Chronic granulomatous disease NADPH-oxidase

NADPH-oxidase j 2O2 + NADPH 20p + NADP -F H+ Key component of the respiratory burst Deficient in chronic granulomatous disease... 

Mutations in the Genes for Components of the NADPH Oxidase System Cause Chronic Granulomatous Disease... 

Leukocytes are activated on exposure to bacteria and other stimuh NADPH oxidase plays a key role in the process of activation (the respiratory burst). Mutations in this enzyme and associated proteins cause chronic granulomatous disease. 

NADPH oxidase deficiency and catalase positive organisms in chronic granulomatous disease... 

In mature neutrophils, interferon-7induces the expression of FC7RI, increases antibody-dependent cytotoxicity, primes the ability to generate reactive oxidants and selectively stimulates protein biosynthesis. These effects are described in detail in Chapter 7. Additionally, this cytokine has been used clinically for the treatment of chronic granulomatous disease (CGD), which is associated with an increased susceptibility to infections due to an impairment of NADPH oxidase function ( 8.2). 

Lomax, K. J., Leto, T. L., Nunoi, H., Gallin, J. I., Malech, H. L. (1989). Recombinant 47-kilodalton cytosol factor restores NADPH oxidase in chronic granulomatous disease. Science 245, 409-12. 

Chronic granulomatous disease is most frequently aused by genetic deficiency of NADPH oxidase in the PMN. Patients are susceptible to infection by catalasepositive organisms such as Staphylococcus aureus, Klebsiella, Escherichia coll, Candida, end Aspergillus, k negative nitroblue tetrazolium test is useful in confirming the diagnosis. 

The O2 formed by NADPH oxidase activity can rapidly be converted into H2O2 and other toxic species that destroy microorganisms and impart injury to surrounding host tissue. The most direct evidence for the role of NADPH oxidase in host defense has come from studies of patients who have genetic defects in NADPH oxidase activity (chronic granulomatous disease). Chronic granulomatous disease patients suffer from recurrent, severe bacterial infections, which are often fatal in early childhood. 

In the inherited syndrome of chronic granulomatous disease (CGD), cytochrome Z 245 is absent and consequently the respiratory burst cannot take place [6], Persistent, but selective, bacterial infections are seen in these patients. NADPH oxidase is useful as part of a controlled acute inflammatory response to bacterial invasion, but excessive activity of this enzyme might lead to tissue destruction. In addition to PMN s, other inflammatory cell types, e.g. lymphocytes and macrophages, possess a membrane NADPH oxidase [7], ROI production by these latter cell types may form part of an intercellular communication pathway important in the inflammatory response [8], and perhaps an absence of this cell signalling route in CGD patients is linked to the development of chronic granulomata in these patients. Interestingly, myeloperoxidase deficiency is not associated with disease. 

The relative importance of the contribution of superoxide/hydrogen peroxide and hypochlorous acid in the bacterial killing mechanism is seen in patients with chronic granulomatous disease (CGD, with a defective NADPH-oxidase system), and those that are myeloperoxidase-deficient. CGD patients show persistent multiple infections especially in the skin, lungs, liver and bones by those bacterial strains whose killing by neutrophils requires oxygen. Individuals who are deficient in myeloperoxidase show no symptoms. 

H3. Hohn, D. C., and Lehrer, R. I., NADPH oxidase deficiency in x-Iinked chronic granulomatous disease. J. Clin. Invest. 55, 707-713 (1975). 

Chronic granulomatous disease (CGD) is a rare, X-hnked deficiency of NADPH oxidase activity that drastically impairs the ability of macrophages and neutrophils to destroy pathogens. Patients are especially vulnerable to infection by Mycobacteria, Escherichia coli and staphylococci since these organisms produce catalase to defend themselves against hydrogen peroxide attack by the phagocytes. 

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