Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Mouse model of X–linked chronic granulomatous disease, an inherited defect in phagocyte superoxide production

Abstract

Chronic granulomatous disease (CGD) is a recessive disorder characterized by a defective phagocyte respiratory burst oxidase, life–threatening pyogenic infections and inflammatory granulomas. Gene targeting was used to generate mice with a null allele of the gene involved in X–linked CGD, which encodes the 91 kD subunit of the oxidase cytochrome b. Affected hemizygous male mice lacked phagocyte superoxide production, manifested an increased susceptibility to infection with Staphylococcus aureus and Aspergillus fumigatus and had an altered inflammatory response in thioglycollate peritonitis. This animal model should aid in developing new treatments for CGD and in evaluating the role of phagocyte–derived oxidants.in inflammation.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

References

  1. 1

    Curnutte, J. in Hematology of Infancy and Childhood (ed. Oski, F. & Nathan, D.G.) 904–977 (Saunders, Philadelphia, 1993).

    Google Scholar 

  2. 2

    Jackson, H. & Cochrane, C. Leukocyte-induced tissue injury. Hematology/ Oncology Clin. N. America 2, 317–334 (1988).

    CAS  Article  Google Scholar 

  3. 3

    Royer-Pokora, B. et al. Cloning the gene for an inherited human disorder — chronic granulomatous disease — on the basis of its chromosomal location. Nature 322, 32–38 (1986).

    CAS  Article  Google Scholar 

  4. 4

    Dinauer, M.C., Orkin, S.H., Brown, R., Jesaitis, A.J. & Parkos, C.A. The glycoproteln encoded by the X-linked chronic granulomatous disease locus is a component of the neutrophil cytochrome b complex. Nature 327, 717–720 (1987).

    CAS  Article  Google Scholar 

  5. 5

    Teahan, C., Rowe, P., Parker, P., Totty, N. & Segal, A.W., X-linked chronic granulomatous disease gene codes for the β-chain of cytochrome b-245. Nature 327, 720–721 (1987).

    CAS  Article  Google Scholar 

  6. 6

    Dinauer, M.C., Pierce, E.A., Bruns, G.A.P., Curnutte, J.T. & Orkin, S.H. Human neutrophil cytochrome b light chain (p22-phox). Gene structure, chromosomal location, and mutations in cytochrome-negative autsomal recessive chronic granulomatous disease. J. clin. Invest. 86, 1729–1737 (1990).

    CAS  Article  Google Scholar 

  7. 7

    Segal, A.W. et al. Cytochrome b-245 is a flavocytochrome containing FAD and the NADPH-binding site of the microbicidal oxidase of phagocytes. Biochem. J. 284, 781–788 (1992).

    CAS  Article  Google Scholar 

  8. 8

    Rotrosen, D., Yeung, C.L., Leto, T.L., Malech, H.L. & Kwong, C.H. Cytochrome b558: the flavin-binding component of the phagocyte NADPH oxidase. Science 256, 1459–1462 (1992).

    CAS  Article  Google Scholar 

  9. 9

    Dinauer, M. The respiratory burst oxidase and the molecular genetics of chronic granulomatous disease. Crit. Rev. clin. lab. Sci. 30, 329–369 (1993).

    CAS  Article  Google Scholar 

  10. 10

    Roos, D. et al. Chronic granulomatous disease with partial deficiency of cytochrome b558 and incomplete respiratory burst: variants of the X-linked, cytochrome b558 -negative form of the disease. J. leuk. Biol. 51, 164–171 (1992).

    CAS  Article  Google Scholar 

  11. 11

    Gallin, J. et al. Recent advances in chronic granulomatous disease. Ann. int. Med. 99, 657–674 (1983).

    CAS  Article  Google Scholar 

  12. 12

    Elsbach, P. & Weiss, J. in Inflammation: basic principles and clinical correlates (eds Gallin, J., Goldstein, I. & Snyderman, R.) 603–636 (Raven Press, New York, 1992).

