The Eosinophil

J. Comp. Path. 1993 Vol. 108, 317-335

REVIEW

The Eosinophil D. G.

Joxles

Moredun Research Institute, 408 Gilmerton Road, Edinburgh EH17 7JH, U.K. Introduction

Eosinophils are white blood cells of the polymorphonuclear leucocyte family characterized by their intense affinity for acidic dyes such as eosin and luxol fast blue. Discovery of these staining properties led to the first definitive description of the cell in 1879 by Paul Ehrlich. This and other pioneering work by Ehrlich on eosinophils has been reviewed in some detail elsewhere (Hirsch and Hirsch, 1980). Eosinophils are produced from lineage-specific progenitors in the bone marrow and migrate through the blood, over a period of a few hours, to their predominant dwelling site in the tissues, where they may survive for several weeks (Spry, 1988). Normally there are many hundreds of times more eosinophils in the tissues than in the blood, and they are particularly prevalent in perivascular sites near mucosal surfaces. A number of disease processes are associated with an eosinophilia, characterized by enhanced production of eosinophils in the bone marrow and their increased accumulation in blood and tissues (Gleich and Adolphson, 1986; Spry, 1988; Weller, 1988; Sanderson, 1992). Eosinophilic responses are typical of allergic reactions, parasitoses and chronic inflammation, but eosinophils may also contribute to immune responses in the absence of disease. The precise functions of the cell are still unclear but are unlikely to be identical under all circumstances. Like neutrophils, eosinophils can act as end-stage effector phagocytes, but their greater longevity and multiple biological capabilities furnish them with the potential for much greater functional diversity. The distinguishing morphological features of mammalian eosinophils are their cytoplasmic granules (Dvorak et al., 1991). These contain a number of cell-specific proteins, the basic nature of which is responsible for the staining characteristics of the cell (Pimenta et al., 1980). Eosinophils express a number of surface receptors (Spry, 1988; Kay, 1991; Weller, 1991) through which they can be activated and stimulated to proliferate, migrate or degranulate. Several proteins are secreted during the degranulation process and these have a range of enzymatic and other biological activities which have been argued by many to be the basis of eosinophil function (Gleich and Adolphson, 1986; Spry, 1988). Eosinophils can synthesize and release a number of bioactive mediators (Weller el al., 1983; Lee el al., 1984; Kay, 1985, 1991) and interact with other cell types (Rothenberg et al., 1989; Del Pozo et al., 1992) in ways which introduce new functional possibilities. Although their role in health and disease 0021-9975/93/040317 + 19 $08.00/0

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remains poorly defined, it is now generally agreed that eosinophils are proinflammatory cells whose effects may be either beneficial or detrimental to the host, depending on the situation (Gleich and Adolphson, 1986; Spry, 1988; Weller, 1991). After a dormancy of several decades, interest in the eosinophil re-emerged in the early 1960s and has continued to flourish, particularly as a result of the rapid advances in molecular technology. Much of the work up to the mid-80s has been excellently summarized and discussed elsewhere (Venge, 1985; Gleich and Adolphson, 1986; Silberstein and David, 1987; Spry, 1988; Weller, 1988; Venge, 1990; Weller, 199I; Dvorak et al., 1991; Thorne and Mazza, 1991; Sanderson, 1992). This review will focus on some of the more recent developments and comparative aspects of the immunobiochemistry and function of these unique and enigmatic cells.

