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968 Part VII: Neutrophils, Eosinophils, Basophils, and Mast Cells Chapter 63: Basophils, Mast Cells, and Related Disorders 969

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together with evidence indicating that tissue mast cells are derived chondroitin sulfates or a mixture of chondroitin sulfates (50 to 84 per-
42
from circulating marrow-derived precursors, 16,18 had suggested to some cent) and heparin (8 to 43 percent). Although the biologic functions of
investigators that basophils might be circulating precursors of mast basophil and mast cell proteoglycans are not fully understood, in mice,
cells. However, the following evidence strongly favors the view that heparin is required for normal packaging of certain neutral proteases in
mature basophils represent terminally differentiated granulocytes and mast cell cytoplasmic granules. 40,43 Both human mast cells and basophils
1,4
not circulating mast cell precursors: (1) no evidence has been presented, synthesize and store histamine. Basophils represent the source of most
44
in any species, indicating that mature circulating basophils are capable (if not all) of the histamine present in normal human blood. Although
44
47
45
46
of either mitosis or differentiation into mast cells; (2) rare reports of macrophages, neutrophils, and platelets, as well as basophils, can
patients with hereditary or acquired abnormalities affecting basophil produce histamine, mast cells represent the source of virtually all the
numbers or morphology indicate that eosinophils also may be affected histamine stored in normal tissues in mice, with the notable exceptions
in these disorders but not mast cells 32–34 ; (3) morphologically identifi- of the glandular stomach and parts of the central nervous system. 48
35
able human tissue mast cells can exhibit mitotic activity, indicating In addition to proteoglycans and histamine, basophils and mast
that mast cells can replicate independently of a stage resembling that of cells generate many other products that can influence the course of
basophils, and (4) in mice, evidence indicates that a mast cell–committed inflammatory processes (see Table 63–1). 1,3–5,49–51 These substances are
progenitor (MCP) present in the marrow is developmentally distinct either preformed and granule associated (e.g., histamine, neutral pro-
during hematopoiesis from a Sca-1 granulocyte-macrophage progen- teases, proteoglycans) or produced during activation of the cell (e.g.,
lo
itor. 19,20 Evidence for a committed bipotential precursor of mast cells prostaglandin D , leukotrienes and other metabolites of arachidonic
2
and basophils during hematopoiesis in the mouse has been reported by acid, and platelet-activating factor). Appropriately stimulated mouse or
some studies 36,37 but not others. 19,20,38 human mast cells can release the cytokine tumor necrosis factor α (TNF-
α), 52,53 and many other cytokines, chemokines, and growth factors with
MORPHOLOGY OF BASOPHILS AND MAST CELLS effects on inflammation, immunity, hematopoiesis, tissue remodeling,
1,3–5,49–51
Routine histologic methods are poorly suited for demonstrating and many other biologic processes. By contrast, the spectrum
of basophil-derived cytokines appears to be more limited but includes
basophils and mast cells. Optimal visualization is achieved in appro- IL-4 and IL-13, vascular endothelial growth factor (VEGF)-A, certain
54
priately prepared 1 μm sections or by electron microscopy. By ultra- chemokines, and, at least in mice, IL-6, TNF-α, and thymic stromal
1,2
structure, human basophils are 5 to 7 μm in spherical diameter, exhibit lymphopoietin (TSLP). 4,5,55–57
a segmented or unsegmented nucleus with marked condensation of
nuclear chromatin, and contain round or oval cytoplasmic granules
surrounded by a membrane and containing a substructure of dense ROLE IN ACUTE REACTIONS
particles, less-dense matrix, and, in some granules, membrane whorls
and Charcot-Leyden crystals (see Fig. 63–1C). A minor population of Basophils and mast cells have specific, high-affinity plasma membrane
1,2
58,59
small, uniform granules is characteristically located near the nucleus. receptors for the Fc region of IgE (FcεRI). When IgE antibodies
39
The cytoplasm of mature human basophils also contains glycogen par- bound to FcεRI on the basophil or mast cell surface are bridged by
ticles, mitochondria, free ribosomes, and small membrane-bound vesi- specific divalent or multivalent antigens, anaphylactic degranulation is
57,58
cles. Lipid bodies are rarely present. Other organelles are inconspicuous. triggered. The critical signal in this event is the aggregation of FcεRI
57,58
In tissue sections, mast cells typically appear as either round or on the plasma membrane. Anaphylactic degranulation involves the
elongated cells, usually with a nonsegmented nucleus with moderate fusion of plasma membranes with the membranes delimiting individ-
condensation of nuclear chromatin, and contain prominent cytoplasmic ual cytoplasmic granules or with groups of granules whose membranes
granules. Mast cell granules are smaller, more numerous, and generally have undergone fusion, leading to rapid noncytolytic release of gran-
1,2
more variable in appearance than in basophils and contain scroll-like ule contents, such as histamine and other preformed mediators. The
structures, particles, and crystals, alone or in combination (see Fig. complex sequence of biochemical events associated with anaphylactic
63–1C). In contrast to the irregularly spaced blunt surface projec- degranulation, the signaling mechanisms that positively and negatively
1,2
tions of basophils, mast cells are covered by uniformly distributed thin regulate this response, and the rationale for the pharmacologic manipu-
57,58
surface processes. Mast cells also differ from basophils in having many lation of these processes have been reviewed.
more cytoplasmic filaments and lacking cytoplasmic glycogen deposits. The sudden, massive release of mediators from basophils and
Human mast cells can contain numerous cytoplasmic lipid bodies. mast cells provokes many of the clinical manifestations of acute imme-
diate hypersensitivity reactions in disorders such as certain forms
of bronchial asthma (including fatal asthma, in which basophils can
BIOCHEMISTRY AND ROLE IN be prominent ); urticaria; allergic rhinitis; and anaphylaxis to foods,
60
IMMUNOGLOBULIN E-ASSOCIATED drugs, insect stings, and other antigens. 1,5,49,50,55–57 Both mast cells and
IMMUNE RESPONSES basophils can bind IgG antibodies (as well as IgE), and the binding
of IgG or IgG immune complexes can contribute to the activation of
Mediators these cells (in certain mouse models of anaphylaxis) or, in other cir-
The cytoplasmic granules of basophils and mast cells contain proteo- cumstances, to the downregulation of their activation (e.g., via Fcγ
glycans, consisting of sulfated glycosaminoglycans covalently linked RIIB). 5,55–57,61–64 Other diverse stimuli, including certain complement
to a protein core. These substances can be stained metachromatically fragments (anaphylatoxins), neutrophil lysosomal proteins, a variety of
40
with basic dyes (see Fig. 63–1A and B). In humans and murine spe- basic peptides and peptide hormones, components of insect or reptile
cies, individual mast cell populations can contain variable mixtures of venoms, radiocontrast solutions, cold, calcium ionophores, and certain
heparin and chondroitin sulfate proteoglycans. 29,40 Although the sul- drugs such as narcotics and muscle relaxants, also may initiate rapid
fated glycosaminoglycans of normal human blood basophils have not release of mediators from basophils and/or mast cells, independently
yet been characterized, two studies of the proteoglycans synthesized by of IgE. 1,4,5,48,49,54–56 The clinical reactions provoked by these agents can
blood leukocytes (containing 10 to 75 percent basophils) of five patients closely mimic those of immediate hypersensitivity. Basophils activated
with myeloid leukemia indicate that such cells may produce solely via FcεRI or other mechanisms can exhibit increased surface levels of

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