These mice developed a progressive inflammatory Atezolizumab encephalopathy with neuropathological features closely recapitulating those observed in AGS. Considering these data, although not proven beyond doubt, we predict that limiting the exposure of the infant brain to an AGS-related type I interferon immune response will attenuate the disease-associated brain damage. AGS is a genetically heterogeneous disease resulting

from mutations in any one of the genes encoding (i) the 3-prime repair exonuclease TREX1 [16] with preferential activity on single-stranded (ss) DNA; (ii) the three non-allelic components of the RNASEH2 endonuclease complex [17] acting on ribonucleotides in RNA : DNA hybrids; (iii) the Sam domain and HD domain containing protein (SAMHD1) [18], which functions as a deoxynucleoside triphosphate triphosphohydrolase; and (iv) adenosine deaminase acting on RNA (ADAR1) [19], which catalyses the hydrolytic deamination of adenosine to inosine in double-stranded (ds) RNA (Table 1). It is possible that at least one further genetic subtype of AGS is yet to be defined. Although most cases of AGS demonstrate an autosomal recessive pattern of inheritance, rare examples due to de-novo dominant TREX1 mutations have been

reported [20-23]. Moreover, the same heterozygous D18N mutation in TREX1 has been Maraviroc research buy seen to cause both (dominant) AGS and familial chilblain lupus (effectively, ‘non-neurological

Fludarabine molecular weight AGS’), thus highlighting the role of unknown, modifying factors (which might be genetic or environmental) and/or stochastic mechanisms. The proteins defective in AGS are all associated with nucleic acid metabolism. The finding of mutations in TREX1 and the genes encoding the RNASEH2 complex in 2006, in the context of a clinical phenotype mimicking congenital infection, led us to hypothesize that (i) these proteins might be involved in clearing cellular nucleic acid ‘debris’; and (ii) that a failure of such waste removal could result in immune activation, specifically triggering an innate immune response more normally induced by viral nucleic acid [24] (Fig. 2). At least with regard to TREX1, cogent evidence has emerged in support of this hypothesis. Thus, Yang et al. [25] demonstrated that TREX1 deficiency results in the intracellular accumulation of abnormal ssDNA species. This finding was confirmed by Stetson and colleagues [26], who showed that in Trex1-null mice, ssDNA activation of a Toll-like receptor (TLR)-independent cytosolic pathway involving IRF3, TBK1 and STING results in the induction of a type I interferon response, and a recruitment of the adaptive immune system requiring functional lymphocytes.