We seek to understand the role of enzyme systems in host 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. We are also pursuing the genetic and cellular basis of another complex host defense defect, hyper-IgE and 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 must be 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 are now in the process of examining the data from over 90 candidate families. In the course of these studies we have identified novel phenocopies of Job's syndrome that are transmitted in a recessive pattern. 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.
| Falcone, E Liana; Petts, Jennifer R; Fasano, Mary Beth et al. (2016) Methylotroph Infections and Chronic Granulomatous Disease. Emerg Infect Dis 22:404-9 |
| Hsu, Amy P; Sowerwine, Kathryn J; Lawrence, Monica G et al. (2013) Intermediate phenotypes in patients with autosomal dominant hyper-IgE syndrome caused by somatic mosaicism. J Allergy Clin Immunol 131:1586-93 |
| Kuhns, Douglas B; Alvord, W Gregory; Heller, Theo et al. (2010) Residual NADPH oxidase and survival in chronic granulomatous disease. N Engl J Med 363:2600-10 |
| Cortes, Lizette M; Mattapallil, Mary J; Silver, Phyllis B et al. (2008) Repertoire analysis and new pathogenic epitopes of IRBP in C57BL/6 (H-2b) and B10.RIII (H-2r) mice. Invest Ophthalmol Vis Sci 49:1946-56 |
| Ling, Jennifer C; Freeman, Alexandra F; Gharib, Ahmed M et al. (2007) Coronary artery aneurysms in patients with hyper IgE recurrent infection syndrome. Clin Immunol 122:255-8 |
| Freeman, Alexandra F; Collura-Burke, Christina J; Patronas, Nicholas J et al. (2007) Brain abnormalities in patients with hyperimmunoglobulin E syndrome. Pediatrics 119:e1121-5 |
| Greenberg, David E; Porcella, Stephen F; Zelazny, Adrian M et al. (2007) Genome sequence analysis of the emerging human pathogenic acetic acid bacterium Granulibacter bethesdensis. J Bacteriol 189:8727-36 |
| Woellner, Cristina; Schaffer, Alejandro A; Puck, Jennifer M et al. (2007) The hyper IgE syndrome and mutations in TYK2. Immunity 26:535;author reply 536 |
| Doerries, Carola; Grote, Karsten; Hilfiker-Kleiner, Denise et al. (2007) Critical role of the NAD(P)H oxidase subunit p47phox for left ventricular remodeling/dysfunction and survival after myocardial infarction. Circ Res 100:894-903 |
| Siddiqui, Sophia; Anderson, Victoria L; Hilligoss, Diane M et al. (2007) Fulminant mulch pneumonitis: an emergency presentation of chronic granulomatous disease. Clin Infect Dis 45:673-81 |
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