Early in precursor development in the marrow, cells destined to be leukocytes of the granulocytic series—neutrophils, eosinophils, and basophils—synthesize proteins and store them as cytoplasmic granules. The synthesis of primary or azurophilic granules defines the conversion of the myeloblast, a virtually agranular, primitive cell that is the earliest granulocyte precursor identifiable by light microscopy, into the promyelocyte, which is rich in azurophilic granules. Synthesis and accumulation of secondary or specific granules follows. The appearance of specific granules marks the progression of the promyelocyte to neutrophilic, eosinophilic, or basophilic myelocytes. Thereafter, the cell continues maturation into an amitotic cell with a segmented nucleus, capable of chemotaxis, phagocytosis and microbial killing. The mature granulocytes also develop cytoplasmic and surface structures that permit them to attach to and penetrate the wall of venules. The mature granulocytes enter the blood from the marrow, circulate briefly, and move to the tissues to carry out their major function of host defense. Blood neutrophils exhibit the capacity for changes in phenotypic characteristics and life span depending on the stimulating milieu of cytokines and chemokines. Gene expression profiling studies indicate the neutrophil is a transcriptionally active cell, responsive to environmental stimuli, and capable of a complex series of early and late changes in gene expression.
Acronyms and Abbreviations
AML1, AML2, AML3, transcription factor for various hematologic lineages; C3a, serum complement fragment 3a; C5a, serum complement fragment 5a; CBFA1, CBFA2, core-binding factor subunit α-1 or -2; CCR, C-C chemokine receptor; C/EBPε, regulating factor of gene expression; CD11b/CD18, Mac-1 or integrin αmβ2; ECP, eosinophil cationic protein; EDN, eosinophil-derived neurotoxin; FcγRIIIB, receptor IIIB for the Fc region of IgG; GATA-1, lineage-specific transcription factor; G-CSF, granulocyte colony-stimulating factor; GM-CSF, granulocyte-macrophage colony-stimulating factor; GRO, growth-regulated protein; IFN, interferon; Ig, immunoglobulin; IL, interleukin; IP-10, interferon-γ–induced protein 10; JAK2, Janus-associated kinase 2; LPS, lipopolysaccharide; MBP, major basic protein; MMP-8, metalloproteinase-8, also called collagenase; MMP-9, metalloproteinase-9, also called gelatinase B; NADPH, reduced form of nicotinamide adenine dinucleotide phosphate; PAF, platelet-activating factor; PMN, polymorphonuclear neutrophil; RUNX1, RUNX2, RUNX3, runt-related transcription factor 1, 2, or 3; SNAP, soluble NSF (N-ethylmaleimide-sensitive factor) attachment protein; TGF, transforming growth factor; TNF, tumor necrosis factor; VAMP, vesicle-associated membrane protein.
In the normal adult human, the life of granulocytes is spent in three environments: marrow, blood, and tissues. Marrow is the site of differentiation of hematopoietic stem cells into granulocyte progenitors and of proliferation and terminal maturation (Fig. 60–1). Precursor 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 capable 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 entering tissues.
Diagrammatic representation of neutrophil (polymorphonuclear neutrophil [PMN]) and stages of maturation (see text for ...
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