    Google Scholar 

  13. 13

    Odell, E. & Segal, A. Killing of pathogens associated with chronic granulomatous disease by the non-oxidative microbicidal mechanisms of human neutrophils. J. med. Microbiol. 34, 129–135 (1991).

    CAS  Article  Google Scholar 

  14. 14

    Malech, H. & Gallin, J. Current concepts: immunology. Neutrophils in human diseases. New Engl. J. Med. 317, 687–694 (1987).

    CAS  Article  Google Scholar 

  15. 15

    Brockdorff, N., Fisher, E.M., Orkin, S.H., Lyon, M.F. & Brown, S.D. Localization of the human X-linked gene for chronic granulomatous disease to the mouse X chromosome: implications for X-chromosome evolution. Cytogenet. Cell Genet. 48, 124–125. (1988).

    CAS  Article  Google Scholar 

  16. 16

    Baehner, R.L. & Nathan, D.G. Quantitative nitroblue tetrazolium test in chronic granulomatous disease. New Engl. J. Med. 278, 971–976 (1968).

    CAS  Article  Google Scholar 

  17. 17

    Parkos, C.A., Allen, R.A., Cochrane, C.G. & Jesaitis, A.J. Purified cytochrome b from human granulocyte plasma membrane is comprised of two polypeptides with relative molecular weights of 91,000 and 22,000. J. clin. Invest. 80, 732–742 (1987).

    CAS  Article  Google Scholar 

  18. 18

    Segal, A. Absence of both cytochrome b-245 subunits from neutrophils in X-linked chronic granulomatous disease. Nature 326, 88–91 (1987).

    CAS  Article  Google Scholar 

  19. 19

    Knoller, S., Shpungin, S. & Pick, E. The membrane-associated component of the amphiphile-activated, cytosol-dependent superoxide-forming NADPH oxidase of macrophages is identical to cytochrome b559 .. J. biol. Chem. 266, 2795–2804 (1991).

    CAS  PubMed  Google Scholar 

  20. 20

    Mayo, L. & Curnutte, J. Kinetic microplate assay for superoxide production by neutrophils and other phagocytic cells. Meth. Enzymol. 186, 567–575 (1990).

    CAS  Article  Google Scholar 

  21. 21

    Segal, A.W., Jones, O.T.G., Webster, D. & Allison, A.C. Absence of a newly described cytochrome b from neutrophils of patients with chronic granulomatous disease. Lancet ii, 446–449 (1978).

    Google Scholar 

  22. 22

    Parkos, C., Dinauer, M., Jesaitis, A., Orkin, S. & Curnutte, J. Absence of both the 91 kD and 22 kD subunits of human neutrophil cytochrome b in two genetic forms of chronic granulomatous disease. Blood 73, 1416–1420 (1989).

    CAS  PubMed  Google Scholar 

  23. 23

    Schaffner, A. in Macrophage-Pathogen Interactions (eds Zwilling, B. & Eisenstein, T.) 545–552 (Marcel Decker, New York, 1994).

    Google Scholar 

  24. 24

    Schaffner, A., Douglas, H. & Braude, A. Selective protection against conidia by mononuclear and against mycelia by polymorphonuclear phagocytes In resistance to aspergillus. J. clin. Invest. 60, 617–631 (1982).

    Article  Google Scholar 

  25. 25

    Diamond, R., Krzesicki, R., Epstein, B. & Jao, W. Damage to hyphal forms of fungi by human leukocytes in vitro: a possible host defense mechanism aspergillosls and mucormycosis. Am. J. Path. 91, 313–328 (1978).

    CAS  PubMed  Google Scholar 

  26. 26

    Gallin, J. & Buescher, E. Abnormal regulation of inflammatory skin responses in male patients with chronic granulomatous disease. Inflammation 7, 227–232 (1983).

    CAS  Article  Google Scholar 

  27. 27

    Xie, Q.-W. & Nathan, C. in Biological Oxidants: Generation and Injurious Consequences (eds Cochrane, C. & Glmbrone, M.J.) 213–235 (Academic, San Diego, 1992).

