Williams Hematology



Eosinophil Production
Eosinophil Heterogeneity
Molecular Basis for Eosinophil Tissue Accumulation

Eosinophilopoiesis and Egress from the Marrow



Prolonged Survival
Synthesis and Release of Eosinophil Mediators

Lipid Mediators

Eosinophil Granule Proteins


Other Eosinophil-Derived Mediators
Eosinophil Secretion and Activation

Eosinophil Survival and Apoptosis
Eosinopenia and Eosinophilia

Causes of an Eosinophilia

Mechanisms of Eosinophilia

Eosinophils and Disease

Chapter References

As a result of their potential role in asthma, eosinophils have received considerable attention from the research community in the last decade. The concept of the eosinophil as a cell that has protective effects against helminthic parasite infection but can cause tissue damage when inappropriately activated remains intact, although the evidence for both these roles remains circumstantial.
Eosinophil production and function are profoundly influenced by interleukin-5 (IL-5), and thus eosinophilia is associated with diseases characterized by Th2-mediated immune responses, including helminthic parasite infections and extrinsic asthma. However, eosinophilia also occurs in diseases not associated with Th2 dominance such as intrinsic asthma, hypereosinophilic syndrome (HES), and inflammatory bowel disease. It is clear that IL-5 and other eosinophil mediators can be generated in various types of inflammatory response.
The eosinophil, like other leukocytes, can generate proinflammatory mediators. Eosinophil-specific granule proteins are toxic for a range of mammalian cells and parasitic larvae. Eosinophils, like mast cells, produce sulfidopeptide leukotrienes, as well as other lipid mediators such as platelet-activating factor (PAF). Cytokine production by eosinophils broadens their potential functions, for example in wound healing through the generation of transforming growth factor (TGF)-a. Synthesis of TGF-b may explain the propensity of eosinophils to be associated with fibrotic reactions such as endomyocardial fibrosis, characteristic of HES, and fibrosing alveolitis.
Considerable effort has gone into trying to unravel the molecular basis of eosinophil tissue recruitment. The selective accumulation of eosinophils is due to a concerted and integrated series of events involving marrow egress, adhesion to endothelium, selective chemotaxis, and prolonged survival in tissues. These events are controlled, either directly or indirectly, by production of IL-4, IL-5, and IL-13. Understanding these events may lead to novel therapies that will help treat diseases caused by eosinophils without inhibiting their potentially beneficial roles.

Acronyms and abbreviations that appear in this chapter include: ECF-A, eosinophil chemotactic factor of anaphylaxis; ECP, eosinophil cationic protein; EDN, eosinophil-derived neurotoxin; EPO, eosinophil peroxidase; GM-CSF, granulocyte-monocyte colony stimulating growth factor; HES, hypereosinophilic syndrome; IL, interleukin; mAbs, monoclonal antibodies; PAF, platelet-activating factor; TGF, transforming growth factor.

Eosinophils are nondividing, end-stage cells that, like other leukocytes, differentiate from the hematopoietic stem cell in the marrow. Eosinophils migrate into the blood, where they circulate with a half-life of about 18 h before entering the tissues. Eosinophils are primarily tissue-dwelling cells, and it has been estimated that there are about 100 tissue eosinophils for each eosinophil in the blood, although relatively few studies have been performed on eosinophil kinetics and even fewer have compared eosinophil turnover in health and disease.1 Normal human adult marrow contains about 3 percent eosinophils of which one-third are mature and two-thirds are precursors. Eosinophilic myelocytes are large cells with a single-lobed nucleus, expanded Golgi, and extensive dilated cisterns of rough endoplasmic reticulum. The myelocytes become identifiable when they develop the core-containing specific granules, which initially are interspersed with large numbers of homogeneous dense granules2 (Fig. 68-1) (see Chap. 64).

FIGURE 68-1 Transmission electron micrograph of an eosinophil showing the characteristic specific granules with their electron dense core (×10,000; courtesy of Dr. A Dewar, National Heart and Lung Institute).

The massive increase in eosinophils associated with helminthic parasitic infection is T-cell dependent. The eosinophilia in rodents infected with helminths is abolished by thymectomy, thoracic duct drainage, or administration of antilymphocyte antiserum.3,4 This effect is mediated by soluble factors released from sensitized lymphocytes.5 Three T-cell–derived cytokines promote eosinophil growth and differentiation, IL-3, IL-5, and GM-CSF. Of these only human IL-5 promotes terminal maturation of eosinophils. It is also a basophil maturation factor.6 Eosinophils and basophils are closely related. Eosinophil and basophil colonies appear together in marrow cell colony-forming assays.7 IL-5 is a disulfide-linked homodimeric glycoprotein of 40–45/kD consisting of 115 amino acids.8,9 The dimers are aligned in a head-to-tail fashion, and dimerization is essential for function.10 IL-5 has a two-domain structure; the formation of each domain requires the participation of both chains. There is similarity between the domains in IL-5 and the cytokine-fold of other growth factors such as GM-CSF.11,12 Transgenic mice with increased amounts of IL-5 have a marked blood and tissue eosinophilia and increased numbers of eosinophil precursors in their marrow suggesting that IL-5 is the rate-limiting step in eosinophil proliferation and maturation.13,14 Despite a marked eosinophilia, these mice have no obvious pathological abnormalities. Both IL-3 and GM-CSF induce eosinophil colony formation in human cord blood culture15 and eosinophilia after administration in vivo, although the increase in eosinophils is modest.16 In humans, the genes for IL-3, IL-4, IL-5, IL-9, IL-13, and GM-CSF are clustered on the long arm of chromosome 5.17 IL-4 and IL-5 are expressed by Th2 but not Th1 lymphocytes.18 The receptors for IL-3, IL-5, and GM-CSF are structurally similar.19 They consist of homologous a chains that bind their respective cytokines with low affinity, with a kD of approximately 10/nM. There is a common b chain that is noncovalently associated with core of the a chains at the cell surface and transforms the receptor into one of high affinity (kD150/pM). The b chain is required for signal transduction. Both the a and b chains are members of the type 1 hematopoietin cytokine receptor family. The a chains are between 60 and 80 kD and the b chain 12kD. Unlike the a chains of IL-3 and GM-CSF, the a chain of the IL-5R can bind IL-5 with relatively high affinity (kD 250–590/pM).20,21 Blood eosinophils and HL-60 cell lines with eosinophilic features express IL-5 receptors with kDs of 170 to 330 and 10 to 50/pM, respectively.22 Expression of the IL-5 alpha chain is down regulated by exposure to IL-5, IL-3, and GM-CSF, thus constituting a negative feedback loop.23
Blood eosinophils from normal individuals are relatively dense cells which can be separated from other leukocytes by density-gradient centrifuge. For many years these differences were the basis for the standard method of purifying eosinophils. This has now been largely superseded by negative immunomagnetic selection based on the expression of the low affinity (FcgRIII, CD16) IgG receptor by neutrophils but not eosinophils. This latter technique has the advantage of improved purity and cell yields as well as enabling purification of eosinophils from individuals with low eosinophil counts.24 A proportion of eosinophils from individuals with elevated eosinophil counts are less dense than eosinophils from normal subjects.25 So-called hypodense eosinophils appear to be vacuolated and contain smaller granules, although in equal numbers to normal-density eosinophils.26 The mechanism for this heterogeneity is unclear, although a correlation with eosinophil activation has been a favored hypothesis.27 The evidence to support this hypothesis, however, is contradictory.28
A striking feature of many eosinophilic diseases is the selective accumulation of these cells in the tissue in the absence of increased numbers of tissue neutrophils. The factors controlling this selective migration have been the subject of intensive study for over three decades, stimulated by the hope of identifying targets for treatment of diseases thought to be caused by eosinophil-mediated tissue damage. In asthma there is an approximately 100-fold enrichment of eosinophils over neutrophils in the bronchial mucosa compared to normal mucosa.29 Historically this was thought to be due to a selective chemoattractant. A factor, termed eosinophil chemotactic factor of anaphylaxis (ECF-A), which appeared to be selectively chemotactic for eosinophils, was detected in supernatants from guinea-pig lung during anaphylaxis.30 ECF-A was subsequently found to consist of leukotriene (LT)B4, which is active on guinea-pig eosinophils but less so on human eosinophils, and 15-hydroxyeicosateraenoicacid (15-HETE).31 ECF-A from human lung, composed of two tetrapeptides, Val-Gly-Ser-Glu and Ala-Gly-Ser-Glu, was identified later.32 However in comparison to PAF these peptides were found to have negligible activity.33 The role of chemokines as selective chemoattractants has also been studied. Selective tissue accumulation of eosinophils is probably not the result of any single event but rather due to selective pressure at every stage in the life-cycle of the eosinophil including eosinophilopoiesis, egress from the marrow, endothelial cell adhesion, chemotaxis, and prolonged survival in tissues under the influence of locally generated growth factors.
Eosinophil growth factors such as IL-5 generated at sites of allergic inflammation act to increase eosinophil production. There is on average about a fourfold increase compared with normal subjects in the number of circulating eosinophils in allergic individuals, and in other diseases this increase can be much greater. There are increased numbers of eosinophil precursors in the blood of allergic patients, and there is an increase in marrow progenitors expressing the IL-5a receptor (IL-5aR) (presumably eosinophil precursors) 24 h after allergen challenge.34 This increase is the consequence of both increased production and increased egress from the marrow. IL-5 selectively promotes the egress of eosinophils from the marrow.35 This egress is enhanced by eotaxin, an eosinophil-selective chemokine, and controlled by the integrin adhesion receptor a4b1 (CD CD49a; VLA-4), inhibition of which accelerates egress, and aMb2 (CD16/CD18) and Mac, the inhibition of which prevents egress.36
The receptors and ligands involved in eosinophil adhesion are listed in Table 68-1.37 Eosinophils adhere with up to tenfold greater avidity to nasal polyp endothelium (a model of eosinophilic inflammation) compared to neutrophils, suggesting that adhesion can account for a substantial part of the selective accumulation of eosinophils. Eosinophils can preferentially bind to P-selectin under flow conditions compared to neutrophils, especially at low levels of expression of this receptor, whereas neutrophils preferentially bind to E-selectin.38,39 The reasons for these differences in adhesion are unclear although possibly related to differences in the glycosylation of the P-selectin receptor PSGL-1 between the two cell types. Endothelial P-selectin expression is increased by the Th2-related cytokines IL-4 and IL-13, although not by IL-1 or TNF-a.40 Treatment of endothelial cells with these cytokines results in constitutive expression of low levels of P-selectin, which is sufficient to support eosinophil but not neutrophil binding to endothelial cells under flowing conditions.41,42 In support of a role for P-selectin in eosinophil adhesion is the observation that eosinophil migration is reduced in a P-selectin gene-deleted mouse.43 IL-4 and IL-13 can also induce low levels of VCAM-1 expression on endothelial cells, which supports P-selectin–mediated eosinophil tethering under flowing conditions. VLA-4/VCAM-1 also support selective transmigration through endothelial cells, and animal models have shown that eosinophil migration into the lung is inhibited by anti-a4b1 mAbs. Eosinophils express all four members of the b2 integrin family (CDa-d/CD18), and aMb2 and aLb2 are both important in mediating eosinophil transmigration.44 The newest member of this family, aDb2, appears to be a ligand for VCAM-1,45 although the physiological relevance of this remains unclear.


Most known eosinophil chemoattractants, such as PAF and C5a, are also active on other cell types. Members of the chemokine family, in particular C-C chemokines, are also involved in selective eosinophil recruitment. Eosinophils express CCR3 and low levels of expression of CCR1 have been detected on the eosinophils of some donors. Eosinophils from eosinophilic donors, but not normal subjects, migrate in response to IL-8, although eosinophils do not appear to express IL-8 receptors.46 Expression of CCR3 is restricted to eosinophils, basophils, and a small subset of Th2 T cells, so it is a potential therapeutic target for inhibition of eosinophil migration.47 Chemokines that bind to CCR3, including RANTES, eotaxin, and MCP-4, are highly effective eosinophil chemoattractants both in vitro and in vivo (Table 68-2).48,49 IL-5 enhances the response of eosinophils to chemoattractants, including eotaxin.50 In an IL-5–deficient mouse, eosinophils are unresponsive to eotaxin.51 A number of CC chemokines have been shown to be expressed in increased amounts in allergic disease. Mouse models of eosinophilic lung disease, generally utilizing peritoneal sensitization with ovalbumin, have also been informative. Increases in eotaxin and RANTES expression parallel eosinophil migration, and blockade of eotaxin reduces eosinophil accumulation by half.52 Blockade of both eotaxin and RANTES partially reduced eosinophil infiltration and bronchial hyperresponsiveness.53 mRNA expression of eotaxin, but not RANTES, is increased in pulmonary eosinophilia, and eotaxin expression is T-cell dependent.54 Chemokines seem to function as eosinophil chemoattractants, although they can also enhance eosinophil adhesion to endothelial cells and purified adhesion receptors. Chemokines do not appear to trigger mediator release.


