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Excerpt
Chronic granulomatous disease (CGD) and generation of superoxide. CGD long has been a paradigmatic convergence of clinical features, biochemical characterization, mechanistic understanding and genetic etiologies: the complete and completed story. 1 Mutations in genes encoding any of four components of reduced nicotinamide adenine dinucleotide oxidase (NADPH oxidase) lead to an inability to produce superoxide and its metabolites hydrogen peroxide and hypochlorous acid (bleach). This defect in turn leads to an inability to kill ingested bacteria and fungi. Because most pathogenic microbes themselves produce H2O2, which complements production in a CGD cell and leads to killing of the ingested organism, only those organisms able to degrade their own H2O2 by catalase were thought to be pathogenic. Therefore failure to produce superoxide predicts recurrent infections with catalase-positive organisms, as well as severe inflammatory problems, because superoxide and its metabolites are also necessary to degrade certain inflammatory mediators (e.g. leukotriene B4, C5a). 2
However, flaws have accumulated in this story. Only relatively few of the many catalase-positive microbes actually cause infection in CGD (e.g. Staphylococcus aureus, Serratia marcescens, Burkholderia cepacia, Nocardia, Aspergillus), 1, 3 and deletion of the catalase gene from a highly pathogenic Aspergillus did not alter virulence in a mouse model of CGD. 4 Deletion of the genes for the primary granule proteins neutrophil elastase and cathepsin G in a mouse model led to marked susceptibility to Aspergillus and staphylococci, despite leaving NADPH oxidase function intact. 5
In partial explanation of these findings, Reeves et al. 6 recently showed that phagocyte production of reactive oxygen species facilitates activation of neutrophil elastase and cathepsin G inside the phagocytic vacuole by liberating these bound enzymes from a matrix. The mechanism for this involves potassium influx into the vacuole in response to the generation of superoxide. Further the vacuole volume is constrained physically, leading to a marked but transient increase in tonicity, which contributes to the microbicidal environment. Therefore this new paradigm for NADPH oxidase-mediated killing suggests that the critical role of reactive oxidants is to serve as intracellular signals for activation of microbicidal enzymes, rather than exerting a microbicidal effect per se. 5, 6 This model further predicts that the feature of organisms causing infection in CGD must be their relative resistance to microbicidal enzymes such as neutrophil elastase, cathepsin G and defensins.
Mycobacterial infections and the mononuclear phagocyte. The mononuclear phagocyte and its signaling pathways are critical in the defense against mycobacteria. 7 Study of patients with infections by relatively nonpathogenic mycobacteria (e.g. Mycobacterium avium complex, rapid growers, BCG) has identifed a discrete set of related gene defects in the interferon γ/interleukin-12 (IFN-γ/IL-12) pathway. 8
In brief mycobacteria-infected macrophages produce IL-12, which stimulates T cells and NK cells through the IL-12 receptor. Activated T cells and natural killer (NK) cells produce IFN-γ in response. In turn IFN-γ binds its receptor, composed of the binding chain, IFN-γ R1, and the signaling chain, IFN-γ R2, on nucleated cells. Binding induces aggregation of the receptor complex, which results in close approximation of the IFN-γ R1 and IFN-γ R2-associated Janus kinases, JAK1 and JAK2. These protein kinases transphosphorylate the intracellular domain of IFN-γ R1 and the latent cytosolic component signal transducer and activator of transcription 1 (STAT1).
