IL-5 plays an important role in the development of eosinophilic airway inflammation. A number of studies have reported an increase in CC chemokines in the airways of asthmatic patients. The airway expression of eotaxin and its receptor, CCR3, are elevated in atopic asthmatics compared with normal controls In patients with acute eosinophilic pneumonia, monocyte chemotactic protein MCP -4, which is also a CCR3 ligand, is involved in the development of eosinophil transendothelial migration 33 ; however, the role of MCP-4 in asthma has yet to be fully clarified.
Moreover, cysLTs may be involved in the eosinophil accumulation in the airways of asthma. Inhalation of LTE 4 stimulates the accumulation of eosinophils in asthmatic airways Furthermore, leukotriene receptor antagonist LTRA suppresses eosinophil airway inflammation in vivo 39 — These findings suggest that cysLTs, along with the Th2 network, contribute to the development and maintenance of airway eosinophilic inflammation in asthma.
Periostin is an extracellular matrix protein that is highly expressed in the airways of asthmatics in response to Th2 cytokines, such as IL 42 , and is a biomarker of Th2-mediated immune responses in bronchial asthma 43 , Periostin also functions as a matricellular protein 42 that binds to cellular receptors and activates cells, including eosinophils.
Viral infection, especially rhinovirus RV infection, is a major cause of asthma exacerbation. RVs have tremendous diversity The numbers of not only neutrophils, but also eosinophils, increase in asthmatic airways during or after a viral infection 53 — Experimental RV infection induces increased recruitment of eosinophils into the airway after segmental allergen challenge in allergic rhinitis patients, but not in non-allergic volunteers Viral infection increases the eosinophil count in the airway epithelium of patients with allergic asthma 55 , and high levels of eosinophilic cationic protein are observed in the sputum of asthmatic patients with viral infection Therefore, eosinophils are indeed recruited to and activated in asthmatic airways during or after a viral infection.
Recent studies have suggested that the presence of eosinophil inflammation may be a risk factor for virus-related asthma exacerbation 56 , High fractional exhaled nitric oxide and sputum eosinophils are associated with an increased risk of future virus-induced exacerbations Epithelial cells are damaged by eosinophil-derived granule products, such as MBP 23 , and this increases the susceptibility to RV infection Figure 2 Therefore, reducing the eosinophil count could be a reasonable strategy for suppressing virus-induced asthma exacerbation.
Figure 2. Interactions of viral infection and eosinophils in the development of asthma exacerbation. RV infection releases a variety of mediators, including CXCL and cysLTs, which can directly activate eosinophils and induce asthma exacerbation, from airway epithelial cells. On the other hand, activated eosinophils release MBP, which induces epithelial cell damage. Therefore, eosinophilic airway inflammation can increase susceptibility to RV infection.
In this context, a coding single nucleotide polymorphism SNP in CDHR3 has been shown to be related to the severe exacerbation of childhood asthma Because the cadherin family members are involved in cell adhesion, eosinophil adhesion to CDHR3 may activate eosinophil functions in a manner similar to that as ICAM CXCL10 may also play a role in the virus-induced asthma exacerbation Figure 2.
Specifically, concentrations of serum CXCL10 are elevated in virus or RV-induced asthma; correlations are reported between higher levels of CXCL10 and disease severity, including airflow limitation CXCL10 induces eosinophil adhesion, O 2 - generation, eosinophil-derived neurotoxin release, and cytokine production through CXCR3, expressed on eosinophils, in vitro CXCL9 induces eosinophil adhesion, O 2 - generation, and eosinophil-derived neurotoxin release in vitro 64 , whereas it inhibits eosinophil chemotaxis through a CCR3-dependent mechanism 67 , CysLTs are upregulated in the asthmatic airways during virus or RV-induced exacerbation 69 , Therefore, cysLTs are likely to be involved in virus-induced eosinophilic inflammation Figure 2 , and LTRA may be useful for virus-induced asthma treatment.
