Alterations in the adenosine metabolism and CD39/CD73 adenosinergic machinery cause loss of Treg cell function and autoimmunity in ADA-deficient SCID
Alterations in the adenosine metabolism and CD39/CD73 adenosinergic machinery cause loss of Treg cell function and autoimmunity in ADA-deficient SCID
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DOI：
10.1182/blood-2011-07-366781
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发表时间：
2012-02-09
期刊：
影响因子：
20.3
通讯作者：
Aiuti, Alessandro
中科院分区：
文献类型：
--
作者：
Sauer, Aisha V.;Brigida, Immacolata;Aiuti, Alessandro
腺苷在免疫系统中起抗炎介质的作用，已被描述为调节性T细胞(Treg)介导的抑制。在缺乏腺苷脱氨酶(ADA)的情况下，腺苷和其他嘌呤代谢物会积累，导致严重的免疫缺陷和反复感染(ADA-SCID)。尤其是晚发型的ADA缺乏症患者，在接受酶替代治疗(PEGADA)后，会表现出免疫失调。在此，我们提供的证据表明，嘌呤代谢的改变干扰了Treg功能，从而有助于ADA缺乏症的自身免疫表现。从接受聚乙二醇ADA治疗的患者中分离出的Tregs数量减少，抑制活性降低，但在基因治疗后它们会得到纠正。未经处理的小鼠ADA(-/-)Treg显示质膜CD39/CD73胞外核糖核酸酶机制的改变，并通过细胞外腺苷抑制活性有限。与接受骨髓移植或基因治疗的小鼠相比，接受PEG-ADA治疗的小鼠出现了多种自身抗体和甲状腺功能减退。从PEG-ADA处理的小鼠中分离出来的Treg缺乏抑制活性，这表明这种治疗干扰了Treg的功能。ADA缺乏的Treg细胞中CD39/CD73腺苷能机制的改变和功能的丧失为ADA-SCID患者的自身免疫易感性和导致外周耐受缺陷的潜在机制提供了新的见解。试验在www.Clinicaltrials.gov上注册为NCT00598481/NCT00599781。(血。2012年；119(6)：1428-1439)
Adenosine acts as anti-inflammatory mediator on the immune system and has been described in regulatory T cell (Treg)-mediated suppression. In the absence of adenosine deaminase (ADA), adenosine and other purine metabolites accumulate, leading to severe immunodeficiency with recurrent infections (ADA-SCID). Particularly ADA-deficient patients with late-onset forms and after enzyme replacement therapy (PEG-ADA) are known to manifest immune dysregulation. Herein we provide evidence that alterations in the purine metabolism interfere with Treg function, thereby contributing to autoimmune manifestations in ADA deficiency. Tregs isolated from PEG-ADA-treated patients are reduced in number and show decreased suppressive activity, whereas they are corrected after gene therapy. Untreated murine ADA(-/-) Tregs show alterations in the plasma membrane CD39/CD73 ectonucleotidase machinery and limited suppressive activity via extracellular adenosine. PEG-ADA-treated mice developed multiple autoantibodies and hypothyroidism in contrast to mice treated with bone marrow transplantation or gene therapy. Tregs isolated from PEG-ADA-treated mice lacked suppressive activity, suggesting that this treatment interferes with Treg functionality. The alterations in the CD39/CD73 adenosinergic machinery and loss of function in ADA-deficient Tregs provide new insights into a predisposition to autoimmunity and the underlying mechanisms causing defective peripheral tolerance in ADA-SCID. Trials were registered at www.clinicaltrials.gov as NCT00598481/NCT00599781. (Blood. 2012; 119(6): 1428-1439)