Eosinophils rapidly undergo apoptosis in the absence of eosinophil growth factors such as IL-5, GM-CSF, and IL-3, which are all generated in the tissue during eosinophilic inflammation. Anti-IL-5 antibodies caused rapid loss of eosinophils from cultured explants of nasal polyps.55 Thus cytokine generation is an important mechanism for selective eosinophil accumulation.
Eosinophils have the capacity to generate and/or release a number of potent inflammatory mediators (Fig. 68-2). These include basic proteins stored in eosinophil granules, lipid mediators (newly formed after eosinophil activation), cytokines, eosinophil proteases, and components of the oxygen burst, including superoxide and hydrogen peroxide.

FIGURE 68-2 Schematic representation of eosinophil-derived mediators. MBP, major basic protein; ECP, eosinophil cationic protein; EDN, eosinophil-derived neurotoxin; EPO, eosinophil-derived peroxidase; GM-CSF, granulocyte-monocyte colony stimulating factor; TGF, transforming growth factor; MIF, macrophage inhibition factor; TNF, tumor necrosis factor; MIP, macrophage inhibitory protein; PAF, platelet activating factor. LTC, leukotriene C; HETE, hydroxyeicosatetraenoic acid; PGE, prostaglandin E; TXB, thromboxane B.

Eosinophils generate an array of lipid mediators, principally eicosanoids and PAF.56 Eosinophils can generate relatively large amounts of the sulfidopeptide leukotriene LTC4, after stimulation with the calcium ionophore via activation of the enzyme 5 lipoxygenase, but only negligible amounts of LTB4.57 This is in contrast to neutrophils which produce large amounts of LTB4 but little, if any, LTC4. LTC4 generation by human eosinophils also occurs after stimulation with opsonized zymosan and beads coated with IgG.58 Eosinophils can also generate substantial quantities of 15-HETE via 15-lipoxygenase. Eosinophils also generate PAF after stimulation with either calcium ionophore or IgG-coated beads.59 Eosinophils can also generate mediators of the cyclooxygenase pathway, including prostaglandins E1 and E2, and thromboxane B2 (TXB2). The principal sites of eicosanoid formation in eosinophils are the lipid bodies which contain large amounts of arachidonic acid and enzymes required for eicosanoid synthesis, including 5-lipoxygenase, LTC4 synthase, and cyclooxygenase.60
Major basic protein (MBP) has a molecular mass of 13.8 kDa and a pI of 10.9. Its 17 arginine residues account for its basicity. It is initially synthesized as an acidic proprotein which is stored in the eosinophil granule61; MBP becomes toxic only after it is released and processed into its final form. Purified MBP is cytotoxic for the schistosomula of S. mansoni, and adherence of eosinophils to IgG-coated schistosomula results in the secretion of MBP onto the tegument of the larvae, resulting in loss of viability.62 MBP at concentrations as low as 10 µg/ml has also been shown to be toxic for both guinea pig and human respiratory epithelial cells, as well as for rat and human pneumocytes.63 The mechanism of action of MBP on epithelial cells appears to be mediated through inhibition of ATPase activity. The inhalation of MBP, albeit at high concentrations (1 mg/ml), produced increased bronchial hyperresponsiveness in monkeys.64 MBP and eosinophil peroxidase (EPO) are strong agonists for platelet activation as well as activation of mast cells, basophils, and neutrophils.65 The mechanisms of action of MBP is likely to be related to its hydrophobicity and strong negative charge. Basophils also contain MBP but only about 2 percent that of eosinophils.
This compound is a heme-containing protein that is synthesized as a single protein and then cleaved into 14- and 58-kD subunits.66 The molecule shares a 68 percent identity in amino acid sequence with human neutrophil myeloperoxidase as well as other peroxidase enzymes. The substance is toxic for parasites, respiratory epithelium, and pneumocytes, either alone, or (more potently) when combined with H2O2 and halide, the preferred ion in vivo being bromide.
Eosinophil cationic protein (ECP) is an arginine-rich protein. The cDNA encodes for a 27 amino acid leader sequence and a 133 amino acid mature polypeptide with a molecular mass of 15.6 kDa. ECP has 66 percent amino acid sequence homology with eosinophil-derived neurotoxin (EDN) and 31 percent homology with human pancreatic ribonuclease,67 but it has low ribonuclease activity compared to EDN. ECP is toxic for helminthic parasites, isolated myocardial cells, and guinea pig tracheal epithelium. ECP also inhibits lymphocyte proliferation in vitro. Both ECP and EDN produce neurotoxicity (the Gordon phenomenon) when injected into the cerebrospinal fluid of experimental animals. ECP may damage cells by a colloid osmotic process, as it can induce non–ion-selective pores in both cellular and synthetic membranes.68 The secreted form of ECP differs structurally and antigenically from the stored form.69
EDN, also called EPX, is a 16-kD, glycosylated protein possessing marked ribonuclease activity. The cDNA predicts a 134 amino acid, mature polypeptide that is identical to human urinary ribonuclease. Like ECP, it is a member of a ribonuclease multigene family.70 EDN expression is not restricted to eosinophils, as it is found in mononuclear cells and possibly neutrophils. It is also probably secreted by the liver. It does not appear to be toxic to parasites or mammalian cells, and its only known effect, other than its ribonuclease activity, is neurotoxicity.
A major constituent of eosinophil is CLC protein, which is a lysophospholipase. It constitutes up to 10 percent of eosinophil protein and is also found in large quantities in basophils.71 Its precise function is unknown.
The first report that eosinophils were cytokine-producing cells was in 1990 when they were shown to generate transforming growth factor alpha (TGF-a).72 This was of particular interest because of the possible role of eosinophils in wound healing. Since then there has been an ever increasing list of cytokines and chemokines produced by eosinophils.73 These include the eosinophil growth factors IL-3, IL-5, and GM-CSF, and the eosinophil cytokine IL-4. The cytokines can act on eosinophils themselves in an autocrine fashion, and, since they are produced in relatively low concentrations, this may be their primary function.74 More recently eosinophils have been shown to generate IL-12, showing that they are not exclusively linked to Th2-mediated inflammatory responses,75 and macrophage migration inhibitory factor (MIF), which could have a role in the adult respiratory distress syndrome as well as asthma.76
Vasoactive intestinal peptide (VIP) has been detected in eosinophils in granulomas from mice infected with schistosomes,77 and the eosinophil contains a number of granule-stored enzymes, whose roles in eosinophil function are not clear.78 These enzymes include acid phosphatase, collagenase, arylsulfatase B, histaminase, phospholipase D, catalase, nonspecific esterases, vitamin B12–binding proteins, and glycosaminoglycans. Eosinophils can undergo a respiratory burst with release of superoxide ion and H2O2 in response to stimulation with both particulate stimuli such as opsonized zymosan, and soluble mediators, such as leukotriene and phorbolmyrisate acetate. Eosinophils are twice as chemoluminescent as neutrophils.
The observation that eosinophils kill schistosomulae of S. mansoni led to the hypothesis that the role of eosinophils is in host defense against helminthic parasites.79 Eosinophils can only kill schistosomes after they have been opsonized with IgG, IgE, or complement. Eosinophils, activated by a wide range of inflammatory mediators, are more effective at killing schistosomula than resting eosinophils. Schistosomula killing involves an initial adherence stage, which is quite rapid, followed by close attachment of the eosinophil to the tegument. Over about a three-hour period, the eosinophil secretes its proteins onto the surface of the larvae; after the tegument is breached, the eosinophil appears to crawl under it and strip the tegument away.80 It has been suggested that eosinophils prefer to secrete their mediators onto a large target rather than engulf them and secrete their toxic mediators into intracellular phagolysosomes as is generally the case with neutrophils and macrophages. Neutrophils can also kill schistosomula after opsonization with IgG but less effectively than eosinophils. In contrast, monocytes and neutrophils are much more effective than eosinophils in engulfing antibody-coated erythrocytes.81 A further illustration of the target specificity of granulocyte killing is that eosinophils are more effective at killing sensitized Daudi lymphoma cells than are neutrophils.82
A striking feature of eosinophil-rich inflammatory reactions is the high concentration of granule proteins, often in the presence of relatively small numbers of intact eosinophils. Mediator secretion can be triggered physiologically by engagement of immunoglobulin Fc receptors, especially after eosinophil activation has been primed with soluble mediators such as PAF and IL-5.83 The eosinophil expresses receptors for IgG, IgA, and IgD (Table 68-3). The eosinophil also binds IgE, and eosinophils can undertake a number of IgE-dependent functions, including killing of schistomsomes opsonized with specific IgE.84 It was thought that the eosinophil IgE receptor was related to the low-affinity IgE receptor found on B-lymphocytes, platelets, and macrophages—FceRIII (CD23).85 However, blood eosinophils inconsistently express messenger RNA (mRNA) for CD23 and do not stain with a panel of mAbs directed against this receptor. Eosinophils express the IgE binding protein Mac-2, but so do neutrophils, which lack IgE-dependent functions.86 Blood eosinophils express weakly the high-affinity IgE receptor FceR1,87 although it may be expressed at higher levels on tissue eosinophils.88 The extent to which this receptor is involved in triggering eosinophil degranulation in allergic disease is still unclear.