The LTRA montelukast suppresses the respiratory symptoms of RSV bronchiolitis 72 as well as the frequency of virus-induced asthma exacerbation Innate immune responses play roles in the development of eosinophilic airway inflammation; this process involves type 2 innate lymphoid cells ILC2 as well as epithelial cell-related cytokines including IL, IL, and thymic stromal lymphopoietin, 75 , In fact, ILC2 are upregulated in severe asthmatics Recent studies have suggested that innate immune responses contribute to virus-induced asthma exacerbation.
For example, ILdependent type 2 inflammation plays an important role in RV-induced asthma exacerbation in vivo During viral infections, damage-associated molecular pattern molecules DAMPs can be released by stressed or damaged cells, and function as endogenous danger signals Damaged epithelial cells are capable of inducing eosinophilic migration, specific granule protein release , and cytokine production, likely via the release of DAMPs Both neutrophilic and eosinophilic inflammation may play roles in severe asthma [ 83 — 85 ].
Neutrophilic inflammation has been shown to be involved in the pathogenesis of asthma exacerbation 86 , which occurs frequently in severe asthma. The European Network for Understanding Mechanisms of Severe Asthma ENFUMOSA study suggested that compared with patients with mild-to-moderate asthma, those with severe asthma have both a greater sputum neutrophil count and an increased release of eosinophil-derived mediators IL-8 plays an important role in the accumulation of neutrophils in inflammation sites, and IL-8 expression is upregulated in the airways of severe asthmatic patients 87 , In addition, we reported that neutrophils that had migrated to IL-8 induce the transbasement membrane migration of eosinophils in vitro , even without eosinophil chemoattractants 89 ; this neutrophil-induced eosinophil migration is suppressed by LTB 4 antagonist or platelet-activating factor PAF antagonist.
Lipopolysaccharide LPS may play a role in inducing IL-8 or neutrophilic inflammation in the airway of severe asthmatics. Several studies have suggested that Gram-negative bacteria or house dust plays a role in the LPS upregulation in the airways of severe asthmatics.
We previously reported that LPS-stimulated neutrophils induce the transbasement membrane migration of eosinophils in vitro IL is another candidate for the upregulation of IL-8 expression Sputum IL concentration correlates with the clinical severity of asthma 97 , and the airway expression of IL is increased in severe asthmatics only Furthermore, a correlation between the number of bronchial cells that produce IL and the number of bronchial neutrophils and frequency of asthma exacerbation has been reported In addition, we reported that the dopamine D1-like receptor antagonist attenuates the Thmediated immune response and neutrophilic airway inflammation in mice 99 this could be reasonable strategy for controlling neutrophilic airway inflammation in severe asthma or asthma exacerbation.
The role of neutrophil extracellular traps NETs in the pathogenesis of asthma exacerbation has recently been highlighted. Furthermore, in humans, a significant correlation is identified between the release of host dsDNA after RV infection and the exacerbation of type-2 allergic inflammation Mast cells also play roles in the development of severe asthma. Mast cell numbers and PGD 2 concentrations are increased in the lower airway of patients with severe asthma , Recently, the role of CRTH2 in the pathogenesis of asthma has been highlighted.
CRTH2 antagonists are already being developed , , and clinical trial data suggest that CRTH2 antagonists may target eosinophilic asthma , Eosinophils are likely to contribute to the development of asthma exacerbation. This process can involve cytokines, such as IL-5 or GM-CSF, chemokines, such as CCR3 ligands, matricellular proteins, a danger signal, and other cells, such as neutrophils or mast cells.
All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Immunological aspects of allergic asthma. Annu Rev Immunol. As a result of the ability of IgE antibodies to influence the functioning of several immune and structural cells of the bronchial wall, IgE is primarily responsible not only for the acute phase but also for the chronic phase of inflammation characteristic of BA, at least in allergic forms Fig.
This feature makes IgE an ideal target in the treatment of asthma [ 10 ]. In contrast, eosinophils, which are responsible for bronchial wall damage, are the final effector cells in the process Fig. It is generally believed that in types of asthma with high eosinophilia frequently non-allergic types , an anti-IL-5 strategy could be considered as the first choice of treatment [ 67 , 68 , 69 ].
