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Defective B cell tolerance in adenosine deaminase deficiency is corrected by gene therapy.

Authors :
Sauer AV
Morbach H
Brigida I
Ng YS
Aiuti A
Meffre E
Source :
The Journal of clinical investigation [J Clin Invest] 2012 Jun; Vol. 122 (6), pp. 2141-52. Date of Electronic Publication: 2012 May 24.
Publication Year :
2012

Abstract

Adenosine deaminase (ADA) gene defects are among the most common causes of SCID. 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). However, autoimmune complications and autoantibody production, including anti-nuclear antibodies (ANAs), frequently occur in ADA-SCID patients after treatment. 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. 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. 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. 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. Hence, ADA plays an essential role in controlling autoreactive B cell counterselection by regulating BCR and TLR functions.

Details

Language :
English
ISSN :
1558-8238
Volume :
122
Issue :
6
Database :
MEDLINE
Journal :
The Journal of clinical investigation
Publication Type :
Academic Journal
Accession number :
22622038
Full Text :
https://doi.org/10.1172/JCI61788