Transgenic Animal Models Of Human Immune Defects

我们试图通过检查免疫缺陷的后果来了解吞噬细胞在免疫功能中的作用。我们的主要关注点是慢性肉芽肿性疾病(CGD)，它是由NADPH氧化酶缺陷引起的。NADPH氧化酶参与炎症的产生和控制，保护免受感染，以及细胞间的信号传递。我们有一个全面的产品组合，涉及患者、动物和实验室标本。 我们继续探索CGD的胃肠道表现，因为几乎50%的患者会发展为炎症性肠病。我们已经在世界上最大的病例队列中描述了胃肠道组织病理学和手术的作用。我们已经对新诊断的革兰氏杆菌变性病例的分子和功能方面进行了表征，包括来自葡萄牙的一株分离物，它在人类报告和CGD小鼠中似乎都更具致病性。 高IgE反复感染综合征(HIEs或Job‘s综合征)是一种常染色体显性遗传病，其特征是由于STAT3引起的IgE异常升高、反复的中国肺部感染、骨量减少、脊柱后凸、肺囊肿和牙齿异常，其遗传学和细胞学基础的确定为广泛的研究领域提供了信息。通过NIAID、NIAMS和校外合作者，我们已经发现STAT3下游的其他细胞因子异常，最明显的是IL-17，它在约伯综合征患者的细胞中非常低。与NIAMS的研究人员合作，我们创建了STAT3缺乏症的小鼠模型，这种缺乏症损害了伤口愈合和葡萄球菌控制。与NHLBI的研究人员合作，我们继续在体外研究STAT3缺陷患者的血管内皮细胞，从表现出趋化因子产生受损的STAT3缺陷患者的血管内皮细胞和肌肉细胞中分离出来。与NCI的研究人员一起，我们开发了一项全面而成功的DOCK8缺乏症骨髓移植计划 最近，我们在支架蛋白WDR1/AIP1中发现了新的缺陷。有趣的是，在过去的25年里，我们在发现同一基因突变的儿童中也发现了同样的缺陷。 这些结合起来的方法仍然是有效的，并帮助我们了解先天免疫和炎症。这些研究将帮助我们在分子遗传和功能水平上了解几种不同的感染，包括丝状真菌感染。

We seek to understand the role of phagocytes in immune function through examination of the consequences of immune defects. Our major focus is on chronic granulomatous disease (CGD), which is caused by defects in the enzyme NADPH oxidase. The NADPH oxidase is involved in the generation and control of inflammation, protection from infection, and cell-cell signaling. We have a comprehensive portfolio involving patients, animals, and laboratory specimens. We have continued our exploration of the gastrointestinal manifestations of CGD, since almost 50% of patients develop inflammatory bowel disease. We have characterized the gastrointestinal histopathology and the role of surgery in the world's largest cohort of cases. We have characterized the molecular and functional aspects of newly diagnosed cases of Granulibacter bethesdensis, including an isolate from Portugal, which appears to be more pathogenic both in human reports and in CGD mice. Identification of the genetic and cellular basis of hyper-IgE recurrent infection syndrome (HIES or Job's syndrome), an autosomal dominant disease characterized by extremely elevated IgE, recurrent sino-pulmonary infections, osteopenia, kyphoscoliosis, pulmonary cysts, and dental abnormalities, as being due to STAT3 has informed broad areas of investigation. With NIAID, NIAMS and extramural collaborators we have identified abnormalities in other cytokines downstream of STAT3, most notably IL-17, which is profoundly low in cells from Job's syndrome patients. Collaborating with investigators in NIAMS we have created a mouse model of STAT3 deficiency which has impaired wound healing and staphylococcal control. Collaborating with investigators in NHLBI we continue to study vascular endothelial cells from patients with STAT3 deficeincy in vitro, deriving endothelial and muscle cells from STAT3 deficient patients that have shown impaired chemokine production. With NCI investigators we have developed a comprehensive and successful bone marrow transplantation program for DOCK8 deficiency Recently we identified novel defects in the scaffolding protein WDR1/AIP1. Interestingly enough, we have found the same defect in children seen here over the last 25 years with identified mutations in the same gene. These combined approaches continue to be productive and help us understand innate immunity and inflammation. These studies will help us understand several different infections, including filamentous fungal infections, at a molecular genetic and functional level.