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The Journal of Immunology, 2004, 172: 636-643.
Copyright © 2004 by The American Association of Immunologists

Gene Expression Profiling Provides Insight into the Pathophysiology of Chronic Granulomatous Disease1

Scott D. Kobayashi*, Jovanka M. Voyich*, Kevin R. Braughton*, Adeline R. Whitney*, William M. Nauseef1,{dagger}, Harry L. Malech{ddagger} and Frank R. DeLeo2,*

* Laboratory of Human Bacterial Pathogenesis, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, MT 59840; {dagger} Inflammation Program, University of Iowa, and Iowa City Veterans Administration Medical Center, Coralville, IA 52241; and {ddagger} Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892

Human polymorphonuclear leukocytes (PMNs or neutrophils) kill invading microorganisms with reactive oxygen species (ROS) and cytotoxic granule components. PMNs from individuals with X-linked chronic granulomatous disease (XCGD) do not produce ROS, thereby rendering these individuals more susceptible to infection. In addition, XCGD patients develop tissue granulomas that obstruct vital organs, the mechanism(s) for which are unknown. To gain insight into the molecular processes that contribute to the pathophysiology of XCGD, including formation of granulomas, we compared global gene expression in PMNs from XCGD patients and healthy control individuals. Genes encoding mediators of inflammation and host defense, including CD11c, CD14, CD54, Fc{gamma}R1, Fc{alpha}R, CD120b, TLR5, IL-4R, CCR1, p47phox, p40phox, IL-8, CXCL1, Nramp1, and calgranulins A and B, were up-regulated constitutively in unstimulated XCGD patient PMNs. By comparing transcript levels in normal and XCGD PMNs after phagocytosis, we discovered 206 genes whose expression changed in the presence and the absence of ROS, respectively. Notably, altered Bcl2-associated X protein synthesis accompanied defective neutrophil apoptosis in XCGD patients. We hypothesize that granuloma formation in XCGD patients reflects both increased proinflammatory activity and defective PMN apoptosis, and we conclude that ROS contribute directly or indirectly to the resolution of the inflammatory response by influencing PMN gene transcription.




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