Eosinophil Structure The eosinophil has a distinctive morphology (Dvorak et al., 1991) which is remarkably conserved throughout the animal kingdom. The classical feature of the cells is their unique eosin-staining crystalloid granules. In mature eosinophils of the peripheral blood these comprise over 95 per cent of the total granule content. The remainder consists of a mixture of large- to medium-sized dense crystalloid-free granules, small dense granules and so-called microgranules (Schaefer et al., 1973) or vesiculotubular structures (Komiyama and Spicer, 1975). Granule distribution can vary with maturity and the degree of activation. Immature eosinophils contain mostly coreless granules, but small granules are generally absent from the myelocytic stages. Conversely, activated mature cells contain large numbers of small granules and relatively fewer large granules (Parmley and Spicer, 1974; Dvorak el al., 1980). This has led to speculation that small granules may be the post-secretory remnants of crystalloid granules (Spry, 1988). The latter contain a variety of cell-specific, biologically active proteins and these have largely provided the basis for hypotheses on eosinophil function, a topic which will be discussed in more detail later. Four major proteins, namely the major basic protein (MBP) (Gleich et al., 1973), eosinophil cationic protein (ECP) (Olsson and Venge, 1974), eosinophil peroxidase (EPO) (Archer and Broome, 1963) and eosinophil-derived neurotoxin (EDN) (Durack et al., 1979), also known as eosinophil protein X (EPX; Petersen and Venge, 1983), were identified in various species during the 1960s and 70s. Immunoassays were quickly developed and extensive study of biochemical and functional properties followed (see Gleich and Adolphson, 1986; Spry, 1988). More recently, with the rapid emergence of molecular biological technology, each of the four proteins has been cloned (Hamann et al., 1991) and expressed as recombinant material, allowing further study of biochemical and functional properties, some of which are discussed in the following section. Eosinophil granules also contain the enzymes arylsulphatase, collagenase, histaminase, beta-glucuronidase, cathepsin D, acid phosphatase and catalase (Spry, 1988; Gleich and Adolphson, 1986; Venge, 1985), which,

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with the possible exception of arylsulphatase (Bainton and Farquhar, 1970), tend not to be cell-specific. One other feature of eosinophils is their high content oflysophospholipase activity. This protein comprises the entire content of Charcot-Leyden crystals (CLCs) and up to 10 per cent of total eosinophil protein (see Spry, 1988; Dvorak et al., 1991). CLCs are a feature of sites of eosinophil degranulation and were originally thought to be eosinophil-specific. However, they are now also known to occur in basophils (Ackerman et al., 1982). The role of CLC lysophospholipase is unknown, but it may provide protection against the toxic effects of endogenous or parasite-derived lysophospholipids. Alternatively, several centres are studying the potential harmful effects of CLCs in respiratory disease, based on the possibility that lysophospholipase may neutralize natural pulmonary surfactants and induce lung collapse. The activated eosinophil is a potent source of toxic oxygen-derived metabolites such as superoxide anions, hydroxyl radicals, hydrogen peroxide and singlet oxygen (Pincus el al., 1981; Petreccia et al., 1987; Kanofsky et al., 1988). It can synthesize and release various lipid mediators including lipoxins (Serham el al., 1987; Steinhilber and Roth, 1989), prostaglandins (Hubscher, 1975; Feogh et al., 1986), leukotrienes C4 (LTC4) (Weller el al., 1983; Shaw et al., 1984; Bruynzeel et al., 1986) and B4 (LTB4) (Hirata et al., 1990), platelet activating factor (PAF) (Lee et al., 1984; Cromwell et al., 1991) and peptide mediators such as substance P (Weinstock et al., 1988). Moreover, recent studies indicate that eosinophils can produce interleukins 1 (IL-1) (Del Pozo et al., 1990), 3 (IL-3) (Kita et al., 1991) and 5 (IL-5) (Desreumoux et al., 1992), granulocyte macrophage colony-stimulating factor (GM-CSF) (Kita et al., 1991; Moqbel et al., 1991) and transforming growth factor alpha (TGF-a) (Wong et al., 1990).

Biological Activities of Eosinophil-specific Granule Proteins Major basic protein (MBP), so-named because of its cationic nature and its major contribution (over 50 per cent) to total eosinophil granule protein content, is an arginine-rich protein with a molecular weight of around 14 kDa (Wasmoen et al., 1988), located exclusively in the crystalloid core (Lewis et al., 1978; Egesten et al., I986). It has no recognized enzymic activity but is cytotoxic for protozoan and helminth parasites (Butterworth et at., 1979), tumour cells and many other mammalian cell types in vitro (Gleich et aI., 1979). MBP has also been shown to stimulate histamine release from mast cells and basophils in a non-cytotoxic fashion (O'Donnell et al., 1983). Mechanisms for tile action of MBP are presently unknown. Eosinophil cationic protein (ECP) is a markedly basic polypeptide of the crystalloid granule matrix with a molecular weight of between 18 and 21 kDa (Olsson et al., 1986). It has weak ribonuclease activity and, like MBP, the capability to kill both mammalian and non-mammalian cells (Venge and Petersen, 1989), possibly by a colloid-osmotic process. ECP is also a potent neurotoxin (Fredens el al., 1982). Several non-cytotoxic properties have been attributed to ECP, including the induction of histamine release from mast

