Project 458995

Our research group studies a protein called adenosine deaminase 2 (ADA2) which is produced by certain immune cells and can be detected in the blood. Most of what we know about ADA2 has come since 2014, when mutations in the gene encoding ADA2 were found to cause a particular form of inflammation-induced damage to blood-vessels (vasculitis) in children that was subsequently named 'Deficiency of ADA2' (DADA2). Early signs of DADA2 include stroke, brain bleeds, and in some cases immune cell deficiencies. However, DADA2 has unusually broad clinical features and how mutations in a single gene can lead to such diverse disease manifestations is not known. ADA2 has both enzymatic and putative growth factor activity, meaning that it may be required for the normal growth and function of cells. Our HYPOTHESIS is that the phenotypic variability in DADA2 patients may be linked to loss of enzymatic activity, dysregulated growth factor activity, or both. We have a special interest in understanding the role of ADA2 in vascular damage versus immune cell deficiency, having previously identified patients with a mutation in ADA2 that resulted in neutropenia (neutrophil deficiency) in the absence of vasculopathy, and was fatal for one child. The main goal of this research project is to study the effects of ADA2 on neutrophils. In particular, we will study (i) how ADA2 normally influences the growth of neutrophils, (ii) whether mutations in ADA2 lead to dysregulated maturation of neutrophils and (iii) whether ADA2 or mutations in ADA2 alter effector functions of mature neutrophils. The findings will improve our understanding of the roles of ADA2 in promoting healthy immune cell development and may reveal key functions that contribute to the broad clinical features observed in DADA2 patients.