Chronic granulomatous disease



Chronic granulomatous disease (CGD) is a rare primary immunodeficiency due to an abnormal function of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase; NADPH oxidase is a key enzyme for the cellular “respiratory burst”, the cellular process that converts molecular oxygen to the oxygen free-radical superoxide. As a consequence of NADPH oxidase defect, CGD patients suffer from recurrent life-threatening infections and from exceeding inflammatory responses leading to granulomas. This article analyzes clinical aspects of CGD. Furthermore, using the CGD model, we focused on the future perspective to reduce atherosclerosis and its complications.


Chronic granulomatous disease NADPH oxidase Oxidative stress Atherosclerosis Microbial killing defect 


  1. 1.
    Winkelstein JA, Marino MC, Johnston RB, Jr, Curnutte J, Gallin JI, Holland SM, Ochs H, Buckley RH, Foster CB, Chanock SJ, Dickler H (2000) Chronic granulomatous disease. Report on a national registry of 368 patients. Medicine (Baltimore) 79:155–169CrossRefGoogle Scholar
  2. 2.
    Cave AC, Brewer AC, Narayanapanicker A, Ray R, Grieve DJ, Walker S, Shah AM (2006) NADPH oxidases in cardiovascular health and disease. Antioxid Redox Signal 8:691–728PubMedCrossRefGoogle Scholar
  3. 3.
    Bedard K, Krause KH (2007) The NOX family of ROS-generating NADPH oxidases: physiology and pathophysiology. Physiol Rev 87:245–313PubMedCrossRefGoogle Scholar
  4. 4.
    Martire B, Rondelli R, Soresina A, Pignata C, Broccoletti T, Finocchi A, Rossi P, Gattorno M, Rabusin M, Azzari C, Dellepiane RM, Pietrogrande MC, Trizzino A, Di Bartolomeo P, Martino S, Carpino L, Cossu F, Locatelli F, Maccario R, Pierani P, Putti MC, Stabile A, Notarangelo LD, Ugazio AG, Plebani A, De Mattia D (2008) Clinical features, long-term follow-up and outcome of a large cohort of patients with Chronic Granulomatous Disease: an Italian multicenter study. Clin Immunol 126:155–164PubMedCrossRefGoogle Scholar
  5. 5.
    van den Berg JM, van Koppen E, Ahlin A, Belohradsky BH, Bernatowska E, Corbeel L, Espanol T, Fischer A, Kurenko-Deptuch M, Mouy R, Petropoulou T, Roesler J, Seger R, Stasia MJ, Valerius NH, Weening RS, Wolach B, Roos D, Kuijpers TW (2009) Chronic granulomatous disease: the European experience. PLoS One 4:e5234PubMedCrossRefGoogle Scholar
  6. 6.
    Richardson MP, Ayliffe MJ, Helbert M, Davies EG (1998) A simple flow cytometry assay using dihydrorhodamine for the measurement of the neutrophil respiratory burst in whole blood: comparison with the quantitative nitrobluetetrazolium test. J Immunol Methods 219:187–193PubMedCrossRefGoogle Scholar
  7. 7.
    Mauch L, Lun A, O’Gorman MR, Harris JS, Schulze I, Zychlinsky A, Fuchs T, Oelschlagel U, Brenner S, Kutter D, Rosen-Wolff A, Roesler J (2007) Chronic granulomatous disease (CGD) and complete myeloperoxidase deficiency both yield strongly reduced dihydrorhodamine 123 test signals but can be easily discerned in routine testing for CGD. Clin Chem 53:890–896PubMedCrossRefGoogle Scholar
  8. 8.
    Kuhns DB, Alvord WG, Heller T, Feld JJ, Pike KM, Marciano BE, Uzel G, DeRavin SS, Priel DA, Soule BP, Zarember KA, Malech HL, Holland SM, Gallin JI (2010) Residual NADPH oxidase and survival in chronic granulomatous disease. N Engl J Med 363:2600–2610PubMedCrossRefGoogle Scholar
  9. 9.
    Matute JD, Arias AA, Wright NA, Wrobel I, Waterhouse CC, Li XJ, Marchal CC, Stull ND, Lewis DB, Steele M, Kellner JD, Yu W, Meroueh SO, Nauseef WM, Dinauer MC (2009) A new genetic subgroup of chronic granulomatous disease with autosomal recessive mutations in p40 phox and selective defects in neutrophil NADPH oxidase activity. Blood 114:3309–3315PubMedCrossRefGoogle Scholar
  10. 10.
    Cale CM, Morton L, Goldblatt D (2007) Cutaneous and other lupus-like symptoms in carriers of X-linked chronic granulomatous disease: incidence and autoimmune serology. Clin Exp Immunol 148:79–84PubMedCrossRefGoogle Scholar
  11. 11.
    Lam GY, Huang J, Brumell JH (2010) The many roles of NOX2 NADPH oxidase-derived ROS in immunity. Semin Immunopathol 32:415–430PubMedCrossRefGoogle Scholar
  12. 12.
