Transgenic Animal Models Of Human Immune Defects

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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. Over the last year we have collaborated in the characterization of the role of residual NADPH activity in survival of CGD patients (Kuhns et al, NEJM 2010). This paper clarified the role of superoxide in infection susceptibility and survival. Surprisingly, it showed that superoxide production is not tied to inflammatory bowel disease but is related to liver disease. We also published a seminal paper on the complications of TNF blockade in CGD-related inflammatory bowel disease, leading to severe infections and death (Uzel et al, CID 2010). This is the first report of the role of residual TNF in protection from infection in CGD and a significant caution for the use of these drugs in CGD. Interestingly, all patients with CGD have elevated levels of antibodies associated with inflammatory bowel disease, both those with and without bowel complaints (Yu et al, ClinImm 2011). Therefore, these serologic tests are of no value in CGD. We have continued our exploration of the seroepidemiology of Granulibacter bethesdensis, a novel Gram negative organism with a host range limited to CGD. We have confirmed a seropositivity rate of almost 75% in CGD patients, but an impressive 25% in normal individuals. 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 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. We have recently shown that salivary levels of IL-17 are important in killing of oral candida and serioulsy impaired in STAT3 deficient humans. 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 have studied 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. Recently we examined a patient with mild neutropenia, thrombocytopenia, recurrent infections, and profoundly impaired oral wound healing. Through careful biochemistry and molecular approaches we have identified this child as having a novel defect in the scaffolding protein WDR1. Interestingly enough, we have found the same defect in a child seen her 25 years ago with similar pathology who and 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 fungal infections, at a molecular genetic and functional level.