Key Points
-
Eosinophils have been traditionally perceived as terminally differentiated cytotoxic effector cells. Recent studies have provided a more sophisticated understanding of eosinophil effector functions and a more nuanced view of their contributions to the pathogenesis of various diseases, including asthma and respiratory allergies, eosinophilic gastrointestinal diseases, hypereosinophilic syndromes and parasitic infection.
-
Eosinophils are granulocytes that develop in the bone marrow from pluripotent progenitors in response to cytokines, such as interleukin-5 (IL-5), IL-3 and granulocyte–macrophage colony-stimulating factor (GM-CSF). Mature eosinophils are released into the peripheral blood and enter tissues in response to cooperative signalling between IL-5 and eotaxin family chemokines.
-
Eosinophils in peripheral blood and tissues are uniquely identified by their bilobed nuclei, their large specific granules that store cytokines, cationic proteins and enzymes, and their expression of the IL-5 receptor and CC-chemokine receptor 3 (CCR3). In addition, the receptors sialic acid-binding immunoglobulin-like lectin 8 (SIGLEC-8) and SIGLEC-F are expressed by human and mouse eosinophils, respectively.
-
IL-5 has a central and profound role in all aspects of eosinophil development, activation and survival. IL-5 is produced by T helper 2 (TH2) cells, and more recently the contributions of the epithelium-derived innate cytokines thymic stromal lymphopoietin (TSLP), IL-25 and IL-33 in promoting eosinophilia via the induction of IL-5 have also been recognized.
-
Although eosinophil responses are influenced by cytokines produced by T cells, eosinophils in turn modulate the functions of B and T cells. Eosinophils also communicate with a range of innate immune cells (such as mast cells, dendritic cells, macrophages and neutrophils). Eosinophils serve to bridge innate and adaptive immunity by regulating the production of chemoattractants and cytokines (including CC-chemokine ligand 17 (CCL17), CCL22, a proliferation-inducing ligand (APRIL) and IL-6) and via antigen presentation.
-
Both successful and unsuccessful attempts to target eosinophils have yielded remarkable insights into their contribution to disease pathogenesis. Many eosinophil-associated inflammatory conditions have been shown to be heterogeneous in nature. As such, successful therapeutic strategies will depend on the correlation of disease activity with dysregulated eosinophil function as well as the identification of the crucial molecules that regulate eosinophil accumulation in the affected tissues.
Abstract
Eosinophils have been traditionally perceived as terminally differentiated cytotoxic effector cells. Recent studies have profoundly altered this simplistic view of eosinophils and their function. New insights into the molecular pathways that control the development, trafficking and degranulation of eosinophils have improved our understanding of the immunomodulatory functions of these cells and their roles in promoting homeostasis. Likewise, recent developments have generated a more sophisticated view of how eosinophils contribute to the pathogenesis of different diseases, including asthma and primary hypereosinophilic syndromes, and have also provided us with a more complete appreciation of the activities of these cells during parasitic infection.
Similar content being viewed by others
Main
Eosinophils were first described in 1879 by Paul Ehrlich, who noted their unusual capacity to be stained by acidophilic dyes. Interestingly, our appreciation of this unique property of eosinophils is clear and steadfast, but a comprehensive understanding of the function of these cells in health and disease remains elusive. Some basic characteristics of eosinophils are established and accepted. It is clear that eosinophils are granulocytes that develop in the bone marrow from pluripotent progenitors. They are released into the peripheral blood in a phenotypically mature state, and they are capable of being activated and recruited into tissues in response to appropriate stimuli, most notably the cytokine interleukin-5 (IL-5) and the eotaxin chemokines. Eosinophils spend only a brief time in the peripheral blood (they have a half-life of ∼18 hrs)1 before they migrate to the thymus or gastrointestinal tract, where they reside under homeostatic conditions2. In response to inflammatory stimuli, eosinophils develop from committed bone marrow progenitors, after which they exit the bone marrow, migrate into the blood and subsequently accumulate in peripheral tissues, where their survival is prolonged (reviewed in REFS 3, 4, 5).
However, much remains unclear. For example, the long-held belief that eosinophils promote immunity to helminths has been called into question by results from animal studies, some of which suggest that eosinophils may be serving to promote the needs and longevity of specific parasites6,7. Likewise, eosinophils are clearly recruited to and activated in lung tissue as part of the pathophysiology of asthma, and most current evidence suggests that eosinophils contribute to airway dysfunction and tissue remodelling in this disorder8,9. Evolution tells us that the ability to induce pathology cannot be a 'raison d'être' for any existing cell lineage, and recent findings on the antimicrobial and antiviral activities of eosinophils suggest that the pathology that arises from dysregulated eosinophilia in the airways may be collateral damage related to host defence. Similarly, although there are now two unique eosinophil-deficient mouse strains10,11, there are no known unique eosinophil-deficiency states in humans to help us to decipher the importance of these cells in vivo.
This Review examines the most recent advances in our understanding of the contributions of eosinophils to the maintenance of health, and how dysregulated eosinophil function promotes various disease states. These advances were made possible by reagents, systems and methods that target eosinophil function and by the first clinical trials using humanized monoclonal antibodies specific for IL-5 (Table 1). These tools have been invaluable for shaping our current views on eosinophil function and for generating new hypotheses for future examination.
The unique biology of the eosinophil
Relatively few mature eosinophils are found in the peripheral blood of healthy humans (less than 400 per mm3), but these cells can be readily distinguished from the more prevalent neutrophils by virtue of their bilobed nuclei and large specific granules (Fig. 1). Human eosinophil granules contain four major proteins: eosinophil peroxidase, major basic protein (MBP) and the ribonucleases eosinophil cationic protein (ECP) and eosinophil-derived neurotoxin (EDN). The granules also store numerous cytokines, enzymes and growth factors. Other prominent features of eosinophils include primary granules that contain Charcot–Leyden crystal protein (also known as galectin 10 and eosinophil lysophospholipase) and lipid bodies, which are the sites of synthesis of cysteinyl leukotrienes, thromboxane and prostaglandins.
Eosinophils have been identified and characterized in all vertebrate species, but their morphology, repertoire of cell-surface receptors and intracellular contents vary significantly between species. Of particular note, there are several crucial differences between mouse and human eosinophils that must be taken into account when interpreting mouse model studies of human disease12 (Fig. 1).
Eosinophils express surface receptors for ligands that support growth, adhesion, chemotaxis, degranulation and cell-to-cell interactions (Fig. 2). Many of the signalling pathways involved in these responses have been detailed in recent reviews3,4,13. Among the main receptors that define the unique biology of the eosinophil are interleukin-5 receptor subunit-α (IL-5Rα) and CC-chemokine receptor 3 (CCR3), as well as sialic acid-binding immunoglobulin-like lectin 8 (SIGLEC-8) in humans and SIGLEC-F (also known as SIGLEC-5) in mice. Pattern-recognition receptors (PRRs) are also likely to be important for eosinophil function, a subject that remains to be fully explored (Box 1).
Factors that promote eosinophilia
IL-5 has a central and profound role in all aspects of eosinophil development, activation and survival (Box 2). Likewise, CC-chemokine ligand 11 (CCL11; also known as eotaxin), which is a ligand for CCR3, promotes eosinophilia both cooperatively with IL-5 and via IL-5-independent mechanisms14,15. Recently, several new factors that promote eosinophilic inflammation in vivo have been identified.
The epithelial cell-derived cytokines thymic stromal lymphopoietin (TSLP), IL-25 (also known as IL-17E) and IL-33 promote eosinophilia by inducing IL-5 production. TSLP is an IL-2 family cytokine that signals through a heterodimeric receptor that comprises the IL-7 receptor α-chain and a specific TSLP receptor β-chain. The TSLP receptor is expressed widely, by myeloid dendritic cells (DCs), CD4+ and CD8+ T cells, B cells, mast cells and airway epithelial cells. The TSLP receptor is also expressed by human eosinophils and modulates their survival and activation16.
IL-25 is produced primarily by activated T helper 2 (TH2) cells and mast cells and induces the production of TH2-type cytokines (including IL-5) from TH2 cells, as well as from the newly described populations of mouse innate lymphoid cells, which include nuocytes and natural helper cells17,18,19. In this manner, IL-25 can amplify the development, recruitment and survival of eosinophils in allergic states. Abundant expression of both IL-25 and the IL-25 receptor was also detected in a recent study of bronchial and skin biopsies from allergic human subjects20, and eosinophils themselves were identified as the primary source of IL-25 in patients with severe systemic vasculitis (Churg–Strauss syndrome)21.
IL-33 — which is a member of the IL-1 cytokine family — is expressed by epithelial cells, endothelial cells, fibroblasts and adipocytes, and is an endogenous danger signal known as an alarmin. IL-33 specifically modulates TH2-type pro-inflammatory signals following its release from necrotic cells. The IL-33 receptor ST2 (also known as IL-1RL1) is found primarily on TH2 cells, but IL-33-dependent responses from mouse nuocytes, natural helper cells and innate type 2 helper cells, and in human eosinophils themselves, have been described22,23,24. Furthermore, an IL-33- and IL-25-responsive innate lymphoid cell population has recently been defined in humans25. Although the biology of this cytokine has not been fully elucidated, IL-33 typically contributes to the synthesis and release of IL-5 from one or more of the aforementioned target cells, and thereby promotes systemic eosinophilia.
IL-23 is a member of the IL-12 family of cytokines that promotes the function of TH17 cells and also regulates allergic airway inflammation. Silencing the expression of IL-23 in mice that were sensitized and challenged with ovalbumin resulted in decreased recruitment of eosinophils to the lung tissue in association with diminished levels of IL-17 and IL-4 (Ref. 26). Accordingly, the overexpression of IL-23 was shown to augment antigen-stimulated eosinophil recruitment27. However, another study found that IL-23 suppressed eosinophilia in a mouse model of fungal infection, a response that was IL-17 independent28.