Although the efficacy of mAbs towards IL-5 is indisputable in eosinophilic asthma, as reported in several studies, the clinical results are more evident in those patients with a high percentage of blood and sputum eosinophilia [ 58 ]. However, in clinical practice, the frequency and severity of asthma symptoms may not always be associated with eosinophil count, particularly in patients with blood eosinophilia close to the cut-off point identified as the predicting marker for prescribing an anti-IL-5 strategy.
Of note, similar values of blood eosinophilia are predictors of response to treatment with both anti-IgE and anti-IL-5 mAbs [ 70 , 71 ]. It is also important to be aware than omalizumab can reduce not only both blood and sputum eosinophils but also tissue eosinophil levels in bronchial biopsies [ 72 ].
Cellular components and pathways involved in a : acute sensitisation , and b : chronic cellular damage phases of allergic asthma pathogenesis. Among specialists there is a common misconception that asthma is always associated with eosinophilic inflammation at the bronchial level. However, not all types of asthma are characterised by the eosinophilic pattern, there are also neutrophilic and pauci-granulocytic variants [ 73 ].
One concept that needs to be considered is that asthma endotypes can change over time, particularly regards the pattern of cellular components. Although respiratory viral infections cause asthma exacerbations, data about the type of cellular infiltrate and underlying molecular mechanisms are not conclusive. The airway inflammatory responses during virus-induced exacerbations depend on the viral species and on host-related factors and may be associated with increases in neutrophils, eosinophils and macrophages [ 75 , 76 , 77 , 78 ].
From a clinical perspective, it is important to note that the efficacy of biological therapies is evident only in patients who have experienced asthma exacerbations.
As previously mentioned, the question is not whether an anti-IgE or anti-eosinophil therapy is more effective but rather what is the cause and pathogenic mechanism prevalent in each patient. The complex biological role of IgE, how IgE mAbs achieve their clinical effects and the ability of IgE to regulate the functioning of several cells has been increasingly studied over the past few years by retracing our steps, that is, starting with the clinical observations of the effectiveness of omalizumab in severe asthma patients and then analysing how IgE mAbs achieved this effect.
Indeed, unlike other biological agents, the clinical efficacy of omalizumab has been appreciated before fully understanding its overall mechanisms of action. The discussion on the pleiotropic role of IgE appears more intriguing when taking into account the fact that omalizumab also exerts its therapeutic effects in non-allergic forms of asthma as well as in patients with nasal polyps [ 79 , 80 ] This raises the question of how can these clinical findings be explained? Indeed, these data appear to contradict the well-established concept about the role of IgE only in allergic asthma.
Two hypotheses have been proposed; the first assumes that in intrinsic asthma patients there is a local allergy, whereas the second hypothesis assumes that there is an immunological imbalance of DC function [ 81 ]. The role of IgE is suggested by the fact that in allergic and non-allergic asthma patients there is an increase of total and specific IgE levels in the serum, and an inverse relationship between IgE levels and lung function FEV 1 [ 82 , 83 ].
Concerning local IgE production, some studies have shown dust mite-specific IgE in the bronchial secretions of intrinsic asthmatics as well as the production of IgE specific to S. Together, these findings suggest that IgE is the cause of allergic airway inflammation rather than the consequence of this process and that IgE could also play a role in intrinsic asthma.
However, despite these biological and clinical data, scepticism still remains, and further studies in non-allergic asthmatic patients as well as dedicated clinical trials must be performed. In fact, while IgE is clearly upstream in allergic asthma, whether it remains the case in non-allergic asthma is far from being clear, and the role of eosinophils might become stronger. While animal models have shown that antibody-mediated neutralisation of Th2 cytokines greatly diminishes airway inflammation [ 85 , 86 , 87 ], clinical trials of some biological agents have not always been particularly successful with positive trials frequently requiring patient stratification [ 88 ].
What has become clear is that the formation of cytokine—anti-cytokine immune complexes does not guarantee cytokine neutralisation; indeed, the formation of these complexes can, in some cases, potentiate target cytokine activity rather than neutralise it. For example, in a lebrikizumab an anti-IL mAb dose-finding study in moderate-to-severe asthma patients with high periostin levels, there was a direct correlation between exacerbation rate and lebrikizumab dose [ 89 ].