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cells/basophils (Bergstrand et al., 1985), the stimulation of glycosaminoglycan production by fibroblasts (Sarnstrand et al., 1989) and the inhibition of Tlymphocyte proliferation (Petersen et al., 1986). In addition, ECP alters fibrinolysis through the preactivation ofplasminogen (Dahl and Venge, 1979) and shortens plasma coagulation time by a factor XII-dependent mechanism (Venge et al., 1979). The latter may explain the greater predisposition for thromboembolism associated with the hypereosinophilic syndrome. ECP, but not MBP, has been shown to enhance mucus production in the bronchi (Lundgren et al., 1991). This, along with its mast cell degranulatory activity, may be of specific importance in the aetiology of bronchial asthma. Eosinophil-derived neurotoxin (EDN), now thought to be identical with eosinophil protein X (Slifman et al., 1989), is a single-chained granule matrix protein of approximately 18 kDa mol. wt. Human EDN has 60 per cent sequence homology and shares at least one epitope with ECP (Tai et al., 1984; Gleich et al., 1986). Both proteins have some sequence homology with pancreatic ribonuclease but EDN has about 100 times more ribonuclease activity than ECP. The major biological property of EDN is its ability to provoke cerebral and cerebellar dysfunction in rabbits and guinea-pigs through the so-called "Gordon phenomenon" (see Gleich and Adolphson, 1986). However, again like ECP and at similar concentrations, EDN is also a non-cytotoxic inhibitor ofT-cell responses (Petersen et al., 1986). Eosinophil peroxidase (EPO) is a two chained protein with a light chain of around 15 kDa and a heavy chain of 52-55 kDa (Carlson et al., 1985), and is distinct from the myeloperoxidase of neutrophils and mononuclear cells. It is localized in the granule matrix and the intensity of peroxidase staining is so great that it can be readily used to enumerate eosinophils. When combined with hydrogen peroxide and halide ions EPO constitutes a potent bactericidal and helminthicidal system as well as being cytotoxic for tumour and host cells (Gleich and Adolphson, 1986; Spry, 1988). The same system induces noncytotoxic mast cell degranulation and histamine release (Henderson el al., 1980). The binding of EPO to several micro-organisms appears to potentiate macrophage-dependent killing mechanisms (see Spry, 1988). In addition to its own putative effector roles, EPO can diminish the effector roles of other inflammatory cells through its ability to inactivate LTB4, LTC4 and LTD4 (Henderson e¢ al., 1982).

Eosinopoiesis The major site of eosinophil production is the bone marrow, where unipotential stem cells develop to a promyelocytic, then a myelocytic and finally a metamyelocytic stage, at which point division ceases but maturation continues. There is now considerable evidence that at least three cytokine growth factors, namely IL-3, IL-5 and GM-CSF (Clutterbuck et al., 1989; Sonoda et al., 1989), contribute significantly to eosinophil differentiation. However, only IL-5 has been ascribed lineage specificity for eosinophils (and basophils) (Denburg, 1992). Eosinophilia is often a highly specific response and it has been argued that IL-5 is the major, and perhaps only, cytokine required for its production