High-mobility group protein B1 (HMGB1) is another example of an alarmin that promotes eosinophilia. However, in contrast to IL-33, there is no evidence that eosinophil activation in response to HMGB1 involves IL-5. First identified as a nuclear protein and transcription factor, HMGB1 is expressed ubiquitously and mediates inflammatory responses via its receptors. The HMGB1 receptors that have been identified so far are receptor for advanced glycation end-products (RAGE), Toll-like receptor 2 (TLR2) and TLR4. Importantly, eosinophil mobilization and activation were observed in response to HMGB1 in tumour cell lysates29. Further work is needed in this area, as a better appreciation of the way in which eosinophils are activated in response to HMGB1 and other, related damage-associated molecular patterns (DAMPs) may explain the eosinophil recruitment that is observed in the setting of tissue destruction associated with myalgias and myopathies.
Eosinophil degranulation
Degranulation — that is, the release of granule contents into the extracellular space — is a prominent eosinophil function. Previously, the release of secretory mediators was assumed to take place primarily through cytolytic degranulation, a mechanism through which a pathogenic assault (real or perceived) results in the complete emptying of the eosinophil's arsenal of preformed cationic proteins. Interestingly, a careful analysis of electron micrographs of eosinophils degranulating in tissues suggested a more controlled process, which was given the name 'piecemeal degranulation'30 to reflect the fact that the eosinophil was able to release bits or pieces of its granule contents in response to a given stimulus, while remaining otherwise intact and apparently viable. Piecemeal degranulation is now accepted as the most commonly observed physiological form of eosinophil degranulation. Eosinophils undergoing piecemeal degranulation in response to cytokines, such as interferon-γ (IFNγ) and CCL11, develop cytoplasmic secretory vesicles, known as eosinophil sombrero vesicles31 (Fig. 2), and remain viable and fully responsive to subsequent stimuli.
A recent study has provided substantial insights into the molecular mechanism of piecemeal degranulation32. Specifically, IL-4 released from CCL11-activated eosinophils first forms a complex with IL-4 receptor subunit-α (IL-4Rα) within the granule membrane, and IL-4Rα thereby chaperones IL-4 to the membrane vesicles before its release from the cell. Although receptor-mediated trafficking pathways have not yet been defined for other eosinophil mediators33, this study provides an insight into the potential for exquisite molecular modulation of piecemeal degranulation32.
Eosinophils also release intact granules, which are capable of storing and releasing mediators in response to physiological secretagogues in the cell-free state34. Cell-free granules have been identified in tissues in association with eosinophil-associated disorders35, although their functional significance and their ability to respond to activating stimuli in situ await further evaluation.
Interactions of eosinophils with other leukocytes
During their transit from the bloodstream to the tissue, eosinophils use selectins and integrins to interact with endothelial cells, and they interact with epithelial cells at mucosal surfaces in a similar manner; these subjects have been reviewed extensively36. Eosinophils also interact with and modulate the functions of other leukocytes (Fig. 3).
Interaction with lymphocytes. Eosinophils clearly respond to signals (such as IL-5) that are provided by T cells. Two recent studies indicate that T cells also respond to signals provided by eosinophils37,38. Although not 'professional' antigen-presenting cells, eosinophils can express cell-surface components that are required for antigen presentation (such as MHC class II molecules and the co-stimulatory molecules CD80 and CD86). Indeed, eosinophils can process antigens and stimulate T cells in an antigen-specific manner, resulting in T cell proliferation and cytokine release39. Furthermore, in experiments performed in both wild-type mice and transgenic mice that lack eosinophils (TgPHIL mice), eosinophils can augment allergic inflammation by regulating the production of TH2-type chemoattractants (including CCL17 and CCL22), which promote the recruitment of TH2 cells, and also through their interactions with DCs40,41. In addition, eosinophils release preformed cytokines (such as IL-4, IL-13 and IFNγ) that promote either TH2 or TH1 cell responses42.
Eosinophils also promote humoral immune responses. Indeed, they are capable of priming B cells for the production of antigen-specific IgM43. Most recently, the production of a proliferation-inducing ligand (APRIL) and IL-6 by eosinophils was shown to be crucial for the support of long-lived plasma cells in mouse bone marrow44. Interestingly, activated eosinophils from the bone marrow of adjuvant-immunized mice were found to be even more effective at supporting plasma cell survival than those from adjuvant-naive mice45.
Interactions with innate immune cells.Alternatively activated macrophages have a pivotal role in recruiting eosinophils to the tissues46,47 through the release of YM1 (also known as CHI3L3), a chitinase-like selective eosinophil chemoattractant48,49. Eosinophils likewise recruit alternatively activated macrophages to, and maintain their viability in, adipose tissue50, promote the maturation of monocyte-derived DCs in vitro51, and are required for the accumulation of myeloid DCs and the systemic production of TH2-type cytokines in mice with allergic airway disease. The eosinophil secretory mediator EDN promotes the activation and migration of DCs52,53.
Eosinophils communicate extensively with tissue-resident mast cells. Eosinophils and mast cells are found in close proximity to one another under homeostatic conditions in the gut, and they also colocalize in the allergic lung and in the inflamed gut in patients with Crohn's disease54. The bidirectional signalling that occurs between eosinophils and mast cells involves several immunomodulatory mediators. These include stem cell factor (also known as KIT ligand), granule proteins, cytokines (such as granulocyte–macrophage colony-stimulating factor (GM-CSF), IL-3, IL-5 and tumour necrosis factor (TNF)), nerve growth factor and mast cell proteases. Actual physical coupling of eosinophils and mast cells has been observed both in vitro and in vivo, and this interaction prolongs eosinophil survival54.
Eosinophil responses to pathogens and parasites
Eosinophils and helminths: who wins? The historic view that eosinophils promote host defence against helminths arose largely from histological images of eosinophils and parasites in tissue specimens and from in vitro studies that documented the antiparasitic activities of the eosinophil granule proteins MBP and ECP. With the development of reagents that block eosinophilia in mice (such as IL-5-specific antibodies) and of IL-5- or eosinophil-deficient mice, the picture has become more complex. For instance, the helminth Schistosoma mansoni, although not a natural mouse pathogen, can infect wild-type mice and can elicit a profound TH2-type cytokine-mediated pathology and cause the accumulation of eosinophils in tissues55. Although the eosinophil granule proteins ECP and MBP are toxic to both schistosomules and the larvae of S. mansoni, the manipulation of eosinophils in mouse models had no significant impact on disease development during S. mansoni infection56,57. However, in Strongyloides stercoralis and Angiostrongylus cantonensis infection models, eosinophil depletion resulted in prolonged survival of tissue-based larval forms of the parasites58,59. Thus, the role of eosinophils in mouse models of helminth infection remains unclear and controversial.
The interaction of eosinophils and helminths during infection in human subjects has been examined using a genomics approach60. The 434G>C polymorphism in the gene encoding ECP results in substitution of the cationic amino acid arginine for the neutral amino acid threonine at position 97. The genotype 434CC — which encodes the more neutral and somewhat less cytotoxic form of ECP — is found commonly among Ugandans, who live in a region endemic for S. mansoni infection. By contrast, the 434CC genotype is quite rare in Sudan, where S. mansoni is not endemic. Although this result suggests that there is no selective advantage for those individuals whose eosinophils might provide stronger antischistosomal host defence, the authors of this study determined that individuals with the 434CC genotype developed substantially less liver fibrosis secondary to S. mansoni infection. As such, the selective advantage may be for those individuals whose eosinophils promote less collateral tissue damage when faced with a similar pathogen burden. Similarly, cerebral malaria, a severe outcome of infection with Plasmodium falciparum, is also associated with eosinophilia and elevated serum levels of ECP. The haplotype strongly associated with susceptibility to severe disease encodes arginine at position 97 and thus the more cationic form of ECP61. The explanation of this finding awaits further clarification of the role of eosinophils in cerebral malaria.
The most recent developments in this field have exploited current concepts of eosinophils as immunomodulatory cells. In wild-type mice, infection with Trichinella spiralis induces eosinophil recruitment to the infected tissues and the formation of nurse cells in skeletal muscle. In eosinophil-deficient ΔdblGATA and TgPHIL mice, T. spiralis larvae do not survive, largely owing to the diminished recruitment of TH2 cells and a concomitant increase in the activity of inducible nitric oxide synthase (iNOS) and the synthesis of nitric oxide in local macrophages6,7. One interpretation of these results is that the parasites recruit eosinophils to support their own persistence and survival; another possibility is that eosinophils are recruited to maintain homeostatic balance by limiting the development of TH1-type immune responses that lead to oxidative damage and tissue destruction. How the parasite elicits this response and whether this finding is unique to Trichinella species are important subjects for future consideration. In addition, it will be interesting to address whether the mechanisms by which T. spiralis recruits eosinophils to muscle tissue, the activation state of the eosinophils at this site and the mediators released in situ are similar to those involved in eosinophilic inflammatory myopathies.
Eosinophils and bacteria: pathogens, probiotics and the microbiome. Early experiments carried out in vitro documented the bactericidal properties of the cationic eosinophil granule proteins MBP and ECP62,63. Subsequent studies exploring the mechanisms involved showed that ECP has a specific affinity for bacterial lipopolysaccharide and peptidoglycan and can agglutinate Gram-negative bacterial pathogens64. More recently, in vivo studies of the interaction of eosinophils with bacteria documented the catapult-like release of structures resembling neutrophil extracellular traps (NETs) from eosinophils, and this was associated with protection from the lethal sequelae of caecal ligation65. In contrast to NETs, which are composed primarily of nuclear DNA and neutrophil-specific proteins, eosinophil NET-like structures are composed of mitochondrial DNA, MBP and ECP66. Whether eosinophils and their secretory mediators have physiological bactericidal functions in vivo requires further study. Although eosinophil-enriched IL-5-transgenic mice were protected from the lethal sequelae of Pseudomonas aeruginosa infection67, recent findings suggest that IL-5-mediated protection during bacterial sepsis might be mediated by cells other than eosinophils68.
