The Human NADPH Oxidase: Primary and Secondary Defects Impairing the Respiratory Burst Function and the Microbicidal Ability of Phagocytes

Phagocytes, such as granulocytes and monocytes/macrophages, contain a membrane‐associated NADPH oxidase that produces superoxide leading to other reactive oxygen species with microbicidal, tumoricidal and inflammatory activities. Primary defects in oxidase activity in chronic granulomatous disease (CGD) lead to severe, life‐threatening infections that demonstrate the importance of the oxygen‐dependent microbicidal system in host defence. Other immunological disturbances may secondarily affect the NADPH oxidase system, impair the microbicidal activity of phagocytes and predispose the host to recurrent infections. This article reviews the primary defects of the human NADPH oxidase leading to classical CGD, and more recently discovered immunological defects secondarily affecting phagocyte respiratory burst function and resulting in primary immunodeficiencies with varied phenotypes, including susceptibilities to pyogenic or mycobacterial infections.

[1]  W. Grossman,et al.  Human phagocyte defect caused by a Rac2 mutation detected by means of neonatal screening for T-cell lymphopenia. , 2011, The Journal of allergy and clinical immunology.

[2]  Frederic D. Bushman,et al.  Efficacy of gene therapy for X-linked severe combined immunodeficiency. , 2010, The New England journal of medicine.

[3]  Hans Martin,et al.  Genomic instability and myelodysplasia with monosomy 7 consequent to EVI1 activation after gene therapy for chronic granulomatous disease , 2010, Nature Medicine.

[4]  S. Holland,et al.  Hematologically important mutations: the autosomal recessive forms of chronic granulomatous disease (second update). , 2000, Blood cells, molecules & diseases.

[5]  S. Holland,et al.  Hematologically important mutations: X-linked chronic granulomatous disease (third update). , 1997, Blood cells, molecules & diseases.

[6]  A. Towbin,et al.  Chronic granulomatous disease , 2010, Pediatric Radiology.

[7]  Xing Jun Li,et al.  A new genetic subgroup of chronic granulomatous disease with autosomal recessive mutations in p40 phox and selective defects in neutrophil NADPH oxidase activity. , 2009, Blood.

[8]  Abdul Hakkim,et al.  Restoration of NET formation by gene therapy in CGD controls aspergillosis. , 2009, Blood.

[9]  D. Roos,et al.  A novel mutation in NCF1 in an adult CGD patient with a liver abscess as first presentation , 2009, Journal of Human Genetics.

[10]  D. Kuhns,et al.  Impaired Priming and Activation of the Neutrophil NADPH Oxidase in Patients with IRAK4 or NEMO Deficiency1 , 2009, The Journal of Immunology.

[11]  K. Berger,et al.  NCF1 gene and pseudogene pattern: association with parasitic infection and autoimmunity , 2008, Malaria Journal.

[12]  J. Casanova,et al.  Essential role of nuclear factor-kappaB for NADPH oxidase activity in normal and anhidrotic ectodermal dysplasia leukocytes. , 2008, Blood.

[13]  W. Nauseef.  Biological Roles for the NOX Family NADPH Oxidases* , 2008, Journal of Biological Chemistry.

[14]  M. Stasia,et al.  Genetics and immunopathology of chronic granulomatous disease , 2008, Seminars in Immunopathology.

[15]  N. Theobald,et al.  Treatment of infections in patients with X-linked chronic granulomatous disease (CGD) with gene therapy , 2008 .

[16]  M. Cappellini,et al.  Glucose-6-phosphate dehydrogenase deficiency , 2008, The Lancet.

[17]  J. Banchereau,et al.  Pyogenic Bacterial Infections in Humans with MyD88 Deficiency , 2003, Science.

[18]  N. Theobald,et al.  Treatment of Infections in Patients with X-Linked Chronic Granulomatous Disease (XCGD) with Gene Therapy. , 2007 .

[19]  Douglas R. McDonald,et al.  Selective predisposition to bacterial infections in IRAK-4–deficient children: IRAK-4–dependent TLRs are otherwise redundant in protective immunity , 2007, The Journal of experimental medicine.

[20]  M. Grez,et al.  Advances in the treatment of Chronic Granulomatous Disease by gene therapy. , 2007, Current gene therapy.

[21]  William Arbuthnot Sir Lane,et al.  Cross-talk between IRAK-4 and the NADPH oxidase. , 2007, The Biochemical journal.

[22]  J. Casanova,et al.  CorrigendumCorrigendum to “Inborn errors of IL-12/23- and IFN-γ-mediated immunity: Molecular, cellular, and clinical features” [Semin. Immunol. 18 (2006) 347–361] , 2007 .

