慢性肉芽肿病（CGD）是由吞噬细胞NADPH酶（NOX2）缺陷导致的原发性免疫缺陷病。除感染外，严重的炎症性疾病也是影响患者生存质量的重要原因。其过度炎症反应发生的机制目前仍不清楚。我们前期研究发现，CGD患者PBMC受LPS刺激后，与对照组相比，NF-kB通路的活化较高，Nrf2通路的活化较低；加入H2O2则可抑制NF-kB的活化，并促进Nrf2的活化。因此推测，NOX2缺陷导致的H2O2生成障碍可能是CGD患者过度炎症反应发生的原因。本项目拟分离CGD患者PBMC、单核细胞和中性粒细胞，研究H2O2生成障碍对其吞噬细胞炎症反应的影响，以及这种影响是否由于Nrf2通路缺陷导致；并拟通过过表达和敲低Nrf2，研究其在H2O2介导的吞噬细胞抑炎反应中的作用；最后构建H2O2生成障碍导致CGD患者过度炎症反应的基因调控网络，以期深入阐明CGD过度炎症反应的分子机制，为其提供新的治疗思路和靶点。

Chronic Granulomatous Disease (CGD) is a rare inherited primary immunodeficiency, which is characterized by recurrent infections due to defective phagocyte NADPH oxidase enzyme (NOX2). Besides infectious disease, CGD patients were also always reported to suffer from inflammatory, non-infectious disease. However, the underling mechanism of hyperinflammation in CGD patients is poorly defined. ..In our previous study, we treated the peripheral blood mononuclear cells (PBMC) from CGD patients and healthy controls with LPS to stimulate inflammatory response. An elevated NF-kB signal activation but a defective Nrf2 signal activation was observed in CGD patients compared to healthy controls. Our further study showed that H2O2 could rescue the hyperinflammation by decreasing NF-kB signal activation and promoting Nrf2 signal activation. This indicated that the H2O2 deficiency caused by NOX2 mutations might contribute to the hyperinflammation in CGD patients...In this study, we aim to find out the molecular mechanism of hyperinflammation in CGD patients with NOX2 mutations. Firstly, we will isolate the PBMC, neutrophils and monocytes from CGD patients and healthy controls, then study the regulation of H2O2 on inflammatory response in phagocytes. Secondly, we will try to figure out the contribution of H2O2 deficiency to the defective Nrf2 signal activation in CGD patients. Thirdly, though overexpression and knocking down Nrf2 in immortalized phagocytic cell lines, we will study the function of Nrf2 signal pathway in H2O2 medicated anti-inflammatory reactions. Finally, we will identify gene regulatory networks underlying the hyperinflammation in CGD patients by high-throughput microarray. As a whole, our study aim at revealing the mechanism of hyperinflammation in CGD patients, which will provide new insights into pathogenesis and treatment of this disease.