Three receptors for IgG have been described: the high-affinity receptor FcgR1 (CD64), and two low-affinity receptors FcgRII (CDw32) and FcgRIII (CD16).89 CD16 is expressed both as a transmembrane form and a form with a phosphotidylinositol anchor, transcribed from two distinct genes. Only FcgRII is constitutively expressed by eosinophils to any significant degree.90 A number of eosinophil functions are mediated via this receptor, including schistosomula killing, phagocytosis, secretion of granule proteins, and generation of newly formed, membrane-derived lipid mediators such as PAF and LTC4. After stimulation for 2 days in vitro with IFN-g, eosinophils express CD16 and CD64 as well as CD32.91 Perhaps the most potent stimulus for eosinophil degranulation is cross-linking of IgA receptors, especially when the cells have been primed with growth factors.92 Consistent with the preference of eosinophils to secrete their mediators onto a large surface, Fc-mediated degranulation is enhanced if the eosinophils are adherent to a protein-coated surface via aMb2.93
The killing of schistosomula opsonized with nonimmune serum is presumed to be mediated via the complement receptors, CR3, CR1, and CR3. Incubation of eosinophils with serum-coated beads results in the release of 15 percent of ECP.94 Similarly, opsonized zymosan interacts with eosinophils, causing generation of hydrogen peroxide and the phagocytosis of the zymosan.95 Soluble mediators such as PAF, LTB4, and 5-oxo-eicosatetraenoate can elicit the direct secretion of both granule proteins and lipid mediators, although only with highly activated eosinophils or when used in conjunction with cytochalasin B, which inhibits microtubule assembly.96 Stimulus-specific differential secretion of granule proteins has been reported. IgG complexes induce the secretion of ECP but not EPO, whereas IgE complexes induce secretion of EPO but not ECP.97 However, secretion is low in both instances. Eosinophils release their granule components by exocytosis, with individual granules fusing with the plasma membrane. This process involves a GTP-binding protein and is modulated by the intracellular calcium concentration.98
IL-5, besides being a growth and maturation factor for eosinophils, also selectively stimulates a number of eosinophil functions, including survival, cytotoxicity toward helminth targets, and increased adhesion to vascular endothelium.99 IL-3 and GM-CSF have similar, though less selective, activities. IFN-g stimulates eosinophil cytotoxicity, prolongs eosinophil survival, and stimulates expression of mRNA for GM-CSF.100,101 TNF-a stimulates eosinophil cytotoxicity toward endothelium.102 IL-3, IL-5, and GM-CSF have both short-term priming effects on eosinophils, which are maximal within an hour, and long-term effects, which depend on protein synthesis and include increased receptor expression. One of their most profound effects is to prolong eosinophil survival by delaying the onset of apoptosis. In inflammatory responses, these cytokines are generated by several cell types, and eosinophils may themselves generate GM-CSF after interaction with extracellular matrix.103
Complex signaling pathways determine eosinophil survival.104 IL-5 signaling involves Lyn, Jak 2, Raf 1, and MAP kinases. Treatment of eosinophils with antisense to Lyn and Raf 1 resulted in inhibition of the survival-enhancing effects of IL-5, as did inhibition of tyrosine phosphorylation of Jak 2 using tyrphostin. However, Lyn and Jak 2 kinases are not involved in the IL-5–induced upregulation of the integrin receptor subunit aM, whereas Raf-1 kinase is.105 Triggers of eosinophil apoptosis include TGFb, cross-linking of CD69, and cross-linking of Fas which is expressed by eosinophils.106,107 and 108 Fas-induced eosinophil apoptosis is blocked by nitric oxide (NO), which may explain the relative resistance of eosinophils from allergic donors to Fas-induced apoptosis. Fas-induced apoptosis is mediated through activation of caspases, is amplified by the sphingomyelinase:ceramide signaling pathway, and is resistant to IL-5.109 A clear link between growth-factor-induced prolongation of survival and expression of the Bcl-2 family proteins has not yet been made. Eosinophils express Bcl-2 weakly, the survival enhancing Bcl-xL to a greater degree, and large amounts of the death-inducing Bax. Expression of these proteins is not closely correlated with IL-5–induced survival. The phosporylation status of Bad, mediated through phosphorylation of Raf-1, may be responsible for the IL-5 effects.110,111
Eosinophils can be enumerated in the blood either by “wet counts” in modified Neubauer chambers, differential counts on dried films, or by automated cell counting by flow cytometry.112 Automated counting that uses detection of eosinophil peroxidase is the most accurate method, followed by counting in a cell chamber. Counting on films is least accurate because of the tendency for eosinophils to congregate at the margins of the slide. Common wet stains for eosinophils include eosin in acetone, phloxin, and Kimura’s stain, which was originally developed to stain basophils.113 Many stains, including May Grunewald/Giemsa, Romanowsky’s stain, Chromotrope 2R, and Bierbrich scarlet, will identify eosinophils in blood films, cytospin preparations, or tissues.
The eosinophil count should be evaluated in absolute numbers rather than as a percentage of white cells, as the latter will depend on the total cell count. The normal eosinophil count is generally taken as less than 0.4 × 109/liter, although healthy medical students in the United States had a range of 0.015 to 0.65 × 109/liter.114 Eosinophil counts are higher in neonates.115 The eosinophil count varies with age, time of day, exercise status, and environmental stimuli, particularly allergen exposure. Blood eosinophil counts undergo diurnal variation, being lowest in the morning and highest at night. This effect results in a greater than 40 percent variation116 and may be related to the reciprocal diurnal variation in cortisol levels, which are highest in the morning. The factors that control blood eosinophil counts in health are imperfectly understood. Concentrations of eosinophil growth factors are likely to be important, but other factors may be involved. Normal counts vary by up to fortyfold, and, in populations where eosinophilia is common, such as endemically parasitized areas, there are marked variations in the blood eosinophil level, independent of the degree of infection. This variation is comparable to variations in IgE levels. There are no differences between ethnic groups in eosinophil counts.117
The causes of eosinophilia can be classified according to the degree and frequency of occurrence (Table 68-4). Division of eosinophil counts is arbitrary, but a mild eosinophilia could be regarded as less than 1.5 × 109/liter, a moderate elevation as 1.5 to 5.0 × 109/liter, and a high count as greater than 5.0 × 109/liter. The most common cause of an eosinophilia worldwide is infection with helminthic parasites, which can often result in a very high eosinophil count. The most common cause of an eosinophilia in industrialized countries is the atopic allergic diseases, seasonal and perennial rhinitis, atopic dermatitis, and asthma. Allergic disease generally results in only a mild increase in eosinophil counts. A moderate or high eosinophil count in asthma raises the possibility of a complication such as Churg-Strauss syndrome or allergic bronchopulmonary aspergillosis.


Eosinophilia is largely T-cell-dependent through the actions of growth factors, especially IL-5. Increased IL-5 production occurs in many conditions associated with increases in eosinophils, including asthma,118 parasitic disease,119 IL-2 therapy,120 HES,121 and eosinophilia/myalgia syndrome.122 IL-5 mRNA has been detected in Reed Sternberg cells in Hodgkin’s disease with an eosinophilia.123 Antibodies against IL-5 abolish the eosinophilia in parasitized animals.124 Although IL-5 has been detected in mast cells and eosinophils,125 T lymphocytes are the principal source of this cytokine. Eosinophils are closely associated with the Th2 immune response and the production of IL-4 and IL-5 by Th2 cells, as opposed to IFNg and IL-2 by Th1 cells.126 A Th2 profile of cytokine gene expression has been described in allergic inflammation,127 whereas a Th1 profile is a feature of cell-mediated reactions to tuberculin.128 T-cell clones from atopic individuals specific for D pterynissimus release IL-4, whereas T-cell clones from nonatopic donors or from atopic donors against tetanus toxoid produce IFN-g and IL-2.129 There is, therefore, good evidence that the eosinophilia of allergic and parasitic disease is due to a specific type of T-cell response to certain types of antigen. Eosinophils, however, are not invariably associated with production of specific IgE, as for example in intrinsic asthma. Drug-induced eosinophilia may be due to the drug acting as a hapten for a Th2 response.
The mechanism for the Th1/Th2 polarization is still unclear but may relate to the cytokine mileu at the time of sensitization, genetically regulated transcriptional control of IL-4, or the route of sensitization and the way in which the antigen is presented.130 The nature of the antigen may also be important. Many allergens have now been purified and sequenced. No common structural features have been established that can explain their allergenicity,131 although many are proteases, which could influence their immunogenicity.132 The HLA haplotype of individuals responsive to certain allergens has also been investigated. A degree of restriction has been observed, particularly to more simple allergens, with, for example, the phenotype DR2.2 being overrepresented in individuals atopic to the ragweed allergen Amb a V.133 However, with the majority of allergens, no clear pattern has emerged. While HLA haplotypes may influence responses to individual allergens, it is unlikely to provide a universal explanation for Th2 type responsiveness.
For years eosinophils were thought to ameliorate inflammatory responses; now they are believed to cause tissue damage in some situations.134,135 Eosinophils are a potentially important source of a range of cytokines.136 The observation that eosinophils secrete TGF-a together with studies showing increased numbers of eosinophils at the edges of healing wounds suggests that they may be important in wound healing.137 Cytokine-stimulated eosinophils secrete IL-1, express HLA Class II receptors, and can present antigen to T cells in vitro, suggesting they may be important as accessory cells in T-cell–mediated reactions. There is evidence that eosinophils slow the rate of progression of solid tumors, presumably by being cytotoxic to tumor cells.138 Eosinophils can cause severe tissue damage under certain circumstances. Chronically high eosinophil counts from many causes including drug reactions, parasitic infections, eosinophilic leukemia, and HES, are associated with endomyocardial fibrosis.139 The observation in the mid-1970s that eosinophils could kill parasite targets led to the hypothesis that the principal role of eosinophils was to counter parasitic infection.140 The realization that eosinophils could release proinflammatory mediators such as PAF and eicosanoids, and the observation that eosinophil basic proteins are toxic for airway epithelium, has led to a consensus that eosinophils are a major effector cell for tissue damage in asthma and could cause many of the pathological features of the disease.141 Eosinophils are therefore associated with a number of different types of pathological and reparative processes ranging from the permanent tissue damage seen in hypereosinophilic syndromes, the partly reversible tissue damage seen in asthma and pulmonary eosinophilia, and tissue repair characteristic of wound healing. The factors that determine which role the eosinophil adopts are unclear.
Large numbers of eosinophils and mononuclear cells are found in and around the bronchi of patients who have died of asthma, and their bronchial tissue contains large amounts of MBP.142 Slight increases in blood eosinophils may occur in both atopic and nonatopic chronic asthma. In one study of glucocorticoid-dependent patients, eosinophil counts correlated with the degree of airflow obstruction.143 Bronchial hyperreactivity inversely correlated with the blood eosinophil count in patients developing a late-phase response after antigen challenge.144
Antigen Challenge Studies in Humans and Animal Models Inhaled antigen in sensitized asthmatics causes an early fall in forced expiratory volume, thought to be due to the bronchoconstricting mediators from mast cells and a late response that consists of an influx of inflammatory cells, including large numbers of eosinophils, thereby mimicking the pathology of asthma.145 Twenty-four hours after antigen challenge administered through a bronchoscope, up to 50 percent of the cells obtained by bronchial lavage are eosinophils.146 An increase in airway neutrophils may also occur, although this is less dramatic. Similar events have been observed after challenge with agents that cause occupational asthma.147,148 Eosinophil recruitment is accompanied by increased numbers of activated T cells and monocytes, and similar findings have been observed in the skin and nose.149,150 Antigen challenge in animal models, many involving gene-deleted mice, have generally provided support for the hypothesis that asthma is an eosinophil-mediated disease driven by Th2-associated cytokines IL-4, IL-5, and IL-13.151,152,153 and 154 However, there has not been a clear correlation between the presence of an airway eosinophilia and bronchial hyperresponsiveness, the latter a marker of an asthma phenotype, in all studies.
Clinical Asthma An increase in the number of eosinophils, detected either by bronchoscopy or examination of sputum, is observed in the airways of asthmatics, if the patient is not using inhaled steroids.155 The eosinophil count in induced sputum is increasingly being used to aid in the diagnosis of asthma and monitor response to treatment.156 Airway eosinophils in asthma are activated,157,158 eosinophil infiltration is accompanied by increased numbers of activated CD25-positive T lymphocytes (which have a Th2-like profile of cytokine secretion),159 and there is evidence of bronchial epithelial desquamation.160 Increased eosinophils are also present in the airways of patients with intrinsic and occupational asthma.161,162 An airway eosinophilia is also a feature of some patients with an exacerbation of smoking-related airflow obstruction,163 and an increase in eosinophils in BAL fluid is seen in pulmonary eosinophilia and fibrosing alveolitis.164 There is a general correlation between the numbers of airway eosinophils and the severity of asthma.165 However, this is not a close relationship, and subjects with marked eosinophilia may have mild asthma and airway hyperresponsiveness, and many severe asthmatics may have minimal airway eosinophilia. Inhibition of airway eosinophilia by DSCG166 or, more effectively, glucocorticoids,167,168 is associated with an improvement in bronchial hyperresponsiveness, asthmatic symptoms, and lung function. Although glucocorticoids do induce eosinophil apoptosis at very high concentrations, their primary mechanism of action is probably inhibition of Th2 cytokine production. For eosinophils to cause tissue damage in the airways, they need to be actively secreting their mediators. Measurements of eosinophilic basic proteins may, therefore, be a better guide to the degree of eosinophilic inflammation than eosinophil numbers. For example, inhaled glucocorticoids may have little effect on the number of airway eosinophils but markedly reduce the amount of ECP in lavage fluid.169
The most common helminthic causes of an eosinophilia are summarized in Table 68-5.170,171 and 172 Eosinophils have been shown to be able to kill a number of opsonized parasites including newborn larvae of Trichinella. spiralis, larvae of Nippostrongylus brasiliensis, a gut parasite in the rat, and larvae of Fasciola hepatica, as well as shistosomulae of S. mansoni.173 In vivo, parasite larvae become opsonized with both specific IgG and IgE antibodies and components of the complement cascade such as C3bi, which can promote adhesion and activation of eosinophils. Dead larvae of S. haematobium and other parasites have been detected in the skin surrounded by eosinophils and eosinophil granule products.174 Adult worms both in vitro and in vivo appear resistant to eosinophil-mediated damage. Despite the circumstantial evidence of eosinophils being involved in host defense against parasites, there remains some doubt about their role. Except for one study in the Gambia,175 there is no obvious correlation between the degree of eosinophilia and protection against infection or reinfection. Moreover, treatment of mice infected with N. brasiliensis or S. mansoni with neutralizing anti-IL-5 mAb’s abolished the eosinophilia without modulating the disease process.176 IL-5 transgenic mice were, however, protected from infection with N. brasiliensis but not T. canis.177 The mechanism of eosinophilia in parasitic disease is thought to be similar to allergic disease, with a Th2-type response to helminthic antigens resulting in increased production of eosinophil growth factors, in particular IL-5.178 The more pronounced eosinophilia in parasitic disease is presumably due to the systemic nature of the disease compared to the localized, single-organ nature of asthma and allergic disease. Helminthic parasites also secrete eosinophil chemotactic factors.179,180 Mast cell degranulation as a result of larval migration through tissue, especially the skin, may contribute to the local tissue eosinophilia. The similarities in the immune responses seen in allergic disease and infection with helminths has led to speculation about the relationship between the two conditions.181 There is limited evidence that the atopic state protects against parasitic infection.182,183 In addition it is possible that parasitic infection could protect against allergic symptoms by increasing the amount of nonallergenic IgE bound to mast cells,184 although epidemiological evidence for this hypothesis is lacking.


Idiopathic Hypereosinophilic Syndrome Definition and History. The sporadic occurrence of striking eosinophilia without apparent cause and with a predisposition to cardiac and neurologic injury185 was identified as a syndrome by Hardy and Anderson in 1968.186 Subsequent reports have referred to it as the hypereosinophilic syndrome.187,188
Etiology and Pathogenesis. The cause of the disorder is unknown. Some cases are manifestations of a polyclonal and others of a monoclonal proliferations of eosinophils. The latter is a primary disturbances in myelopoiesis.189,190 Other cases may be a reflection of polyclonal or monoclonal expansion of T lymphocytes that elaborate eosinophilopoietic cytokines.191,192 and 193,256,257 The organ damage is thought to be largely a result of noxious effects of eosinophil granule contents in certain tissues, especially the heart and nervous system.194,195 Damage to tissues is mediated by eosinophilic secretory products, especially cationic proteins, peroxidase, and neurotoxin. Analysis of patterns of X-chromosome inactivation in the hypereosinophilic syndrome using HUMARA analysis showed a clonal pattern in some patients suggesting that in these patients this syndrome is a neoplastic disorder.196
Clinical Features. The onset is often marked by anorexia, weight loss, fatigue, nausea, abdominal pain, diarrhea, non-productive cough, pruritic rash, and fever accompanied by night sweats. Hepatic and splenic enlargement is common, as is dependent edema.188 Virtually all patients have cardiac involvement and most have clinical evidence of congestive heart failure, new heart murmurs, or electrocardiographic abnormalities, including conduction defects or arrhythmias.195,197 Interstitial pulmonary infiltrates and pleural effusion may occur.198 Nervous system dysfunction may be profound, including confusion, delirium, coma, and signs of dementia. Blurred vision, slurred speech, or a peripheral neuritis may be present.199 Erythematous or papular rashes can occur in a minority of patients. A predisposition to venous thrombosis may be present.
Laboratory Features.
The hematocrit is below normal in most patients, and the anemia mimics that of chronic inflammation. The platelet count is usually normal but may be decreased. The key finding is a leukocytosis with a striking eosinophilia, usually greater than 1500 eosinophils/µl (1.5 × 109/liter), occasionally as high as 100,000 eosinophils/µl (100 × 109/liter). Marrow examination shows eosinophilia with few other specific findings. Eosinophilia may be progressive, with eosinophil counts of 50,000 cells/µl (50 × 109/liter) or more occurring in over half the patients during the course of the illness.190 Circulating immune complexes, elevated IgE, or hypergammaglobulinemia occur frequently.188
Differential Diagnosis. When the condition is fully expressed, the diagnosis is evident because of the absence of other causes of extreme hypereosinophilia with tissue injury. In more subtle forms, determining that another cause of eosinophilia is not present may require a longer period of observation. In geographic areas in which parasitic infestation is common, the differential diagnosis requires good microbiological diagnostic facilities. The distinction from eosinophilic leukemia, a very rare disorder, is made principally by determining the presence or absence of leukemic blast cells in the marrow (and blood). The presence of a clonal cytogenetic abnormality and progressive anemia and thrombocytopenia also indicates that leukemia is more likely the correct diagnosis. Another condition to consider is familial eosinophilia.200 This is an autosomal dominant disorder characterized by peripheral hypereosinophilia of unidentifiable cause with or without other organ involvement. The disorder has been mapped to the cytokine gene cluster on chromosome 5q31-q33, although it doesn’t appear to involve any of the known eosinophil growth factors in this region.201 A rare condition characterized by hypereosinophilia and immunodeficiency is Omenn syndrome, which is due to mutations in the Rag 1 or Rag 2 genes that control genomic rearrangement of the T-cell antigen receptor.202
Therapy, Course, and Prognosis.
The disease is chronic, sometimes indolent, but more often progressive, and can be rapidly fatal. Although symptoms may remit and relapse, the organ damage is usually steadily progressive, with cardiac failure resulting from endomyocardial fibrosis that often involves the valve leaflets. Central nervous system dysfunction is commonly progressive, leading to encephalopathy, polyneuropathy, or stroke. Episodes of venous thrombosis may complicate the course. In one series, over three-quarters of the patients died after three years of observation, despite therapy with glucocorticoids or cytotoxic agents.203 In occasional patients with mild disease without apparent progression, no therapy may be advisable. Careful observation is important, however, since patients with an apparently indolent course may be having tissue damage. Symptomatic or progressive disease requires therapy. Glucocorticoids and hydroxyurea have been the mainstays of treatment and have been used with apparent success in some patients. Prednisone 60 mg/day, orally, for one week followed by 60 mg every other day for three months is one suggested regimen. Glucocorticoid-unresponsive patients have responded to hydroxyurea at 1 to 2 g/day orally so as to decrease the white cell count to about 5000/µl (5 × 109/liter). Responses to other cytostatic agents (e.g., methotrexate, cyclophosphamide) have been very infrequent. Etoposide has been used successfully in a glucocorticoid- and hydroxyurea-resistant patient.204 Interferon-a may be a very useful agent in some patients with this disorder; occasional dramatic responses having been recorded,205,206 and 207 although this treatment may on occasion cause renal damage.208 Cladribine has been useful in some patients (258). Leukapheresis209 and marrow transplantation have also been used.210
Surgical replacement of severely damaged heart valves has been accomplished successfully.211,212
Troleandamycin and methylprednisolone have also been successful in one patient. The former antibiotic has a glucocorticoid-sparing effect on methylprednisolone.213 Occasional patients may evolve into overt malignancy, either hemopoietic214,215 or lymphocytic,216,217 and it is unclear whether the eosinophilia is the most striking early reaction to a clonal lymphocytic disorder. In certain cases the primary tissue involved may be T lymphocytes that elaborate IL-5, with the eosinophilic hyperplasia being a secondary phenomenon.
Eosinophilia-Myalgia Syndrome This disorder was first described in 1989 in New Mexico.218 Over 1500 cases were reported over the next 2 years, with over 30 deaths.219 The syndrome was caused by the ingestion of L-tryptophan and is thought to be the result of a contaminant, possibly 1,1′-ethylidenebis (tryptophan). The syndrome is characterized histologically by a perivascular lymphocytic and eosinophilic infiltrate in the dermis, fascia, and skeletal muscle, with a pulmonary vasculitis and alveolitis mimicking eosinophilic fasciitis.
Severe myalgias and an eosinophil count greater than 1000 cells/µl (1 × 109/liter) are constant features. Arthralgias, cough, shortness of breath, dependent edema, and hair loss are very common. A significant proportion of patients, perhaps 50 percent, develop parasthesias, peripheral neuropathy, and/or sclerodermalike skin changes. A high proportion of patients have symptoms and signs one year after onset of the disease.220,221 and 222
Glucocorticoid or nonsteroidal anti-inflammatory therapy has had little effect on the course of the disease, although some improvement may occur in symptoms. Cytotoxic drug therapy has also had little effect on symptoms or the course of the disease.223
Toxic Oil Syndrome In 1981, more than 20,000 cases of a syndrome manifested by fever, cough, dyspnea and leukocytosis, neutrophilia, and an eosinophil count greater than 750 cells/µl (0.75 × 109/liter) were reported in Spain.225 Occasionally, the eosinophil count rose above normal only after the onset of the pulmonary symptoms. Pulmonary infiltrates were evident on X-rays of the chest. Pleural effusion was common, and hypoxemia was frequent. There were over 300 deaths (about 1.5 percent of affected subjects). About half the patients went on to a chronic course that mimicked the eosinophilia-myalgia syndrome, with myalgias, eosinophilia, peripheral neuritis, sclerodermalike skin lesions, hair loss, and a sicca syndrome. Most patients improved from the acute or chronic symptoms and signs, but some residual nerve, muscle, or skin damage persisted. Endothelial cell proliferation, mononuclear cell infiltrates around blood vessels (vasculitis), and perineural inflammatory infiltrates were identified histopathologically. Glucocorticoid therapy may have decreased the pulmonary symptomatology. The disease was thought to be a response to an unlabeled food oil, aniline-denatured rapeseed oil, marketed as pure olive oil.226
Reactive Hypereosinophilia and Neoplasms Exaggerated eosinophilia has been reported in association with a variety of lymphoid227,228 and solid tumors.229,230 In these cases, the eosinophilia is thought to be the result of an increase to IL-5 and other cytokines or chemokines (259) elaborated by the tumor cells, although the expression by eosinophils of receptors of the TNF-a family suggest that they could regulate tumor growth.231 The eosinophilia may precede the clinical diagnosis of the tumor but is usually manifested concomitantly. In some cases successful treatment of the tumor is associated with amelioration of the eosinophilia. Angiolymphoid hyperplasia also has been associated with eosinophilia.232,233
Eosinophilic Leukemia This rare disorder is described in Chap. 93.
Eosinophilia, Angiitis, and Asthma A group of related diseases, including polyarthritis nodosa and allergic granulomatosis (Churg-Strauss angiitis), are associated with a prominent eosinophilia.234,235 In a review of subjects with asthma and necrotizing angitiis, all patients had anemia and hypereosinophilia, with a mean blood eosinophil count over 8000 cells/µl (8 × 109/liter).238 Remission can be achieved in about 90 percent of patients. About 10 percent of patients die of the vasculitis.239 In subjects with asthma and exaggerated eosinophilia, the development of multiorgan signs (skin, nervous system, kidney, joints, lung, heart, gastrointestinal tract) should lead to consideration of this disorder.
Eosinophilic Fasciitis This syndrome may occur at any age in both sexes and is characterized by stiffness, pain, and swelling of the arms, forearms, thighs, legs, hands, and feet in descending order of frequency.
Malaise, fever, weakness, and weight loss also occur.240,241 Eosinophilia greater than 1000 cells/µl (1 × 109/liter) is present in most patients but may be intermittent. A biopsy, usually required for the diagnosis, shows inflammation, edema, thickening, and fibrosis of the fascia. Synovial tissue may show similar changes. Aplastic anemia, isolated cytopenias, pernicious anemia, and leukemia have been associated with eosinophilic fasciitis.242,243
Eosinophiluria and Eosinophilorrhachia The urinary excretion of eosinophils is seen in several inflammatory disorders of the kidney but most often in urinary tract infection or acute interstitial nephritis.244,245 Hansel stain is superior to Wright stain in identifying eosinophils in a stained urinary sediment. Cerebrospinal fluid eosinophilia may occur with infection, shunts, and allergic reactions involving the meninges.246,247 Eosinophilic meningoencephalitis with cerebrospinal fluid eosinophilia, but no blood eosinophilia, can occur in Hodgkin’s disease.248
The eosinophil count in hospitalized patients is less than 10 cells/µl (0.01 × 109/liter) in only 0.1 percent of patients, and in virtually all patients the eosinopenia can be ascribed to glucocorticoids or to disease.115 Acute infection, or treatment with glucocorticoids or adrenaline, decreases eosinophil counts.249,250 In contrast, beta blockers inhibit adrenaline-induced eosinopenia and can cause a rise in the eosinophil count.
There have been several isolated case reports of patients with absent eosinophils in the blood and marrow.251 Several patients without eosinophils were reported as having asthma and allergic symptoms.252 In one case, it occurred after drug-induced agranulocytosis,253 and in another there was a serum inhibitor of eosinophil colony formation.254 A rare disorder, eosinophil peroxidase deficiency, may be brought to light by automatic counting that uses detection of EPO to count eosinophils. EPO deficiency does not have any adverse clinical consequences.255

Spry CJF: The natural history of eosinophils, in The Immunopharmacology of Eosinophils, edited by H Smith and RM Cook, pp 1–9. Academic, London, 1993.

Saito H, Hatake K, Dvorak AM, et al: Selective differentiation and proliferation of hematopoietic cells induced by recombinant human interleukins. Proc Natl Acad Sci USA 85:2288, 1988.

Baston A, Beeson PB: Mechanism of eosinophilia. II: Role of the lymphocyte. J Exp Med 131:1288, 1970.

Hsu CK, Hsu SH, Whitney RA, Hansen CT: Immunopathology of schistosomiasis in athymic mice. Nature 262:397, 1976.

Colley D: Lymphokine-related eosinophil responses. Lymphokine Research 1:133, 1980.

Bischoff SC, Brunner T, De Weck AL, Dahinden CA: Interleukin 5 modifies histamine release and leukotriene generation by human basophils in response to diverse agonists. J Exp Med 172:1577, 1990.

Leary AG, Ogawa M: Identification of pure and mixed basophil colonies in culture of human peripheral blood and marrow cells. Blood 64:78, 1984.

Kinashi T, Harada N, Severinson E, et al: Cloning of a complementary DNA encoding T cell replacement factor and identity with B cell growth factor II. Nature 324:70, 1986.

Campbell HD, Sanderson CJ, Wang Y, et al: Molecular cloning, nucelotide sequence and expression of the gene encoding human eosinophil differentiation factor (interleukin 5). Proc Natl Acad Sci USA 84:6629, 1987.

McKenzie ANJ, Ely B, Sanderson CJ: Mutated interleukin-5 monomers are biologically inactive. Mol Immunol 28:155, 1991.

Milburn MV, Hassell AM, Lambert MH, et al: A novel dimer configuration revealed by the crystal structure at 2.4A resolution of human interleukin-5. Nature 363:172, 1993.

Sanderson CJ, Campell HD, Young IG: Molecular and cellular biology of eosinophil differentiation factor (IL-5) and its effects on human and mouse B cells. Immunol Rev 102:29, 1988.

Tominaga A, Takaki S, Koyama N, et al: Transgenic mice expressing a B cell growth and differentiation factor gene (interleukin 5) develop eosinophilia and autoantibody production. J Exp Med 173:429, 1991.

Dent LA, Strath M, Mellor AL, Sanderson CJ: Eosinophilia in transgenic mice expressing interleukin 5. J Exp Med 172:1425, 1990.

Saeland S, Caux C, Favre C, et al: Combined and sequential effects of human IL-3 and GM-CSF on the proliferation of CD34+ hematopoietic cells from cord blood. Blood 73:1195, 1989.

Ottman OG, Ganser A, Seipelt G, et al: Effects of recombinant human interleukin 3 on human hematopoietic progenitor and precursor cells in vivo. Blood 76:1494, 1990.

Van-Leeuwen BH, Martinson ME, Webb GC, Young IG: Molecular organization of the cytokine gene cluster, involving the human IL-3, IL-4 IL-5 and GM-CSF genes on human chromosomes. Blood 73:1142, 1989.

Mossman TR, Coffman RL: Th1 and Th2 cells:different patterns of lymphokine secretion lead to different functional properties. Annu Rev Immunol 7:145, 1989.

Miyajima A, Kitamura T, Harada N, et al: Cytokine receptors and signal transduction. Annu Rev Immunol 10:295, 1992.

Tavernier J, Devos R, Cornelis S, et al: A human high affinity interleukin-5 receptor (IL-5R) is composed of an IL-5-specific a chain and a b chain shared with the receptor for GM-CSF. Cell 66:1175, 1991.

Murata Y, Takaki S, Migita M, et al: Molecular cloning and expression of the human interleukin 5 receptor. J Exp Med 175:341, 1992.

Plaetinck G, der Heyden JV, Tavernier J, et al: Characterization of interleukin 5 receptors on eosinophilic sublines from human promyelocytic leukemia (HL60) cells. J Exp Med 172:683, 1990.

Wang P, Wu P, Cheewatrakoolpong B, Myers JG, Egan RW, Billah MM: Selective inhibition of IL-5 receptor alpha-chain gene transcription by IL-5, IL-3 and granulocyte-macrophage colony stimulating factor in human blood eosinophils. J Immunol 160:4427, 1998.

Hansel TT, Braunstein JB, Walker C: An improved immunomagnetic procedure for the isolation of highly purified human blood eosinophils. J Immunol Methods 145:105, 1991.

Bass DA, Grover WH, Lewis JC, et al: Comparison of human eosinophils from normals and patients with eosinophilia. J Clin Invest 66:1265, 1980.

Caulfield JP, Hein A, Rothenburg ME, et al: A morphometric study of normodense and hypodense human eosinophils that are derived in vivo and in vitro. Am J Pathology 137:27, 1991.

Fukuda T, Makino S: Heterogeneity and activation, in Eosinophils Biological and Clinical Aspects, edited by T Fukuda and S Makino, pp 156–170. CRC, Boca Raton, FL, 1993.

Wardlaw AJ: Eosinophil density: What does it mean? Clin Exp Allergy 25:1145, 1995.

Azzawi M, Bradley B, Jeffery PK, et al: Identification of activated T lymphocytes and eosinophils in bronchial biopsies in stable atopic asthma. Am Rev Respir Dis 142:1407, 1990.

Kay AB, Stechschulte DJ, Austen KF: An eosinophil leukocyte chemotactic factor of anaphylaxis. J Exp Med 133:602, 1971.

Sehmi R, Cromwell O, Taylor GW: Identification of guinea pig eosinophil chemotactic factor of anaphylaxis as leukotriene B4 and 8(S),15(S)-dihydroxy-5,9,11,13 (Z,E Z,E)-eicosatetranoic acid. J Immunol 147:2276, 1991.

Goetzl EJ, Austen KF: Purification and synthesis of eosinophilotactic tetrapeptides of human lung. Identification as eosinophil chemotactic factor of anaphylaxis. Proc Natl Acad Sci USA 72:4123, 1975.

Wardlaw AJ, Moqbel R, Cromwell O, Kay AB: Platelet activating factor is a potent chemotactic and chemokinetic factor for human eosinophils. J Clin Invest 78:1701, 1986.

Sehmi R, Wood LJ, Watson R, et al: Allergen induced increases in IL-5 receptor alpha subunit expression on bone marrow derived CD34+ cells from asthmatic subjects. A novel marker of progenitor cell committment towards eosinophilic differentiation. J Clin Invest 100:2466, 1997.

Collins PD, Marleau S, Griffiths-Johnson DA, et al: Co-operation between interleukin 5 and the chemokine eotaxin to induce eosinophil accumulation in vivo. J Exp Med 182:1169, 1995.

Palframan RT, Collins PD, Severs NJ, et al: Mechanisms of acute eosinophil mobilization from the bone marrow stimulated by inerleukin 5: the role of specific adhesion molecules and phosphotidylinositol 3-kinase. J Exp Med 188:1621, 1998.

Wardlaw AJ, Symon FA, Walsh GM: Eosinophil adhesion in allergic inflammation. The role of basophils and eosinophils in human disease. J Allergy Clin Immunol 94(pt 2):1163, 1994.

Symon FA, Lawrence MB, Walsh GM, et al: Characterisation of the eosinophil P-selectin ligand. J Immunol 157:1711, 1996.

Sriramarao P, Norton CR, Borgstrom P, et al: E-selectin preferentially supports neutrophil but not eosinophil rolling under conditions of flow in vitro and in vivo. J Immunol 157:4672, 1996.

Yao L, Pan J, Setiadi H, et al: Interleukin 4 or Oncostatin M induces a prolonged increase in P-selectin mRNA and protein in human endothelial cells. J Exp Med 184:81, 1996.

Patel KD: Eosinophil tethering to interleukin-4-activated endothelial cells requires both p-selectin and vascular cell adhesion molecule-1. Blood 92:3904, 1998.

Woltmann G, McNulty CA, Dewson G, et al: IL-13 induces eosinophil but not neutrophil binding to HUVECs via PSGL-1. Blood 95:3146, 2000.

Reinhardt PH, Kubes P: Differential leukocyte recruitment from whole blood via endothelial adhesion molecules under shear conditions. Blood 92:4691, 1998.

Bochner BS, Luskinsas FW, Gimbrone MA: Adhesion of human basophils, eosinophils and neutrophils to interleukin-1 activated human vascular endothelial cells: contribution of endothelial cell adhesion molecules. J Exp Med 173:1553, 1991.

Grayson MH, Van der Vieren M, Sterbinsky SA, et al: Alpha d beta 2 integrin is expressed on human eosinophils and functions as an alternative ligand for vascular cell adhesion molecule 1 (VCAM-1). J Exp Med 188:2187, 1998.

Petering H, Gotze O, Kimmig D, et al: The biologic role of interleukin-8: Functional analysis and expression of CXCR1 and CXCR2 on human eosinophils. Blood 93:694, 1999.

Kitaura M, Nakajima T, Imai T, et al: Molecular cloning of human eotaxin, an eosinophil-selective CC chemokine and identification of a specific eosinophil eotaxin receptor, CC chemokine receptor 3. J Biol Chem 271:7725, 1996.

Kita H, Gleich GJ: Chemokines active on eosinophils. Potential roles in allergic inflammation. J Exp Med 183:2421, 1996.

Uguccioni M, Loetscher P, Forsmann U, et al: Monocyte chemotactic protein 4 (MCP-4) a novel structural and functional analogue of MCP-3 and eotaxin. J Exp Med 183:2379, 1996.

Collins PD, Marleau S, Grifiths-Johnson DA, et al: Co-operation between interleukin 5 and the chmeokine eotaxin to induce eosinophil accumulation in vivo J Exp Med 182:1169, 1995.

Mould AW, Matthaei KI, Young IG, et al: Relationship between interleukin-5 and eotaxin in regulating blood and tissue eosinophilia in mice. J Clin Invest 99:1064, 1997.

Gonzalo JA, Lolyd CM, Kremer L, et al: Eosinophil recruitment to the lung in a murine model of allergic inflammation. The role of T cells, chemokines and adhesion receptors. J Clin Invest 98:2332, 1996.

Gonzalo JA, Lloyd CM, Wen D, et al: The co-ordinated action of CC chemokines in the lung orchestrates allergic inflammation and airway hyperresponsiveness. J Exp Med 188:157, 1998.

MacLean JA, Ownbey R, Luster AD: T cell-dependent regulation of eotaxin in antigen-induced pulmonary eosinophilia. J Exp Med 184:1461, 1996.

Simon H-U, Yousefi S, Schranz C, Schapowal A, Bachert C, Blaser K: Direct demonstration of delayed eosinophil apoptosis as a mechanism causing tissue eosinophilia. J Immunol 158:3902, 1997.

Weller PF: Eicosanoids, cytokines and other mediators elaborated by eosinophils, in Eosinophils, Biological and Clinical Aspects, edited by S Makino, T Fukuda, pp 125–154. CRC, Boca Raton, FL, 1993.

Weller PF, Lee CN, Foster DW, et al: Generation and metabolism of 5-lipoxygenase pathway leukotrienes by human eosinophils; predominant production of leukotriene C4. Proc Natl Acad Sci USA 80:7625, 1983.

Shaw RJ, Walsh GM, Comwell O, et al: Activated human eosinophils generate SRS-A leukotrienes following physiological (IgG dependent) stimulation. Nature 316:150, 1985.

Cromwell O, Wardlaw AJ, Champion A, et al: IgG-dependent generation of platelet activating factor by normal and low density eosinophils. J Immunol 145:3862, 1990.

Bozza PT, Yu W, Penrose JF, Morgan ES, Dvorak AM, Weller PF: Eosinophil lipid bodies: specific, inducible intracellular sites for enhanced eicosanoid formation. J Exp Med 186:909, 1997.

Barker RL, Gleich GJ, Pease LR: Acidic precursor revealed in human eosinophil granule major basic protein cDNA. J Exp Med 168:1493, 1988.

Butterworth AE, Wassom DL, Gleich GJ, Loegering DA, David JR: Damage to schistosomula of S. manson induced directly by eosinophil major basic protein. J Immunol 122:221, 1979.

Gleich GJ: The eosinophil and bronchial asthma: current understanding. J Allergy Clin Immunol 85:422, 1986.

Gundel RH, Letts LG, Gleich GJ: Human eosinophil major basic protein induces airway constriction and airway hyperresponsiveness in primates. J Clin Invest 87:1470, 1991.

Rohrbach MS, Wheatley CL, Slifman NR, Gleich GJ: Activation of platelets by eosinophil granule proteins. J Exp Med 172:1271, 1990.

Ten RM, Pease LR, McKean DJ, Bell MP, Gleich GJ: Molecular cloning of the human eosinophil peroxidase. J Exp Med 169:1757, 1989.

Rosenburg HF, Ackerman SJ, Tenen DG: Human eosinophil cationic protein. Molecular cloning of a cytotoxin and helminthotoxin with ribonuclease activity. J Exp Med 170:163, 1989.

Young JDE, Peterson CGB, Venge P, Cohn ZA: Mechanism of membrane damage mediated by human eosinophil cationic protein. Nature 321:613, 1986.

Tai PC, Spry CJF, Peterson C, Venge P, Olsson I: Monoclonal antibodies distinguish between storage and secreted forms of eosinophil cationic protein. Nature 309:182, 1984.

Rosenburg HF, Tenen DG, Ackerman SJ: Molecular cloning of the human eosinophil-derived neurotoxin: a member of the ribonuclease gene family. Proc Natl Acad Sci USA 86:4460, 1989.

Weller PF, Goetzl EJ, Austen KF: Identification of human eosinophil lysophospholipase as the constituent of Charcot-Leyden crystals. Proc Natl Acad Sci USA 77:7440, 1980.

Wong DT, Weller PF, Galli SJ, et al: Human eosinophils express transforming growth factor a. J Exp Med 172:673, 1990.

Wardlaw AJ, Moqbel R, Kay AB: Eosinophils: biology and role in disease. Adv Immunol 80:151, 1995.

Elovic AE, Ohyama H, Sauty A, et al: IL-4 dependent regulation of TGF-alpha and TGF-beta expression in human eosinophils. J Immunol 160:6121, 1998.

Grewe M, Czech W, Morita A, et al: Human eosinophils produce biologically active IL-12: implications for control of T cell responses. J Immunol 161:415, 1998.

Rossi AG, Haslett C, Hirani N, et al: Human circulating eosinophils secrete macrophage migration inhibitory factor (MIF). Potential role in asthma. J Clin Invest 101:2869, 1998.

Weinstock JV: Production of neuropeptides by inflammatory cells within granulomas of murine schistosomiasis mansoni. Eur J Clin Invest 21:145, 1991.

Spry C: Eosinophils, p 29. Oxford and London: Oxford University Press, 1988.

Butterworth AE, Sturrock RF, Houba V, et al: Eosinophils as mediators of antibody-dependent damage to schistosomula. Nature 256:727, 1975.

McLaren DJ, Mackenzie CD, Ramahlo-Pinto FJ: Ultrastructural observations on the in vitro interaction between rat eosinophils and some parasitic helminths (Schistosoma mansoni, Trichinella spiralis and Nippostongylus brasiliensis). Clin Exp Immunol 30:105, 1977.

Fanger MW, Shen L, Graziano RF, Guyre P: Cytotoxicity mediated by human Fc receptors for IgG. Immunol Today 10:92, 1989.

Valerius T, Repp R, Kalden JR, Platzer E: Effects of interferon g on human eosinophils in comparison with others cytokines. J Immunol 145:2950, 1990.

Kita H, Weiler DA, Abu-Ghazaleh R, et al: Release of granule proteins from eosinophils cultured with IL-5. J Immunol 149:629, 1992.

Capron M, Capron A, Dessaint J-P, et al: Fc receptors for IgE on human and rat eosinophils. J Immunol 126:2087, 1981.

Capron M, Joualt T, Prin L, et al: Functional study of a monoclonal antibody to IgE Fc receptor (Fc R2) of eosinophils, platelets and macrophages. J Exp Med 164:72, 1986.

Capron M, Troung M-J, Desreumaux P, et al: Eosinophil membrane receptors: Function of IgE and IgA binding molecules, in Eosinophils: Immunological and Clinical Aspects, Edited by GJ Gleich, AB Kay. Marcel Dekker, New York, in press.

Gounni AS, Lamkhioued B, Ochiai K, et al: High affinity IgE receptor on eosinophils is involved in defense against parasites. Nature 367:183, 1994.

Ying S, Barata LT, Meng O, et al: High affinity immunoglobulin E receptor (Fc epsilon R1–bearing eosinophils, mast cells, macrophages and langerhans cells in allergen induced late-phase cutaneous reactions in atopic subjects. Immunology 93:281, 1998.

Unkeless JC, Scigliano E, Freedman VH: Structure and function of human and murine receptors for IgG. Annu Rev Immunol 6:251, 1988.

Hartnell A, Moqbel R, Walsh GM, et al: Fcg and CD11/CD18 receptor expression on normal density and low density human eosinophils. Immunology 69:264, 1990.

Hartnell A, Kay AB, Wardlaw AJ: IFN-g induces expression of FcgRIII(CD16) on human eosinophils. J Immunol 148:1471, 1992.

Abu-Ghazaleh RI, Fujisawa T, Mestecky J, et al: IgA-induced eosinophil degranulation. J Immunol 142:2393, 1989.

Kaneko M, Horie S, Kato M, et al: A crucial role for beta 2 integrins in the activation or eosinophils stimulated by Ig. J Immunol 155:2631, 1995.

Winquist I, Olofsson T, Olofsson I: Mechanisms for eosinophil degranulation. Release of the eosinophil granule protein. Immunology 51:1, 1984.

Yazdanbakhsh M, Eckmann CM, Roos D: Characterization of the interaction of human eosinophils and neutrophils with opsonized particles. J Immunol 135:1378, 1985.

O’Flaherty JTO, Kuroki M, Nixon AB, et al: 5-Oxo-Eicosatetraenoate is a broadly active eosinophil selective stimulus for human granulocytes. J Immunol 157:336, 1996.

Khaliffe J, Capron M, Cesbron JY, et al: Role of specific IgE antibodies in peroxidase (EPO) release from human eosinophils. J Immunol 137:1659, 1986.

Nusse O, Lindau M, Cromwell O, Kay AB, Gomperts BD: Intracellular application of guanosine-5′-O-(3-thiotriphosphate) induces exocytic granule fusion in guinea pig eosinophils. J Exp Med 171:775, 1990.

Roboz GJ, Rafii S: Interleukin-5 and the regulation of eosinophil production. Curr Opin Hematol 6:148, 1999.

Hartnell A, Kay AB, Wardlaw AJ: IFNg induces expression of FcgRIII(CD16) on human eosinophils. J Immunol 142:2393, 1992.

Moqbel R, Hamid Q, Sun Y, et al: Expression of mRNA and immunoreactivity for the granulocyte macrophage colony stimulating factor (GM-CSF) in activated human eosinophils. J Exp Med 174:749, 1991.

Slungard A, Vercellotti GM, Walker G, et al: Tumor necrosis factor a/cachectin stimulates eosinophil oxidant production and toxicity towards human endothelium. J Exp Med 171:2025, 1990.

Walsh GM, Symon FA, Wardlaw AJ: Human eosinophils preferentially survive on tissue compared with plasma fibronectin. Clin Exp Allergy 25:1128, 1995.

Simon H-U, Alam R: Regulation of eosinophil apoptosis: transduction of survival and death signals. Int Arch Allergy Immunol 118:7, 1999.

Padrak K, Olszewska-Pazdrak B, Stafford S, et al: Jak 2 and Raf-1 kinases are critical for the antiapoptotic effect of interleukin 5, whereas only Raf-1 kinases is essential foe eosinophil activation and degranulation. J Exp Med 188:421, 1998.

Alam R, Forsythe P, Stafford S, Fukuda Y: Transforming growth factor b abrogates the effects of hematopoietins on eosinophils and induces their apoptosis. J Exp Med 179:1041, 1994.

Walsh GM, Williamson MS, Symon FA, et al: Ligation of CD69 induces apoptosis and cell death in human eosinophils cultured with GM-CSF. Blood 87:2815, 1996.

Matsumoto K, Schleimer RP, Saito H, et al: Induction of apoptosis in human eosinophils by anti-Fas antibody treatment in vitro. Blood 86:1437, 1995.

Hebestreit H, Dibbert B, Balatti B, et al: Disruption of Fas receptor signaling by nitric oxide in eosinophils. J Exp Med 187:415, 1998.

Dibbert B, Daigle I, Braun D, et al: Role for Bcl-XL in delayed eosinophil apoptosis mediated by grnaulocyte-macrophage colony stimulating factor and interleukin-5. Blood 92:778, 1998.

Dewson G, Walsh GM, Wardlaw AJ: Expression of Bcl-2 and its homologues in human eosinophils: Modulation by interleukin-5. Am J Resp Cell Mol Biol 20:720, 1999.

Laviolette S, Bosse M, Boulet L-P, et al: Identification and analysis of eosinophils by flow cytometry using the depolarized side scatter-saponin method. Cytometry 29:197, 1997.

Kimura I, Moritani Y, Tanizaki Y: Basophils in bronchial asthma with reference to reagin-type allergy. Clin Allergy 3:195, 1973.

Krause JR, Boggs DR: Search for eosinophilia in hospitalized patients with normal blood leukocyte concentration. Am J Haematol 24:55, 1987.

Matheson A, Rosenblum A, Glazer R, Dacanay E: Local tissue and blood eosinophils in newborn infants. J Pediatr 51:502, 1957.

Winkel P, Statland BE, Saunders AM, et al: Within day physiologic variation of leukocyte types in healthy subjects as assayed by two automated leukocyte differential analyzers. Am J Clin Pathol 75:693, 1981.

Bain BJ, Seed M, Godsland I: Normal values for peripheral blood white cell counts in women of four different ethnic origins. J Clin Pathol 37:188, 1984.

Hamid Q, Azzawi M, Sun Ying, et al: Expression of mRNA for interleukin-5 in mucosal bronchial biopsies from asthma. J Clin Invest 87:1541, 1991.

Limaye AP, Abrams JS, Silver JE, et al: Regulation of parasite induced eosinophilia: selectively increased interleukin 5 production in helminth-infected patients. J Exp Med 172:399, 1990.

Enokihara H, Furusawa S, Nakakubo H: T cells from eosinophilic patients produce interleukin 5 with interleukin 2 stimulation. Blood 73:1809, 1989.

Owen WF, Rothenberg ME, Peterson J: Interleukin 5 and phenotypically altered eosinophils in the blood of patients with the idiopathic hypereosinophilic syndrome. J Exp Med 170:343, 1989.

Owen WF, Peterson J, Sheff DM: Hypodense eosinophils and interleukin 5 activity in the blood of patients with the eosinophilia-myalgia syndrome. Proc Natl Acad Sci USA 87:8647, 1990.

Samoszuk M, Nansen L: Detection of interleukin-5 messenger RNA in Reed-Sternberg cells of Hodgkins disease with eosinophlia. Blood 75:13, 1990.

Coffman RL, Seymour BW, Hudak S, Jackson J, Rennick D: Antibody to interleukin-5 inhibits helminth-induced eosinophilia in mice. Science 245:308, 1989.

Desreumaux P, Janin A, Colombel JF, et al: Interleukin 5 messenger RNA expression by eosinophils in the intestinal mucosa of patients with coeliac disease. J Exp Med 175:293, 1992.

Mossman R, Coffman RL: Th1 and Th2 cells: different patterns of lymphokine secretion lead to different functional properties. Annu Rev Immunol 7:145, 1989.

Kay AB, Sun Ying, Varney V: Messenger mRNA expression of the cytokine gene cluster, IL-3, IL-4, IL-5 and GM-CSF in allergen-induced late-phase cutaneous reactions in atopic subjects. J Exp Med 173:775, 1991.

Tsicopolous A, Hamid Q, Varney V, et al: Preferential mRNA expression of Th1-type cells (IFNgamma+, IL-2+) in classical delayed-type hypersentivity reactions in human skin. J Immunol 148:2085, 1992.

Wierenga EA, Snoek M, De Groot C: Evidence for compartmentalization of functional subsets of CD4+ T lymphocytes in atopic patients. J Immunol 144:4651, 1990.

Kirman J, Le Gros G: Which is the true regulator of Th2 cell development in allergic immune responses? Clin Exp Allergy 28:908, 1998.

King T-P: Immunochemical properties of antigens that cause atopic diseases, in Bronchial Asthma, Mechanisms and Therapuetics, 3d ed, edited by EB Weiss, M Stein, pp 4349. Little, Brown, Boston, 1993.

Hewitt CRA, Horton H, Jones RM, Pritchard DI: Heterogeneous proteolytic specificity and activity of the house dust mite proteinase allergen. Clin Exp Allergy 27:201, 1997.

Marsh DG, Hsu SH, Roebber M: HLA-Dw2: a genetic marker for human immune response to short ragweed pollen allergen Ra5.1. Response resulting primarily from natural antigenic exposure. J Exp Med 155:1439, 1982.

Weller PF, Goetzl EJ: The regulatory and effector roles of eosinophils. Adv Immunolgy 27:339, 1979.

Rothenberg ME: Eosinophilia. N Engl J Med 338:1592, 1998.

Kita H: The eosinophil: a cytokine producing cell? J Allergy Clin Immunol 97:966, 1996.

Todd R, Donoff BR, Chiang T: The eosinophil as a cellular source of transforming growth factor alpha in healing cutaneous wounds. Am J Pathol 138:1307 1991.

Lowe D, Jorizzo J, Hutt MSR: Tumor associated eosinophilia, a review. J Clin Path 34:1343, 1981.

Weller PF: The idiopathic hypereosinophilic syndrome. Blood 83:2759, 1994.

Butterworth AE: Cell mediated damage to helminths. Adv Parasitology 23:143, 1984.

Seminario C, Gleich GJ: Role of the eosinophil in asthma. Curr Opinion Immunol 6:860, 1994.

Filley WV, Holley KE, Kephart GM, Gleich GJ: Identification by immunofluorescence of eosinophil granule major basic protein in lung tissue of patients with bronchial asthma. Lancet 2:11, 1982.

Horn BR, Robin ED, Theodore J, Van Kessel A: Total eosinophil counts in the management of bronchial asthma. N Engl J Med 292:1152, 1975.

Durham SR, Kay AB: Eosinophils, bronchial hyperreactivity and late-phase asthmatic reactions. Clin Allergy 15:411, 1985.

De Monchy JGR, Kauffman HF, Venge P, et al: Bronchoalveolar eosinophilia during allergen-induced late asthmatic reactions. Am Rev Respir Dis 139:1383, 1985.

Metzger WJ, Zavala D, Richerson HB, et al: Local allergen challenge and bronchoalveolar lavage of allergic asthmatic lungs: description of the model and local airway inflammation. Am Rev Respir Dis 135:433, 1987.

Lam S, LeRichie J, Phillips D, et al: Cellular and protein changes in bronchial lavage fluid after late asthmatic reaction in patients with red cedar wood asthma. J Allergy Clin Immunol 80:44, 1987.

Fabbri LM, Boschetto P, Zocca E: Bronchoalveolar neutrophilia during late asthmatic reactions induced by toluene diisocyanate. Am Rev Respir Dis 136:36, 1987.

Frew AJ, Kay AB: The relationship between infiltrating CD4+ lymphocytes, activated eosinophils and the magnitude of the allergen induced late-phase response in man. J Immunol 141:4158, 1988.

Bentley AM, Jacobson MR, Cumberworth V, et al: Immunohistology of the nasal mucosa in seasonal allergic rhinitis: increase in activated eosinophils and epithelial mast cells. J Allergy Clin Immunol 89:877, 1992.

Hogan SP, Mould AW, Young JM, et al: Cellular and molecular regulation of eosinophil trafficking to the lung. Immunol Cell Biol 76:454, 1998.

Akimoto T, Numato F, Tamura M, et al: Abrogation of bronchial eosinophilic inflammation and airway hyperreactivity is signal transducers and activators of transcription (STAT) 6-deficient mice. J Exp Med 187:1537, 1998.

Gonzalo JA, Lloyd CM, Wen D, et al: The co-ordinated action of CC chemokines in the lung orchestrates allergic inflammation and airway hyperresponsiveness. J Exp Med 188:157, 1998.

Gonzalo JA, Lloyd CM, Kremer L, et al: Eosinophil recruitment to the lung in a murine model of allergic inflammation. The role of T cells, chemokines and adhesion receptors. J Clin Invest 98:2332, 1996.

Wardlaw AJ, Dunnette S, Gleich GJ, et al: Eosinophils and mast cells in bronchoalveolar lavage fluid and mild asthma: relationship to bronchial hyperreactivity. Am Rev Respir Dis 137:62, 1988.

Pavord ID, Pizzichini MM, Pizzichini E, Hargreave FE: The use of induced sputum to investigate airway inflammation. Thorax 52:498, 1997.

Azzawi M, Bradley B, Jeffery PK, et al: Identification of activated T lymphocytes and eosinophils in bronchial biopsies in stable atopic asthma. Am Rev Respir Dis 142:1407, 1990.

Hartnell A, Robinson DS, Kay AB, Wardlaw AJ: CD69 is expressed by human eosinophils activated in vivo in asthma and in vitro by cytokines. Immunology 80:281, 1993.

Robinson DS, Hamid Q, Sun Ying: Evidence for a predominant Th2-type bronchoalveolar lavage T lymphocyte population in atopic asthma. N Engl J Med 326:298, 1992.

Jeffery PK, Wardlaw AJ, Nelson FC, Collins JV, Kay AB: Bronchial biopsies in asthma: an ultrastructural, quantitative study and correlation with hyperreactivity. Am Rev Respir Dis 140:1745, 1990.

Bentley AM, Maestrelli P, Saetta M, et al: Activated T lymphocytes and eosinophils in the bronchial mucosa in isocyanate-induced asthma J Allergy Clin Immunol 89:821, 1992.

Bentley AM, Menz G, Storz CHR, et al: Identification of T lymphocytes, macrophages and activated eosinophils in the bronchial mucosa in intrinsic asthma: relationship to symptoms and bronchial responsiveness. Am Rev Respir Dis 146:500, 1992.

Jeffery PK: Structural and inflammatory changes in COPD: a comparison with asthma. Thorax 53:129, 1998.

Allen JN, Davis WB, Pacht ER: Diagnostic significance of increased bronchoalveolar lavage fluid eosinophils. Am Rev Respir Dis 142:642, 1990.

Bousquet J, Chanez P, Lacoste JY, et al: Eosinophilic inflammation in asthma. N Engl J Med 323:1033, 1990.

Diaz P, Galleguillos FR, Gonzales MC, et al: Bronchoalveolar lavage in asthma: the effect of disodium cromoglycate (cromolyn) on leukocyte counts, immunoglobulins and complement. J Allergy Clin Immunol 74:41, 1984.

Schleimer RP, Bochner BS: The effects of glucocorticoids on human eosinophils. J Allergy Clin Immunol 94:1202, 1994.

Juniper EF, Kline PA, Vanzieleghem A, Ramsdale H, O’Byrne PM, Hargreave FE: Effect of long term treatment with an inhaled corticosteroid (budesonide) on airway hyperresponsiveness and clinical asthma in nonsteroid dependent asthmatics. Am Rev Respir Dis 142:832, 1990.

Adelroth E, Rosenhall L, Johansson S, Linden M, Venge P: Inflammatory cells and esoinophilic activity in asthma investigated by bronchoalveolar lavage. The effects of anti-asthmatic treatment with budesonide or terbutaline. Am Rev Respir Dis. 142:91 1990.

Kojima S: Eosinophils in parasitic diseases, in Eosinophils, Biological and Clinical Aspects, edited by S Makino, T Fukuda, pp 391–402. CRC, Boca Raton, FL, 1993.

Spry CJF: Eosinophils, Chap. 10, p 136. Oxford University, Oxford, 1988.

Butterworth AE, Thorne KJI: Eosinophils and parasitic diseases, in Immunopharmacology of Eosinophils, edited by H Smith, RM Cook, p 119. Academic, London, 1993.

Gleich GJ, Adolphson CR: The eosinophil leukocyte: structure and function. Adv Immunol 39: 177, 1986.

Kephart GM, Gleich GJ, Connor DH, et al: Deposition of eosinophil granule major basic protein onto micofilariae of Onchocerca volvulus in the skin of patients treated with diethylcarbamazine. Lab Invest 50:51, 1984.

Hagan P, Wilkins HA, Blumenthal UJ, et al: Eosinophilia and resistance to Schistosoma haematobium in man. Parasite Immunol 7:625, 1985.

Sher A, Coffman RL, Hieny S, Cheever AW: Ablation of eosinophil and IgE responses with anti-IL-5 and anti-IL-4 antibodies fails to affect immunity against Schistosoma mansoni larvae in the mouse. J Immunol 145:3911, 1990.

Dent LA, Daly CM, Mayrhofer G, et al: Interleukin-5 transgenic mice show enhanced resistance to primary infections with Nippostrongylus brasiliensis but not primary infections with Toxocara canis. Infection Immunity 67: 989, 1999.

Limaye AP, Abrams JS, Silver JE, et al: Regulation of parasite-induced eosinophilia: selectively increased interleukin 5 production in helminth-infected patients. J Exp Med 172:399, 1990.

Tanaka J, Torisu M: Ascaris and the eosinophil II: isolation and characterization of eosinophil chemotactic factor and neutrophil chemotactic factor of parasite in Ascaris antigen. J Immunol 122:302, 1979.

Owashi M, Ishii A: Purification and characterization of a high molecular weight eosinophil chemotactic factor from Schistosoma japonicum eggs. J Immunol 129:2226, 1982.

Moqbel R: Allergy and Immunity to Helminths: Common Mechanisms or Divergent Pathways? Taylor and Francis, London, 1992.

Grove DI: What is the relationship between asthma and worms? Allergy 37:139, 1982.

Van Dellen RG, Thompson JH: Absence of intestinal parasites in asthma. N Engl J Med 285:146, 1971

Turton JA: IgE, parasites and allergy. Lancet ii:686, 1976.

Engfeldt B, Zetterstrom R: Disseminated eosinophilic “collagen disease.” Acta Med Scand 153:337:1956.

Hardy WR, Anderson RE: The hyperesoniophilic syndromes. Ann Intern Med 68:1220, 1968.

Resnick M, Myerson RM: Hypereosinophilic syndromes. Am J Med 51:560, 1971.

Weller PF, Bubley GJ: The idiopathic hypereosinophilic syndrome. Blood 83:2759, 1994.

Chang H-W, Leong K-H, Koh D-R, Leen S-H: Clonality of isolated eosinophils in the hypereosinophilic syndrome. Blood 93:1651, 1999.

Luppi M, Marasca R, Morselli M, et al: Clonal nature of hypereosinophilic syndrome. Blood 84:349, 1994.

Raghavachar A, Fleischer S, Frickhoven N: T lymphocyte control of human eosinophil granulopoiesis. J Immunol 139:3753, 1987.

Owen WF, Rothenberg ME, Peterson J, et al: Interleukin 5 and phenotypically altered eosinophils in the blood of patients with the idiopathic hypereosinophilic syndrome. J Exp Med 170:343, 1989.

Cogan E, Shandene L, Crusiaux A, et al: Clonal proliferation of type 2 helper cells in a man with hypereosinophilic syndrome. N Engl J Med 330:535, 1994.

Shah AM, Brutsaert DL, Menlemans AL, et al: Eosinophils from hypereosinophilic patients damage endocardium of isolated feline heart muscle preparations. Circulation 81:1081, 1990.

Olsen EG, Spry CJ: Relations between eosinophilia and endomyocardial disease. Prog Cardiovasc Dis 27:241, 1985.

Chang HW, Leon KH, Koh DR, Lee SH: Clonality of isolated eosinophils in the hypereosinophilic syndrome. Blood 93:1651, 1999.

Parillo JE, Borerts WL, Henry WL, et al: The cardiovascular manifestations of hypereosinophilic syndrome. Am J Med 67:572, 1979.

Schooley RT, Flaum MA, Gralnick HR, Fauci AS: A clinicopathologic correlation of the idiopathic hypereosinophilic syndrome. II: Clinical manifestations. Blood 58:1021, 1981.

Moore PM, Harley JB, Fauci AS: Neurologic dysfunction in the idiopathic hypereosinophilic syndrome. Ann Intern Med 102:109, 1985.

Lin AY, Nutman TB, Kasow D, et al: Familial eosinophilia: clinical and laboratory results on a US Kindred. Am J Med Genet 76:229, 1998.

Rioux JD, Stone VA, Daly MJ, et al: Familial eosinophilia maps to the cytokine gene cluster on human chromosomal region 5q31-q33. Am J Hum Genet 63:1086, 1998.

Villa A, Santagata S, Bozzi F, et al: Partial V9D)J recombination activity leads to Omenn syndrome. Cell 93:885, 1998.

Parillo JE, Fauci AS, Wolff SM: Therapy of the hypereosinophilic syndrome. Ann Intern Med 87:167, 1978.

Smit AJ, Van Essen LH, de Vries EGE: Successful long term control of idiopathic hypereosinophilic syndrome with etoposide. Cancer 67:2820, 1991.

