ADA-deficient SCID is associated with a specific microenvironment and bone phenotype characterized by RANKL/OPG imbalance and osteoblast insufficiency

Abstract

Adenosine deaminase (ADA) deficiency is a disorder of the purine metabolism leading to combined immunodeficiency and systemic alterations, including skeletal abnormalities. We report that ADA deficiency in mice causes a specific bone phenotype characterized by alterations of structural properties and impaired mechanical competence. These alterations are the combined result of an imbalanced receptor activator of nuclear factor-B ligand (

Alterations in the adenosine metabolism and CD39/CD73 adenosinergic machinery cause loss of Treg cell function and autoimmunity in ADA-deficient SCID

“…29 BMT with WT BM and lentiviral GT were performed as described previously. 18,20 As shown in supplemental Figure 2A, the long-term survival of PEG-ADA-, GT-, and BMT-treated mice was comparable between the 3 groups (60%-70% with respect to WT). This outcome was the result of an early mortality in the BMT-and GT-treated groups, whereas PEG-ADA-treated mice had a less stable long-term survival.…”

“…RT-PCR into cDNA and real-time PCR reactions using Assay-on-Demand gene expression arrays (Applied Biosystems) were carried out as described previously. 20 Arrays used included the following: FoxP3 (Mm00475156_m1), CD4 (Mm00442754_m1), and HPRT (Mm00446968_m1) as internal housekeeping control.…”

Role of reduced intensity conditioning in T-cell and B-cell immune reconstitution after HLA-identical bone marrow transplantation in ADA-SCID

“…7,8 In the absence of conditioning, HSC, B cells, myeloid cells and erythroid cells generally remain of recipient origin 9 and poor B-cell reconstitution has been shown to be associated to a significantly higher number of clinical events during follow up. 7,10 In the case of ADA-SCID, the engraftment of donorderived cells in all lineages, even as mixed chimerism, could also improve systemic alterations linked to the accumulation of toxic metabolites, such as skeletal defects 11 or neuro-psychological defects.…”

Regulation of bone and cartilage by adenosine signaling

“…These abnormalities resolve following 6-12 months of ADA enzyme replacement which presumably normalizes adenosine levels [19]. Deletion of ADA in mice leads to low trabecular bone volume, reduced numbers of trabeculae, as well as decreased expression of RANKL [20].…”