Neutrophil Functional Disorders

Abstract

Neutrophils are phagocytes and constitute the most numerous and important effector cells of the innate immune system, especially in the defence against bacteria and fungi. They are rapidly recruited to inflamed tissue in response to inflammatory signals. Egression from the bone marrow and blood stream, adhesion, migration, activation, phagocytosis and killing of pathogens describe the basic mechanisms associated with neutrophils. Neutrophil shortage and functional disorders arise from different rare genetic mutations and can lead to a profound immunodeficiency, often presenting early in life with severe, recurrent and persistent or opportunistic bacterial and fungal infections. An increasing number of such diseases have been identified, especially as whole‐exome sequencing is getting more accessible. This results in better insights in genotypic–phenotypic correlations, susceptibility to specific pathogens and the use of different treatment modalities.

Key Concepts

  • In healthy adults, 1011 neutrophils are generated daily. In steady state, their life span is approximately 1–2 days, which increases up to 3–4 days after neutrophil activation.
  • 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.
  • 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, induce similar clinical symptoms.
  • 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 NADPH oxidase components. The NADPH oxidase consists of a flavocytochrome 558 in the wall of the phagocytic vacuole that transports electrons across the membrane to oxygen, thus producing superoxide. The flavocytochrome consists of two proteins, gp91phox (the beta subunit) and p22phox (the alpha subunit), and is inactive until cytosolic proteins associate with it. These cytosolic proteins are p40phox, p47phox and p67phox and the small GTP‐binding proteins, rac1 or rac2. Activation involves phosphorylation of the phox proteins and the exchange of GDP bound to the rac for GTP. The complex of these cytosolic 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 GDP, the system is inactivated. P67phox is tightly associated with p40phox, which is especially involved in NADPH oxidase activity enhancement during phagocytosis. 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. The genetic basis of chronic granulomatous disease (CGD). The location of genes encoding the components of NADPH oxidase and the frequency of their abnormality in CGD.
Figure 3. CARD9 deficiency. CARD9 in the C‐type lectin pathway, indicating the relevant interactions of the CARD9 protein and the consequences of its deficiency. Both the NFκB‐derived cytokines and the production of cytokines after CD4+ T‐cell stimulation, like Th17 cells and consequently IL‐17, are diminished when CARD9 is absent.
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Further Reading

Dinauer MC (2016) Primary immune deficiencies with defects in neutrophil function. Hematology. American Society of Hematology. Education Program 2016: 43–50.

Nauseef WM (2016) Neutrophils, from cradle to grave and beyond. Immunological Reviews 273: 5–10.

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van de Geer, Annemarie, Gazendam, Roel P, Kuijpers, Taco W, and Roos, Dirk(Jun 2017) Neutrophil Functional Disorders. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0002182.pub3]