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352 Part two Host Defense Mechanisms and Inflammation

parasites but also in contributing to tissue dysfunction and damage be elicited without other attributes by mediators and mechanisms
in eosinophil-related allergic and other diseases. that remain to be delineated.
Cytokines and Chemokines MECHANISMS OF EOSINOPHIL DEGRANULATION
Eosinophils are capable of elaborating at least four dozen diverse
cytokines and chemokines, and studies continue to identify more As eosinophil granules contain four major cationic proteins and
cytokines released by eosinophils. The potential activities of a multitude of preformed cytokines and chemokines, the processes
eosinophil-derived cytokines are extensive. Eosinophil-derived by which eosinophils mobilize these granule constituents for
cytokines include those with autocrine growth factor activities their extracellular release are important in understanding the
for eosinophils and those with potential roles in acute and chronic regulated functioning of eosinophils. Unlike mast cells or basophils
inflammatory responses. A notable feature of eosinophils as a that undergo acute exocytotic degranulation in response to
source of cytokines is that they contain stores of these cytokines cross-linking of their high-affinity Fcε receptors, an analogous
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preformed within eosinophil granules and secretory vesicles. mechanism to elicit comparable exocytotic degranulation of
Thus in contrast to most lymphocytes, which must be induced fluid-phase eosinophils has not been identified. Cross-linking
to synthesize de novo cytokines destined for release, eosinophils of eosinophil IgG or IgA Fc receptors in vitro can stimulate
can immediately release preformed cytokine and chemokine release of eosinophil cationic proteins, but this rapid FcR-mediated
proteins into the surrounding milieu. The local, rapid release of acute “degranulation” process is cytolytic for eosinophils. In
eosinophil-derived cytokines in tissues to effect adjacent cells contrast, observations of eosinophils on the surfaces of large
could, and has been shown to, readily induce responses in varied nonphagocytosable multicellular helminth parasites do provide
cell types. evidence that eosinophils can degranulate by exocytosis to
Eosinophils synthesize the three growth factor cytokines wholesale release granule contents on the surfaces of target
GM-CSF, IL-3 and IL-5, which promote eosinophil survival, parasites.
antagonize eosinophil apoptosis, and enhance eosinophil effec- An alternative mechanism of mobilizing granule contents for
tor responses. Other cytokines elaborated by human eosinophils secretion that eosinophils utilize is a process of vesicular transport-
that may have activities in acute and chronic inflammatory mediated “piecemeal” degranulation. Electron microscopic
responses include IL-1α, IL-6, IL-8, IFN-γ, TNF-α, and MIP- observations of lesional eosinophils provided evidence that
1α. Human eosinophils can elaborate other various “growth” eosinophil granule contents were mobilized in vivo by selective
factors, including transforming growth factor (TGF)- α, incorporation into small vesicles that traffic to the cell surface
TGF-β 1 , vascular endothelial growth factor, platelet-derived and release these granule contents. By this process, there may
growth factor (PDGF)-β, heparin-binding epidermal growth be agonist-elicited selective secretion of certain eosinophil-derived
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factor, and a proliferation-inducing ligand (APRIL). These cytokines. Ultrastructural studies have demonstrated that
cytokines have roles in contributing to epithelial hyperplasia secretory vesicles arise from granules and transport cytokines,
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and fibrosis, as well as other immune homeostatic activities. such as IL-4. Insights into the selectivity and mechanisms of
In addition, eosinophils are recognized as sources of specific differential cytokine secretion have been gained by the finding,
cytokines and chemokines capable of stimulating or inhibiting at least for IL-4, that a receptor for IL-4 mediates the transport
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lymphocyte responses, including IL-2, IL-4, IL-10, IL-12, IL-16, of IL-4 from granules and within secretory vesicles. How this
RANTES, and TGF-β 1 . Of note, eosinophil cytokines include process of vesicular transport is regulated and functions to
those associated with Th2 (IL-4, IL-5, IL-13), Th1 (IL-12, IFN- selectively mobilize specific eosinophil granule–derived cytokines
γ), and T-regulatory (IL-10, TGF-β) responses, emphasizing the or cationic proteins remains under investigation.
diverse immunoregulatory potentials for eosinophil-secreted In addition to regulated release of granule contents from
cytokines. 10 viable eosinophils, a common, but often overlooked, occurrence
is the lysis of eosinophils. Both cutaneous and pulmonary biopsy
ACTIVATED EOSINOPHILS specimens of eosinophil-associated diseases contain free, extracel-
lular, but still membrane-bound, eosinophil granules. These free
A well-recognized attribute of eosinophils is that, in conjunc- extracellular granules express cytokine, chemokine, and cysteinyl
tion with eosinophilic diseases, some blood and tissue eosino- leukotriene receptors and are secretion competent even outside of
phils may exhibit various alterations, indicating that these cells intact eosinophils. 13,14 Cytolytic stimuli elicit both the release of
have been “activated.” These changes include increased meta- nuclear DNA to form extracellular DNA “traps” and the release
bolic activity, diminished density (“hypodense”), enhanced of free secretion-competent eosinophil granules in humans. 15
LTC 4 formation, and morphological alterations, including
cytoplasmic vacuolization, alterations in granule numbers and FUNCTIONS OF EOSINOPHILS
size, and losses within specific granules of MBP-containing
cores or matrices. Activated eosinophils may exhibit enhanced Conventional considerations of the roles that eosinophils may
plasma membrane expression of some proteins, including play have been guided by quantitative considerations so that
CD69, human leukocyte antigen–D related (HLA-DR), and those diseases characteristically marked by more prominent
CD25. eosinophilia have occasioned the most interest. Thus studies
Features associated with in vivo “activated” eosinophils can have focused on the “effector” roles eosinophils play in host
be elicited, in part, by exposing eosinophils to specific stimuli, defense against helminth infections and in the immunopatho-
including GM-CSF, IL-3, and IL-5. In addition, interactions with genesis of allergic and other eosinophilic diseases. Additional
extracellular matrix components can further contribute to roles for eosinophils must be considered in immune or inflam-
eosinophil activation. Eosinophil “activation,” however, is not a matory responses not conventionally recognized to contain
singularly binary process, and some attributes of activation can abundant eosinophils. 4