Understanding ADA2 and the etiology of DADA2: connecting the loose ends

Adenosine deaminase 2 (ADA2) deficiency (DADA2) is a recently discovered autosomal recessive immunodeficiency primarily affecting the bone marrow and vascular system. Previously ADA2 was regarded as a secretory glycoprotein downregulating inflammation by deaminating adenosine and functioning as a growth factor of immune cells. An alternative model was recently proposed suggesting that ADA2 binds and modifies oligonucleotides within the lysosomes. A lysosomal role is not easily reconciled with the increased secretion of ADA2 during inflammation, such as for example tuberculosis, suggesting that ADA2 has an immunoregulatory role in plasma. Here we present a new model where ADA2 may be stored in lysosome-like vesicles after sorting into the lysosomal pathway and released by exocytosis upon signaling. Thus, ADA2 may serve two roles, in the extracellular space contributing to targeting and clearance of oligonucleotide complexes and in the lysosomes taking part in the oligonucleotide metabolism.