NF-κB is an essential transcription factor for multiple genes rel

NF-κB is an essential transcription factor for multiple genes related to the immune response www.selleckchem.com/products/Trichostatin-A.html and development [70, 73]. Previous studies with

dexamethasone, a multifunctional steroid hormone that inhibits NF-κB function among many other effects, demonstrated inhibition of phagocyte NADPH oxidase genes (CYBB and NCF1) at the transcriptional level in THP-1 myelomonocytic cells [74]. Studies investigating the functional role of NF-κB in respiratory burst activity and in expression of CYBB, CYBA, NCF1 and NCF2 in U937 cells stably transfected with a repressor of NF-κB (IkBα-S32A/S36A) demonstrated significantly lower superoxide release and lower CYBB and NCF1 gene expression compared to control U937 cells [75]. Hereditary defects affecting components involved in NF-κB activation can result in heterogeneous diseases including a clinical syndrome of anhidrotic ectodermal dysplasia (EDA), with or without associated lymphoedema, osteopetrosis or immune deficiency

(EDA-ID). It may be inherited in either X-linked Mendelian recessive or autosomal dominant patterns. The former derives from mutations in the gene encoding NEMO, IKKG or IKBKG (OMIM # 300291). The latter, rarer disease is caused by a mutation in the IKBA gene (OMIM # 129490), in which substitution or deletion of the two critical serine residues in the N-terminus make the protein resistant to degradation and therefore a dominant negative that prevents NF-kB activation [76, 77]. In these syndromes, selleckchem mutations affecting the NF-κB pathway lead to a CGD-like functional defect in myeloid cells, in addition to the better-known defects in the acquired immune system, and may contribute to the severe immunodeficiency [75]. Future studies

examining primary phagocytes from EDA-ID patients for respiratory burst and bactericidal activity will help to correlate specific NF-κB pathway mutations with biochemical defects, as well as with agents causing infections. SSR128129E Another primary human immunodeficiency occurs in patients with mutations in the IRAK4 gene, a key early enzyme in the Toll-like receptor/IL-1R/IL-18R signalling pathway (OMIM # 610799). These patients suffer from recurrent, life-threatening pyogenic bacterial diseases, typically caused by Streptococcus pneumoniae [78–80]. IRAK4 deficiency, caused by homozygous or compound heterozygous mutations, is rare (approximately 28 cases reported worldwide) [81], but the severe presentation may result in significant underreporting because of early death. With early recognition and appropriate clinical management, the susceptibility to infection of IRAK4-deficient patients typically decreases with age, suggesting that adaptive immunity progressively compensates for this innate immune defect [81].

Comments are closed.