br Acknowledgements This work was supported by Conselho Naci

Acknowledgements This work was supported by Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), Fundação de Amparo à Pesquisa do Estado do Rio Grande do Sul (FAPERGS) FINEP research grant “Rede Instituto Brasileiro de Neurociência (IBN-Net)” #01.06.0842-00, DECIT/SCTIEMS through CNPq and FAPERGS (Proc. FAPERGS 10/0036-5 – PRONEX) and by the Instituto Nacional de Ciência e Tecnologia em Excitotoxicidade e Neuroproteção. E.P.R. and A.S.L. were recipients of fellowships from CNPq. D.B.R. was a recipient of a fellowship from CAPES.
Autoinflammatory diseases is a relatively new term that describes a group of disorders characterized by recurrent or persistent inflammation, seemingly unprovoked, that appear in the absence of infectious or other apparent cause., , Monogenic defects of genes involved in innate immunity cause the majority of autoinflammatory diseases., , Whole exome sequencing (WES) has become an important tool in deciphering genetic disorders and in improving our understanding of genotype-phenotype associations. In 2014, 2 groups using WES discovered recessive loss-of-function mutations of the cat eye syndrome chromosome region candidate 1 (CECR1) gene, encoding adenosine deaminase (ADA) 2, associated with vasculopathy with a highly variable clinical expression. Navon Elkan et al described mutations in this gene in familial polyarteritis nodosa. Further cases of systemic vasculopathy, early onset lacunar strokes, hepatosplenomegaly, and livedo reticularis were reported by Zhou et al. Since then, variable clinical manifestations of this disorder have been reported, all with vasculitic components., , , , , ,
Introduction Sickle cell anemia (SCA) is a hereditary disorder of hemoglobin caused by a single missense mutation in the human β-globin gene leading to an amino acid substitution (Glu → Val) in the sixth position of the β-globin chain. The polymerization results into HbS Pirinixic Acid sale under hypoxic conditions, induces a mechanical distortion of red blood cells and indicates a key event in the complex pathophysiology of SCA (Hebbel, 2011). It is a chronic hemolytic anemia characterized by ongoing vaso occlusion; persistent endothelial damage and progressive organ damage (Fasano et al., 2015). Sickle cell disease may be associated with the extracellular release of nucleotides and nucleoside, particularly adenosine triphosphate (ATP), adenosine diphosphate (ADP) and adenosine into the circulation (Jackson et al., 1996). ATP is as an important extracellular messenger and a major metabolic currency that is expended in cellular activities (Di Virgilio et al., 2009). In healthy tissues, ATP is almost exclusively localized intracellularly (Di Virgilio et al., 2009) but in pathological processes is released from damaged cells and the concentration in the extracellular space rises rapidly (Cekic and Linden, 2016). ATP can be hydrolyzed by ectonucleotidases that are situated on the surface of cells, in soluble forms in the interstitial medium or within body fluids (Zimmermann et al., 2012). These circulating soluble nucleotidases play significant role in controlling the availability of ATP, ADP, AMP and adenosine in the extracellular environment within physiological limits (Agteresch et al., 1999; Zimmermann et al., 2012). An enzymatic cascade coordinates these dual functions of removing one signal in the form of ATP and generating another in form of adenosine (Agteresch et al., 1999). The measurement of the rate of ATP enzymatic hydrolysis in human blood may serve as a promising diagnostic tool for cellular damage in various pathophysiological conditions (Yegutkin, 1997). Extracellular adenine nucleotides are hydrolyzed by series of enzymes; nucleoside triphosphate diphosphohydrolase family (NTPDases), nucleotide phosphate/phosphodiesterase family, alkaline phosphatases and 5′-nucleotidase. NTPDases hydrolyze ATP and ADP while 5′-nucleotidase hydrolyzes AMP to adenosine (Zimmermann, 2000). Adenosine deaminase is another important enzyme that is released to the extracellular space by monocytes, macrophages and dendritic cells. It is responsible for the deamination of adenosine to inosine (Zavialov et al., 2010).