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(Sanderson, 1992). All three cytokines can induce eosinophil proliferation in vitro, but the doses required for optimum eosinophil production by IL-3 and GM-CSF are at least tenfold higher than those needed to induce neutrophil/ macrophage production (Clutterbuck et al., 1989). IL-3 and GM-CSF probably act respectively on early multipotential and oligopotential stem cell stages, whereas IL-5 induces specific eosinophil differentiation from unipotential stem cells (Sonoda et al., 1989). Work on human bone marrow cultures confirmed that IL-5 acts on a smaller and possibly different population of eosinophil precursors than IL-3 and GM-CSF (Denberg, 1992). Whilst it may act on fewer progenitors, IL-5 can stimulate more proliferative steps than either IL-3 or GM-CSF (Sanderson, 1992). It is possible that eosinophil production requires a cytokine network. Evidence for interaction between IL-3, IL-5 and GM-CSF is provided by the cross-inhibition of their binding to human eosinophils (Lopez et al., 1989; Lopez et al., 1990). Moreover, along with IL-4, their encoding genes share several structural features and are present as gene clusters on a single chromosome in man and in the mouse (Lee et al., 1989; Van Leeuwen et al., 1989). Whether they are members of a single gene family under the regulation of common expression mechanisms is still uncertain. There is evidence that IL4 and IL-5 are co-expressed by a single (Th2) helper (CD4+) T-lymphocyte subset, but IL-3 and GM-CSF are produced by both Thl- and Th2-helper subsets (Coffman el al., 1988). This concurs with the well established T-cell dependence of both systemic and granulomatous eosinophilia in vivo. The specific IL-5 dependency of the latter has been endorsed by the complete ablation of eosinophilic responses in parasitized mice after treatment with specific antibodies to IL-5 (Sher et al., 1990; Rennick et al., 1990). Transgenic mice expressing IL-5 show profound lifelong eosinophilia (Dent el al., 1990). Mice carrying haematopoietic cells infected with a retrovirus carrying the IL-5 gene produced a high degree of blood and tissue eosinophilia for at least a year (Vaux et al., 1990). In contrast, in-vivo clinical trials and animal experiments with IL-3 and GM-CSF indicate that, although they both stimulate eosinophil production, their effects are relatively minor compared with those on other cell lineages (Ganser et al., 1990; Ottman et al., 1990). These findings serve as a timely reminder of the potential dangers in extrapolating from in-vitro observations to the living animal. The reader's attention is drawn to two recent reviews on the biology of IL-5 (Takatsu, 1992) and its relationship with eosinophils (Sanderson, 1992).

Eosinophil Activation and Metabolism Mature eosinophils can be stimulated by a range of signals from a variety of sources to become activated and migrate to specific sites, usually areas of acute and chronic inflammation. At such sites, activated eosinophils synthesize and secrete their repertoire of stored and newly formed biologically active molecules. Activated eosinophils also have the capacity to ingest and kill microorganisms, although they are far less efficient phagocytes than neutrophils or macrophages (Gleich and Adolphson, 1986; Spry, 1988).

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Two distinct populations of blood and tissue eosinophils have now been recognized, which are readily separable on the basis of buoyant density and cell morphology (Fukuda and Gleich, 1989; Hamada et al., 1992). These have been termed "normodense" (normal density) and "hypodense" (low density) eosinophils. The latter predominate in eosinophilia and are thought to be the activated, effector form of the cell. An alternative possibility is that hypodense eosinophils are immature rather than activated cells. This seems unlikely, given the demonstration that IL-5, particularly in the presence of fibroblasts, can mediate the conversion of normodense human eosinophils to the hypodense phenotype (Rothenberg et al., 1989). Precisely how "activation" is brought about remains obscure, but the capacity of eosinophils to carry out their effector functions is only fully developed in activated cells. Studies on eosinophil activation have generally followed the pattern laid down for macrophages, with activating factors being defined on the basis of their effects on a limited panel of in-vitro assays of effeetor function such as chemotaxis, oxidative metabolism, and microbicidal activity (Silberstein and David, 1987). Most of the factors which have been shown to induce eosinophil degranulation or secretion are also activa~tors, but there are exceptions. For example, bacterial lipopolysaccharide (LPS) and phorbol myristate acetate (PMA) induce secretion in vitro but do not activate eosinophils for complement-dependent killing of schistosomula (Thorne et al., 1986). It is also clear that eosinophil function and metabolism are mediated through a wide repertoire of cell surface receptors, but some controversy remains as to whether receptor expression is altered by activation. For example, Kay (1991) found no differences in receptor expression between low and normal density human eosinophils, whereas other reports suggest that enhanced expression of specific receptors occurs and may even provide a useful marker of activation (Thorne et al., 1990; Nishikawa et al., 1992). The properties of endogenous eosinophil-activating factors have recently been reviewed (Thorne and Mazza, 1991). They can be divided broadly into three groups: colony-stimulating factors, chemotactic factors and activators of mature eosinophils. The major eosinopoietic cytokines, IL-3, IL-5 and GMCSF, are all capable of activating eosinophils, prolonging their survival in vitro, and reducing their density. They can also enhance generation of leukotriene C4 (LTC4) and immunoglobulin-mediated degranulation, and stimulate helminthotoxic capacity. IL-5 has recently been reported as a selective eosinophil chemoattractant (Wang et al., 1989). Moreover, IL-5 can induce the release of granule proteins in vitro (Kita et al., 1992) and enhance eosinophil accumulation and degranulation in human nasal mucosa in vivo (Terada et al., 1992). Interleukin-2, through interaction with specific cell surface receptors, can also promote the migration of human eosinophils (Rand et al., 1991b). It has recently been demonstrated that antibody-mediated release of human eosinophil granule enzymes is selectively regulated by IL-1 b (Baskar and Pincus, 1992). Other T-cell products such as the CD4-binding ligand, lymphocyte chemoattractant factor (LCF) (Rand et al., 1991a), RANTES (regulated upon activation in normal T cells expressed and secreted) and the macrophage inhibitory factor MIF-la (Rot el al., 1992), apart from

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being potent cell activators, have been cited as the only truly selective eosinophil chemotactic agonists so far described. The most potent in-vitro eosinophil chemotoxin, platelet activating factor (PAF), enhances both IgG- and IgE-mediated killing of schistosomes by eosinophils and increases cell adherence. PAF also increases cell surface receptor expression, induces degranulation and superoxide production, and enhances LTC4 production. Leukotriene B4 (LTB4), histamine and the ECF-A tetrapeptides are all eosinophilotactic and will all induce enhanced helminthotoxic activity. Very recently, another mast cell mediator, prostaglandin D2 (PGD2) has been shown, along with histamine, to be capable of activating eosinophils (Raible et al., 1992). The myeloid growth factor, human interleukin for DA cells (HILDA/leukaemia inhibitory factor (LIF), released from alloreactive human T-lymphocytes, is chemotactic for mouse eosinophils and also stimulates respiratory burst activity in human eosinophils. The complement-derived anaphylatoxin, C5a, also a potent eosinophilotactic agent, can stimulate PAF secretion from eosinophils (Lee et al., 1984), and have its own chemotactic activity modified by IL-3 and GM-CSF (Warringa et al., 1991). Recombinant human GM-CSF, but not IL-3, also enhanced PAF-induced eosinophil accumulation in the airways of guinea-pigs (Sanjar et al., 1990). These observations are among the many emerging examples of the complex and selective interactions between agents capable of modulating eosinophil function. Three monocyte/lymphocyte-derivedfactors which are neither eosinopoietic nor eosinophilotactic, namely tumour necrosis factor alpha (TNFa), eosinophil cytotoxicity-enhancing factor (ECEF) and eosinophil-activating factor (EAF), have been shown to influence the function of mature eosinophils lsee Thorne and Mazza, 1991). TNFa enhances cell adherence and receptor expression and may or may not stimulate superoxide production, depending on conditions. TNFa also enhances the antibody-dependent killing of schistosomula but has little effect on eosinophil degranulation or calcium ionophore-induced LTC4 production. EAF increases IgG- but not IgE-mediated killing ofschistosomula and ECEF also enhances the toxicity of human blood eosinophils for the same parasite in vitro. ECEF can activate eosinophils (Silberstein et al., 1989) and both EAF and ECEF induce eosinophil degranulation, spontaneous superoxide production and LTC4 synthesis. As shown by the foregoing summary, there has been extensive research on eosinophil activation, but most has focused on identifying individual mediators by means of a limited number of in-vitro detection systems. Factors shown to influence the in-vitro production, activation and function of eosinophils are summarized in Table 1. Few in-vivo studies, in which the situation may be quite different from that simul.ated in vitro, have yet emerged. In vivo, several different factors will probably be present together in any particular eosinophilic situation and eosinophil function(s) may therefore be under the influence of multiple control mechanisms; this could lead to important differences in the way the cell acts in individual circumstances. Moreover, recent studies indicate that eosinophil activation may be profoundly influenced by different types of biological surface, with endothelial cells being

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particularly potent in this respect (Driet al., 1991). Another complication in evaluating the role of activating factors in vivo is the presence of endogenous inhibitors. For example, IL-4 can inhibit cytotoxicity, degranulation and receptor expression (Baskar et al., 1990). A specific protein has also recently been identified in human serum which suppresses the cytotoxic capability of cytokine-stimulated eosinophils (Silberstein et al., 1990).

