Neutrophils Figure 172a Development and function

Neutrophils are the predominant white blood cells involved in phagocytic killing of bacteria and certain fungi. They are also referred to as polymorphonuclear or segmented, owing to their characteristic lobulated nucleus (their nucleus is segmented into two to five lobes, connected by thin chromatin strands). They are at the end stage of maturation (Figures 17.3 and 17.4) and generally uniform in size (13 |im in diameter), with pink cytoplasm and fine azurophilic granules. The production of neutrophil leucocytes involves the action of a variety of growth factors including granulocyte colony-stimulating factor (G-CSF ), granulocyte-macrophage-colony-stimulating factor (GM-CSF), IL-3, and macrophage colony-stimulating factor (M-CSF). Other factors such as IL-11, stem cell factor (SCF) and FLT-3 ligand enhance clonal neutrophil expansion in vitro. GM-CSF induces neutrophil, eosinophil and macrophage colony expansion in vitro, but there is no evidence that it induces neutrophil differentiation in the absence of G-CSF.

Neutrophils contain four types of granules that can be identified by marker enzymes or proteins (Table 17.4). The lysozyme-like azurophil granules, otherwise known as primary

Production, structure and dysfunction of phagocytes

Monocyte Macrophages Csf

Figure 17.2 Morphology of phagocyte cell types. (a) Neutrophil. (b) Eosinophil. (c) Basophil. (d) Monocyte. (e) Macrophage.

Figure 17.2 Morphology of phagocyte cell types. (a) Neutrophil. (b) Eosinophil. (c) Basophil. (d) Monocyte. (e) Macrophage.

Promyelocyte Myeloblast
Figure 17.3 Stages of neutrophil maturation: shown are a myeloblast, a promyelocyte, several myelocytes and metamyelocytes, a band cell and a segmented neutrophil.

granules, present in the promyelocytes and all further stages of neutrophil differentiation and contain microbicidal proteins and acid hydrolases (such as myeloperoxidase, defensins, and lysozyme) involved in oxidative and non-oxidative killing of bacteria and fungi. These granules release their contents exclusively into phagocytic granules, with little discharge outside the cell except for release from disintegrating neutrophils. Specific or secondary granules are smaller than azurophil granules and contain other distinct hydrolases, as well as chemotactic, opsonic, and adhesion protein receptors. They release their contents both into phagocytic vesicles and into the extracellular medium. Other granules, collectively known as tertiary granules, include secretory vesicles, which contain alkaline phosphatase, and gelatinase granules rich in gelatinase. Degranulation of neutrophils begins with the onset of phagocytosis and involves their translocation and fusion with phagocytic vacuoles created by invagination of the plasma membrane. Degranulation may also occur by reversed endocytosis as a result of the action of complement, aggregated immunoglobulin or certain cytokines. Although the release of granule contents is important for phagocytosis and bacterial killing, extracellular release can also lead to tissue injury and inflammation.

Neutrophils exist in one of three states: quiescent, activated or primed. They circulate in the blood in the quiescent state and react weakly to stimuli, thus limiting potential damage to vascular walls. Priming of neutrophils is a process that does not immediately stimulate an effector response but allows an exaggerated response upon later stimulation. Therefore, this is a mechanism whereby phagocytes are selectively activated upon recruitment to sites of infection and inflammation. Three main types of agonists are responsible for priming neutrophils, including chemo-tactic inflammatory mediators, serum immunoglobulin and complement opsonins, and inflammatory cytokines and growth factors. Upon neutrophil activation, a significant increase in oxygen consumption, termed respiratory burst, occurs leading to the production of reactive oxygen species responsible for microbial killing.

Figure 17.4 Neutrophil lifespan and stages of maturation. Of every 100 nucleated cells in the bone marrow, 2% are myeloblasts, 5% promyelocytes, 12% myelocytes, 22% metamyelocytes and bands and 20% mature neutrophils (i.e. about 60% developing neutrophils). The times indicated for the various compartments were obtained by isotopic labelling techniques. The ordinate shows the flux, and the abscissa the time, in each compartment. The stepwise increase in cell numbers through the dividing compartments represents serial divisions. Note that no mitoses occur after the myelocyte stage (reproduced with permisssion from Bainton DF, Developmental Biology of Neutrophils and Eosinophils, and Cronkite EP, Vincent PC, 1969, Ser Haematology 3: 3-43).

