Carson D A, Seto S, Wasson D B
J Exp Med. 1986 Mar 1;163(3):746-51. doi: 10.1084/jem.163.3.746.
The metabolic causes for immune impairment in patients with severe chronic inflammatory diseases have not been clearly defined. Recently, the overproduction of poly(ADP-ribose) in resting lymphocytes with unrepaired DNA strand breaks has been suggested to contribute to immune dysfunction in adenosine deaminase-deficient patients. Our experiments have determined to what extent DNA damage and poly(ADP-ribose) synthesis might also explain the impaired mitogen responsiveness of PBL exposed to toxic oxygen species. Treatment of normal resting human lymphocytes with xanthine oxidase and hypoxanthine dose-dependently induced DNA strand breaks and triggered the rapid synthesis of poly(ADP-ribose). Subsequently, NAD+ and ATP pools decreased precipitously. Lymphocytes exposed previously to the enzymatic oxidizing system did not synthesize DNA after stimulation with PHA. However, if the medium was supplemented with 3-aminobenzamide or nicotinamide, two compounds that inhibit poly(ADP-ribose) formation, cellular NAD+ and ATP pools were preserved, and the lymphocytes responded vigorously to a mitogenic challenge. Excessive poly(ADP-ribose) synthesis, provoked by DNA strand breakage, may represent a common pathway that connects the immunodeficiency syndromes associated with (a) exposure of lymphocytes to toxic oxygen species during chronic inflammatory states, (b) adenosine deaminase deficiency, and (c) certain DNA repair disorders.
严重慢性炎症性疾病患者免疫功能受损的代谢原因尚未明确界定。最近有研究表明，静止淋巴细胞中存在未修复的DNA链断裂时，聚（ADP - 核糖）的过度产生可能导致腺苷脱氨酶缺乏患者的免疫功能障碍。我们的实验已确定DNA损伤和聚（ADP - 核糖）合成在多大程度上也可能解释暴露于毒性氧物质的外周血淋巴细胞丝裂原反应性受损的原因。用黄嘌呤氧化酶和次黄嘌呤对正常静止的人淋巴细胞进行处理，会剂量依赖性地诱导DNA链断裂并引发聚（ADP - 核糖）的快速合成。随后，NAD⁺和ATP池急剧减少。先前暴露于酶促氧化系统的淋巴细胞在用PHA刺激后不合成DNA。然而，如果培养基中添加了3 - 氨基苯甲酰胺或烟酰胺这两种抑制聚（ADP - 核糖）形成的化合物，细胞内的NAD⁺和ATP池得以保留，并且淋巴细胞对丝裂原刺激有强烈反应。由DNA链断裂引发的过度聚（ADP - 核糖）合成可能代表了一条共同途径，它将与以下情况相关的免疫缺陷综合征联系起来：（a）慢性炎症状态下淋巴细胞暴露于毒性氧物质，（b）腺苷脱氨酶缺乏，以及（c）某些DNA修复障碍。
