Transgenic Animal Models Of Human Immune Defects

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We seek to understand the role of enzyme systems in normal host function and immune defense, specifically the NADPH oxidase. The NADPH oxidase is involved in the generation and control of inflammation, protection from infection, and cell-cell signaling. Understanding these will let us better appreciate how to manipulate the immune system pharmacologically, immunologically, and genetically. We have a complex portfolio involving patients, animals, and laboratory specimens. We follow a large number of patients with the NADPH oxidase deficiency, chronic granulomatous disease (CGD), and we have been involved in characterizing their infections and the complications they develop. We have also used a mouse created in my laboratory that is deficient in the NADPH oxidase and therefore closely mimics human CGD. Numerous studies in these mice have shown a critical role for this enzyme system in not only protection from infection but also in the magnitude and character of the inflammatory response. This mixed approach to understanding the NADPH oxidase in CGD has been very informative about the role of the innate immune system in both early and late aspects of the inflammatory response. Through the study of patients with CGD we have identified a new bacteria that causes infection in CGD, Granulibacter bethesdensis. This organism has been injected into animal models of CGD and shown to be a significant pathogen in CGD. We have now identified a total of 5 cases of G. bethesdensis in CGD patients, indicating that this is an important infection in CGD. The frequency of this infection in normals as determined by serology is high. This conjoined bench and bedside approach to CGD will allow us to identify important aspects of both host and bacterial physiology that will help us treat patients with CGD better, and to understand inflammation better. Working with collaborators in the mouse model we have determined that CGD pathogens interact with CGD cells diferntly than do non-pathogens, giving us a set of pathways to explore to understand CGD virulence. We have identified several novel fungal infections in CGD this year, including Neosartorya udagawae, and identified novel syndromic presentations with Aspergillus viridinutans in CGD and HIES. 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 activated broad areas of investigation. From clinical grounds we knew that the gene involved in Job's must be critically important to innate immunity, the early and late host immune responses, skeletal growth and development, and tooth deciduation. We have recreated STAT3 mutations in vitro to study their permutations and possible genotype-phenotype correlations. With NIAID and NIAMS 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. These combined approaches continue to be productive and will lead to better understanding of the pathways of innate immunity and inflammation. We believe that these studies will help us understand several different infections, including fungal infections, at a molecular genetic and functional level.