Four Compartments Neutrophils

Table 17.4 Neutrophil granules and their contents.

Granule Azurophilic (primary) Specific (secondary) Gelatinase (tertiary) Secretory vesicles

Table 17.4 Neutrophil granules and their contents.

Granule Azurophilic (primary) Specific (secondary) Gelatinase (tertiary) Secretory vesicles

Marker enzyme

Myeloperoxidase

Lactoferrin

Gelatinase

Alkaline phosphatase

Membrane

CD63, granulophysin, CD68, V-type H+-ATPase

CD15, CD66, CD67, CD11b/CD18, Cytochrome b, fMLP-R, fibronectin-R, G-protein a-subunit, laminin-R, NB-1 antigen, 19-kDa protein, 155 kDa protein, Rap-1, Rap-2, SCAMP, thrombospondin-R, TNF-R, urokinase type plasminogen activator-R, VAMP-2, vitronectin

CD11b/CD18, cytochrome b, diacylglycerol-deacylating enzyme, fMLP-R, SCAMP, urokinase type plasminogen activator-R, VAMP-2, V-type H+-ATPase

CD10, CD13, CD45, CD14, CD16, CD35 (CR1), CD11b/CD18, alkaline phosphatase, fMLP-R, SCAMP, urokinase type plasminogen activator-R, V-type H+-ATPase, VAMP-2, C1q-receptor, decay activating factor

Matrix, microbicidal

Myeloperoxidase, nitric oxide (NO) synthase, lysozyme, BPI protein, defensins, serprocidins, elastase, cathepsins, proteinase 3, azurocidin (CAP 37)

Lactoferrin, lysozyme

Lysozyme

Matrix, hydrolases

Acid P-glycerophosphatase, a-mannosidase,

P-glucuronidase,

P-glycerophosphatase,

N-acetyl-P-glucosaminidase, sialidase

Gelatinase, collagenase, histaminase, heparanase, NGAL, sialidase

Gelatinase, acetyltransferase

Matrix, other

Acid-mucopolysaccharide, heparin binding protein

ß2-microglobulin, urokinase-type plasminogen activator, vitamin-B12 binding protein

ß2-microglobulin,

Plasma proteins (including tetranectin)

Fmlp, f-Met-Leu-Phe; R, receptor; SCAMP, secretory carrier membrane protein; VAMP, vesicle associated membrane protein.

Fmlp, f-Met-Leu-Phe; R, receptor; SCAMP, secretory carrier membrane protein; VAMP, vesicle associated membrane protein.

Neutrophils are the most numerous leucocytes comprising 65% of circulating phagocytes with a normal range in the peripheral blood of 1.5 -7.7 X 109/L. The largest proportion of neutrophils is within the marrow (reserve pool), with circulating and tissue pools comprising smaller fractions (Figure 17.4). The circulating pool itself consists of a marginated pool of cells that are loosely adherent to the vascular endothelium and a freely circulating pool with the compartments in a constant state of dynamic equilibrium. Several factors including corticosteroids, exercise and infection can lead to an increase in the free circulating pool. Corticosteroids promote the release of neutrophils from the reserve pool into the circulation and prevent migration from the blood into the tissue pool. Endotoxin and some complement components (C5a) on the other hand, result in increased margination and reduction in the circulatory pool. The half-life of a circulating neutrophil is short (6-8 h) (Figure 17.4). In Figure 17.5, the variations in neutrophil morphology are shown. These include: (a) Barr body, a drumstick appendage to the neutrophils in females; (b) Pelger-Huet anomaly, with bilobed nuclei; and (c) Alder-Reilly anomaly. Also shown are May-Hegglin (d), toxic granulation (e), hypersegmented neutrophils (f) and Chediak-Hegasin (g).

The May-Hegglin anomaly is a rare autosomal dominant condition. The neutrophils contain basophilic inclusions of RNA, resembling Döhle bodies (Figure 17.5). Giant platelets with thrombocytopenia are common, leukopenia less so.

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