UCL Great Ormond Street Institute of Child Health, London, UK.
Department of Experimental and Clinical Biomedical Sciences, University of Florence and Newborn Screening, Clinical Chemistry and Pharmacology Lab, Meyer Children's Hospital, Florence, Italy.
Sci Rep. 2021 Dec 1;11(1):23221. doi: 10.1038/s41598-021-02572-w.
Deficiency of adenosine deaminase (ADA, EC3.5.4.4), a housekeeping enzyme intrinsic to the purine salvage pathway, leads to severe combined immunodeficiency (SCID) both in humans and mice. Lack of ADA results in the intracellular accumulation of toxic metabolites which have effects on T cell development and function. While untreated ADA-SCID is a fatal disorder, there are different therapeutic options available to restore ADA activity and reconstitute a functioning immune system, including enzyme replacement therapy (ERT). Administration of ERT in the form of pegylated bovine ADA (PEG-ADA) has proved a life-saving though non-curative treatment for ADA-SCID patients. However, in many patients treated with PEG-ADA, there is suboptimal immune recovery with low T and B cell numbers. Here, we show reduced thymus cellularity in ADA-SCID mice despite weekly PEG-ADA treatment. This was associated with lack of effective adenosine (Ado) detoxification in the thymus. We also show that thymocyte development in ADA-deficient thymi is arrested at the DN3-to-DN4 stage transition with thymocytes undergoing dATP-induced apoptosis rather than defective TCRβ rearrangement or β-selection. Our studies demonstrate at a detailed level that exogenous once-a-week enzyme replacement does not fully correct intra-thymic metabolic or immunological abnormalities associated with ADA deficiency.
腺苷脱氨酶（ADA，EC3.5.4.4）缺乏症是一种内在的嘌呤补救途径的管家酶，可导致人类和小鼠的严重联合免疫缺陷（SCID）。ADA 的缺乏导致细胞内有毒代谢物的积累，这些代谢物对 T 细胞的发育和功能有影响。虽然未经治疗的 ADA-SCID 是一种致命的疾病，但有不同的治疗选择可用于恢复 ADA 活性并重建正常的免疫系统，包括酶替代疗法（ERT）。以聚乙二醇化牛 ADA（PEG-ADA）形式的 ERT 已被证明是 ADA-SCID 患者的救命而非治愈性治疗。然而，在许多接受 PEG-ADA 治疗的患者中，T 和 B 细胞数量较少，免疫恢复不理想。在这里，我们尽管每周进行 PEG-ADA 治疗，但在 ADA-SCID 小鼠中观察到胸腺细胞减少。这与胸腺中腺苷（Ado）的有效解毒缺乏有关。我们还表明，ADA 缺陷型胸腺中的胸腺细胞发育在 DN3 到 DN4 阶段过渡时停滞不前，胸腺细胞经历 dATP 诱导的凋亡，而不是 TCRβ 重排或β选择缺陷。我们的研究在详细水平上表明，每周一次的外源性酶替代不能完全纠正与 ADA 缺乏相关的胸腺内代谢或免疫异常。
