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。我们主要关注慢性肉芽肿病（CGD），这是由NADPH氧化酶缺陷引起的。NADPH氧化酶参与炎症的产生和控制，保护免受感染和细胞-细胞信号传导。 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%的患者发生炎症性肠病。我们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。我们已经表征了新诊断的贝塞登颗粒杆菌病例的分子和功能方面，包括来自葡萄牙的分离株，该分离株在人类报告和CGD小鼠中似乎更具致病性。我们还定义了CGD肠病的微生物组学方面，这在炎症诱导中很重要。 高IgE复发性感染综合征（HIES或Job综合征）是一种常染色体显性遗传疾病，其特征是IgE极高、复发性鼻窦-肺感染、骨质减少、脊柱后凸、肺囊肿和牙齿异常，其遗传和细胞基础的鉴定是由于STAT 3引起的，这为广泛的研究领域提供了信息。通过NIAID，NIAMS和校外合作者，我们已经确定了STAT 3下游其他细胞因子的异常，最值得注意的是IL-17，其在Job综合征患者的细胞中非常低。与NIAMS的研究人员合作，我们建立了一个STAT 3缺陷的小鼠模型，该模型损害了伤口愈合和葡萄球菌控制。此外，这些小鼠的感染部分是由促炎分子肿瘤坏死因子驱动的，这为治疗提供了新的途径。与NHLBI的研究人员合作，我们继续在体外研究来自STAT 3缺陷患者的血管内皮细胞，从显示出趋化因子产生受损的STAT 3缺陷患者中获得内皮细胞和肌肉细胞。与NCI研究人员一起，我们开发了一种全面而成功的DOCK 8缺乏症骨髓移植计划。 最近，我们发现蛋白质RAC 2中的从头显性突变可导致严重的T和B细胞淋巴细胞减少症、骨髓功能障碍和反复呼吸道感染。在3例患者中发现显性激活突变。 这些结合的方法继续是富有成效的，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. 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.