Moreover, treatment with neutralising antibodies may also increase cytokine levels in the circulation; for example, mepolizumab-treated patients had higher circulating levels of IL-5 with the majority of it bound in IL-5—anti-IL-5 complexes [ 90 ], and treatment of asthma patients with anti-IL antibodies directly increased serum levels of IL [ 91 ].
These findings would suggest that direct targeting of the cytokine itself might not be particularly effective and that targeting a pathway or multiple cytokines might have a greater clinical effect. Anti-IgE mAbs have been successfully used for more than 10 years in the treatment of BA, and now the spectrum of available biological drugs is expanding with different mAbs targeting different pathways involved in the pathogenesis of airways inflammation.
Most cases of BA are related to an IgE-mediated pathogenic mechanism, at least in patients sensitised to allergens. Taking into account that IgE is clearly involved both at the onset of allergic asthma as well as during the chronic phase of the disease, it is perhaps unsurprising that omalizumab has proved to be clinically effective in SAA. The ability of omalizumab to reduce sputum eosinophilia and increase of the dose of methacholine required to induce a fall in FEV 1 shows that in addition to inhibiting free IgE, omalizumab also has an effect on inflammatory cells [ 22 ].
So, through its effect on T cells, omalizumab exerts an indirect effect on eosinophils. Furthermore, it induces apoptosis of these cells, but does not result in lysis [ 72 ]. As a result of omalizumab exerting its therapeutic anti-inflammatory effects through several pathways, long-term treatment is associated with beneficial effects on airway remodeling by reversing already established histological changes [ 93 ].
As mentioned previously, several new biological agents have recently been launched that target specific pathways, particularly in patients with typehigh or eosinophilic asthma, and are currently included in the therapeutic guidelines. Among these drugs, there is a great deal of interest in the anti-IL-5 mAbs mepolizumab and reslizumab, and the anti-IL-5R benralizumab.
The importance of targeting IL-5 derives from its role in the induction of differentiation, survival and activation of eosinophils, which are key cells in a subgroup of BA. The effect of mepolizumab and reslizumab is related to their ability to bind with high affinity to IL-5 and block the interaction between IL-5 and its receptor on the surface of eosinophils. The availability of anti-IL-5 mAbs has directed attention towards eosinophils as the main target of asthma treatment, neglecting the central role of IgE in SAA despite increasing awareness of the role of IgE in allergic inflammation.
While among clinicians the importance of anti-IL-5 mAbs has been related to their ability to indirectly target eosinophils, some concerns have been raised. Anti-IL-5 mAbs have been unable to completely abolish both blood and airway eosinophils in asthma patients [ 94 ]; these data could be explained by cytokines others than IL-5, such as IL-3, GM-CSF, and IL-9, sustaining the eosinophilic airway inflammation [ 95 , 96 ]. Benralizumab is approved the US and under review in Europe and has been shown to be effective and safe as add-on therapy in patients with severe asthma and eosinophilia who are inadequately controlled with high-dose ICS plus LABA [ 98 ].
It is well known that a complex network of cytokines plays a role in the pathogenesis of BA. Among this network, attention has been given to IL-4 and IL Indeed, a therapeutic strategy is based on the use of drugs able to interfere with the IL-4 and IL pathways. IL-4 and IL are involved in the production of IgE and the pathogenesis of several aspects of bronchial inflammation in asthma [ 99 ]. IL-4 is an essential factor in the differentiation of Th2 cells; both IL-4 and IL induce the switch to IgE production; IL induces the expression of adhesion molecules and is responsible for some of the changes seen in BA such as airway remodelling and smooth muscle hypertrophy.
Dupilumab has demonstrated significant results in both eosinophilic and non-eosinophilic asthma, and in patients with atopic dermatitis [ ].
Future directions in asthma treatment also include the use small molecules such as fevipiprant, an antagonist of the DP2 receptor, which has been shown to reduce eosinophilic airway inflammation in patients with moderate-to-severe asthma [ ].
This receptor has been found to be expressed on major human cell types involved in asthma pathogenesis, such as Th2 lymphocytes, innate lymphoid cells ILC 2, eosinophils, and basophils [ ].
