Residual NADPH oxidase and survival in chronic granulomatous disease.
Residual NADPH oxidase and survival in chronic granulomatous disease.
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DOI：
10.1056/nejmoa1007097
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发表时间：
2010-12-30
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影响因子：
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通讯作者：
Gallin JI
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作者：
Kuhns DB;Alvord WG;Heller T;Feld JJ;Pike KM;Marciano BE;Uzel G;DeRavin SS;Priel DA;Soule BP;Zarember KA;Malech HL;Holland SM;Gallin JI
不能产生吞噬细胞衍生的超氧化物和相关的活性氧中间体（ROIs）是慢性肉芽肿病的主要缺陷，导致反复感染和肉芽肿并发症。慢性肉芽肿疾病是由p22phox、p40phox、p47phox、p67phox（常染色体慢性肉芽肿病）或gp91phox （x连锁慢性肉芽肿病）基因的错义、无义、移码、剪接或缺失突变引起的，这些基因导致中性粒细胞衍生的roi产生变化。我们假设剩余ROI产生可能与慢性肉芽肿疾病患者的生存有关。我们对244种慢性肉芽肿性疾病的287例患者的患病和死亡风险进行了评估。使用超氧化物依赖性铁细胞色素c还原和二氢何旦氧化法流式细胞术测量剩余ROI的产生。通过免疫印迹法检测NADPH氧化酶组分蛋白的表达，并对受影响的基因进行测序以确定致病突变。慢性肉芽肿性疾病患者的生存与剩余ROI产生作为一个连续变量密切相关，独立于受影响的特定基因。p47phox突变和大多数gp91phox错义突变（核苷酸结合域和血红素结合域的错义突变除外）的患者比gp91phox无义、移码、剪接或缺失突变的患者产生更多的剩余ROI。青春期后，死亡率曲线根据剩余ROI产生的程度而分化。患有慢性肉芽肿性疾病且ROI残余产生适度的患者，其严重程度明显低于ROI残余产生很少的患者，且长期生存的可能性更大。剩余ROI的产生可以通过特定的NADPH氧化酶突变来预测，而不管受影响的特定基因是什么，它是慢性肉芽肿病患者生存的一个预测因素。（由美国国立卫生研究院资助。）
Failure to generate phagocyte-derived superoxide and related reactive oxygen intermediates (ROIs) is the major defect in chronic granulomatous disease, causing recurrent infections and granulomatous complications. Chronic granulomatous disease is caused by missense, nonsense, frameshift, splice, or deletion mutations in the genes for p22phox, p40phox, p47phox, p67phox (autosomal chronic granulomatous disease), or gp91phox (X-linked chronic granulomatous disease), which result in variable production of neutrophil-derived ROIs. We hypothesized that residual ROI production might be linked to survival in patients with chronic granulomatous disease. We assessed the risks of illness and death among 287 patients with chronic granulomatous disease from 244 kindreds. Residual ROI production was measured with the use of superoxide-dependent ferricytochrome c reduction and flow cytometry with dihydrorhodamine oxidation assays. Expression of NADPH oxidase component protein was detected by means of immunoblotting, and the affected genes were sequenced to identify causal mutations. Survival of patients with chronic granulomatous disease was strongly associated with residual ROI production as a continuous variable, independently of the specific gene affected. Patients with mutations in p47phox and most missense mutations in gp91phox (with the exception of missense mutations in the nucleotide-binding and heme-binding domains) had more residual ROI production than patients with nonsense, frameshift, splice, or deletion mutations in gp91phox. After adolescence, mortality curves diverged according to the extent of residual ROI production. Patients with chronic granulomatous disease and modest residual production of ROI have significantly less severe illness and a greater likelihood of long-term survival than patients with little residual ROI production. The production of residual ROI is predicted by the specific NADPH oxidase mutation, regardless of the specific gene affected, and it is a predictor of survival in patients with chronic granulomatous disease. (Funded by the National Institutes of Health.)