intracellular bacteria and fungi, usually from early childhood. Catalase 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. Activated macrophages try to limit or to eliminate the microbes despite defective production of reactive oxygen species. This histologic appearance is the basis for the name of the disorder. The disease is often fatal, even with aggressive antibiotic therapy.

The cytokine interferon-γ (IFN-γ) enhances transcription of the gene encoding phox-91 and also stimulates other components of the phagocyte oxidase enzyme complex. Therefore, IFN-γ 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-γ therapy is now commonly used for the treatment of X-linked CGD.