All the phases leading to inflammation of the airways, and therefore clinical expression of allergic asthma, must be considered as dynamic processes. This helps to make sense of the clinical effectiveness observed with anti-IgE mAbs in bronchial asthma and the effects of anti-IL-5 mAbs in specific eosinophilic asthma patient populations.
However, the question of whether an anti-IgE or anti-eosinophil therapy will be more effective in the clinical practice with patients suffering from eosinophilic asthma is still an open question and further studies are needed.
Asthma WSE. Asthma endotypes: a new approach to classification of disease entities within the asthma syndrome. J Allergy Clin Immunol. Article PubMed Google Scholar. The importance of Th2-like cells in the pathogenesis of airway allergic inflammation.
Clin Exp Allergy. Woodfolk JA. T-cell responses to allergens. Romagnani S. Predominant TH2-like bronchoalveo-lar T-lymphocyte population in atopicasthma. New Engl J Med. T-helper type 2-driven inflammation defines major subphenotypes of asthma. J Immunol. Epithelial damage and angiogenesis in the airways of children with asthma.
Asthma phenotype and IgE responses. Eur Respir J. The prevalence of severe refractory asthma. Ray A, Kolls JK. Trends Immunol. Heterogeneity of phenotypes in severe asthmatics. Respiratory Medicine. Asthma phenotypes in inner-city children. Proceeding of the ATS workshop on refractory asthma.
These mediators can either be preformed e. Mast cells are resident in vascularized tissues throughout the body and are particularly prominent within tissues that interface the external environment. The pathological roles of eosinophils, mast cells, and basophils in allergy are either directly or indirectly linked with the presence of allergen-specific IgE in allergic individuals. Mast Cells : Mast cells rapidly degranulate upon crosslinking of specific IgE by corresponding allergens and release preformed histamine, proteases chymase, tryptase and cytokines TNF-alpha , followed by the rapid synthesis and release of prostaglandins and leukotrienes.
Overall, mast cells are the main players in the early phase of the allergic reaction, due to their resident localization at sites where they are most likely to encounter environmental or food allergens e.
Much of the acute phase allergic reaction can be ascribed to the direct effects of histamine on the surrounding tissues, for example the swelling, itching, sneezing in allergic rhinitis; and this also explains the benefits of using histamine receptor antagonists.
Mast cells are also associated with a multitude of other conditions such as asthma, drug reactions, anaphylaxis, mastocytosis, urticarial. Far less well appreciated and understood are their possible supporting roles in obesity, atherosclerosis and tumor growth and development.
Thus, therapies that target eosinophils may help control diverse diseases, including atopic disorders such as asthma and allergy, as well as diseases that are not primarily associated with eosinophils, such as autoimmunity and malignancy. Eosinophil-targeted therapeutic agents that are aimed at blocking specific steps involved in eosinophil development, migration and activation have recently entered clinical testing and have produced encouraging results and insights into the role of eosinophils.
In this Review, we describe recent advances in the development of first-generation eosinophil-targeted therapies and highlight strategies for using personalized medicine to treat eosinophilic disorders. Lee, J. Defining a link with asthma in mice congenitally deficient in eosinophils.
Science , — Humbles, A. A critical role for eosinophils in allergic airways remodeling. Castro, M. Reslizumab for poorly controlled, eosinophilic asthma: a randomized, placebo-controlled study. Care Med. Haldar, P. Mepolizumab and exacerbations of refractory eosinophilic asthma. This study reveals an important role for eosinophils in asthma exacerbations in patients with refractory eosinophilic asthma.
Treatment with mepolizumab resulted in significantly fewer severe exacerbations in a population of patients with a history of recurrent severe exacerbations.
Jacobsen, E. The expanding role s of eosinophils in health and disease. Blood , — This review highlights studies that have implicated a role for eosinophils in several diseases and healthhomeostasis. Eosinophils in health and disease: the LIAR hypothesis. Allergy 40 , — Lowe, D. Tumour-associated eosinophilia: a review. Cormier, S. Pivotal advance: eosinophil infiltration of solid tumors is an early and persistent inflammatory host response.
Simson, L. Regulation of carcinogenesis by IL-5 and CCL a potential role for eosinophils in tumor immune surveillance. Chu, V. Eosinophils are required for the maintenance of plasma cells in the bone marrow.