    Google Scholar 

  28. 28

    Shuster, D., Kehrli, M., Ackermann, M. & Gilbert, R. Identification and prevalence of a genetic defect that causes leukocyte adhesion deficiency in Holstein cattle. Proc. natn. Acad. Sci. U.S.A. 89, 9225–9229 (1992).

    CAS  Article  Google Scholar 

  29. 29

    Padgett, E., Chediak-Higashi syndrome. Adv. Vet. Sci. 12, 239–255 (1968).

    Google Scholar 

  30. 30

    Deschenes, S. et al. Comparative mapping of canine and human proximal Xq and genetic analysis of canine X-linked severe combined immunodeficiency. Genomics 23, 62–68 (1994).

    CAS  Article  Google Scholar 

  31. 31

    Deng, C. & Capecchi, M. Reexamination of gene targeting frequency as a function of the extent of homology between the targeting vector and the target locus. Molec. cell. Biol. 12, 3365–3371 (1992).

    CAS  Article  Google Scholar 

  32. 32

    McBumey, M. et al. The mouse Pgk-1 gene promoter contains an upstream activator sequence. Nucl. Acids Res. 19, 5755–5761 (1991).

    Article  Google Scholar 

  33. 33

    Pevny, L. et al. Erythroid differentiation in chimaeric mice blocked by a targeted mutation in the gene for transcription factor GATA-1. Nature 349, 257–260 (1991).

    CAS  Article  Google Scholar 

  34. 34

    Robertson, E.J. ed. Teratocarcinomas and Embryonic Stem Cells: A Practical Approach (IRL Press, Oxford, 1987).

    Google Scholar 

  35. 35

    Zhen, L. et al. Gene targeting of X-linked chronic granulomatous disease locus in a human myeloid leukemia cell line and rescue by expression of recombinant gp91phox. Proc. natn. Acad. Sci. U.S.A. 90, 9832–9836 (1993).

    CAS  Article  Google Scholar 

  36. 36

    Du, X., Neben, T., Goldman, S. & Williams, D. Effects of recombinant human interleukin-11 on hematopoietic reconstitution in transplant mice: Acceleration of recovery of peripheral blood neutrophils and platelets. Blood 81, 27–34 (1993).

    CAS  PubMed  Google Scholar 

  37. 37

    Ochs, H. & Igo, R. The NBT slide test: a simple screening method for detecting chronic granulomatous disease and female carriers. J. Pediatr. 83, 77–85 (1973).

    CAS  Article  Google Scholar 

  38. 38

    Heyworth, P.G. et al. Neutrophil nicotinamide adenine dinucleotide phosphate oxidase assembly. Translocation of p47-phox and p67-phox requires interaction between p47-phox and cytochrome b-558. J. clin. Invest. 87, 352–356 (1991).

    CAS  Article  Google Scholar 

  39. 39

    Dinauer, M.C. et al. Point mutation in the cytoplasmic domain of the neutrophil p22-phox cytochrome b subunit is associated with a nonfunctional NADPH oxidase and chronic granulomatous disease. Proc. natn. Acad. Sci. U.S.A. 88, 11231–11235 (1991).

    CAS  Article  Google Scholar 

  40. 40

    Savill, J. et al. Macrophage phagocytosis of aging neutrophils in inflammation. J. clin. Invest. 83, 865–875 (1989).

    CAS  Article  Google Scholar 

  41. 41

    Graybill, J. & Kaster, S. Experimental murine aspergillosis: comparison of amphotericin B and a new polyene antifungal drug, SCH 28191. Am. Rev. Respir. Dis. 129, 292–295 (1984).

    CAS  PubMed  Google Scholar 

  42. 42

    Dixon, D., Polak, A. & Walsh, T. Fungus dose-dependent primary pulmonary aspergillosis in immunosuppressed mice. Infect. Immun. 57, 1452–1456 (1989).

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Affiliations

Authors

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Pollock, J., Williams, D., Gifford, M. et al. Mouse model of X–linked chronic granulomatous disease, an inherited defect in phagocyte superoxide production. Nat Genet 9, 202–209 (1995). https://doi.org/10.1038/ng0295-202

Download citation

Further reading

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing