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CHaPtEr 24 Eosinophils and Eosinophilia 353

ROLES IN HOST DEFENSE OTHER EOSINOPHIL FUNCTIONS
Because the host response to infections with multicellular hel- Other potential functions for the eosinophil are not fully defined.
minth parasites is characteristically associated with eosinophilia, In addition to the acute release of lipid, peptide, and cytokine
it is often believed that eosinophils evolved to have a role in mediators of inflammation, eosinophils probably contribute to
killing helminths, especially during their larval stages. Indeed, chronic inflammation, including the development of fibrosis.
in vitro eosinophils can kill numerous helminths, organisms too Eosinophils can be a major source of the fibrosis-promoting
large to be phagocytosed. Eosinophils adhere to the parasite and cytokine TGF-β. Additional roles of eosinophils in modulating
deposit eosinophil granule contents onto its surface. Cell products extracellular matrix deposition and remodeling are suggested
that can contribute to parasite death include MBP, ECP, EDN, by studies of normal wound healing. During dermal wound
and EPO. healing, eosinophils infiltrate into wound sites and sequentially
16
As reviewed earlier, the helminthotoxic roles of eosinophils express TGF-α early and TGF-β 1 later during wound healing.
in vivo are less certain in humans and rodents. In eosinophil- These findings suggest that eosinophils may contribute to the
depleted mice, the intensities of primary and secondary infections more chronic subepithelial airway fibrosis characteristic of chronic
with some helminths have not been greater than in eosinophilic asthma.
mice, nor have IL-5 transgenic mice exhibited increased resistance Additional functions for eosinophils are indicated by the
to infection with some helminth species. Moreover, schistosome findings that they may be induced to express class II MHC proteins
20
infections in two lines of eosinophil-ablated mice have shown and can function as APCs. Blood eosinophils lack HLA-DR
no differences in measures of infection compared with normal expression, but eosinophils recovered from the airways 48 hours
17
mice. Nevertheless, murine studies need to be interpreted with after segmental antigen challenge have been shown to express
caution. Many experimental infections involve introducing HLA-DR. Cytokines, including GM-CSF, IL-3, IL-4, and IFN-γ,
helminth infections that are often host species–restricted into induce eosinophil HLA-DR expression. Both murine and human
unnatural host mice, in which innate immune responses may eosinophils can function as HLA-DR–dependent MHC-restricted
be prominent. Natural human infections are usually a consequence APCs in stimulating the proliferation of T cells. In vivo, murine
of repeated exposures, during which acquired, rather than innate, eosinophils can process exogenous antigens in the airways, traffic
immunity becomes prominent. Thus eosinophil functions as to regional lymph nodes, and function as antigen-specific APCs
helminthotoxic cells in vivo remain unclear. Eosinophils might to stimulate responses of CD4 T cells. 21
have alternative functions in host responses to helminths, includ- Eosinophils, that normally become resident in submucosal
ing functioning as APCs and even favoring the survival of and less prominently in other tissues, undoubtedly participate
Trichinella larvae in muscles. 18,19 in ongoing homeostatic immune responses at these sites. Some
of these responses are mediated by cytokines secreted by eosino-
ROLES IN DISEASE PATHOGENESIS phils, including IL-6 and APRIL to stimulate plasma cells
22
development and IL-4 to activate macrophages in fat tissue
23
The abilities of eosinophils to release biologically active lipids and effect glucose metabolism. Further investigations will help
as paracrine mediators of inflammation and to release preformed delineate eosinophil’s functional roles and interactions with other
cationic and cytokine granule constituents enable eosinophils cells, so that the scope of eosinophil functions will probably
to contribute to the immunopathogenesis of various diseases, extend beyond its currently more defined role as an effector cell
1
including asthma. Eosinophils form several classes of biologically contributing to allergic inflammation.
active lipids. Eosinophils may liberate PAF, whose diverse activities
can be mediated either directly or by stimulating other cells to EOSINOPHILIA AND EOSINOPHILIC DISORDERS
release leukotrienes, prostaglandins, and complement peptides.
Stimulated eosinophils release LTC 4 . LTD 4 and LTE 4 are formed Diverse infectious, allergic, neoplastic and idiopathic disease
from LTC 4 by the sequential enzymatic removal of glutamic acid processes can be associated with increased blood and/or tissue
and glycine from its tripeptide glutathione side chain. LTC 4 and eosinophil numbers. Blood eosinophilia, present when eosino-
especially LTD 4 have bronchoconstrictor activities, constrict phil numbers are in excess of their usual level of <450/µL of
terminal arterioles, dilate venules, and stimulate airway mucus blood, may be intermittently, modestly, or (less frequently)
secretion. Thus eosinophils are a potential source of two major markedly increased. Blood eosinophil numbers are not neces-
types of mediator lipids, the sulfidopeptide leukotrienes and sarily indicative of the extent of eosinophil involvement in
PAF. affected tissues.
Oxidants released by eosinophils, including superoxide anion, Some patients with sustained blood eosinophilia can develop
hydroxyl radical, and singlet oxygen, as well as EPO-catalyzed organ damage, especially cardiac damage. This cardiac involvement
hypothiocyanous acid and other hypohalous acids, have the can include the formation of intraventricular thrombi and
potential to damage host tissues. endomyocardial fibrosis with secondary mitral or tricuspid
Released eosinophil granule proteins are immunologically regurgitation (Fig. 24.3). Such damage can complicate the
detectable in fluids, including blood, sputum, and synovial fluids, sustained eosinophilia of hypereosinophilic syndromes and has
and in tissues, including the respiratory and GI tracts, skin, and been noted with eosinophilias accompanying other diseases,
heart, in association with various eosinophil-related diseases. including eosinophilia with carcinomas, lymphomas, GM-CSF,
The eosinophil cationic proteins, including MBP, ECP, and EPO, or IL-2 administration, drug reactions, and parasitic infections.
can damage various cell types. Thus extracellular release of Most patients with eosinophilia, however, develop no evidence
eosinophil granule proteins, by degranulation or cytolysis of of endomyocardial damage. Conversely, cardiac disease can rarely
eosinophils, could contribute to local tissue damage by causing present in patients without known eosinophilia. The pathogenesis
dysfunction and damage to adjacent cells. of eosinophil-mediated cardiac damage involves both usually