Recently, tremendous interest has developed regarding the immunomodulatory impact of probiotic or health-promoting bacteria. Although the mechanisms remain uncertain, oral administration of live probiotic Lactobacillus or Bifidobacterium species suppressed eosinophil recruitment in mouse models of allergic airway disease69,70. However, the therapeutic impact of probiotics in human studies of allergic disease has been less impressive. Indeed, in a recent prospective study in which allergic children were provided with oral supplementation with Lactobacillus rhamnosus GG or a placebo control, no significant differences were recorded in the number of asthma exacerbations per year, the number of days on medication, the peripheral blood eosinophil count or the serum ECP levels71.
In parallel, the interactions between commensal bacteria and tissue-resident eosinophils in the intestine have been the subject of recent investigations. Mice raised under germ-free conditions exhibited exaggerated eosinophilia in a model of allergic airway inflammation; this phenotype was reversed when the gastrointestinal tract was colonized with normal microflora72. Likewise, a large prospective study involving over 400 healthy infants73 concluded that individuals with greater bacterial diversity in the gastrointestinal tract had a lower risk of developing allergic sensitization later in life.
Eosinophils and viruses. Human respiratory viruses — such as influenza virus, parainfluenza virus, respiratory syncytial virus (RSV), coronaviruses and, most prominently, rhinoviruses — are among the most common causes of asthma exacerbation. Although asthma typically involves dysregulated eosinophil recruitment, and eosinophils are generally perceived as promoting disease pathology in this setting, the outcome of eosinophil–virus interactions has not been fully explored. A recent concept to emerge is that eosinophils and their secretory mediators may have a role in promoting antiviral host defence. An initial study showed that eosinophil secretory mediators decrease the ability of RSV to infect target host epithelial cells74. This was followed by a later report75 that found that eosinophils that were induced by allergen sensitization decreased viral loads during parainfluenza virus infection in a guinea pig asthma model. Accelerated clearance of RSV has been demonstrated in the lungs of eosinophil-enriched Cd2-IL-5-transgenic mice (which overexpress IL-5 under the control of the Cd2 promoter)76, and activated eosinophils protect mice from the lethal sequelae of acute pneumovirus infection (C. Percopo, K.D.D., S. Ochkur, J. Lee, J. Domachowske and H.F.R., unpublished observations). Moreover, both human and mouse eosinophils release immunomodulatory mediators, notably IL-6, in response to infection with respiratory virus pathogens77,78.
Hypereosinophilia is a frequent finding in late-stage HIV infection, typically in association with allergic and/or immune dysfunction and low CD4+ T cell counts79. Furthermore, one study documented large numbers of CD8+CD30+ T cell clones expressing TH2-type cytokines (including IL-5) in HIV-positive donors80, although another did not confirm this finding81. Interestingly, the granule protein EDN has been shown to have HIV-inhibitory activity82. However, the precise mechanisms by which eosinophils and their secretory mediators interact with viral pathogens remain to be elucidated.
Eosinophils and disease
There is extensive literature on eosinophil dysregulation associated with diseases such as asthma and eosinophilic oesophagitis. Although we know a substantial amount regarding how eosinophils develop and how they are recruited into various organs and tissues, there is a lack of understanding regarding the roles of eosinophils in eosinophil-associated diseases — even the relatively common ones. Targeting eosinophils therapeutically has revealed the complex and heterogeneous nature of eosinophil-associated diseases. We have selected the examples that follow to illustrate these principles; a more extensive list of diseases associated with eosinophilia is included in Supplementary information S1 (table) (see also Ref. 83).
Eosinophils and asthma. Asthma is a chronic inflammatory disease that is characterized by reversible airway obstruction and airway hyperreactivity in response to nonspecific spasmogenic stimuli. Eosinophils are a common feature of the inflammatory response that occurs in asthma, as they are recruited to the lungs and airways by cytokines that are released from activated TH2 cells and by a range of chemokines, most notably those of the eotaxin family.
A role for eosinophils in promoting the pathogenesis of some forms of asthma is supported by a large body of literature, primarily from studies of acute and chronic allergen-challenged mouse models of allergic airway disease84,85. Antigen sensitization and challenge, typically with ovalbumin or Aspergillus species, induces an allergic airway disease that replicates many of the hallmark features of allergic asthma, including increased numbers of cytokine-secreting TH2 cells and eosinophils in the airways, mucus hypersecretion and airway hyperreactivity. Chronic exposure to these antigens results in features of airway remodelling, including fibrosis and thickening of the basement membrane. Collectively, these studies suggest that targeting eosinophils themselves, eosinophil migration and/or eosinophilopoiesis should provide therapeutic benefit for the treatment of asthma.
These findings ultimately led to the development of two humanized IL-5-specific monoclonal antibodies, mepolizumab and reslizumab, which block the binding of IL-5 to IL-5Rα. In two of the earliest studies86,87, mepolizumab was administered to patients with mild atopic asthma and to healthy volunteers. In response, eosinophil numbers in the bronchial mucosa decreased by 50%, an observation that correlated with reduced levels of the prominent pro-fibrotic eosinophil secretory cytokine, transforming growth factor-β1 (TGFβ1), and with diminished deposition of extracellular matrix proteins. Similarly, another study showed that mepolizumab suppressed eosinophil maturation in the bone marrow and resulted in fewer CD34+IL-5Rα+ eosinophil progenitors in the lungs87.
In initial clinical trials, small cohorts of patients with mild or moderate asthma were treated with mepolizumab or reslizumab, respectively88,89. Both monoclonal antibodies were well tolerated by patients, and both reduced eosinophil numbers in the blood and airways. However, no objective measures of clinical improvement emerged (Box 3).
In part owing to the results from these clinical trials, the complex nature of the inflammatory response in asthma has been revisited90,91. Four distinct phenotypes based on the inflammatory cell profile in induced sputum have been introduced (Box 3) and, likewise, categories of asthma endogenous phenotypes (referred to as endotypes) based on molecular mechanisms and environmental influences have been defined. In subsequent studies, the therapeutic potential of IL-5-specific monoclonal antibodies was explored in a subset of asthmatics who were steroid dependent and had persistent sputum eosinophilia91,92,93,94,95. In these trials, the numbers of eosinophils in sputum fell to almost zero, a finding that correlated with decreased frequencies of exacerbations, a steroid-sparing effect, improved lung function and long-term improvements in asthma control.
These studies highlight the heterogeneous nature of asthma90,91 and, most importantly, define a clinical phenotype — known as steroid-resistant eosinophilic asthma — in which eosinophils make a clear and direct contribution to current disease and its management. New approaches that target eosinophils directly, such as the cytotoxic IL-5Rα-specific monoclonal antibody benralizumab, or indirectly, such as the IL-13-specific monoclonal antibody lebrikizumab, may further enhance therapeutic outcomes96,97.
Eosinophilic oesophagitis. Eosinophils are normally found in the gastrointestinal tract, notably in the caecum, but not in the oesophagus. First described by Landres and colleagues in 1978, eosinophilic oesophagitis is the most common of the eosinophil-associated gastrointestinal diseases. In 2007, an international consortium — the First International Gastrointestinal Eosinophil Research Symposium (FIGERS) — published consensus guidelines for diagnosis, which were revised in 2011. These criteria include: clinical evidence of oesophageal dysfunction (including dysphagia, abdominal pain and/or food bolus impaction); 2–4 biopsy samples from the proximal and distal oesophagus with ≥15 eosinophils per field at ×400 magnification; and no response to 6–8 weeks of high-dose proton-pump inhibitor therapy, ruling out gastro-oesophageal reflux disease. As we focus here on eosinophil-mediated mechanisms, we refer readers to a recent review on the complete natural history of eosinophilic oesophagitis98.
All evidence points to dysregulated eosinophilia as being central to the pathophysiology of eosinophilic oesophagitis. The aetiology appears to be dependent on the TH2-type cytokines IL-5 and IL-13. Patients often report concurrent allergic responses to food and airborne allergens, along with a family history of allergy, and there is an unexplained male predominance. Although absolute eosinophil numbers in biopsy samples at any given time may or may not correlate directly with disease severity, evidence of eosinophil activation — including the presence of extracellular granules and degranulated cationic proteins (such as MBP) — is prominent in tissue biopsy samples99. The eosinophil chemoattractant CCL26 (also known as eotaxin 3) is a prominent biomarker of eosinophilic oesophagitis. Indeed, CCL26 is highly upregulated in diseased tissues and also in peripheral blood cells in patients with this disorder. A single-nucleotide polymorphism (2,496T>G) in the 3′ untranslated region of the gene encoding CCL26 has been associated with increased susceptibility to eosinophilic oesophagitis, although the mechanisms involved are not yet known100. Susceptibility to eosinophilic oesophagitis has also been correlated with polymorphisms in the gene encoding TSLP101.
There are several mouse models of eosinophilic oesophagitis. Some of these models use oral or intranasal delivery of allergens to elicit tissue pathology, and others promote eosinophil recruitment to the oesophagus via the overexpression of IL-5 or IL-13. Among these models, one uses repeated intranasal delivery of fungal or insect aeroallergens102,103, which induces the expression of TH2-type cytokines and the eotaxin family member CCL11 (mice do not express CCL26), resulting in eosinophil recruitment to the oesophagus. Another mouse model involves systemic sensitization with ovalbumin in aluminium hydroxide adjuvant followed by repeated intra-oesophageal challenge104, which induces eosinophil recruitment associated with angiogenesis, basal zone hyperplasia and tissue fibrosis. Interestingly, although the administration of eosinophil-depleting SIGLEC-F-specific antibodies to these mice inhibits eosinophil recruitment and the associated tissue remodelling104, in another investigation, in which oesophageal remodelling was driven by lung-specific expression IL-13, no role for eosinophils was observed105. Similarly, ablation of CD4+ T cells — which presumably leads to a reduction in the levels of TH2-type cytokines — has only a limited impact on the recruitment of eosinophils to the oesophagus after chronic administration of Aspergillus species antigens102. Among the issues to be addressed in future studies is the role of eosinophil degranulation into the oesophageal tissue in these mouse models. Furthermore, mouse models that incorporate relevant clinical symptoms, such as failure to thrive, would certainly be of significant value.
