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Phagocyte Deficiencies

Steven M. Holland, Gülbü Uzel

We have learned a great deal about phagocytes since their discovery Promyelocyte, myelocyte, metamyelocyte, band form, and mature
by Metchnikoff in 1905: Neutrophils, monocytes, macrophages, neutrophil formation follow consecutively under the ongoing
and eosinophils traffic to sites of infection or inflammation and control of G-CSF and GM-CSF. The maturation process from
engulf microorganisms and apoptotic cells as the lead players stem cell to the myelocyte stage takes 4–6 days and an additional
in the innate immune response. 5–7 days for the myelocyte to form the mature neutrophil, all
in bone marrow.
NEUTROPHILS Macrophage differentiation is similar to granulocyte differ-
entiation in many respects. CFU-GM differentiates into the
Neutrophils, also known as granulocytes because of their numerous colony-forming unit–macrophage (CFU-M) followed by the
cytoplasmic granules, are crucial for the host defense against formation of the monoblast, promonocyte, and monocyte under
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bacteria and fungi. They are bone marrow–derived, terminally the influence of macrophage colony-stimulating factor (M-CSF).
differentiated cells incapable of further cellular division. They After monocytes are released into blood, they circulate for 1–4
have a short life span in the circulation (t 1/2 ≈7 hours), but survive days before entering tissues, where they further differentiate into
an additional 1–2 days in tissue. In peripheral blood, they are macrophages.
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normally maintained at 3000–6000 cells/mm and represent
30–50% of the circulating leukocytes. There are four pools of EVOLUTION OF NEUTROPHIL GRANULES
neutrophils in vivo: (i) the bone marrow pool (≈90% of the
total); (ii) the circulating pool (≈3% of the total); (iii) the During myelopoiesis in bone marrow, the first granules form at
marginated pool (adherent to the endothelium, ≈4% of the total); about the promyelocyte stage, stain blue with the Wright or
and (iv) those located in the tissues as extravasated or exudative Romanowsky stain, and are called primary granules or azurophilic
neutrophils. About 55–60% of bone marrow is dedicated to the granules. Their formation ceases at the myelocyte stage, and they
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production of neutrophils, producing around 10 cells daily, are distributed among the daughter cells. These primary granules
but this is upregulatable in times of stress. contain microbicidal enzymes, including defensins, hydrolases,
Myeloid cell differentiation is a complex stepwise process that and proteases (Table 22.1). As the granulocyte precursors mature
typically extends over 2 weeks in bone marrow. The pluripotent and divide, the number of primary granules per cell decreases.
stem cell, the precursor for all hematopoiesis, develops into After the promyelocyte stage, secondary or specific granules form.
lineage-committed progenitors proceeding to terminally dif- In the mature neutrophil, they comprise about two-thirds of
ferentiated distinct cells, all the while preserving and regenerating the granules. The secondary granules are less dense and contain
more pluripotent stem cells. 1 cytochrome b 558 , lysozyme, lactoferrin, and collagenase. The
gelatinase-containing tertiary granule probably forms after the
PRODUCTION OF MACROPHAGES metamyelocyte stage and can be detected in the band form and
AND GRANULOCYTES the mature granulocyte.
The pluripotent stem cell gives rise to the myeloid stem cell from DISORDERS OF NEUTROPHIL PRODUCTION
which the colony-forming unit granulocyte/erythrocyte/
macrophage/megakaryocyte (CFU-GEMM) is derived. Among Chronic neutropenia refers to conditions with absolute neutrophil
the growth factors that are influential at this step are stem cell counts (ANCs) of less than 500 cells/µL lasting more than 6
factor (SCF), interleukin-3 (IL-3), and granulocyte macrophage– months. Chronic neutropenia can have many etiologies, as listed
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colony-stimulating factor (GM-CSF). CFU-GEMM further in Table 22.2.
differentiates into the colony-forming unit–granulocyte macro-
phage (CFU-GM) under the continuing influence of these growth Severe Congenital Neutropenia and Cyclic Neutropenia
factors. The colony-forming unit–granulocyte (CFU-G), a Kostmann originally described extensive northern Swedish kindred
neutrophil lineage committed precursor, is derived from CFU-GM with both recessive and dominant neutropenia, but subsequently
under the control of IL-3, GM-CSF, and granulocyte–colony- sporadic cases were added, making this a confusing melange of
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stimulating factor (G-CSF). The myeloblast is formed from the neutropenia syndromes. Severe congenital neutropenia (SCN)
CFU-G under the influence of GM-CSF and G-CSF and is the is now known to be a heterogeneous group of disorders that
first morphologically distinct cell of the neutrophil lineage. present similarly. The genes recognized as mendelian causes of

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