Physiological Role of Eosinophils Historically, the eosinophil, like the neutrophil to which it has frequently been compared, was seen exclusively as a protective effector end-cell. However, unlike neutrophils, which act primarily against small pathogens such as bacteria and viruses, the eosinophil's major defensive role is against larger multicellular pathogens such as helminth parasites. Indeed, although eosinophils are capable bactericidal phagocytes in vitro, in vivo they cannot effectively defend against bacterial infections when neutrophil function is diminished, e.g., in drug-induced neutropaenia and the leucocyte adhesion deficiency syndrome (Anderson et al., 1985). Also ascribed to the eosinophil was a prominent protective role in hypersensitivity reactions, in which it was believed to limit the damage caused by cytotoxic mast cell products. The unified view of the eosinophil as a protective cell remained largely unchallenged for much of the century and was bolstered by the finding that eosinophil granule proteins are potent helminthotoxins for a wide range of parasite species, as are EPO-generated hypohalous acids and other oxidative products of eosinophils (Klebanoff et al., 1989). However, over the last decade or so there has been an increasing awareness that the mature eosinophil, particularly when activated, is a highly dynamic and metabolically active cell with a wide range of functional capabilities which could contribute to a variety of important immune defence mechanisms. Thus, the eosinophil now appears to resemble the macrophage more closely than the neutrophil (Sanderson, 1992). It is also evident that the eosinophil has considerable tissue-injuring potential. This has contributed to the contemporary view that eosinophils are potent pro-inflammatory cells equally capable of damaging or protecting the host, depending on the situation. For example, the hypereosinophilic syndrome is now classified as a separate disease associated with eosinophilia and tissue injury (Spry, 1988). There is now also considerable evidence of direct correlations between eosinophil numbers or activity and the severity of inflammatory diseases such as asthma (Kay, 1989; Hoidal, 1990). An interesting anomaly is that constitutive expression of IL-5 in mice induces life-long eosinophilia without apparent ill-effects (Vaux et al., 1990), suggesting that other factors may be required to provoke cytotoxic effects. Despite the more recent controversy, the major protective role of the eosinophil still appears to lie in the host's defence against parasitic invasion. However, it is now recognized, albeit based mainly on in vitro observations, that the relationship between eosinophils, the immune system and parasitic helminths is an extremely complex one. This is illustrated diagrammatically in

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Fig. 1. Associations between eosinophils and helminthiasis have been extensively documented, but evidence for their mobilization in protozoan and ectoparasitic infections is more fragmentary (Spry, 1988). Observations that eosinophils could kill schistosomula of Schistosoma mansoni were followed by many similar descriptions for numerous parasites (Butterworth, 198¢). In vitro, helminthotoxic properties have been ascribed to several eosinophil products and effector functions of the cell can be mediated by antibody, including secretory IgA (Abu-Ghazaleh, 1989), and complement. These properties can in turn be modulated by a variety of soluble cytokines. Evidence for an in vivo role for eosinophils in immunity to parasites is less convincing and perhaps the most persuasive support remains the association between eosinophilia and parasitic resistance reported in two African studies on schistosomiasis (Sturrock el al., 1983; Hagan a al., 1985). Given the high conservation of the IL-5 sequence and the prevalence of parasites in nature, it is possible that resistance to parasites has provided the selective pressure for the evolution of IL-5 and the specific Th2 helper T-cell subset mainly responsible for its production (Urban et al., 1992). The mechanisms for specific eosinophil infiltration into parasitic lesions is somewhat uncertain, with traditional concepts again under challenge. NumerOUS reports over the past two decades, mainly based on in vitro studies, have demonstrated eosinophil chemoattractant activity for many factors, including products of invading helminths themselves (McEwen, 1992). However, evidence for the in vivo participation of chemotactic factors in eosinophil recruitment is fragmentary. More recently, localization of eosinophils has been associated with families of adhesion molecules specifically induced on eosinophils and endothelial cells during inflammation (Weller, 199 I). Whilst none of these adhesion molecules is unique to eosinophils, specific upregulation of their expression by IL-5 (Kay, 1991) following immune activation of Th2 cells provides a potential mechanism for specific eosinophil localization. Prevention of the latter through the blockade of eosinophil adhesion has been reported to have therapeutic potential in the control of asthma. Thus, antibody to intracellular adhesion molecule-1 (ICAM-1), which inhibited eosinophil adhesion to endothelial cells in vitro, when administered to primates in vivo decreased eosinophil migration into the lung and markedly reduced asthmatic reactions (Wegner et al., 1990). The unique role of IL-5 in the production, activation and localization of eosinophils has, not surprisingly, led to speculation that it constitutes another prime target for therapeutic intervention in asthma and other eosinophilic diseases (Sanderson, 1992). Much of the tissue damage associated with eosinophilia appears to depend on the same mechanisms thought to play a role in protection against parasites. In diseases such as asthma, the cytotoxic potential of eosinophils, evolved originally to defend against parasites, may be turned against the host's own tissues. Control of this potential may therefore have beneficial consequences in such disorders. Moreover, recent studies suggest that tissue longevity and removal may be controlled through apoptosis and ingestion by macrophages and that this process is delayed by IL-5 (Stcrn et al., 1999). Recent evidence suggests that the mechanism of action of at least