[23]  K. Krause,et al.  The NOX family of ROS-generating NADPH oxidases: physiology and pathophysiology. , 2007, Physiological reviews.

[24]  J. Casanova,et al.  Inborn errors of IL-12/23- and IFN-γ-mediated immunity: molecular, cellular, and clinical features , 2006 .

[25]  Yang Du,et al.  Correction of X-linked chronic granulomatous disease by gene therapy, augmented by insertional activation of MDS1-EVI1, PRDM16 or SETBP1 , 2006, Nature Medicine.

[26]  P. Newburger,et al.  Chronic granulomatous disease in Latin American patients: Clinical spectrum and molecular genetics , 2006, Pediatric blood & cancer.

[27]  J. Casanova,et al.  Inborn errors of IL-12/23- and IFN-gamma-mediated immunity: molecular, cellular, and clinical features. , 2006, Seminars in immunology.

[28]  A. Hoffmann,et al.  Circuitry of nuclear factor kappaB signaling. , 2006, Immunological reviews.

[29]  Chunliu Zhu,et al.  HoxA10 Represses Transcription of the Gene Encoding p67phox in Phagocytic Cells , 2005, The Journal of Immunology.

[30]  P. Moynagh,et al.  The NF-κB pathway , 2005, Journal of Cell Science.

[31]  J. Frank.  Diagnosis and management of G6PD deficiency. , 2005, American family physician.

[32]  H. Ho,et al.  G6PD--an old bottle with new wine. , 2005, Chang Gung medical journal.

[33]  J. Casanova,et al.  Shigella sonnei meningitis due to interleukin-1 receptor-associated kinase-4 deficiency: first association with a primary immune deficiency. , 2005, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[34]  R. Zandomeni,et al.  Molecular characterization of a novel splice site mutation within the CYBB gene leading to X‐linked chronic granulomatous disease , 2005, Pediatric blood & cancer.

[35]  E. Eklund,et al.  JAK2 is necessary and sufficient for interferon‐γ‐induced transcription of the gene encoding gp91PHOX , 2005, Journal of leukocyte biology.

[36]  F. Rossi,et al.  Biochemical aspects of phagocytosis in poly-morphonuclear leucocytes. NADH and NADPH oxidation by the granules of resting and phagocytizing cells , 1964, Experientia.

[37]  P. Moynagh,et al.  The NF-kappaB pathway. , 2005, Journal of cell science.

[38]  S. Holland,et al.  Long-Term Interferon-γ Therapy for Patients with Chronic Granulomatous Disease , 2004 .

[39]  T. Nakahata,et al.  From bloodjournal.hematologylibrary.org at PENN STATE UNIVERSITY on February 23, 2013. For personal use only. , 2004 .

[40]  S. T. Olalla-Saad,et al.  Association of glucose‐6‐phosphate dehydrogenase deficiency and X‐linked chronic granulomatous disease in a child with anemia and recurrent infections , 2004, American journal of hematology.

[41]  Capucine Picard,et al.  Inherited disorders of NF-κB-mediated immunity in man , 2004 .

[42]  A. Smahi,et al.  Inherited disorders of NF-kappaB-mediated immunity in man. , 2004, Current opinion in immunology.

[43]  S. Holland,et al.  Long-term interferon-gamma therapy for patients with chronic granulomatous disease. , 2004, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[44]  Dirk Roos,et al.  Oxidative killing of microbes by neutrophils. , 2003, Microbes and infection.

[45]  D. Kuhns,et al.  Distinct Mutations in IRAK-4 Confer Hyporesponsiveness to Lipopolysaccharide and Interleukin-1 in a Patient with Recurrent Bacterial Infections , 2003, The Journal of experimental medicine.

[46]  A. Al-ghonaium,et al.  Pyogenic Bacterial Infections in Humans with IRAK-4 Deficiency , 2003, Science.

[47]  D. Noack,et al.  Identification of a novel NCF-1 (p47-phox) pseudogene not containing the signature GT deletion: significance for A47 degrees chronic granulomatous disease carrier detection. , 2002, Blood.

[48]  P. Vignais.  The superoxide-generating NADPH oxidase: structural aspects and activation mechanism , 2002, Cellular and Molecular Life Sciences CMLS.

[49]  Giorgio Gabella,et al.  Killing activity of neutrophils is mediated through activation of proteases by K+ flux , 2002, Nature.

[50]  E. Eklund,et al.  SHP1 protein-tyrosine phosphatase inhibits gp91PHOX and p67PHOX expression by inhibiting interaction of PU.1, IRF1, interferon consensus sequence-binding protein, and CREB-binding protein with homologous Cis elements in the CYBB and NCF2 genes. , 2001, The Journal of biological chemistry.