    Kraaij MD, Savage ND, van der Kooij SW, Koekkoek K, Wang J, van den Berg JM, Ottenhoff TH, Kuijpers TW, Holmdahl R, van Kooten C, Gelderman KA (2010) Induction of regulatory T cells by macrophages is dependent on production of reactive oxygen species. Proc Natl Acad Sci USA 107:17686–17691PubMedCrossRefGoogle Scholar
  13. 13.
    Yu JE, De Ravin SS, Uzel G, Landers C, Targan S, Malech HL, Holland SM, Cao W, Harpaz N, Mayer L, Cunningham-Rundles C (2011) High levels of Crohn’s disease-associated anti-microbial antibodies are present and independent of colitis in chronic granulomatous disease. Clin Immunol 138:14–22PubMedCrossRefGoogle Scholar
  14. 14.
    Levine S, Smith VV, Malone M, Sebire NJ (2005) Histopathological features of chronic granulomatous disease (CGD) in childhood. Histopathology 47:508–516PubMedCrossRefGoogle Scholar
  15. 15.
    Marks DJ, Miyagi K, Rahman FZ, Novelli M, Bloom SL, Segal AW (2009) Inflammatory bowel disease in CGD reproduces the clinicopathological features of Crohn’s disease. Am J Gastroenterol 104:117–124PubMedCrossRefGoogle Scholar
  16. 16.
    Seger RA (2010) Hematopoietic stem cell transplantation for chronic granulomatous disease. Immunol Allergy Clin North Am 30:195–208PubMedCrossRefGoogle Scholar
  17. 17.
    Grez M, Reichenbach J, Schwable J, Seger R, Dinauer MC, Thrasher AJ (2011) Gene therapy of chronic granulomatous disease: the engraftment dilemma. Mol Ther 19:28–35PubMedCrossRefGoogle Scholar
  18. 18.
    Steinberg D, Witztum JL (2002) Is the oxidative modification hypothesis relevant to human atherosclerosis? Do the antioxidant trials conducted to date refute the hypothesis? Circulation 105:2107–2111PubMedCrossRefGoogle Scholar
  19. 19.
    Heitzer T, Schlinzig T, Krohn K, Meinertz T, Munzel T (2001) Endothelial dysfunction, oxidative stress, and risk of cardiovascular events in patients with coronary artery disease. Circulation 104:2673–2678PubMedCrossRefGoogle Scholar
  20. 20.
    Forstermann U (2008) Oxidative stress in vascular disease: causes, defense mechanisms and potential therapies. Nat Clin Pract Cardiovasc Med 5:338–349PubMedCrossRefGoogle Scholar
  21. 21.
    Bendall JK, Rinze R, Adlam D, Tatham AL, de Bono J, Wilson N, Volpi E, Channon KM (2007) Endothelial Nox2 overexpression potentiates vascular oxidative stress and hemodynamic response to angiotensin II: studies in endothelial-targeted Nox2 transgenic mice. Circ Res 100:1016–1025PubMedCrossRefGoogle Scholar
  22. 22.
    Oelze M, Warnholtz A, Faulhaber J, Wenzel P, Kleschyov AL, Coldewey M, Hink U, Pongs O, Fleming I, Wassmann S, Meinertz T, Ehmke H, Daiber A, Munzel T (2006) NADPH oxidase accounts for enhanced superoxide production and impaired endothelium-dependent smooth muscle relaxation in BKbeta1−/− mice. Arterioscler Thromb Vasc Biol 26:1753–1759PubMedCrossRefGoogle Scholar
  23. 23.
    Jung O, Schreiber JG, Geiger H, Pedrazzini T, Busse R, Brandes RP (2004) gp91phox-containing NADPH oxidase mediates endothelial dysfunction in renovascular hypertension. Circulation 109:1795–1801PubMedCrossRefGoogle Scholar
  24. 24.
    Donato AJ, Eskurza I, Silver AE, Levy AS, Pierce GL, Gates PE, Seals DR (2007) Direct evidence of endothelial oxidative stress with aging in humans: relation to impaired endothelium-dependent dilation and upregulation of nuclear factor-kappaB. Circ Res 100:1659–1666PubMedCrossRefGoogle Scholar
  25. 25.
    Violi F, Sanguigni V, Carnevale R, Plebani A, Rossi P, Finocchi A, Pignata C, De Mattia D, Martire B, Pietrogrande MC, Martino S, Gambineri E, Soresina AR, Pignatelli P, Martino F, Basili S, Loffredo L (2009) Hereditary deficiency of gp91(phox) is associated with enhanced arterial dilatation: results of a multicenter study. Circulation 120:1616–1622PubMedCrossRefGoogle Scholar
  26. 26.
    Martino F, Loffredo L, Carnevale R, Sanguigni V, Martino E, Catasca E, Zanoni C, Pignatelli P, Violi F (2008) Oxidative stress is associated with arterial dysfunction and enhanced intima-media thickness in children with hypercholesterolemia: the potential role of nicotinamide-adenine dinucleotide phosphate oxidase. Pediatrics 122:e648–e655PubMedCrossRefGoogle Scholar

Copyright information

© SIMI 2011

Authors and Affiliations

  1. 1.I Clinica Medica, Sapienza UniversityRomeItaly

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