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one anti-asthmatic drug, nedocromil sodium, may depend at least in part on the inhibition of eosinophil function (Sedgwick et al., 1992). By contrast, eosinophilia has been shown to be a positive prognostic indicator for a variety of human neoplasms (see Sanderson, 1992). This raises the intriguing possibility that monitoring and manipulation of eosinophil numbers may provide a useful adjunct in anti-tumour therapy.

Comparative Aspects Much of the research on eosinophils has centred on man and laboratory rodents. Knowledge of eosinophilic responses and function in other species is comparatively rudimentary. The phylogeny of eosinophils has not been formally delineated, but they have been identified in most vertebrates, cartilaginous fishes and several more primitive organisms such as the tuatara, a lizard-like native of New Zealand (see Spry, 1988). Eosinophils have not so far been described in insects and are not present in hagfishes, which are amongst the lowest surviving vertebrates. Interestingly, the hagfish possesses blood cells similar to mammalian neutrophils, and the absence of eosinophils and basophils may indicate that these cell types evolved later (Linthicum, 1975). Notwithstanding this, eosinophils appear to have survived, with a remarkably conserved morphology, well in excess of 300 million years of evolution, as demonstrated by their presence in primitive torpedo species like the nurse shark. As discussed earlier, the major features of eosinophils are the specific cytoplasmic granules, with their complement of unique basic proteins (Dvorak et al., 1991). In most mammals, with the notable exception of the horse, eosinophilic granules are further characterized by the presence of a central crystalline core. Cores are frequently, but not always, absent in fish and other lower organisms (Ellis, 1977), but eosinophils from many avian species contain crystalloids (Maxwell, 1987). Despite the relatively poor understanding of eosinophil function and phylogeny, one unifying concept for the evolution and persistence of these cells throughout much of the animal kingdom may be their ubiquitous presence and contribution to host defence against parasitic invasion. It seems highly unlikely that specialized cells and proteins, such as eosinophils, mast cells and IgE, would have been evolved and conserved for their injurious effects. Therefore, in evolutionary terms, it is tempting to speculate that for the survival of most species the advantages of limiting parasite access greatly outweighed the disadvantages of mounting tissuedamaging allergic and other responses to antigens possibly mistakenly identified as of parasitic origin. It is worth noting that, in sheep, there have been several recent reports linking eosinophilic responsiveness with genetically derived resistance to gastrointestinal nematodes (Dawkins el al., 1989; Gill,

1991).

Concluding Remarks Over recent years there have been many significant advances in the understanding of the biology of eosinophils and their properties in specific disease

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states. Despite this, their precise role in the multitude of disease and physiological situations in which they are found remains obscure. Given the diversity of situations associated with eosinophilia, it appears increasingly unlikely that any unified hypothesis is possible or indeed warranted. Their once widely accepted roles as modulators of inflammation and effector cells against parasites has become more controversial. The tissue-damaging potential of eosinophils and their products is now receiving more and more attention, particularly in regard to inflammatory diseases. Apart from their involvement in antibody-mediated hypersensitivity reactions, it is now clear that production, maturation and function of eosinophils is profoundly influenced by their interactions with the cellular arm of the immune system. The eosinophil is now recognized to have considerable functional heterogeneity and this discovery is reminiscent of early reports on lymphocyte and macrophage diversity. Whilst this is a fascinating observation, perhaps more crucial is the realization that tissue localization of eosinophils depends on a complex network of reactions involving chemotactic factors and interactions with endothelial cells. Further understanding of these mechanisms will help to define how and why lesional eosinophilia develops. Finally, with the rapid advances in molecular technology, there is now a realistic potential for pharmacological modulation of eosinophil-mediated diseases, particularly through blockage of pathways leading from T-cell responses to eosinophil proliferation, activation and secretion into tissues.

References

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February5th, Accepted, March 5th, IReceived,

1993-] 1993 J