[51]  J. Siegel,et al.  Increased incidence of sepsis and altered monocyte functions in severely injured type A− glucose-6-phosphate dehydrogenase-deficient African American trauma patients , 2001, Critical care medicine.

[52]  G. Bren,et al.  IκB Kinase-Dependent Chronic Activation of NF-κB Is Necessary for p21WAF1/Cip1 Inhibition of Differentiation-Induced Apoptosis of Monocytes , 2001, Molecular and Cellular Biology.

[53]  S. Chanock,et al.  Mutational analysis of patients with p47-phox-deficient chronic granulomatous disease: The significance of recombination events between the p47-phox gene (NCF1) and its highly homologous pseudogenes. , 2001, Experimental hematology.

[54]  J. Taylor,et al.  IkappaB kinase-dependent chronic activation of NF-kappaB is necessary for p21(WAF1/Cip1) inhibition of differentiation-induced apoptosis of monocytes. , 2001, Molecular and cellular biology.

[55]  R. B. Johnston,et al.  Clinical aspects of chronic granulomatous disease. , 2001, Current opinion in hematology.

[56]  David A. Williams,et al.  Dominant negative mutation of the hematopoietic-specific Rho GTPase, Rac2, is associated with a human phagocyte immunodeficiency. , 2000, Blood.

[57]  Richard B. Johnston,et al.  Chronic Granulomatous Disease: Report on a National Registry of 368 Patients , 2000, Medicine.

[58]  G L Johnson,et al.  Human neutrophil immunodeficiency syndrome is associated with an inhibitory Rac2 mutation. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[59]  M. Dinauer,et al.  Inherited Neutrophil Disorders: Molecular Basis and New Therapies. , 2000, Hematology. American Society of Hematology. Education Program.

[60]  C. V. van Noorden,et al.  Molecular basis and enzymatic properties of glucose 6-phosphate dehydrogenase volendam, leading to chronic nonspherocytic anemia, granulocyte dysfunction, and increased susceptibility to infections. , 1999, Blood.

[61]  P. Patiño,et al.  Molecular characterization of autosomal recessive chronic granulomatous disease caused by a defect of the nicotinamide adenine dinucleotide phosphate (reduced form) oxidase component p67-phox. , 1999, Blood.

[62]  M. Totani,et al.  [Glucose-6-phosphate dehydrogenase]. , 1999, Nihon rinsho. Japanese journal of clinical medicine.

[63]  P. Patiño,et al.  Molecular analysis of chronic granulomatous disease caused by defects in gp91‐phox , 1999, Human mutation.

[64]  P. Newburger,et al.  NADPH oxidase activity and cytochrome b558 content of human Epstein-Barr-virus-transformed B lymphocytes correlate with expression of genes encoding components of the oxidase system. , 1998, Archives of biochemistry and biophysics.

[65]  P. Newburger,et al.  Dexamethasone but not indomethacin inhibits human phagocyte nicotinamide adenine dinucleotide phosphate oxidase activity by down-regulating expression of genes encoding oxidase components. , 1998, Journal of immunology.

[66]  P. Newburger,et al.  X-Linked chronic granulomatous disease: mutations in the CYBB gene encoding the gp91-phox component of respiratory-burst oxidase. , 1998, American journal of human genetics.

[67]  M J May,et al.  NF-kappa B and Rel proteins: evolutionarily conserved mediators of immune responses. , 1998, Annual review of immunology.

[68]  E. Green,et al.  A p47-phox pseudogene carries the most common mutation causing p47-phox- deficient chronic granulomatous disease. , 1997, The Journal of clinical investigation.

[69]  S. Orkin,et al.  Regulation of the myeloid-cell-expressed human gp91-phox gene as studied by transfer of yeast artificial chromosome clones into embryonic stem cells: suppression of a variegated cellular pattern of expression requires a full complement of distant cis elements , 1997, Molecular and cellular biology.

[70]  E. Green,et al.  Genomic structure, chromosomal localization, start of transcription, and tissue expression of the human p40-phox, a new component of the nicotinamide adenine dinucleotide phosphate-oxidase complex. , 1996, Blood.

[71]  W. Luo,et al.  Characterization of three promoter elements and cognate DNA binding protein(s) necessary for IFN-gamma induction of gp91-phox transcription. , 1996, Journal of immunology.

[72]  P. Mason,et al.  New insights into G6PD deficiency. , 1996, British journal of haematology.

[73]  G. De Nucci,et al.  Effect of therapy with recombinant human interferon-gamma on the release of nitric oxide by neutrophils and mononuclear cells from patients with chronic granulomatous disease. , 1996, Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research.

[74]  C. Meischl,et al.  Mutations in the X-linked and autosomal recessive forms of chronic granulomatous disease. , 1996, Blood.

