Deficiency of Adenosine Deaminase 2 (DADA2) is an autosomal recessive condition caused by biallelic variants in the Adenosine Deaminase 2 (ADA2) gene. Clinical manifestations are broad and include vasculitis, immunodeficiency and haematological involvement. The aim of this thesis was to explore the role of ADA2 in endothelial homeostasis and in the pathogenesis of vascular injury.
My work has confirmed that ADA2 is expressed by endothelial cells (EC) as a shortened transcript called ADA2 202 with undetectable protein and adenosine deaminase activity. We have demonstrated this using multiple transcriptomic technologies in both primary human endothelial cell lines and in patient derived endothelial colony forming cells (ECFC). This raises the question as to whether ADA2 202 RNA may function as a long non-coding RNA, or whether it is present as a protein at low undetectable levels in the cell, possibly in the insoluble fraction.
ADA2 202 was shown to have a role in endothelial homeostasis and its deficiency leads to inflammatory EC activation with a gene signature suggestive of both type I and type II interferon and Tumour Necrosis Factor α pathway activation together with induction of apoptotic pathways. ECFC from DADA2 patients were observed to have a stressed morphology, upregulation of interferon related genes, evidence of reduced proliferation and increased senescence. These data all suggest that EC deficient of ADA2 202 are more susceptible to activation, injury and subsequent vasculitis and therefore may play a role in DADA2 pathogenesis.
Despite the heterogeneity of DADA2, we did not find evidence of any patients with plasma ADA2 deficiency in a cohort of patients with large and small vessel vasculitis. Consistent with other inflammatory conditions, plasma ADA2 activity was elevated in vasculitis patients and correlated with immune cells and markers of inflammation.