Nature Immunol. This study documents a novel role for eosinophils in promoting the survival of long-lived plasma cells in the bone marrow. Immunization induces activation of bone marrow eosinophils required for plasma cell survival. Hruz, P. Escalating incidence of eosinophilic esophagitis: a year prospective, population-based study in Olten County, Switzerland. Allergy Clin. Article PubMed Google Scholar. Bohm, M. Article Google Scholar.
Mori, Y. Identification of the human eosinophil lineage-committed progenitor: revision of phenotypic definition of the human common myeloid progenitor. This study identified the lineage-committed eosinophil progenitor in human bone marrow and also showed increased numbers of eosinophil progenitors in patients with eosinophilia.
Iwasaki, H. Identification of eosinophil lineage-committed progenitors in the murine bone marrow. Sehmi, R. A novel marker of progenitor cell commitment towards eosinophilic differentiation.
Hogan, S. Eosinophils: biological properties and role in health and disease. Allergy 38 , — Ahlstrom-Emanuelsson, C.
Eosinophil degranulation status in allergic rhinitis: observations before and during seasonal allergen exposure. Filley, W. Identification by immunofluorescence of eosinophil granule major basic protein in lung tissues of patients with bronchial asthma. Lancet 2 , 11—16 Kephart, G. Marked deposition of eosinophil-derived neurotoxin in adult patients with eosinophilic esophagitis. Noguchi, H. Tissue eosinophilia and eosinophil degranulation in syndromes associated with fibrosis.
Chung, H. Deposition of eosinophil-granule major basic protein and expression of intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 in the mucosa of the small intestine in infants with cow's milk-sensitive enteropathy. Brottman, G. Effect of eosinophil peroxidase on airway epithelial permeability in the guinea pig.
Gleich, G. Cytotoxic properties of the eosinophil major basic protein. Tai, P. Toxic effects of human eosinophil products on isolated rat heart cells in vitro. Rosenberg, H. Domachowske, J. Hernnas, J. Eosinophil cationic protein alters proteoglycan metabolism in human lung fibroblast cultures.
Cell Biol. Muniz, V. Eosinophil crystalloid granules: structure, function, and beyond. Meagher, L. Opposing effects of glucocorticoids on the rate of apoptosis in neutrophilic and eosinophilic granulocytes. Druilhe, A. Glucocorticoid-induced apoptosis in human eosinophils: mechanisms of action. Apoptosis 8 , — Her, E. Eosinophil hematopoietins antagonize the programmed cell death of eosinophils.
Cytokine and glucocorticoid effects on eosinophils maintained by endothelial cell-conditioned medium. Jain, N. Ogbogu, P. Hypereosinophilic syndrome: a multicenter, retrospective analysis of clinical characteristics and response to therapy. Hamelmann, E. Anti-interleukin 5 but not anti-IgE prevents airway inflammation and airway hyperresponsiveness.
Rothenberg, M. Treatment of patients with the hypereosinophilic syndrome with mepolizumab. This clinical trial showed that administration of mepolizumab to steroid-dependent patients with hypereosinophilic syndrome resulted in significant reductions in the dose of corticosteroid needed and also resulted in corticosteroid discontinuation.
Stein, M. Anti-IL-5 mepolizumab therapy for eosinophilic esophagitis. Pavord, I. Mepolizumab for severe eosinophilic asthma DREAM : a multicentre, double-blind, placebo-controlled trial.
Lancet , — Gong, L. CCR3 antagonists: a survey of the patent literature. Expert Opin. Pease, J. Eotaxin and asthma. Tenscher, K. Blood 88 , — Kampen, G. Eotaxin induces degranulation and chemotaxis of eosinophils through the activation of ERK2 and p38 mitogen-activated protein kinases. Blood 95 , — Fulkerson, P. Eosinophils and CCR3 regulate interleukin transgene-induced pulmonary remodeling. Natl Acad. USA , — Ahrens, R. Waddell, A. Ying, S. Association with airway hyperresponsiveness and predominant co-localization of eotaxin mRNA to bronchial epithelial and endothelial cells.
Wegmann, M.
0コメント