Current therapies for patients with eosinophilic oesophagitis include the introduction of an elemental diet and treatment with steroids, which target the global inflammatory response and have an impact on eosinophil-derived cytokines106. Therapies that specifically target eosinophils are also being tested. For example, a randomized placebo-controlled double-blind trial in which adults with eosinophilic oesophagitis were treated with a humanized IL-5-specific monoclonal antibody (mepolizumab) resulted in a reduction in oesophageal inflammation and the reversal of tissue remodelling, but only minimal relief of symptoms107. Similar results were obtained in a prospective study in children, with clinical improvement observed in both experimental and placebo groups108. Interestingly, mepolizumab did not deplete eosinophils found in the duodenal mucosa of these patients109. However, the aforementioned studies suggest that this disorder may be primarily regulated by CCL26. As with asthma, the stratification of patients into subgroups that respond to specific therapies may ultimately improve clinical outcomes.
Eosinophilic myopathies. These conditions are among the most rare and poorly characterized of the eosinophil-related disorders, and include eosinophilic fasciitis (also known as Shulman's syndrome), toxic oil syndrome and eosinophilia–myalgia syndrome110 (Box 4). Although eosinophils are associated with these conditions, it is not clear how they are recruited to the affected tissue or what their contributions are to the pathology observed.
Eosinophilic myositis is a relatively rare condition in which the infiltration of muscle tissue by eosinophils is observed, sometimes in association with peripheral blood and bone marrow eosinophilia. The disease can result from helminth infection, or it can be toxin induced or idiopathic in nature. Recently, specific mutations in the gene encoding calpain 3 were identified in association with idiopathic eosinophilic myositis111. Calpain 3 is a muscle-specific neutral cysteine protease that interacts with intracellular myofibrillar proteins and has a role in sarcomere adaptation. However, there is no direct or obvious relationship between the actions of this enzyme and eosinophils or eosinophilia. It is not clear why mutations in calpain 3 result in signals that elicit eosinophil accumulation, what these signals might be, whether eosinophils are a primary or indirect target, and whether eosinophils are promoting tissue damage or altering the local immune status. One possibility is that inflamed, damaged muscle tissue releases endogenous alarmins (such as IL-33 and/or HMGB1) that activate innate immune signalling pathways that lead to peripheral blood and tissue eosinophilia. Of note, limb-girdle muscular dystrophy type 2A, which is a common autosomal recessive form of muscular dystrophy, has also been directly linked to mutations in the gene encoding calpain 3. Although eosinophils do not have a prominent role in this disorder, transient eosinophilia has been reported in the early stages of the disease. Similarly, no infiltration of eosinophils into muscle tissue was reported in calpain 3-deficient mice112, although this observation should be reassessed in other mouse strains.
Hypereosinophilic syndromes. Hypereosinophilic syndromes are disorders of eosinophil haematopoiesis that result in hypereosinophilia (defined as >1,500 eosinophils per mm3) in peripheral blood in the absence of any known aetiology. Although these disorders were recognized early on as clinically heterogeneous, recent studies have revealed the molecular basis for a few of the distinct phenotypes. The identification of myeloproliferative hypereosinophilic syndrome (MHES) emerged from the dramatic therapeutic responses observed in a subset of patients with hypereosinophilic syndrome following empirical treatment with imatinib, a tyrosine kinase inhibitor first developed for the treatment of chronic myeloid leukaemia113. This clinical observation led to the detection of a deletion in chromosome 4 that results in the fusion of the genes encoding pre-mRNA 3′-end-processing factor FIP1 (FIP1L1) and platelet-derived growth factor receptor-α (PDGFRA)114. This leads to the production of a FIP1L1–PDGFRA fusion protein that constitutively activates proliferation and survival pathways, resulting in the clonal proliferation of eosinophils, elevated serum levels of tryptase and vitamin B12 (also known as cobalamin), severe peripheral eosinophilia and end-organ damage, the most severe form of which is endomyocardial fibrosis. Other fusion kinases have also been identified in individuals with MHES; other individuals display clinical symptoms consistent with MHES but without a clear molecular diagnosis. Thus far, all of the PDGFRA- or PDGFRB-derived mutant fusion proteins that have been identified in humans have been associated with eosinophilia, for reasons that remain obscure.
The constitutive cellular activation and proliferation promoted by the FIP1L1–PDGFRA fusion protein has been explored in cell-culture models. For example, Ba/F3 immortalized mouse pro-B cells require the cytokine IL-3 for survival and proliferation in culture, but stable expression of the FIP1L1–PDGFRA fusion gene activates intracellular signalling pathways and eliminates the requirement for this cytokine113. Likewise, imatinib inhibits the growth of the human eosinophil leukaemia EoL-1 cell line, which expresses the FIP1L1–PDGFRA fusion protein115. Most intriguingly, the uncontrolled activity of the fusion protein lies within the PDGFRA component, as the fusion eliminates an inhibitory juxtamembrane region encoded by exon 12 of the PDGFRA gene, resulting in constitutive signalling by PDGFRA in the absence of its ligand116.
In contrast to the myeloproliferative variants, eosinophilia in lymphocytic-variant hypereosinophilic syndrome (LHES) results from aberrantly activated T cell clones that constitutively produce eosinophilopoietic cytokines, including IL-5. The resulting eosinophilia is thus reactive. The aberrant T cell clones (which typically have a CD3−CD4+ phenotype) are also associated with elevated serum levels of IgE and CCL17, and elicit predominantly skin manifestations, including pruritus, eczema, erythroderma, urticaria and angio-oedema. Individuals with this diagnosis respond to treatment with steroids, with cytotoxic agents (such as hydroxyurea) and with mepolizumab117, which reduced the requirement for corticosteroids in clinical studies.
These two defined variants of hypereosinophilic syndrome currently represent a minority of cases. Indeed, a recent study showed that FIP1L1–PDGFRA fusions were associated with only 11% of cases of hypereosinophilic syndrome, and LHES accounted for only 17% of cases118. The classification of hypereosinophilic syndrome is currently a work in progress, and attempts are being made to balance the clinical diagnosis with the predicted response to therapy119.
In an initial mouse model, bone marrow transplantation using haematopoietic progenitors that had been retrovirally transduced with FIP1L1–PDGFRA resulted in myeloproliferative disease120. Another group created a model that combines features of both myeloproliferative and lymphocytic-variant disease121 by transducing haematopoietic progenitors from Cd2-IL-5-transgenic mice with FIP1L1–PDGFRA, which resulted in profound peripheral eosinophilia in association with tissue infiltration. Most recently, mice lacking the serine/threonine kinase NIK (also known as MAP3K14) were found to develop a CD4+ T cell-dependent blood and tissue eosinophilia122. However, future studies will be necessary to determine whether these mouse models will be useful in identifying the disease mechanisms underlying distinct hypereosinophilic syndromes.
Eosinophils: changing perspectives
The field of eosinophil research is one of changing perspectives and emerging new directions. Eosinophils are clearly capable of more sophisticated immune functions than previously thought, as shown by their nuanced degranulation responses to distinct stimuli and their complex interactions with other leukocytes and pathogens. Both successful and unsuccessful attempts to target eosinophils have yielded remarkable insights into disease pathogenesis. Asthma and hypereosinophilic syndromes are now understood to be complex heterogeneous disorders that require tailored therapeutic strategies. Assessing the role of endogenous and exogenous PRR ligands in eosinophil responses and clarifying the relationship between eosinophil degranulation and tissue remodelling will be important goals for future research. A better understanding of these and other aspects of eosinophil biology will aid the development of new therapeutic strategies for diseases characterized by eosinophil dysregulation.
References
Steinbach, K. H. et al. Estimation of kinetic parameters of neutrophilic, eosinophilic, and basophilic granulocytes in human blood. Blut 39, 27–38 (1979).
Lamousé-Smith, E. S. & Furuta, G. T. Eosinophils in the gastrointestinal tract. Curr. Gastroenterol. Rep. 8, 390–395 (2006).
Hogan, S. P. et al. Eosinophils: biological properties and role in health and disease. Clin. Exp. Allergy 38, 709–750 (2008).
Blanchard, C. & Rothenberg, M. E. Biology of the eosinophil. Adv. Immunol. 101, 81–121 (2009).
Foster, P. S. et al. Elemental signals regulating eosinophil accumulation in the lung. Immunol. Rev. 179, 173–181 (2001).
Fabre, V. et al. Eosinophil deficiency compromises parasite survival in chronic nematode infection. J. Immunol. 182, 1577–1583 (2009). This study demonstrated that, in the absence of eosinophils, muscle-residentlarvae of the parasite Trichinella spiralis died in large numbers in an infected mouse model. These results suggest that, among other possibilities, eosinophils are recruited to sustain rather than eliminate parasitic infection, a potentially interesting reversal of the traditional view.
Gebreselassie, N. G. et al. Eosinophils preserve parasitic nematode larvae by regulating local immunity. J. Immunol. 188, 417–425 (2012).
Wegmann, M. Targeting eosinophil biology in asthma therapy. Am. J. Respir. Cell. Mol. Biol. 45, 667–674 (2011).
Jacobsen, E. A., Ochkur, S. I., Lee, N. A. & Lee, J. J. Eosinophils and asthma. Curr. Allergy Asthma Rep. 7, 18–26 (2007).
Yu, C. et al. Targeted deletion of a high-affinity GATA-binding site in the GATA-1 promoter leads to selective loss of the eosinophil lineage in vivo. J. Exp. Med. 195, 1387–1395 (2002). This paper describes the serendipitous creation of the ΔdblGATA eosinophil-deficient mouse model.
