Defective B cell tolerance in adenosine deaminase deficiency is corrected by gene therapy
Defective B cell tolerance in adenosine deaminase deficiency is corrected by gene therapy
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DOI：
10.1172/jci61788
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发表时间：
2012-06-01
影响因子：
15.9
通讯作者：
Meffre, Eric
中科院分区：
文献类型：
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作者：
Sauer, Aisha V.;Morbach, Henner;Meffre, Eric
腺苷脱氨酶（ADA）基因缺陷是SCID最常见的病因之一。嘌呤代谢和免疫功能的恢复可以通过酶替代疗法来实现，或者通过骨髓移植或HSC基因治疗（HSC- gt）更有效。然而，自身免疫并发症和自身抗体的产生，包括抗核抗体（ANAs），在ADA-SCID患者治疗后经常发生。为了评估ADA缺乏是否影响B细胞耐受的建立，我们测试了从ADA- scid患者的单个B细胞中分离的重组抗体在HSC-GT前后的反应性。我们发现，在HSC-GT之前，来自ADA-SCID患者的新迁移/过渡性和成熟幼稚B细胞含有更多的自身反应性和表达ana的克隆，表明中枢和外周B细胞耐受检查点存在缺陷。我们进一步观察到ADA抑制后B细胞中B细胞受体（BCR）和TLR功能受损，这可能是B细胞耐受性缺陷的基础。引人注目的是，在HSC-GT后，ADA-SCID患者表现出近乎正常的早期B细胞耐受检查点，这可以通过恢复清除正在发育的自身反应性和表达ana的B细胞来证明。因此，ADA通过调节BCR和TLR功能，在控制自身反应性B细胞反选择中发挥重要作用。
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.