Human adenosine deaminase type 2 (ADA2) deficiency (DADA2) is a rare inborn error of immunity, caused by genetic pathogenic variants in the ADA2 gene. DADA2 patients suffer from vasculitis with diverse manifestations ranging from stroke (due too ischemia or bleeding) to severe vasculitis with digital necrosis and ulcerations, to skin vasculitis. The presentation of DADA2 can be quite diverse though, with bone marrow failure (red blood cells, platelets and white blood cells aplasia, isolated or combined), auto-immune manifestations and immunodeficiency. The mortality of DADA2 is around 10%, mostly in children. However, it is becoming increasingly clear that diagnosis is being missed due to the diverse manifestations of the condition. This is also why it is relevant for society: all organ systems can be affected and awareness of the disease is crucial for diagnosis. Up until now it is hypothesized that the main culprit in the development of the disease, is differentiation of patient monocytes into pro-inflammatory macrophages which result in dysfunction of the endothelium, the cells lining he blood vessels, due to insufficient ADA2 in the cellular environment. Although ADA2 indeed has adenosine deaminase activity, it remains a matter of debate whether this is the only relevant physiological function of ADA2. The mainstay of treatment consists of anti-inflammatory treatment with TNF-inhibitors. However, some manifestations don’t respond to this treatment, like the bone marrow failure. Hematopoietic stem cell transplantation has been shown to cure all manifestations of the disease, unfortunately not without risk of mortality and morbidity. To gain insight into the function of ADA2 and the disease mechanisms will not only aid in providing alternative treatments but is likely to offer insight into the disease mechanisms of other conditions of endothelial dysfunction and other causes of vasculitis or bone marrow failure or immunodeficiency, for instance other causes of stroke, undefined vasculitis, aplastic anemia, neutropenia etc. The main objectives of this project are therefore: 1/To show that ADA2 deficiency is underdiagnosed 2/To develop a biomarker to diagnose and measure disease activity and to measure response to treatment. 3/To unravel the pathophysiology of ADA2 deficiency in its phenotypical variety 4/To investigate the role of ADA2 in phenocopies (lookalikes of the disease) of ADA2 deficiency 5/To define new druggable targets in ADA2 deficiency using inducible pluripotent stem cell technology.
In short, we believe that there is much more to ADA2 than meets the eye and that the study of ADA2 deficiency can open new avenues to studying many, less rare, conditions.