[75]  I. Matsuda,et al.  AG dinucleotide insertion in a patient with chronic granulomatous disease lacking cytosolic 67-kD protein. , 1995, Blood.

[76]  A. de Klein,et al.  Cytochrome b558-negative, autosomal recessive chronic granulomatous disease: two new mutations in the cytochrome b558 light chain of the NADPH oxidase (p22-phox). , 1992, American journal of human genetics.

[77]  S. Orkin,et al.  Targeting of transgene expression to monocyte/macrophages by the gp91-phox promoter and consequent histiocytic malignancies. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[78]  P. Newburger,et al.  In vitro regulation of human phagocyte cytochrome b heavy and light chain gene expression by bacterial lipopolysaccharide and recombinant human cytokines. , 1991, The Journal of biological chemistry.

[79]  A. de Klein,et al.  Point mutations in the beta-subunit of cytochrome b558 leading to X-linked chronic granulomatous disease. , 1991, Blood.

[80]  D. Bentley,et al.  Autosomal recessive chronic granulomatous disease caused by deletion at a dinucleotide repeat. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[81]  A. Segal,et al.  Killing of pathogens associated with chronic granulomatous disease by the non-oxidative microbicidal mechanisms of human neutrophils. , 1991, Journal of medical microbiology.

[82]  J. Curnutte,et al.  Molecular basis of chronic granulomatous disease [see comments] , 1991 .

[83]  R. M. Smith,et al.  Molecular basis of chronic granulomatous disease. , 1991, Blood.

[84]  S. Orkin,et al.  Human neutrophil cytochrome b light chain (p22-phox). Gene structure, chromosomal location, and mutations in cytochrome-negative autosomal recessive chronic granulomatous disease. , 1990, The Journal of clinical investigation.

[85]  H. Malech,et al.  Cloning of a 67-kD neutrophil oxidase factor with similarity to a noncatalytic region of p60c-src. , 1990, Science.

[86]  S. Orkin,et al.  A missense mutation in the neutrophil cytochrome b heavy chain in cytochrome-positive X-linked chronic granulomatous disease. , 1989, The Journal of clinical investigation.

[87]  J. Donelson,et al.  Cloning of the cDNA and functional expression of the 47-kilodalton cytosolic component of human neutrophil respiratory burst oxidase. , 1989, Proceedings of the National Academy of Sciences of the United States of America.

[88]  P. Newburger,et al.  Cellular and molecular effects of recombinant interferon gamma in chronic granulomatous disease. , 1988, Hematology/oncology clinics of North America.

[89]  J. Curnutte.  Classification of chronic granulomatous disease. , 1988, Hematology/oncology clinics of North America.

[90]  S. Orkin,et al.  Primary structure and unique expression of the 22-kilodalton light chain of human neutrophil cytochrome b. , 1988, Proceedings of the National Academy of Sciences of the United States of America.

[91]  A. Jesaitis,et al.  Purified cytochrome b from human granulocyte plasma membrane is comprised of two polypeptides with relative molecular weights of 91,000 and 22,000. , 1987, The Journal of clinical investigation.

[92]  J. Haines,et al.  DNA linkage analysis of X chromosome-linked chronic granulomatous disease. , 1986, Proceedings of the National Academy of Sciences of the United States of America.

[93]  A. Monaco,et al.  Cloning the gene for the inherited disorder chronic granulomatous disease on the basis of its chromosomal location. , 1986, Cold Spring Harbor symposia on quantitative biology.

[94]  A. Segal,et al.  ABSENCE OF A NEWLY DESCRIBED CYTOCHROME b FROM NEUTROPHILS OF PATIENTS WITH CHRONIC GRANULOMATOUS DISEASE , 1978, The Lancet.

[95]  Schraibman Ig,et al.  Letter: Intravenous regional sympathetic block with guanethidine. , 1974 .

[96]  G. Löhr,et al.  Glucose-6-phosphate Dehydrogenase , 1974 .

[97]  B. Babior,et al.  Biological defense mechanisms. The production by leukocytes of superoxide, a potential bactericidal agent. , 1973, The Journal of clinical investigation.

[98]  H. Notopuro,et al.  Glucose-6-phosphate dehydrogenase deficiency. , 1972, Paediatrica Indonesiana.

[99]  R. Good,et al.  Fatal granulomatous disease of childhood. An inborn abnormality of phagocytic function. , 1966, Lancet.

[100]  R. Good,et al.  A fatal granulomatous disease of childhood; the clinical, pathological, and laboratory features of a new syndrome. , 1959, A.M.A. journal of diseases of children.

[101]  R. Good,et al.  A fatal granulomatosus of childhood: the clinical study of a new syndrome. , 1957, Minnesota medicine.