Gene expression profiling provides insight into the pathophysiology of chronic granulomatous disease.
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, FcgammaR1, FcalphaR, CD120b, TLR5, IL-4R, CCR1, p47(phox), p40(phox), 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.
Kobayashi
Scott D
SD
Laboratory of Human Bacterial Pathogenesis, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, 903 South 4th Street, Hamilton, MT 59840, USA
Voyich
Jovanka M
JM
Braughton
Kevin R
KR
Whitney
Adeline R
AR
Nauseef
William M
WM
Malech
Harry L
HL
DeLeo
Frank R
FR
D000293:Adolescent; D000328:Adult; D017209:Apoptosis / Q000235:genetics / Q000276:immunology; D041321:Chromosomes, Human, X / Q000235:genetics; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology; D020869:Gene Expression Profiling / Q000379:methods; D008040:Genetic Linkage; D006105:Granulomatous Disease, Chronic / Q000235:genetics* / Q000276:immunology / Q000473:pathology / Q000503:physiopathology*; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000503:physiopathology; D018836:Inflammation Mediators / Q000378:metabolism; D018375:Neutrophil Activation / Q000235:genetics / Q000276:immunology; D009504:Neutrophils / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D010587:Phagocytosis / Q000235:genetics / Q000276:immunology; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000235:genetics; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D019914:Taq Polymerase; D051028:bcl-2-Associated X Protein
D018836:Inflammation Mediators; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; D019914:Taq Polymerase