Page 1038 - Williams Hematology ( PDFDrive )

1012 Part VII: Neutrophils, Eosinophils, Basophils, and Mast Cells Chapter 66: Disorders of Neutrophil Function 1013

TABLE 66–1. Physical-Chemical and Functional Properties of Neutrophil Granules (Continued)
Granule Protein Localization Physicochemical Properties Function
Cytochrome b , (gp91 phox , SG ~60%; GG Heterodimeric flavoheme pro- Together with p47 phox , p67 phox , and p40 phox ,
558
p22 phox ) ~25%; SV ~15% tein; 91-kDa glycoprotein subunit cytochrome b constitutes the superoxide
558
(heme-flavin binding); 22-kDa generating nicotinamide adenine dinucleotide
protein subunit, possibly heme phosphate (NADPH) oxidase of phagocytes
binding
CD11b/CD18 (Mac-1, Mo1, SG ~60%; GG Most prominent β -integrin in neu- Multifunctional integrin that functions as an
2
CR3, α β ) ~25%; SV ~15% trophils; CD11B = α and is a glyco- adhesion receptor binding to members of the
M 2 M
protein of 170 kDa; CD18 = β and immunoglobulin family intercellular adhesion
2
is a glycoprotein of 95 kDa molecule (ICAM)-1, to fibronectin, collagen; is
important in mediating firm adhesion to vas-
cular endothelial cells; functions as a phagocy-
tosis receptor for C3bi-coated particles
Pentraxin-3 SG Pentamer of 47-kDa subunits Binds complement C1q, selected
microorganisms
Ficolin-1 GG Multimer of 32-kDa subunits Binds acetylated carbohydrates on microor-
ganisms; may activate mannose-binding lect-
in-associated serine proteases
Arginase 1 GG 37-kDa glycoprotein Degrades arginine, the substrate for nitric
oxide (NO) synthase

high levels of BPI has enhanced resistance against endotoxin. peptidase 1, removes two inhibitory N-terminal amino acids from the
141
Important effects not related to LPS have been described, such as serine proteases prior to their storage in granules. Patients with the
158
chemotaxis, opsonization, and dendritic cell function, as reviewed in Papillon-Lefèvre syndrome lack cathepsin C activity and are not able to
Ref. 142. store serine proteases in their neutrophils. The condition is charac-
159
Defensins are small antibacterial cationic peptides with a broad terized by severe juvenile periodontitis and keratosis in hands and feet,
spectrum of antibacterial activity. They share a characteristic but not by major systemic infections, arguing against the notion the
143
160
three-disulfide-bond motif. 82,144,145 Based on this, mammalian defensins serine proteases are important for immune defense. 161
are divided into α defensins, β defensins, and the cyclical θ defensins. The membrane of azurophil granules contains CD63 (granulo-
146
Only α defensins are found in human neutrophils, and reside exclu- physin), which is implicated in transmembrane signaling with the β
2
sively in azurophil granules. They are by far the dominating proteins integrins in the activated neutrophil. 85,86,162 Also, the CD68 antigen 100,163
of azurophil granules, yet are only expressed in a subset of granules and presenilin appear localized exclusively to the membrane of azurophil
that are formed late in the promyelocyte stage. 83,100,107 Three defensins granules, whereas stromatin is found in the membrane of all gran-
164
have been isolated from azurophil granules, HNP-1 to HNP-3. Large ules and the vacuolar-type H -ATPase is shared between azurophil,
+
165
82
amounts of unprocessed defensing, that is, prodefensin, are secreted gelatinase granules and secretory vesicles. These membrane proteins
166
from late promyelocytes and myelocytes in the marrow and may serve will translocate to the phagocytic vacuole or to the plasma membrane
as a marker of normal myelopoietic activity. In contrast to lysozyme when neutrophils are activated and engaged in phagocytosis.
111
and MPO, prodefensins are not expressed by acute leukemia cells. A rise
of prodefensin in plasma precedes detectable neutrophils by 6 days and Proteins of Peroxidase-Negative Granules
is a measure of normal granulopoiesis which may be of clinical use in For an overview, see Table 66–1.
the setting of myeloablative treatment for acute leukemia. 111 Lactoferrin is the dominating protein of specific granules. It is a
167
The serine proteases of azurophil granules include elastase, cathep- 78-kDa iron-chelator, member of the transferrin protein family with a
sin G, proteinase-3, and NSP4. 147,148 Azurocidin, which is also named high affinity for iron and similar binding characteristics as ferritin. 168,169
CAP37 or heparin-binding protein (HBP), is an enzymatically inactive The antibacterial activity of lactoferrin does not depend exclusively on
serine protease. 149–153 Both elastase and cathepsin G have direct antibac- its ability to sequester iron because proteolytic fragments of lactoferrin,
terial activities that are not dependent on their enzymatic activity. Pro- some of which are known as lactoferricin, are directly bactericidal. 170,171
teinase 3 expression leads to autoantibodies against itself in Wegener NGAL, or lipocalin 2, is a 25-kDa N-glycosylated member of
granulomatosis, which is known as cANCA (cytoplasmic antineu- the lipocalin protein family. Lipocalins are transport proteins that
79
trophil cytoplasmic antibody). Proteinase 3 is also bound to the sur- bind small and often lipophilic substances in their canonical lipocalin
154
face of circulating neutrophils at levels that vary considerably amongst pocket. Some NGAL is associated with gelatinase (MMP-9) in a sub-
172
individuals but are highly constant throughout life in a given individual. set of specific granules, but the majority is present either as a mono-
173
The binding is mediated by the NB1 antigen (CD177). 155,156 A secreted mer or as a homodimer in specific granules. NGAL interferes with the
precursor of proteinase 3 has been suggested to inhibit normal mye- activation and stability of MMPs, but the major function of NGAL
174
lopoiesis and to play a role in regulation of myelopoiesis. So far, the is to bind and sequester siderophores. NGAL binds enterochelin/
157
only specific substrate of proteinase 3 identified is the cathelicidin of enterobactin with high affinity, and blocks growth of Escherichia coli by
specific granules hCAP-18. Proteinase 3 activates hCAP-18 by remov- sequestering siderophore-iron complexes, which might not be only a
175
ing the cathelicidin part, and unleashing the antibacterial activity of neutrophil-specific antibacterial defense because NGAL can be induced
the C-terminal LL-37 peptide. Cathepsin C, also known as dipeptidyl in a variety of epithelial cells during inflammation by IL-1. NGAL
90
176
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