Murphy PT, Fennelly DF, Stuart M, O’Donnell JR: Alpha interferon in a case of hypereosinophilic syndrome. Br J Haematol 75:6189, 1990.

Zielinski RM, Lawrence WD: Interferon-alpha for the hypereosinophilic syndrome. Ann Intern Med 113:716, 1990.

Butterfield JH, Gleich GJ: Interferon-a treatment of six patients with the idiopathic hypereosinophilic syndrome. Ann Intern Med 121:648, 1994.

Nassar GM, Pedro P, Remmers RE, et al: Reversible renal failure in a patient with the hypereosinophilia syndrome during therapy with alpha interferon. Am J Kidney Dis 31:121, 1998.

Ellman L, Miller L, Rappeport J: Leukaphereis therapy of a hypereosinophilic disorder. JAMA 230:1004, 1974.

Esteva-Lorenzo F, Meehan KR, Spitzer TR, Mazumeder A: Allogenic bone marrow transplantation in a patient with hypereosinophilic syndrome. Am J Hematol 51:164, 1996.

Smith MD, Metcalfe M, DeMaria AN, et al: Hypereosinophilic syndrome resulting in aortic and mitral stenosis. A case requiring double valve replacement. Am Heart J 117:475, 1989.

Boustang CW, Murphy GW, Hicks GL Jr: Mitral valve replacement in idiopathic hypereosinophilic syndrome. Ann Thorac Surg 51:1007, 1991.

Edwards D, Wald JA, Dobozen BS, et al: Troleandomycin and methylprednisolone for treatment of the hypereosinophilic syndrome. N Engl J Med 317:573, 1987.

Betran JD, Rowley JD, Plapp F, et al: Chromosomal aneuploidy in a patient with hypereosinophilic syndrome. Am J Med 63:1010, 1977.

Owen J, Scott C: Transition of hypereosinophilic syndrome to myelomonocytic leukemia. Can Med Assoc J 121:1489, 1979.

Prin L, Legeurn M, Ameissen JC, et al: HTLV-1 and malignant hypereosinophilic syndrome. Lancet 2:569, 1988.

Keidan AJ, Catovsky D, DeCastro JT, et al: Hypereosinophilic syndrome preceding T cell lymphblastic lymphoma. Clin Lab Haematol 7:83, 1985.

Eosinophilia-myalgia syndrome—New Mexico. MMWR 38:765, 1989.

Eosinophilia-myalgia syndrome and L-tryptophan containing products—New Mexico, Minnesota, Oregon and New York. MMWR 38: 785, 1989.

Culpepper RC, Williams RG, Mease PJ, et al: Natural history of the eosinophilia-myalgia syndrome. Ann Intern Med 115:437, 1991.

Belonga EA, Mayeno AN, Gleich GJ, et al: An investigation of the cause of the eosinophilia-myalgia syndrome associated with tryptophan use. N Engl J Med 323:357, 1990.

Varga J, Witts J, Jiminez SA: The cause and pathogenesis of the eosinophilia-myalgia syndrome. Ann Intern Med 116:140, 1992.

Belonga EA, Mayeno AN, Gleich GJ, Kita H: Eosinophilia-myalgia syndrome, in Eosinophils, Biological and Clinical Aspects, edited by S Makino, T Fukado, pp 421–440. CRC, Boca Raton, FL, 1993.

Kilbourne EM, Posada de la Paz M, Borda IA, et al: Toxic oil syndrome. J Am Coll Cardiol 18:711, 1991.

Kilbourne EM, Posada de la Paz M, Borda IA, et al: Toxic oil syndrome. J Am Coll Cardiol 18:711, 1991.

Kilbourne EM, Rigau Perez JG, Health CW Jr, et al: Clinical epidemiology of toxic oil syndrome. N Engl J Med 309:1408, 1983.

Spitzer C, Carson OM: Lymphoblastic leukaemia with marked eosinophilia. Blood 42:377, 1973.

Vukelja SJ, Weiss RB, Perry DJ, Longo DL: Eosinophilia associated with adult T-cell leukaemia/lymphoma. Cancer 62:1527, 1988.

Slumgaard A, Ascensao J, Zanjani E, Jacobs HS: Pulmonary carcinoma with eosinophila. N Engl J Med 309:778, 1983.

Stefanini M, Claustro JC, Motos RA, Bendigo LL: Blood and marrow eosinophilia in malignant tumors. Cancer 68:543, 1991.

Pinto A, Aldinucci D, Gloghini A, et al : The role of eosinophils in the pathobiology of Hodgkin’s disease. Ann Oncol 8:(suppl 2) s89, 1997.

Sharp JF, Rodgers MJC, MacGregor FB, et al: Angiolymphoma hyperplasia with eosinophilia. J Laryngol Otol 104:977, 1990.

Hallam LA, MacKinlay GA, Wright AMA: Angiolymphoid hyperplasia with eosinophilia. J Clin Pathol 42:944, 1989.

Nazum JW Jr, Nuzum JW: Polyarteritis nodosa: statisitical review of on one hundred and seventy five cases from the literature and report on one typical case. Arch Intern Med 94:942, 1954.

Lhote F, Guillevin L: Polyarteritis nodosa, microscopic polyangiitis and Churg Strauss syndrome. Sem Resp Crit Care Med 191:27, 1998.

Churg J, Strauss L: Allergic granulomatosis, allergic angiititis and periarteritis nodosa. Am J Pathol 27:277, 1951.

Fauci AS: Vasculitis. J Allergy Clin Immunol 72:211, 1983.

Guillevin L, Guittard T, Bletry O, et al: Systemic necrotizing angiitis with asthma. Causes and precipitating factors in 43 cases. Lung 165:165, 1987.

Guillevin L, Cohen P, Gayraud M, et al: Churg-Strauss syndrome. Clinical study and long term follow up of 96 patients. Medicine (Baltimore) 78:26, 1999.

Abeleles M, Belin DC, Zurier AB: Eosinophilic fasciitis. Arch Intern Med 139:586, 1979.

Lakhanpal S, Ginsburg WW, Michet CJ, et al: Eosinophilic fasciitis: clinical spectrum and therapeutic responses in 52 cases. Semin Arthritis Rheum 17:221, 1988.

Doyle JA, Ginsburg WW: Eosinophilic fasciitis. Med Clin North Am 73:1157, 1989.

Bidula LP, Myers AR: Eosinophilic fasciitis associated with hematologic disorders. Clin Rheumatol Pract 3:117, 1985.

Corwin HL, Bray RA, Haber MH: The detection and interpretation of urinary eosinophils. Arch Pathol Lab Med 113:1256, 1989.

Nolan CR III, Anger MS, Kelleher SP: Eosinophilia—a new method of detection and definition of the clinical spectrum. N Engl J Med 315:1516, 1986.

Bosch I, Oehmichen M: Eosinophilic granulocytes in cerebrospinal fluid specimens and review of the literature. J Neurol 219:93, 1978.

Weingarten JS, O’Shea SF, Margolis WS: Eosinophilic meningitis and the hypereosinophilic syndrome. Am J Med 78:674, 1985.

Calame JJ, Von’t Woret JW, VanDijk JG, Botsgth AM: A case of eosinophilic meningoencephalitis accompanied by eosinophilic inflammation of the myenteric plexus in Hodgkin’s disease. Histopathology 10:535, 1986.

Beeson PB, Bass DA: Mechanisms of Eosinopenia, in The Eosinophil, edited by PB Beeson, DA Bass, p 92. WB Saunders, Philadelphia, 1977.

Bass DA, Gonwa TA, Szejda P, et al: Eosinopenia of acute infection. J Clin Invest 65:1265, 1980.

Juhlin L, Michaelsson G: A new syndrome characterized by absence of eosinophils and basophils. Lancet i:1233, 1977.

Juhlin L, Venge P: Total absence of eosinophils in a patient with chronic urticaria and vitiligo. Eur J Haematol 40:368, 1987.

Telerman A, Amson RB, Delforge A, et al: A case of chronic aneosinocytosis. Am J Hematol 12:187, 1982.

Nakahata T, Spicer SS, Leary AG, et al: Circulating eosinophil colony-forming cells in pure eosinophil aplasia. Ann Intern Med 101:321, 1984.

Joshua H, Zucker A, Presentey B: Peroxidase and phospholipid deficiency in eosinophilic granulocytes among Arabs of the Nazareth district. Isr J Med Sci 12:71, 1976.

Brugnoni D, Airò P, Rossi G, et al: A case of hypereosinophilic syndrome is associated with the expansion of a CD3–CD4+ T-cell population able to secrete large amounts of interleukin-5. Blood 87:1416, 1996.

Roufosse F, Schandené L, Sibille C, et al: T-cell receptor-independent activation of clonal Th2 cells associated with chronic hypereosinophilia. Blood 94:994, 1999.

Ueno NT, Zhaos S, Robertson LE, et al: 2-chlorodeoxyadenosine therapy for idiopathic hypereosinophilic syndrome. Leukemia 11:1386, 1997.

Teroya-Feldstein J, Jaffe ES, Burd PR, et al: Differential chemokine expression in tissues involved by Hodgkin’s disease: Direct correlation of eotaxin expression and tissue eosinophilia. Blood 93:2463, 1999.
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Ernest Beutler, Marshall A. Lichtman, Barry S. Coller, Thomas J. Kipps, and Uri Seligsohn
Williams Hematology



  1. […] CHAPTER 68 EOSINOPHILS AND THEIR DISORDERS | Free … Chapter References. As a result of their potential role in asthma, eosinophils have received considerable attention from the research community in the last decade. The concept of the eosinophil as a cell that has protective effects against helminthic parasite infection but can cause tissue damage when . Except for one study in the Gambia,175 there is no obvious correlation between the degree of eosinophilia and protection against infection or reinfection. Moreover . […]

  2. […] CHAPTER 68 EOSINOPHILS AND THEIR DISORDERS | Free … Synthesis and Release of Eosinophil Mediators. Lipid Mediators. Eosinophil Granule Proteins. Cytokines. Other Eosinophil-Derived Mediators Eosinophil Secretion and Activation. Eosinophil Survival and Apoptosis . and IL-5 are expressed by Th2 but not Th1 lymphocytes.18 The receptors for IL-3, IL-5, and GM-CSF are structurally similar.19 They consist of homologous a chains that bind their respective cytokines with low affinity, with a kD of approximately 10/nM. […]

  3. 90. Månsson A, Fransson M, Adner M, et al. TLR3 in human eosinophils: functional effects and decreased expression during allergic rhinitis. Int Arch Allergy Immunol 2010;151:118–28.

  4. cells) secrete eosinophil-activating cytokines, including IL-5, which promote local survival and degranulation of eosinophils.

  5. cells) secrete eosinophil-activating cytokines, including IL-5, which promote local survival and degranulation of eosinophils.

  6. with 16% eosinophils on peripheral smear. Electrolytes and liver and renal functions were all normal. With further investigation diminished levels of immunoglobulin G, total protein and albumin were noted. The total IgG was 341 mg/dl (normal 613–1295 mg/dl), total protein was 5.0 g/dl (normal 6–8 g/dl) and albumin 3.1 g/dl (normal 3.2–5.0 g/dl). Pnemococcal vaccination responses were normal suggesting that the IgG deficiency did not result in a functional antibody defect as would be seen in common variable immune deficiency. The serum C3, C4, CH-50, and C-1 esterase were within normal limits. Serum amylase and lipase levels were in the normal ranges. Urine analysis showed no proteinuria or active sediment. The following tests were either negative or normal: ESR, ANA, anti-Ro, anti-La, SCL-70, rheumatoid factor, p-ANCA, and anti-myeloperoxidase antibodies. Stool studies and serum serology are listed in Table ​Table1.1 . Allergy skin testing was negative for a panel of commonly eaten foods. Given the gastrointestinal symptoms, an upper GI series was also carried out. It showed evidence of a small hiatal hernia and reflux. Echocardiogram showed no evidence of systolic dysfunction or restrictive cardiomyopathy, a feature of some hypereosinophilic syndromes. Pulmonary function tests displayed a minimal obstructive lung defect with normal diffusion capacity. Computerized tomography of the head (carried out because of the vomiting) was negative for space occupying lesions.


  8. […] CHAPTER 68 EOSINOPHILS AND THEIR DISORDERS | Free … Comments Off […]

  9. […] of an influx of inflammatory cells, including large numbers of eosinophils, thereby mimicking the Pathology Of Asthma.145 Twenty-four hours after antigen challenge administered through a bronchoscope, up to 50 percent […]


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