Neutrophil Functional Disorders

Sergio D Rosenzweig, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland, USA
Harry L Malech, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland, USA

Published online: March 2010

DOI: 10.1002/9780470015902.a0002182.pub2

The phagocytic system is one of the first lines of defence against invading microorganisms. Diseases and disorders that impair phagocyte function can lead to a profound immunodeficiency. Egression from the bone marrow, adhesion, migration, activation, phagocytosis and microorganism killing describe basic mechanisms associated to phagocytic cells. When any of these activities is affected, severe, recurrent and relapsing bacterial as well as fungal infections usually occur. Chronic granulomatous disease is a paradigmatic example of a functional disorder in phagocytic cells. This clinically and genetically heterogenous disease has served during the past 50 years as a model for understanding genotypic–phenotypic correlations of infections susceptibility in primary immunodeficiencies, the utility of anti-infectious and cytokine prophylactic therapy, hematopoietic stem cell transplantation and gene therapy.

Key Concepts

  • Patients with neutrophil functional disorders usually present early in life with recurrent bacterial or fungal infections.
  • Certain infections, such as Burkholderia cepacia, Nocardia, Aspergillus nidulans or nontuberculous mycobacteria should always prompt an inquiry to the possibility of an underlying immune defect.
  • Specific infection locations, such as omphalitis, gingivitis or osteomyelitis, should raise the suspicion of phagocytic cell abnormalities.
  • Abnormal aspects of host response, such as lack of fever, local inflammation or pus, should immediately alert the clinician to the possibility of a neutrophil defect.
  • It is better to perform the right test once than the entire battery of immune defect tests several times. Careful consideration of the clinical and microbiologic presentation usually indicates the right path to pursue.
  • There is no substitute for the right drug, and that requires knowing the pathogen. Because the spectrum of infection in these diseases may range over several microbiologic kingdoms, empiric therapy is to be discouraged in favour of firm diagnoses.
  • Prophylactic antibiotics, antifungal agents and cytokines are highly successful in treating chronic granulomatous disease, and appear to be useful in some other immunodeficiencies as well.
  • A molecular diagnosis should be sought whenever possible. The expanding knowledge of genotype–phenotype relationships suggests that not all defects, even those within the same gene, are created equal.
  • BCG vaccination should be avoided in individuals with CGD, as well as in their newborn close relatives until the defect is ruled out. In general, attenuated viral vaccines are not contraindicated in individuals with primary neutrophil disorders, as antiviral cell-mediated immunity is intact.

Keywords: neutrophil; leucocyte; immunodeficiency; NADPH oxidase; phagocyte

Figure 1. Interactions of the components of NADPH oxidase. The NADPH oxidase consists of a flavocytochrome b558 in the wall of the phagocytic vacuole which transports electrons across the membrane on to oxygen, to produce superoxide. The flavocytochrome consists of two proteins, gp91phox (the b subunit) and p22phox (a subunit), and is inactive until cytosolic proteins associate with it. These cytosolic proteins are p47phox, p67phox and the small GTP-binding proteins, rac1 and rac2. Activation involves phosphorylation of the phox proteins and the exchange of GDP bound to the rac for GTP. The complex of these proteins then translocates to the membrane, where they attach to the flavocytochrome and activate it. The rac acts as a molecular switch and, when the GTP bound to it is hydrolysed to GTP, the system is inactivated. p67phox is tightly associated with another protein, p40phox, the detailed function of which remains to be elucidated. GDI, guanine nucleotide dissociation inhibitor; GDP, guanosine diphosphate; GTP, guanosine triphosphate; NADP, nicotinamide–adenine dinucleotide phosphate; P, phosphate and p21rac, rac1 and rac2.
Figure 2. Genetic basis of chronic granulomatous disease (CGD), indicating the location of genes for the components of NADPH oxidase and the frequency of their abnormality in CGD (note that recently a single case of p40phox deficiency CGD has now been described).
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 Further Reading
    book Hsieh MM and Malech HL (2009) "Neutrophil disorders and neutropenias". In: Young N and Rodgers G (eds) Bethesda Handbook of Hematology, Chapter 9, pp. 106–115. Philadelphia: Lippioncott Williams & Wilkins.
    Malech HL and Hickstein DD (2007) Genetics, biology and clinical management of myeloid cell primary immune deficiencies: chronic granulomatous disease and leukocyte adhesion deficiency. Current Opinion in Hematology 14: 29–36.
    Matute JD, Arias AA, Wright NA et al. (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(15): 3309–3315.
    book Wintergerst U, Rosenzweig SD, Abinun M et al. (2008) "Phagocyte defects". In: Rezaei N, Aghamohammadi A and Notarangelo LD (eds) Primary Immunodeficiency Diseases: Definition, Diagnosis, and Management, Chapter 4, pp. 131–159. Berlin and Heidelberg: Springer.

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Immunodeficiency | Cells of the Immune System
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Article Title: Neutrophil Functional Disorders
 
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Rosenzweig, Sergio D, and Malech, Harry L(Mar 2010) Neutrophil Functional Disorders. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0002182.pub2]