Mitchell B S, Kelley W N
Ann Intern Med. 1980 Jun;92(6):826-31. doi: 10.7326/0003-4819-92-6-826.
Deficiencies of two enzymes that catalyze sequential reactions in the purine catabolic pathway have been causally associated with immunodeficiency states. Adenosine deaminase (ADA) deficiency results in severe combined immunodeficiency disease, while purine nucleoside phosphorylase (PNP) deficiency results in an isolated T-cell defect. Recent work in this area has provided major new insights into the molecular pathology of these syndromes. Deoxyadenosine and deoxyguanosine, substrates that accumulate in ADA and deoxyguanosine, substrates that accumulate in ADA and PNP deficiency, respectively, appear to be selectively phosphorylated by lymphoid cells to the corresponding deoxynucleoside triphosphate, resulting in inhibition of DNA synthesis in these cells. Both deoxynucleosides are far more toxic to cultured T lymphoblasts than to B lymphoblasts. Adenosine and deoxyadenosine may have additional lymphotoxic effects mediated by inhibition of essential methylation reactions. These observations help to explain the immunologic manifestations of ADA and PNP deficiency. Perhaps more important, they lay the foundation for the use of deoxynucleosides or enzyme inhibitors, or both, as selective immunosuppressive and chemotherapeutic agents.
催化嘌呤分解代谢途径中连续反应的两种酶的缺陷已被证实与免疫缺陷状态存在因果关系。腺苷脱氨酶（ADA）缺乏会导致严重联合免疫缺陷病，而嘌呤核苷磷酸化酶（PNP）缺乏会导致单纯T细胞缺陷。该领域最近的研究为这些综合征的分子病理学提供了重要的新见解。脱氧腺苷和脱氧鸟苷分别是在ADA和PNP缺乏时积累的底物，它们似乎被淋巴细胞选择性地磷酸化为相应的三磷酸脱氧核苷，从而抑制这些细胞中的DNA合成。这两种脱氧核苷对培养的T淋巴母细胞的毒性远比对B淋巴母细胞的毒性大。腺苷和脱氧腺苷可能通过抑制必需的甲基化反应而具有额外的淋巴细胞毒性作用。这些观察结果有助于解释ADA和PNP缺乏的免疫学表现。也许更重要的是，它们为使用脱氧核苷或酶抑制剂，或两者兼用，作为选择性免疫抑制剂和化疗药物奠定了基础。
