Transgenic Animal Models Of Human Immune Defects

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Abstract

We seek to understand the role of enzyme systems in normal host function and immune defense, specifically the NADPH oxidase. We study the NADPH oxidase in the generation and control of inflammation, its role in protection from infection, and its role in how cells signal to each other. These are important issues to understand in order to better appreciate how to manipulate the immune system pharmacologically, immunologically, and genetically. We actively pursue a mixed approach to these issues by studying patients, animals, and laboratory specimens. We follow a large number of patients with NADPH oxidase deficiency, chronic granulomatous disease (CGD), and we have been involved in characterizing the infections and complications that 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. [unreadable] [unreadable] Through the study of patients with CGD we have identified a new bacteria that causes infection in CGD, Granulibacter bethesdensis. Biochemical and genetic studies including full genome sequence show it to be the type strain for a new genus and species. 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 4 cases of G. bethesdensis in CGD patients, indicating that this is an important infection in CGD. The frequency of this infection in other populations, including normals, is a topic of active study. We are using the genome of this new agent to compare to the recently published genomes of other well-known CGD pathogens, such as Burkholderia and Francisella, to identify genes that are uniquely associated with virulence in CGD. We belive that this conjoined bench and bedside approach to CGD will allow us to identify importat aspects of both host and infection physiology that will help us treat pateints with CGD better, and to understand inflammation better.[unreadable] [unreadable] Working with neurobiologists we have determined a critical role for the NADPH in the normal neurologic function in mice, specifically in memory. The intact NADPH is critical to normal learning and behavior in mice, and there are subtle differences between the p47 and gp91 deficient animals, suggesting important aspects of genotype and phenotype correlation.[unreadable] [unreadable] We continue to pursue the genetic and cellular basis of another complex host defense defect, hyper-IgE recurrent infection syndrome (Job's syndrome or HIE), an autosomal dominant disease characterized by extremely elevated IgE, recurrent sino- pulmonary infections, osteopenia, kyphoscoliosis, pulmonary cysts, and dental abnormalities. The gene(s) involved in Job's are critically important to innate immunity, the early and late host immune responses, skeletal growth and development, and tooth deciduation. We have developed a comprehensive patient evaluation system and have now implemented it in over 90 candidate families. We have identified that low bone density, which is common in Job's, and the fracture risk, which is high in Job's, are unassociated. That is, patients with Job's have a defect in bone integrity that is independent of bone density, suggesitng other pathways that are involved in the risk of pathologic fracture. We have documented numerous demyelinated lesions in the brains of pateints with Job's, occurring in about two-thirds of patients. These lesions begin early in life and accrue with time. We have also identified numerous aneurysms in Job's syndrome, which enrich the phenotype and suggest new genes for investigation.[unreadable] The search for the genes responsible for these syndromes continues and will eventually lead to pathways that we can disrupt in mice to perform functional studies.[unreadable] [unreadable] These combined approaches continue to be productive and will lead to better understanding of the pathways of innate inflammation. Some of these will be of great interest in other diseases like aneurysm formation, brain demyelination, and bone fractures.