Lee, J. J. et al. Defining a link with asthma in mice congenitally deficient in eosinophils. Science 305, 1773–1776 (2004). In this paper, the authors describe the creation of the TgPHIL eosinophil-deficient mouse model using a cytosuicide approach and demonstrate the role of eosinophils in inflammation and tissue remodelling in allergic airway disease.
Lee, J. J. et al. Human versus mouse eosinophils: “that which we call an eosinophil, by any other name would stain as red”. J. Allergy Clin. Immunol. 130, 572–584 (2012).
Shamri, R., Xenakis, J. J. & Spencer, L. A. Eosinophils in innate immunity: an evolving story. Cell Tissue Res. 343, 57–83 (2011).
Mould, A., Matthaei, K., Young, I. & Foster, P. Relationship between interleukin-5 and eotaxin in regulating blood and tissue eosinophilia in mice. J. Clin. Invest. 99, 1064–1071 (1997). The findings of this study demonstrate the interactions between IL-5 and CCL11 in promoting eosinophil release from the bone marrow and eosinophil homing to tissues.
Collins, P. D., Marleau, S., Griffiths-Johnson, D. A., Jose, P. J. & Williams, T. J. Cooperation between interleukin-5 and the chemokine eotaxin to induce eosinophil accumulation in vivo. J. Exp. Med. 182, 1169–1174 (1995).
Wong, C. K., Hu, S., Cheung, P. F. & Lam, C. W. Thymic stromal lymphopoietin induces chemotactic and prosurvival effects in eosinophils: implications in allergic inflammation. Am. J. Respir. Cell. Mol. Biol. 43, 305–315 (2010).
Moro, K. et al. Innate production of TH2 cytokines by adipose tissue-associated c- Kit+Sca-1+ lymphoid cells. Nature 463, 540–544 (2010).
Neill, D. R. et al. Nuocytes represent a new innate effector leukocyte that mediates type-2 immunity. Nature 464, 1367–1370 (2010). As shown in this manuscript, stimulation with IL-25 and IL-33 causes a newly discovered innate effector leukocyte population to expand and to release the eosinophil-activating cytokines IL-5 and IL-13.
Ikutani, M. et al. Identification of innate IL-5-producing cells and their role in lung eosinophil regulation and antitumor immunity. J. Immunol. 188, 703–713 (2012).
Corrigan, C. J. et al. Allergen-induced expression of IL-25 and IL-25 receptor in atopic asthmatic airways and late-phase cutaneous responses. J. Allergy Clin. Immunol. 128, 116–124 (2011).
Terrier, B. et al. Interleukin-25: a cytokine linking eosinophils and adaptive immunity in Churg-Strauss syndrome. Blood 116, 4523–4531 (2010).
Mirchandani, A. S., Salmond, R. J. & Liew, F. Y. Interleukin-33 and the function of innate lymphoid cells. Trends Immunol. 33, 389–396 (2012).
Cherry, W. B., Yoon, J., Bartemes, K. R., Iijima, K. & Kita, H. A novel IL-4 family cytokine, IL-33, potently activates human eosinophils. J. Allergy Clin. Immunol. 121, 1484–1490 (2008).
Matsuba-Kitamura, S. et al. Contribution of IL-33 to induction and augmentation of experimental allergic conjunctivitis. Int. Immunol. 22, 479–489 (2010).
Mjösberg, J. M. et al. Human IL-25- and IL-33-responsive type 2 innate lymphoid cells are defined by expression of CRTH2 and CD161. Nature Immunol. 12, 1055–1062 (2011).
Li, Y. et al. Silencing IL-23 expression by small hairpin RNA protects against asthma in mice. Exp. Mol. Med. 43, 197–204 (2011).
Peng, J., Yang, X. O., Chang, S. H., Yang, J. & Dong, C. IL-23 signaling enhances Th2 polarization and regulates allergic airway inflammation. Cell Res. 20, 62–71 (2010).
Szymczak, W. A., Sellers, R. S. & Pirofski, L. A. IL-23 dampens theallergic response to Cryptococcus neoformans through IL-17-independent and -dependent mechanisms. Am. J. Pathol. 180, 1547–1559 (2012).
Lotfi, R., Lee, J. J. & Lotze, M. T. Eosinophilic granulocytes and damage-associated molecular pattern molecules (DAMPs): role in the inflammatory response within tumors. J. Immunother. 30, 16–28 (2007). This paper is one of the first to consider a role for endogenous DAMPs in the induction of eosinophilic inflammation.
Dvorak, A. M., Estrella, P. & Ishizaka, T. Vesicular transport of peroxidase in human eosinophilic myelocytes. Clin. Exp. Allergy 24, 10–18 (1994).
Melo, R. C. et al. Human eosinophils secrete preformed, granule-stored interleukin-4 through distinct vesicular compartments. Traffic 6, 1047–1057 (2005).
Spencer, L. A. et al. Cytokine receptor-mediated trafficking of preformed IL-4 in eosinophils identifies an innate immune mechanism of cytokine secretion. Proc. Natl Acad. Sci. USA 103, 3333–3338 (2006). This work documents the complexity of receptor-mediated intracellular trafficking and its contributions to piecemeal degranulation.
Lacy, P. & Stow, J. L. Cytokine release from innate immune cells: association with diverse membrane trafficking pathways. Blood 118, 9–18 (2011).
Neves, J. S. et al. Eosinophil granules function extracellularly as receptor-mediated secretory organelles. Proc. Natl Acad. Sci. USA 105, 18478–18483 (2008).
Neves, J. S. & Weller, P. F. Functional extracellular eosinophil granules: novel implications in eosinophil immunobiology. Curr. Opin. Immunol. 21, 694–699 (2009).
Walsh, G. M. Antagonism of eosinophil accumulation in asthma. Recent Pat. Inflamm. Allergy Drug Discov. 4, 210–213 (2010).
Mackenzie, J., Mattes, J., Dent, L. & Foster, P. Eosinophils promote allergic disease of the lung by regulating CD4+ Th2 lymphocyte function. J. Immunol. 167, 3146–3155 (2001).
Mattes, J. et al. Intrinsic defect in T cell production of interleukin (IL)-13 in the absence of both IL-5 and eotaxin precludes the development of eosinophilia and airways hyperreactivity in experimental asthma. J. Exp. Med. 195, 1433–1444 (2002).
Wang, H. B., Ghiran, I., Matthaei, K. & Weller, P. F. Airway eosinophils: allergic inflammation recruited professional antigen-presenting cells. J. Immunol. 179, 7585–7592 (2007).
Jacobsen, E. A. et al. Allergic pulmonary inflammation in mice is dependent on eosinophil-induced recruitment of effector T cells. J. Exp. Med. 205, 699–710 (2008). An intriguing manuscript in which the authors use the eosinophil-deficient TgPHIL mouse model to demonstrate eosinophil-dependent recruitment of effector T cells to the lungs of allergen-challenged mice.
Jacobsen, E. A., Zellner, K. R., Colbert, D., Lee, N. A. & Lee, J. J. Eosinophils regulate dendritic cells and Th2 pulmonary immune responses following allergen provocation. J. Immunol. 87, 6059–6068 (2011).
Spencer, L. A. et al. Human eosinophils constitutively express multiple Th1,Th2 and immunoregulatory cytokines that are secreted rapidly and differentially. J. Leukoc. Biol. 85, 117–123 (2009).
Wang, H. B. & Weller, P. F. Pivotal advance: eosinophils mediate early alum adjuvant-elicited B cell priming and IgM production. J. Leukoc. Biol. 83, 817–821 (2008).
Chu, V. T. et al. Eosinophils are required for the maintenance of plasma cells in the bone marrow. Nature Immunol. 12, 151–159 (2011). In this study, the authors show that eosinophils and plasma cells colocalize in mouse bone marrow and that plasma cell survival is supported by the eosinophil secretory mediators APRIL and IL-6.
Chu, V. T. & Berek, C. Immunization induces activation of bone marrow eosinophil required for plasma cell survival. Eur. J. Immunol. 42, 130–137 (2012).
Voehringer, D., van Rooijen, N. & Locksley, R. M. Eosinophils develop in distinct stages and are recruited to peripheral sites by alternatively activated macrophages. J. Leukoc. Biol. 81, 1434–1444 (2007).
Dasgupta, P. & Keegan, A. D. Contribution of alternatively activated macrophages to allergic lung inflammation: a tale of mice and men. J. Innate Immun. 4, 478–488 (2012).
Falcone, F. H. et al. Brugia malayi homolog of macrophage migration inhibitory factor reveals an important link between macrophages and eosinophil recruitment during nematode infection. J. Immunol. 167, 5348–5354 (2001).
Webb, D. et al. Expression of the Ym2 lectin-binding protein is dependent on interleukin (IL)-4 and IL-13 signal transduction: identification of a novel allergy-associated protein. J. Biol. Chem. 276, 41969–41976 (2001).
Wu, D. et al. Eosinophils sustain adipose alternatively activated macrophages associated with glucose homeostasis. Science 332, 243–247 (2011).
Lotfi, R. & Lotze, M. Eosinophils induce DC maturation, regulating immunity. J. Leukoc. Biol. 83, 456–460 (2008).
Yang, D. et al. Eosinophil-derived neurotoxin (EDN), an antimicrobial protein with chemotactic activities for dendritic cells. Blood. 102, 3396–3403 (2003).
Yang, D. et al. Eosinophil-derived neurotoxin acts as an alarmin to activate the TLR2–MyD88 signal pathway in dendritic cells and enhances Th2 immune responses. J. Exp. Med. 205, 79–90 (2008).
Elishmereni, M. et al. Physical interactions between mast cells and eosinophils: a novel mechanism enhancing eosinophil survival in vitro. Allergy 66, 376–385 (2011).
Pearce, E. J. & MacDonald, A. S. The immunobiology of schistosomiasis. Nature Rev. Immunol. 2, 499–511 (2002).
Sher, A., Coffman, R. L., Hieny, S. & Cheever, A. W. Ablation of eosinophil and IgE responses with anti-IL-5 or anti-IL-4 antibodies fails to affect immunity against Schistosoma mansoni in the mouse. J. Immunol. 145, 3911–3916 (1990).
Swartz, J. M. et al. Schistosoma mansoni infection in eosinophil lineage-ablated mice. Blood 108, 2420–2427 (2006).
Sasaki, O., Sugaya, H., Ishida, K. & Yoshimura, K. Ablation of eosinophils with anti-IL-5 antibody enhances the survival of intracranial worms of Angiostrongylus cantonensis in the mouse. Parasite Immunol. 15, 349–454 (1993).
Rotman, H. L. et al. Strongyloides stercoralis: eosinophil-dependent immune-mediated killing of third stage larvae in BALB/cByJ mice. Exp. Parasitol. 82, 267–278 (1996).
Eriksson, J. et al. The 434(G>C) polymorphism within the coding sequence of eosinophil cationic protein (ECP) correlates with the natural course of Schistosoma mansoni infection. Int. J. Parasitol. 37, 1359–1366 (2007).
Adu, B. et al. Polymorphisms in the RNASE3 gene are associated with susceptibility to cerebral malaria in Ghanaian children. PLoS ONE 6, e29465 (2011).
Lehrer, R. I. et al. Antibacterial properties of eosinophil major basic protein and eosinophil cationic protein. J. Immunol. 142, 4428–4434 (1989). This is one of the first papers to suggest an antimicrobial role for eosinophils.
Rosenberg, H. F. Recombinant human eosinophil cationic protein: ribonuclease activity is not essential for cytotoxicity. J. Biol. Chem. 270, 7876–7881 (1995).
Torrent, M., Navarro, S., Moussaoui, M., Nogués, M. V. & Boix, E. Eosinophil cationic protein high-affinity binding to bacteria-wall lipopolysaccharides and peptidoglycans. Biochemistry 47, 3544–3555 (2008).
Yousefi, S. et al. Catapult-like release of mitochondrial DNA by eosinophils contributes to antibacterial defense. Nature Med. 14, 949–953 (2008).
von Köckritz-Blickwede, M. & Nizet, V. Innate immunity turned inside-out: antimicrobial defense by phagocyte extracellular traps. J. Mol. Med. 87, 775–783 (2009).
Linch, S. N. et al. Mouse eosinophils possess potent antibacterial properties in vivo. Infect. Immun. 77, 4976–4982 (2009).
Linch, S. N. et al. IL-5 is protective during sepsis in an eosinophil-independent manner. Am. J. Respir. Crit. Care Med. 186, 246–254 (2012).
Huang, J. et al. The effects of probiotics supplementation timing on an ovalbumin-sensitized rat model. FEMS Immunol. Med. Microbiol. 60, 132–141 (2010).
Yu, J. et al. The effects of Lactobacillus rhamnosus on the prevention of asthma in a murine model. Allergy Asthma Immunol. Res. 2, 199–205 (2010).
Rose, M. A., Schubert, R., Schulze, J. & Zielen, S. Follow-up of probiotic Lactobacillus GG effects on allergic sensitization and asthma in infants at risk. Clin. Exp. Allergy 41, 1819–1821 (2011).
Herbst, T. et al. Dysregulation of allergic airway inflammation in the absence of microbial colonization. Am. J. Respir. Crit. Care Med. 184, 198–205 (2011).
Bisgaard, H. et al. Reduced diversity of the intestinal microbiota during infancy is associated with increased risk of allergic disease at school age. J. Allergy Clin. Immunol. 128, 646–652 (2011).
Domachowske, J. B., Dyer, K. D., Bonville, C. A. & Rosenberg, H. F. Recombinant human eosinophil-derived neurotoxin/RNase 2 functions as an effective antiviral agent against respiratory syncytial virus. J. Infect. Dis. 177, 1458–1464 (1998). This is the first paper to propose a role for eosinophils in antiviral host defence.
Adamko, D. J., Yost, B. L., Gleich, G. J., Fryer, A. D. & Jacoby, D. B. Ovalbumin sensitization changes the inflammatory response to subsequent parainfluenza infection. Eosinophils mediate airway hyperresponsiveness, M2 muscarinic receptor dysfunction, and antiviral effects. J. Exp. Med. 190, 1465–1478 (1999).
Phipps, S. et al. Eosinophils contribute to innate antiviral immunity and promote clearance of respiratory syncytial virus. Blood 110, 1578–1586 (2007).
Davoine, F. et al. Virus-induced eosinophil mediator release requires antigen-presenting and CD4+ T cells. J. Allergy Clin. Immunol. 122, 69–77 (2008).
Dyer, K. D., Percopo, C. M., Fischer, E. R., Gabryszewski, S. J. & Rosenberg, H. F. Pneumoviruses infect eosinophils and elicit MyD88-dependent release of chemoattractant cytokines and interleukin-6. Blood 114, 2649–2656 (2009).
Skiest, D. J. & Keiser, P. Clinical significance of eosinophilia in HIV-infected individuals. Am. J. Med. 102, 449–453 (1997).
Manetti, R. et al. CD30 expression by CD8+ T cells producting type 2 helper cytokines. Evidence for large numbers of CD8+CD30+ T cell clones in human immunodeficiency virus infection. J. Exp. Med. 180, 2407–2411 (1994).
Empson, M., Bishop, G. A., Nightingale, B. & Garsia, R. Atopy, anergic status, and cytokine expression in HIV-infected subjects. J. Allergy Clin. Immunol. 103, 833–842 (1999).
Rugeles, M. T. et al. Ribonuclease is partly responsible for the HIV-1 inhibitory effect activated by HLA alloantigen recognition. AIDS 17, 481–486 (2003).
Bochner, B. S. et al. Workshop report from the National Institutes of Health Taskforce on the Research Needs of Eosinophil-Associated Diseases (TREAD). J. Allergy Clin. Immunol. 130, 587–596 (2012).
Bochner, B. S. & Gleich, G. J. What targeting eosinophils has taught us about their role in diseases. J. Allergy Clin. Immunol. 126, 16–25 (2010).
Foster, P. S., Rosenberg, H. F., Asquith, K. L. & Kumar, R. K. Targeting eosinophils in asthma. Curr. Mol. Med. 8, 585–590 (2008).
Flood-Page, P. et al. Anti-IL-5 treatment reduces deposition of ECM proteins in the bronchial subepithelial basement membrane of mild atopic asthmatics. J. Clin. Invest. 112, 1029–1036 (2003).
Menzies-Gow, A. et al. Anti-IL-5 (mepolizumab) therapy induces bone marrow eosinophil maturational arrest and decreases eosinophil progenitors in the bronchial mucosa of atopic asthmatics. J. Allergy Clin. Immunol. 111, 714–719 (2003).
Leckie, M. J. et al. Effects of an interleukin-5 blocking monoclonal antibody on eosinophils, airway hyper-responsiveness, and the late asthmatic response. Lancet 356, 2144–2148 (2000).
Flood-Page, P. et al. A study to evaluate safety and efficacy of mepolizumab in patients with moderate persistent asthma. Am. J. Respir. Crit. Care Med. 176, 1062–1071 (2007).
Gibson, P. G. Inflammatory phenotypes in adult asthma: clinical applications. Clin. Respir. J. 3, 198–206 (2009).
Anderson, G. P. Endotyping asthma: new insights into key pathogenic mechanisms in a complex, heterogeneous disease. Lancet 372, 1107–1109 (2008).
Nair, P. et al. Mepolizumab for prednisone-dependent asthma with sputum eosinophilia. N. Engl. J. Med. 360, 985–993 (2009).
Haldar, P. et al. Mepolizumab and exacerbations of refractory eosinophilic asthma. N. Engl. J. Med. 360, 973–984 (2009). References 92 and 93 were the first two manuscripts to document a significant role for eosinophils in the pathogenesis of a specific asthma phenotype; patients were stratified for disease activity.
Castro, M. et al. Reslizumab for poorly controlled, eosinophilic asthma: a randomized, placebo-controlled study. Am. J. Respir. Crit. Care Med. 184, 1125–1132 (2011).
Pavord, I. D. et al. Mepoliuzmab for severe eosinophilic asthma (DREAM): a multicenter, double-blind, placebo-controlled trial. Lancet 380, 651–659 (2012).
Molfino, N. A., Gossage, D., Kolbeck, R., Parker, J. M. & Geba, G. P. Molecular and clinical rationale for therapeutic targeting of interleukin-5 and its receptor. Clin. Exp. Allergy 42, 712–737 (2012).
Corren, J. et al. Lebrikizumab treatment in adults with asthma. N. Engl. J. Med. 365, 1088–1098 (2011).
Furuta, G. T. Eosinophilic esophagitis: update on clinicopathological manifestations and pathophysiology. Curr. Opin. Gastroenterol. 27, 383–388 (2011).
Mueller, S., Aigner, T., Neureiter, D. & Stolte, M. Eosinophil infiltration and degranulation in oesophageal mucosa from adult patients with eosinophilic oesophagitis: a retrospective and comparative study on pathological biopsy. J. Clin. Pathol. 59, 1175–1180 (2006).
Blanchard, C. et al. Eotaxin-3 and a uniquely conserved gene-expression profile in eosinophilic esophagitis. J. Clin. Invest. 116, 536–547 (2006). In this study, the authors found that CCL26 was the most highly induced gene in an extensive study of oesophageal tissue from patients with eosinophilic oesophagitis.
Sherrill, J. D. et al. Variants of thymic stromal lymphopoietin and its receptor associate with eosinophilic esophagitis. J. Allergy Clin. Immunol. 126, 160–165 (2010).
Mishra, A., Schlotman, J., Wang, M. & Rothenberg, M. E. Critical role for adaptive T cell immunity in experimental eosinophilic esophagitis in mice. J. Leukoc. Biol. 81, 916–924 (2007).
Rayapudi, M. et al. Indoor insect allergens are potent inducers of experimental eosinophilic esophagitis in mice. J. Leukoc. Biol. 88, 337–346 (2010).
Rubinstein, E. et al. Siglec-F inhibition reduces esophageal eosinophilia and angiogenesis in a mouse model of eosinophilic esophagitis. J. Pediatr. Gastroenterol. Nutr. 53, 409–416 (2011).
Zuo, L. et al. IL-13 induces esophageal remodeling and gene expression by an eosinophil-independent, IL-13Rα2-inhibited pathway. J. Immunol. 185, 660–669 (2010).
Lucendo, A. J., De Rezende, L., Comas, C., Caballero, T. & Bellón, T. Treatment with topical steroids downregulates IL-5, eotaxin-1/CCL11, and eotaxin-3/CCL26 gene expression in eosinophilic esophagitis. Am. J. Gastroenterol. 103, 2184–2193 (2008).
Straumann, A. et al. Anti-interleukin-5 antibody treatment (mepolizumab) in active eosinophilic oesophagitis: a randomised, placebo-controlled, double-blind trial. Gut 59, 21–30 (2010).
Assa'ad, A. H. et al. An antibody against IL-5 reduces numbers of esophageal intraepithelial eosinophils in children with eosinophilic esophagitis. Gastroenterology 141, 1593–1604 (2011).
Conus, S., Straumann, A., Bettler, E. & Simon, H. U. Mepolizumab does not alter levels of eosinophils, T cells, and mast cells in the duodenal mucosa in eosinophilic esophagitis. J. Allergy Clin. Immunol. 126, 175–177 (2010).
Varga, J. & Kahari, V. M. Eosinophilia–myalgia syndrome, eosinophilic fasciitis, and related fibrosing disorders. Curr. Opin. Rheumatol. 9, 562–570 (1997).
Krahn, M. et al. CAPN3 mutations in patients with idiopathic eosinophilic myositis. Ann. Neurol. 59, 905–911 (2006).
Kramerova, I., Kudryashova, E., Tidball, J. G. & Spencer, M. J. Null mutation of calpain 3 (p94) in mice causes abnormal sarcomere formation in vivo and in vitro. Hum. Mol. Genet. 13, 1373–1388 (2004).
Cools, J. et al. A tyrosine kinase created by fusion of the PDGFRA and FIP1L1 genes as a therapeutic target of imatinib in idiopathic hypereosinophilic syndrome. N. Engl. J. Med. 348, 1201–1214 (2003). This manuscript provided the first evidence for the use of a receptor tyrosine kinase inhibitor, imatinib, as a disease-directed therapy for a specific variant of hypereosinophilic syndrome.
Valent, P. et al. Pathogenesis and classification of eosinophil disorders: a review of recent developments in the field. Expert Rev. Hematol. 5, 157–176 (2012).
Cools, J. et al. The EOL-1 cell line as an in vitro model for the study of FIP1L1-PDGFRA-positive chronic eosinophilic leukemia. Blood 103, 2802–2805 (2004).
Stover, E. H. et al. Activation of FIP1L1–PDGFRα requires disruption of the juxtamembrane domain of PDGFRα and is FIP1L1-independent. Proc. Natl Acad. Sci. USA 103, 8078–8083 (2006).
Roufosse, F. et al. Mepolizumab as a corticosteroid-sparing agent in lymphocytic variant hypereosinophilic syndrome. J. Allergy Clin. Immunol. 126, 828–835 (2010).
Ogbogu, P. U. et al. Hypereosinophilic syndrome: a multicenter, retrospective analysis of clinical characteristics and response to therapy. J. Allergy Clin. Immunol. 124, 1319–1325 (2009).
Valent, P. et al. Contemporary consensus proposal on criteria and classification of eosinophilic disorders and related syndromes. J. Allergy Clin. Immunol. 130, 607–612 (2012).
Cools, J. et al. PKC412 overcomes resistance to imatinib in a murine model of FIP1L1–PDGFRα-induced myeloproliferative disease. Cancer Cell 3, 459–469 (2003).
Yamada, Y., Cancelas, J. A. & Rothenberg, M. E. Murine model of hypereosinophilic syndromes/chronic eosinophilic leukemia. Int. Arch. Allergy Immunol. 149 (Suppl. 1), 102–107 (2009).
Häcker, H., Chi, L., Rehg, J. E. & Redecke, V. NIK prevents the development of hypereosinophilic syndrome-like disease in mice independent of IKKα activation. J. Immunol. 188, 4602–4610 (2012).
Pease, J. E. & Williams, T. J. Eotaxin and asthma. Curr. Opin. Pharmacol. 1, 248–253 (2001).
Takatsu, K., Kouro, T. & Nagai, Y. Interleukin-5 in the link between innate and acquired immune response. Adv. Immunol. 101, 191–236 (2009).
Wechsler, M. E. et al. Novel targeted therapies for eosinophilic disorders. J. Allergy Clin. Immunol. 130, 563–571 (2012).
Lloyd, C. M. & Rankin, S. M. Chemokines in allergic airway disease. Curr. Opin. Pharmacol. 3, 443–448 (2003).
Bochner, B. S. Siglec-8 on human eosinophils and mast cells, and Siglec-F on murine eosinophils, are functionally related inhibitory receptors. Clin. Exp. Allergy 39, 317–324 (2009).
Kiwamoto, T., Kawasaki, N., Paulson, J. C. & Bochner, B. S. Siglec-8 as a drugable target to treat eosinophil and mast cell-associated conditions. Pharmacol. Ther. 135, 327–336 (2012).
Hudson, S. A., Bovin, N. V., Schnaar, R. L., Crocker, P. R. & Bochner, B. S. Eosinophil-selective binding and proapoptotic effect in vitro of a synthetic Siglec-8 ligand, polymeric 6′- sulfated sialyl Lewis X. J. Pharmacol. Exp. Ther. 330, 608–612 (2009).
Kvarnhammar, A. M. & Cardell, L. O. Pattern recognition receptors in human eosinophils. Immunology 136, 11–20 (2012).
Månsson, A. & Cardell, L. O. Role of atopic status in Toll-like receptor (TLR)7- and TLR9-mediated activation of human eosinophils. J. Leukoc. Biol. 85, 719–727 (2009).
Ackerman, S. J. & Bochner, B. S. Mechanisms of eosinophilia in the pathogenesis of hypereosinophilic disorders. Immunol. Allergy Clin. North Am. 27, 357–375 (2007).
Bedi, R., Du, J., Sharma, A. K., Gomes, I. & Ackerman, S. J. Human C/EBP-ε activator and repressor isoforms differentially reprogram myeloid lineage commitment and differentiation. Blood 113, 317–327 (2009).
Mori, Y. et al. Identification of the human eosinophil lineage-committed progenitor: revision of phenotypic definition of the human common myeloid progenitor. J. Exp. Med. 206, 183–193 (2009). In this study, the authors define the cell-surface antigen profile of a fully committed eosinophil progenitor in human bone marrow.
Iwasaki, H. et al. Identification of eosinophil lineage-committed progenitors in the murine bone marrow. J. Exp. Med. 201, 1891–1897 (2005).
Southam, D. S. et al. Increased eosinophil-lineage committed progenitors in the lung of allergen-challenged mice. J. Allergy Clin. Immunol. 115, 95–102 (2005).
Busse, W. W., Ring, J., Huss-Marp, J. & Kahn, J. E. A review of treatment with mepolizumab, an anti-IL-5 mAb, in hypereosinophilic syndromes and asthma. J. Allergy Clin. Immunol. 125, 803–813 (2010).
Foster, P., Hogan, S., Ramsay, A., Matthaei, K. & Young, I. Interleukin-5 deficiency abolishes eosinophilia, airways hyperreactivity, and lung damage in a mouse asthma model. J. Exp. Med. 183, 195–201 (1996).
Humbles, A. A. et al. A critical role for eosinophils in allergic airways remodeling. Science 305, 1776–1779 (2004).
Walsh, E. R. et al. Strain-specific requirement for eosinophils in the recruitment of T cells to the lung during the development of allergic asthma. J. Exp. Med. 205, 1285–1292 (2008).
Hertzman, P. A. et al. Association of the eosinophilia–myalgia syndrome with the ingestion of tryptophan. N. Engl. J. Med. 322, 869–873 (1990).
Mayeno, A. N. et al. Characterization of “peak E”, a novel amino acid associated with eosinophilia–myalgia syndrome. Science 250, 1707–1708 (1990).
Smith, M. J. & Garrett, R. H. A heretofore undisclosed crux of eosinophilia–myalgia syndrome: compromised histamine degradation. Inflamm. Res. 54, 435–450 (2005).
Okada, S. et al. Immunogenetic risk and protective factors for development of L-tryptophan-associated eosinophilia–myalgia syndrome and associated symptoms. Arthritis Rheum. 61, 1305–1311 (2009).
Allen, J. A. Post-epidemic eosinophilia–myalgia syndrome associated with L-tryptophan. Arthritis Rheum. 63, 3633–3639 (2011).
Haskell, M. D., Moy, J. N., Gleich, G. J. & Thomas, L. L. Analysis of signaling events associated with activation of neutrophil superoxide anion production by eosinophil granule major basic protein. Blood 86, 4627–4637 (1995).
Munitz, A. & Levi-Schaffer, F. Eosinophils: 'new' roles for 'old' cells. Allergy 59, 268–275 (2004).
Dyer, K. D., Garcia-Crespo, K. E., Killoran, K. E. & Rosenberg, H. F. Antigen profiles for the quantitative assessment of eosinophils in mouse tissues by flow cytometry. J. Immunol. Methods 369, 91–97 (2011).
Meyerholz, D. K., Griffin, M. A., Castilow, E. M. & Varga, S. M. Comparison of histochemical methods for murine eosinophil detection in an RSV vaccine-enhanced inflammation model. Toxicol. Pathol. 37, 249–255 (2009).
