Nakano Yoko, Longo-Guess Chantal M, Bergstrom David E, Nauseef William M, Jones Sherri M, Bánfi Botond
Department of Anatomy and Cell Biology, Inflammation Program, University of Iowa, Iowa City, Iowa, USA.
J Clin Invest. 2008 Mar;118(3):1176-85. doi: 10.1172/JCI33835.
In humans, hereditary inactivation of either p22(phox) or gp91(phox) leads to chronic granulomatous disease (CGD), a severe immune disorder characterized by the inability of phagocytes to produce bacteria-destroying ROS. Heterodimers of p22(phox) and gp91(phox) proteins constitute the superoxide-producing cytochrome core of the phagocyte NADPH oxidase. In this study, we identified the nmf333 mouse strain as what we believe to be the first animal model of p22(phox) deficiency. Characterization of nmf333 mice revealed that deletion of p22(phox) inactivated not only the phagocyte NADPH oxidase, but also a second cytochrome in the inner ear epithelium. As a consequence, mice of the nmf333 strain exhibit a compound phenotype consisting of both a CGD-like immune defect and a balance disorder caused by the aberrant development of gravity-sensing organs. Thus, in addition to identifying a model of p22(phox)-dependent immune deficiency, our study indicates that a clinically identifiable patient population with an otherwise cryptic loss of gravity-sensor function may exist. Thus, p22(phox) represents a shared and essential component of at least 2 superoxide-producing cytochromes with entirely different biological functions. The site of p22(phox) expression in the inner ear leads us to propose what we believe to be a novel mechanism for the control of vestibular organogenesis.
在人类中，p22(phox)或gp91(phox)的遗传性失活会导致慢性肉芽肿病（CGD），这是一种严重的免疫紊乱疾病，其特征是吞噬细胞无法产生破坏细菌的活性氧（ROS）。p22(phox)和gp91(phox)蛋白的异二聚体构成了吞噬细胞NADPH氧化酶产生超氧化物的细胞色素核心。在本研究中，我们将nmf333小鼠品系鉴定为我们认为的首个p22(phox)缺陷动物模型。对nmf333小鼠的特征分析表明，p22(phox)的缺失不仅使吞噬细胞NADPH氧化酶失活，还使内耳上皮中的另一种细胞色素失活。因此，nmf333品系的小鼠表现出一种复合表型，包括类似CGD的免疫缺陷和由重力感应器官异常发育引起的平衡障碍。因此，除了鉴定出一种p22(phox)依赖性免疫缺陷模型外，我们的研究表明可能存在一类临床上可识别的患者群体，他们存在重力传感器功能隐匿性丧失的情况。因此,p22(phox)代表了至少两种具有完全不同生物学功能的超氧化物产生细胞色素的共同且必需的成分。p22(phox)在内耳中的表达位点使我们提出了一种我们认为控制前庭器官发生的新机制。
