![]() The metabolic basis underlying this immune cell deficiency is related to the physiological effect of accumulating adenosine and deoxyadenosine ADA substrates. Immunological defects associated with this disease include impaired T, B, and NK cell development and function, complete absence of cellular and humoral immunity, and recurrent infections ( 1). Genetic defects in the adenosine deaminase ( ADA) gene are among the most common causes of SCID ( 1). Hence, ADA plays an essential role in controlling autoreactive B cell counterselection by regulating BCR and TLR functions. Strikingly, after HSC-GT, ADA-SCID patients displayed quasi-normal early B cell tolerance checkpoints, as evidenced by restored removal of developing autoreactive and ANA-expressing B cells. ![]() We further observed impaired B cell receptor (BCR) and TLR functions in B cells after ADA inhibition, which may underlie the defects in B cell tolerance. We found that before HSC-GT, new emigrant/transitional and mature naive B cells from ADA-SCID patients contained more autoreactive and ANA-expressing clones, indicative of defective central and peripheral B cell tolerance checkpoints. To assess whether ADA deficiency affects the establishment of B cell tolerance, we tested the reactivity of recombinant antibodies isolated from single B cells of ADA-SCID patients before and after HSC-GT. However, autoimmune complications and autoantibody production, including anti-nuclear antibodies (ANAs), frequently occur in ADA-SCID patients after treatment. Restoration of purine metabolism and immune functions can be achieved by enzyme replacement therapy, or more effectively by bone marrow transplant or HSC gene therapy (HSC-GT). ![]() Adenosine deaminase ( ADA) gene defects are among the most common causes of SCID. ![]()
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