Mitochondrial basis for immune deficiency. Evidence from purine nucleoside phosphorylase-deficient mice.
Mitochondrial basis for immune deficiency. Evidence from purine nucleoside phosphorylase-deficient mice.
复制标题
DOI：
10.1084/jem.191.12.2197
复制
发表时间：
2000-06-19
影响因子：
15.3
通讯作者：
Cohen, A
中科院分区：
文献类型：
--
作者：
Arpaia, E;Benveniste, P;Di Cristofano, A;Gu, Y;Dalal, I;Kelly, S;Hershfield, M;Pandolfi, P P;Roifman, C M;Cohen, A
我们产生了嘌呤核苷磷酸化酶(PNP)缺陷小鼠，以深入了解与PNP缺陷相关的人类免疫缺陷疾病的机制。与人类疾病类似，小鼠的PNP缺陷会导致免疫缺陷，对T淋巴细胞的影响比B淋巴细胞更严重。PNP基因敲除小鼠表现出胸腺细胞分化受损，有丝分裂反应和同种异体反应减少，成熟胸腺细胞和外周T细胞数量减少。PNP基因缺陷小鼠的T淋巴细胞在体内表现出更高的凋亡率，在体外对伽玛射线具有更高的敏感性。我们认为，PNP缺乏症的免疫缺陷是由于dGTP在线粒体中的积累而抑制线粒体DNA修复的结果。最终结果是T细胞对自发的线粒体DNA损伤的敏感性增加，导致T细胞因凋亡而枯竭。
We generated purine nucleoside phosphorylase (PNP)-deficient mice to gain insight into the mechanism of immune deficiency disease associated with PNP deficiency in humans. Similar to the human disease, PNP deficiency in mice causes an immunodeficiency that affects T lymphocytes more severely than B lymphocytes. PNP knockout mice exhibit impaired thymocyte differentiation, reduced mitogenic and allogeneic responses, and decreased numbers of maturing thymocytes and peripheral T cells. T lymphocytes of PNP-deficient mice exhibit increased apoptosis in vivo and higher sensitivity to gamma irradiation in vitro. We propose that the immune deficiency in PNP deficiency is a result of inhibition of mitochondrial DNA repair due to the accumulation of dGTP in the mitochondria. The end result is increased sensitivity of T cells to spontaneous mitochondrial DNA damage, leading to T cell depletion by apoptosis.