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CHAPTER 60 In the normal adult human, the life of granulocytes is spent in three
environments: marrow, blood, and tissues. Marrow is the site of dif-
STRUCTURE AND ferentiation of hematopoietic stem cells into granulocyte progenitors
and of proliferation and terminal maturation (Fig. 60–1). Precursor
COMPOSITION OF cell proliferation, which consists of approximately five divisions, occurs
only during the first three stages of maturation (blast, promyelocyte,
and myelocyte). After the myelocyte stage, the cells are no longer capa-
NEUTROPHILS, ble of mitosis and enter a large marrow storage pool from which they
are released into the blood where they circulate for a few hours before
EOSINOPHILS, AND entering tissues.

NEUTROPHILS
BASOPHILS LIGHT MICROSCOPY AND ELECTRON

MICROSCOPY
C. Wayne Smith The Myeloblast
The myeloblast is an immature cell with a large, oval nucleus, sizable
nucleoli, and few or no granules. As the earliest precursor in the evolu-
SUMMARY tion of the neutrophil from the colony forming unit, it is an immature
cell with a large nucleus and multiple nucleoli (Fig. 60–2). The nucle-
Early in precursor development in the marrow, cells destined to be leukocytes of olus is the site of assembly of ribosomal proteins and ribosomal RNA,
the granulocytic series—neutrophils, eosinophils, and basophils—synthesize and is a prominent feature of early maturing cells. The scant cytoplasm
proteins and store them as cytoplasmic granules. The synthesis of primary or contains reaction product for peroxidase within the rough-surfaced
azurophilic granules defines the conversion of the myeloblast, a virtually agran- endoplasmic reticulum and Golgi cisternae and, sometimes, in early
developing azurophilic granules. The dense product of the peroxidase
ular, primitive cell that is the earliest granulocyte precursor identifiable by light reaction serves as a marker of azurophilic granules in human marrow
microscopy, into the promyelocyte, which is rich in azurophilic granules. Synthesis and blood cells for electron and for light microscopy. 1–4
and accumulation of secondary or specific granules follows. The appearance of
specific granules marks the progression of the promyelocyte to neutrophilic, The Promyelocyte
eosinophilic, or basophilic myelocytes. Thereafter, the cell continues maturation In the promyelocyte stage, the azurophilic or primary granules, large
into an amitotic cell with a segmented nucleus, capable of chemotaxis, phago- peroxidase-positive granules that stain metachromatically (red-
cytosis and microbial killing. The mature granulocytes also develop cytoplasmic dish-purple) with a polychromatic stain such as Wright stain, are formed.
and surface structures that permit them to attach to and penetrate the wall of Figure 60–3 shows that the promyelocyte produces and accumulates a
venules. The mature granulocytes enter the blood from the marrow, circulate large population of peroxidase-positive granules. Most of the granules
briefly, and move to the tissues to carry out their major function of host defense. are spherical and have a diameter of 500 nm, but ellipsoid, crystalline
5
Blood neutrophils exhibit the capacity for changes in phenotypic characteristics forms and small granules connected by filaments also are present. As
with other secretory cells, peroxidase is present throughout the secre-
and life span depending on the stimulating milieu of cytokines and chemokines. tory apparatus of the promyelocyte, including cisternae of the rough
Gene expression profiling studies indicate the neutrophil is a transcriptionally endoplasmic reticulum, all Golgi cisternae, some vesicles, and all devel-
active cell, responsive to environmental stimuli, and capable of a complex series oping granules. 2
of early and late changes in gene expression.
The Neutrophilic Myelocyte
During the myelocyte stage of maturation, the specific or secondary
granules, which are peroxidase negative, are formed (see Fig. 60–2). At
Acronyms and Abbreviations: AML1, AML2, AML3, transcription factor for various the end of the promyelocyte stage, peroxidase abruptly disappears from
hematologic lineages; C3a, serum complement fragment 3a; C5a, serum complement rough endoplasmic reticulum and Golgi cisternae, and the production
fragment 5a; CBFA1, CBFA2, core-binding factor subunit α-1 or -2; CCR, C-C chemok- of azurophilic granules ceases. The myelocyte stage begins with produc-
ine receptor; C/EBPε, regulating factor of gene expression; CD11b/CD18, Mac-1 or tion of peroxidase-negative specific granules. 2
integrin α β ; ECP, eosinophil cationic protein; EDN, eosinophil-derived neurotoxin; The only peroxidase-positive elements at this stage are the
m 2
FcγRIIIB, receptor IIIB for the Fc region of IgG; GATA-1, lineage-specific transcription azurophilic granules. The specific granules are formed by the Golgi
factor; G-CSF, granulocyte colony-stimulating factor; GM-CSF, granulocyte-macro- complex. The granules vary in size and shape but typically are spherical
phage colony-stimulating factor; GRO, growth-regulated protein; IFN, interferon; (approximately 200 nm) or rod shaped (130 × 1000 nm). Figure 60–4
Ig, immunoglobulin; IL, interleukin; IP-10, interferon-γ–induced protein 10; JAK2, shows the cell also labeled with immunogold particles to illustrate the
Janus-associated kinase 2; LPS, lipopolysaccharide; MBP, major basic protein; MMP- presence of lactoferrin, a specific granule marker. Approximately three
8, metalloproteinase-8, also called collagenase; MMP-9, metalloproteinase-9, also cell divisions occur at this stage of maturation. Mitoses can be observed
called gelatinase B; NADPH, reduced form of nicotinamide adenine dinucleotide (Fig. 60–5), and the two types of granules appear to be distributed to the
phosphate; PAF, platelet-activating factor; PMN, polymorphonuclear neutrophil; daughter cells in fairly equal numbers.
RUNX1, RUNX2, RUNX3, runt-related transcription factor 1, 2, or 3; SNAP, soluble NSF
(N-ethylmaleimide-sensitive factor) attachment protein; TGF, transforming growth Metamyelocyte, Band, and Mature Neutrophil
factor; TNF, tumor necrosis factor; VAMP, vesicle-associated membrane protein. The metamyelocyte and band neutrophils are nonproliferating cells that
precede the development of the mature neutrophil (see Fig. 60–2).

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