These disorders indicate that in human neutrophils, NEMO and IRAK

These disorders indicate that in human neutrophils, NEMO and IRAK4 are required for normal LPS-induced priming of superoxide production. Despite being able to respond normally to phorbol ester stimulation, NEMO-deficient neutrophils failed to produce normal levels of superoxide in response to chemotactic peptide (fMLF) alone and more strikingly fMLF after pretreatment with LPS [82]. Phosphorylation of p47phox LBH589 solubility dmso was normal in NEMO-deficient cells, suggesting

that additional regulatory signals, such as p67phox translocation, play a role in regulating NADPH oxidase activity. IRAK4 has also been shown to bind and directly phosphorylate p47phox in neutrophils upon LPS stimulation [83]. Consistent with this finding, p47phox phosphorylation was not detected in response to LPS alone in IRAK4-deficient PMN, but it

was detected in response to fMLF and PMA. More importantly, the clinical syndromes indicate that defective NADPH oxidase activation in NEMO or IRAK4 deficiency play a role during the innate immune response to infection in vivo. Although the defect in NADPH oxidase activation in NEMO deficiency is less dramatic than IRAK4 deficiency in vitro, the consequences may be more severe in the background of altered acquired immunity in EDA-ID caused by NEMO deficiency [82]. G6PD, the key regulatory enzyme in the hexose monophosphate shunt, catalyses the oxidation of glucose-6-phosphate (G6P) to 6-phosphogluconolactone and the production of reducing equivalents in the form of NADPH to meet cellular needs for reductive biosynthesis and maintenance of the cellular redox status [84]. NADPH is the electron donor used by the NADPH Seliciclib oxidase to reduce the molecular Cyclin-dependent kinase 3 oxygen to superoxide. Gene mutations affecting G6PD are found on the distal long arm of the X chromosome (OMIM # 305900). Notably, the G6PD and NEMO genes are encoded in opposite directions on the X chromosome and share the same promoter. The diversity of point mutations and possible interactions with other

genes account for the phenotypic heterogeneity of G6PD deficiency [85]; over 400 biochemical variants have been reported [86]. The level of G6PD activity in affected erythrocytes is generally much lower than in other cells [87], as most mutations affect protein stability rather than function, and anucleate erythrocytes cannot synthesize more enzymes. G6PD-deficient persons are predisposed to the development of sepsis and complications related to sepsis after a severe injury [88]. Patients with sufficiently severe G6PD deficiency to affect leucocyte enzyme levels may demonstrate low NADPH oxidase activity because of impaired substrate supply and suffer recurrent infections, mimicking the phenotype of CGD [89]. Agudelo-Florez et al. [90] reported an unusual association of X-linked CGD and the usually mild African variant of G6PD deficiency in a boy with recurrent respiratory infections, chronic lung disease and anaemia [91].

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