Recently, a defect in the NCF4 gene that encodes the p40phox has been shown to produce a disease phenotype

limited Rapamycin in vitro to a chronic inflammatory feature of CGD, at least in this single patient. Matute et al. [45] reported the autosomal recessive mutations in NCF4 in a boy who presented with granulomatous colitis. His neutrophils showed a substantial defect in intracellular, but not extracellular, superoxide production during phagocytosis, which is distinct from other forms of CGD where both intracellular and extracellular oxidant production is affected. Genetic analysis of NCF4 showed compound heterozygosity for a frameshift mutation (K52RfsX79) with premature stop codon and a missense mutation predicting a R105Q substitution in the PX domain. The importance of the small G protein Rac2 (OMIM # 608203) was underlined when a severe immunodeficiency different from classical CGD was described in male child and related to a dominant negative

mutation in the RAC2 gene (D57N). A male infant of non-consanguineous parents presented with a perirectal abscess and delayed umbilical cord fall at Wnt inhibitor 5 weeks of age. In the subsequent 4 months, he had recurrent perirectal abscesses, infected urachal cyst, failure to heal surgical wounds and the absence of pus in infected areas. His older sibling was healthy, and there was no family history of an increased incidence of infections or poor wound healing. A second, recently reported patient also had omphalitis, as well as a paratracheal abscess that grew

Stenotrophomonas and Prevotella but showed dramatically decreased pus formation [46, 66]. Rac2 is a member of the Rho family of GTPases that regulates both actin cytoskeleton and superoxide anion production; this isoform constitutes more than 96% of RAC expression in neutrophils [67]. During NADPH activation, Rac2 binds Selleck Ixazomib GTP and migrates to the membrane independently of the p67phox/p47phox complex [68, 69]. The transcription factor nuclear factor-κB (NF-κB) is a heterodimer formed from members of the mammalian rel gene family, which includes p105/p50, 100/p52, p65 (RelA), RelB and c-Rel [70, 71]. The general mechanism of activation of the conventional and most common NF-κB complex (p50/RelA) starts with its sequestration in the cytoplasm by interaction with a family of inhibitory proteins, termed inhibitors of κB (IκBs), and the proto-oncogene Bcl-3. Activation by extracellular signals induces phosphorylation of IκB by specific IκB kinases (IκKα and IκKβ) on critical serine residues, Ser32 and Ser36, within the N-terminal signal response domain [72]. IκB phosphorylation leads rapidly to its ubiquitinization and rapid proteolytic degradation, thus releasing the NF-κB heterodimer to move into the cell nucleus.