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。我们的主要重点是慢性肉芽肿病（CGD），这是由酶NADPH氧化酶缺陷引起的。NADPH氧化酶参与炎症的产生和控制，防止感染和细胞-细胞信号传导。我们有一个涉及患者、动物和实验室标本的综合投资组合。

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. We have also defined the microbiomic aspects of CGD bowel disease, which are important in the induction of inflammation. 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. Further, the infections in these mice are driven in part by the proinflammatory molecule tumor necrosis factor, offering new avenues for therapy. 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 that de novo dominant mutations in the protein RAC2 can cause severe T- and B-cell lymphopenia, myeloid dysfunction, and recurrent respiratory infections. Dominant activating mutations were found in 3 patients. 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.