![]() ![]() The central B cell tolerance checkpoint is mostly controlled by intrinsic B cell factors that sense whether B cell receptors (BCRs) recognize self-antigens ( 16– 18). However, it is unknown how patients’ B cells contribute to autoimmune complications and whether B cell tolerance is established properly in ADA-deficient patients before and after treatment.Īutoreactive B cells generated by random V(D)J Ig gene assembly are normally eliminated during their development by both central and peripheral B cell tolerance checkpoints ( 15). In patients undergoing PEG-ADA treatment, after an initial increase, B cell counts remained low and showed a restricted Ig repertoire ( 9, 14). Few reports are available on the contribution of B cells to the autoimmune manifestations in ADA-SCID. Although autoimmunity is commonly observed in certain B cell and/or T cell immunodeficiencies, it remains unclear to what extent some tolerance mechanisms might be specifically affected in ADA deficiency ( 13). Recently, autoimmune manifestations have also been reported in patients receiving BMT ( 11, 12) and in patients treated with HSC-GT ( 3). ![]() ![]() Key findings of milder forms of the disease or in patients undergoing PEG-ADA are complications of immune dysregulations, including autoimmunity and allergic manifestations ( 7– 10). Gene therapy with retroviral vector–transduced CD34 + BM cells resulted in sustained engraftment with multilineage differentiation, increased lymphocyte counts, and improved cellular and humoral responses ( 5, 6).Īlthough varying degrees of immune reconstitution can be achieved by these treatments, breakdown of tolerance is a major concern in ADA-SCID. Recent trials provided the first demonstration of long-term clinical efficacy of HSC gene therapy (HSC-GT) for ADA-SCID, underlining that HSC-GT has a favorable safety profile and is effective in restoring purine metabolism and immune function ( 3, 4). Hence, like in other forms of SCID, bone marrow transplantation (BMT) from an HLA-identical sibling donor is the treatment of choice in ADA-deficient patients, but is available only for a minority of patients ( 2). ![]() Enzyme replacement therapy with pegylated bovine ADA (PEG-ADA) results in clinical improvement with about 70%–80% survival, but often incomplete immunological reconstitution. 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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