Yamaguchi, Y. et al. Models of lineage switching in hematopoietic development: a new myeloid-committed eosinophil cell line (YJ) demonstrates trilineage potential. Leukemia 12, 1430–1439 (1998).
Histoshi, Y. et al. Distribution of IL-5 receptor-positive B cells. Expression of IL-5 receptor on Ly-1(CD5)+ B cells. J. Immunol. 144, 4218–4225 (1990).
Wise, E. L., Bonner, K. T., William, T. J. & Pease, J. E. A single nucleotide polymorphism in the CCR3 gene ablates receptor export to the plasma membrane. J. Allergy Clin. Immunol. 126, 150–157 (2010).
Willetts, L. et al. Immunodetection of occult eosinophils in lung tissue biopsies may help predict survival in acute lung injury. Respir. Res. 12, 116 (2011).
Macias, M. P. et al. Identification of a new murine eosinophil major basic protein (mMBP) gene: cloning and characterization of mMBP-2. J. Leukoc. Biol. 67, 567–576 (2000).
Ito, W. et al. Hepatocyte growth factor suppresses production of reactive oxygen species and release of eosinophil-derived neurotoxin from human eosinophils. Int. Arch. Allergy Immunol. 147, 331–337 (2008).
Ochkur, S. I. et al. The development of a sensitive and specific ELISA for mouse eosinophil peroxidase: assessment of eosinophil degranulation ex vivo and in models of human disease. J. Immunol. Methods 375, 138–147 (2012).
Blyth, D. I., Wharton, T. F., Pedrick, M. S., Savage, T. J. & Sanjar, S. Airway subepithelial fibrosis in a murine model of atopic asthma: suppression by dexamethasone or anti-interleukin-5 antibody. Am. J. Respir. Cell. Mol. Biol. 23, 241–246 (2000).
Grimaldi, J. C. et al. Depletion of eosinophils in mice through the use of antibodies specific for C-C chemokine receptor 3 (CCR3). J. Leukoc. Biol. 65, 846–853 (1999).
Song, D. J. et al. Anti-Siglec-F antibody reduces allergen-induced eosinophilic inflammation and airway remodeling. J. Immunol. 183, 5333–5341 (2009).
Dyer, K. D. et al. Functionally competent eosinophils differentiated ex vivo in high purity from normal mouse bone marrow. J. Immunol. 181, 4004–4009 (2008).
Kopf, M. et al. IL-5-deficient mice have a developmental defect in CD5+ B-1 cells and lack eosinophilia but have normal antibody and cytotoxic T cell responses. Immunity 4, 15–24 (1996). This is the first description of a mouse model devoid of the eosinophilopoietic cytokine IL-5.
Yoshida, T. et al. Defective B-1 cell development and impaired immunity against Angiostrongylus cantonensis in IL-5Rα-deficient mice. Immunity 4, 483–494 (1996).
Dent, L. A., Strath, M., Mellor, A. L. & Sanderson, C. J. Eosinophilia in transgenic mice expressing interleukin 5. J. Exp. Med. 172, 1425–1431 (1990).
Lee, N. A. et al. Expression of IL-5 in thymocytes/ T cells leads to the development of a massive eosinophilia, extramedullary eosinophilopoiesis, and unique histopathologies. J. Immunol. 158, 1332–1344 (1997).
Rothenberg, M. E., MacLean, J. A., Pearlman, E., Luster, A. D. & Leder, P. Targeted disruption of the chemokine eotaxin partially reduces antigen-induced tissue eosinophilia. J. Exp. Med. 185, 785–790 (1995).
Pope, S. M. et al. Identification of a cooperative mechanism involving interleukin-13 and eotaxin-2 in experimental allergic lung inflammation. J. Biol. Chem. 280, 13952–13961 (2005).
Pope, S. M., Zimmermann, N., Stringer, K. F., Karow, M. L. & Rothenberg, M. E. The eotaxin chemokines and CCR3 are fundamental regulators of allergen-induced pulmonary eosinophilia. J. Immunol. 175, 5341–5350 (2005).
Ochkur, S. I. et al. Coexpression of IL-5 and eotaxin-2 in mice creates an eosinophil-dependent model of respiratory inflammation with characteristics of severe asthma. J. Immunol. 178, 7879–7889 (2007).
Humbles, A. A. et al. The murine CCR3 receptor regulates both the role of eosinophils and mast cells in allergen-induced airway inflammation and hyperresponsiveness. Proc. Natl Acad. Sci. USA 99, 1479–1484 (2002).
Zhang, M. et al. Defining the in vivo function of Siglec-F, a CD33-related Siglec expressed on mouse eoisnophils. Blood 109, 4280–4287 (2007).
Leckie, M. J. Anti-interleukin-5 monoclonal antibodies: preclinical and clinical evidence in asthma models. Am. J. Resp. Med. 2, 245–259 (2003).
Acknowledgements
The authors thank R. Dreyfuss (Medical Arts Branch, Office of the Director, US National Institutes of Health (NIH)) for photographic images and E. R. Fischer (Research Technologies Section, Rocky Mountain Laboratories, US National Institute of Allergy and Infectious Diseases (NIAID), NIH) for preparing the transmission electron micrograph of the mouse eosinophil. H.F.R. receives funding from the NIAID Division of Intramural Research (grants AI000941 and AI000943); P.S.F. receives funding from the National Health and Medical Research Council of Australia and fellowship support from the Harvard Club of Australia.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing financial interests.
Supplementary information
Supplementary information S1 (table)
Disorders associated with eosinophilia and/or eosinophil accumulation in organs and tissues (PDF 100 kb)
Related links
Glossary
- Innate lymphoid cells
-
Cells that produce cytokines typically attributed to T helper cell subsets (for example, IL-5) but that have no rearranged antigen-specific receptors.
- Alarmin
-
A term used to describe endogenous molecules that interact with pattern- recognition receptors and thereby signal danger to the host. These molecules are typically released from necrotic cells and complement the function of the more familiar pathogen-associated molecular patterns. Examples discussed in this Review include HMGB1 and IL-33. Another name for an alarmin is a damage- or danger-associated molecular pattern.
- Cytolytic degranulation
-
A mechanism through which eosinophils lyse, thereby releasing either free granule proteins or fully intact granules. This renders the cells non-viable. Intact granules released in this manner can respond to physiological secretagogues.
- Piecemeal degranulation
-
A mechanism through which eosinophils (as well as basophils and mast cells) release specific mediators from cytoplasmic granules by transporting them to the cell surface in membrane-bound cytoplasmic vesicles. The eosinophils remain viable and fully responsive to subsequent stimuli.
- Secretagogues
-
Substances that induce the secretion of another substance from a cell or storage granule.
- Promyelocyte
-
A cell in the bone marrow that has differentiated from a haematopoietic stem cell and that will ultimately generate mature granulocytes, including neutrophils, basophils and eosinophils. A promyelocyte can be identified in bone marrow smears as a relatively large cell with a full, non-condensed nucleus and lineage-specific cytoplasmic granules.
- Common myeloid progenitors
-
(CMPs). In current models of haematopoiesis, the most primitive cells are multipotent, self-renewing haematopoietic stem cells. By definition, CMPs are the subset of progenitor cells that are capable of generating all myeloid cells (that is, monocytes, macrophages, dendritic cells, erythrocytes, megakaryocytes, platelets, basophils, eosinophils and neutrophils) under appropriate cytokine stimulation, but that are no longer capable of generating cells of the lymphoid lineages (such as B cells, T cells and NK cells).
- Granulocyte–macrophage progenitors
-
(GMPs). By definition, GMPs are the subset of progenitor cells that are capable of generating monocytes, macrophages and all granulocyte lineages (that is, basophils, eosinophils and neutrophils), but not the other lineages. However, as noted in the text, human eosinophils are not derived from the cells currently identified as GMPs.
- Alternatively activated macrophages
-
One of the major differences between these cells and classically activated macrophages is that these macrophages are not primed with IFN. Instead, alternatively activated macrophages are stimulated by TH2-type cytokines (such as IL-4 or IL-13) and present soluble antigens to T cells. Alternatively activated macrophages release CCL17, CCL18, CCL22, IL-10, TGF, YM1, YM2 and RELM, and they characteristically function to promote the resolution of inflammation.
- Nurse cells
-
As used in this Review, this term refers to skeletal muscle cells that have been infected with the larval forms of Trichinella species parasites. A capillary network forms around the nurse cells, which provides crucial support for the parasites as they develop.
- Neutrophil extracellular traps
-
(NETs). Fibrous networks that are released into the extracellular environment by neutrophils. They are composed mainly of DNA, but also contain proteins from neutrophil granules. NETs act as a mesh that traps microorganisms and exposes them to neutrophil-derived effector molecules.
Rights and permissions
About this article
Cite this article
Rosenberg, H., Dyer, K. & Foster, P. Eosinophils: changing perspectives in health and disease. Nat Rev Immunol 13, 9–22 (2013). https://doi.org/10.1038/nri3341
Published:
Issue Date:
DOI: https://doi.org/10.1038/nri3341
This article is cited by
-
Autotaxin–lysolipid signaling suppresses a CCL11–eosinophil axis to promote pancreatic cancer progression
Nature Cancer (2024)
-
Eosinophils preserve bone homeostasis by inhibiting excessive osteoclast formation and activity via eosinophil peroxidase
Nature Communications (2024)
-
Neutrophil-to-lymphocyte ratio and monocyte-to-eosinophil ratio as prognostic indicators for advanced nasopharyngeal carcinoma
European Archives of Oto-Rhino-Laryngology (2024)
-
The impact of helminth-induced immunity on infection with bacteria or viruses
Veterinary Research (2023)
-
Omics and imaging combinatorial approach reveals butyrate-induced inflammatory effects in the zebrafish gut
Animal Microbiome (2023)