Invited ReviewThe phagocyte respiratory burst: Historical perspectives and recent advances
Section snippets
Discovery and characterisation of the phagocyte respiratory burst
The first studies on the oxygen metabolism of phagocytes were carried out in the 1930s by Baldrige and Gerrard who showed that canine neutrophils undergo a marked increase in oxygen consumption while phagocytosing bacteria. No further investigation of this rather startling finding took place until the 1950s when the metabolic properties of neutrophils ingesting foreign material were re-examined. This work demonstrated several unusual features of oxygen consumption by leucocytes and ultimately
Characterisation and function of the cytoplasmic components of the phagocyte NADPH oxidase
The discovery of cytochrome b558 represented years of incisive work on the basic biochemistry of phagocytes. This combined with shrewd clinical observation of CGD had delineated an entire system of anti-microbial defence. Nevertheless, the recognition that chronic granulomatous disease resulted from deficiency of an NADPH oxidase did not tell the whole story. The CYBB gene encoding gp91phox is situated on the X-chromosome but work by Borregaard and colleagues [32] demonstrated that some cases
Current understanding of oxidase activation
Armed with the information above, it is possible to build a picture of how the oxidase is activated when phagocytes encounter pathogens. Activation of the NADPH oxidase requires the translocation of the cytosolic components either to the plasma membrane (in the case of extracellular ROS) or to the phagosome (in the case of intracellular ROS). This spatial separation of the cytosolic and membrane components prevents the oxidase being activated at rest [54]. After phagocytosis of a particle and
Recent work on control gp91phox/p22phox expression
Recently, significant advances have been made in understanding the abundance of the gp91phox-p22phox heterodimer is controlled. It is clear that expression of cytochrome b558 can be controlled at both the transcriptional and post-transcriptional level. gp91phox and p22phox biosynthesis appears to be a relatively inefficient process as described in a key study by DeLeo and colleagues [63]. Using pulse chase experiments, they found that gp91phox was made as a high mannose precursor and
Chronic granulomatous disease and the role of ROS in regulating inflammation
As stated previously, the importance of the phagocyte NADPH oxidase is underlined by chronic granulomatous disease − deficiency of one of the subunits. Several cohorts have now been analysed. In Europe [71], [72], [73], [74], the USA [75] and Japan [76], X-linked CGD is the predominant form accounting for around 60% of cases. Of those that remain, around 30% are the result of p47phox deficiency and 10% are p67phox or p22phox deficiency. In cohorts where consanguinous marriage is more prevalent,
Reactive oxygen species as regulators of immunity
An emerging theme of the last few years has been the role of reactive oxygen species not just as anti-microbial agents but as regulators of the immune system. ROS can have profound influences on redox sensitive cellular pathways. This function in immuno-regulation is not surprising as auto-inflammatory complications, particularly inflammatory bowel disease, have been recognised as a feature of CGD even from the initial characterisation of the syndrome.
There are myriad ways in which reactive
ROS and type 1 interferon signalling
The work of Holmdahl and colleagues on p47phox as a regulator of innate immunity provides some key insights into the regulatory role played by ROS in the immune system. This group has investigated p47phox-deficiency as a driver of inflammatory arthritis in rat and mouse with complementary studies in human cells ex vivo. They identified Ncf1 (p47phox) as a susceptibility locus in pristine induced arthritis by examining a resistant and susceptible rat strain and making a series of genetically
ROS regulation of adaptive immunity
It is clear, therefore that reactive oxygen species influence many fundamental processes in the innate immune system. There is also good evidence that reactive oxygen species can also modulate the activity of cells of the adaptive immune system. These effects can be indirect because of the influence of ROS on innate immune signaling and antigen presentation and by paracrine diffusion of hydrogen peroxide from antigen presenting cells. However, there is also evidence that lymphocytes can express
Conclusions
The phagocyte respiratory burst is essential for host defence and the study of chronic granulomatous disease has not only emphasised this point but has illuminated the complex biochemistry of this pathway. Recent work on chaperone proteins that control levels of gp91phox and p22phox demonstrate that we still have much to learn about the respiratory burst. A particularly exciting development in the last few years has been the recognition that the phagocyte NADPH oxidase regulates not only major
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