NATURE IMMUNOLOGY VOLUME 16 NUMBER 1 JANUARY 2015 45 IMMUNOLOGY OF THE LUNG REVIEW Asthma is a chronic inflammatory disease of the conducting airways in which many cells of the innate and adaptive immune systems act together with epithelial cells to cause bronchial hyper-reactivity (BHR) (the tendency of smooth muscle cells in people with asthma to react to nonspecific stimuli such as cold air and exercise), mucus overproduction, airway wall remodeling and airway narrowing. In susceptible patients, this leads to repeated periods of shortness of breath, wheezing and chest tightness. The disease is very common in affluent societies, in which almost 1 in 10 children and 1 in 12 adults is affected, which results in substantial morbidity and annual health- care expenditure. Worldwide, up to 300 million people are affected. The total cost of the disease, both in direct medical costs and indirect costs caused by loss of productivity, is estimated to exceed $18 billion annually in the USA. In many patients, the disease can be controlled by a combination of an inhaled corticosteroid (which acts to suppress the inflammation) and a short- or long-acting β 2 -adrenergic agonist (which acts to open the constricting bronchial smooth muscle), but in some 5–10% of patients, the disease is refractory to corticosteroid treatment and often leads to hospital admissions caused by respiratory viral infection with rhinovirus. Traditionally, two forms of asthma have been defined in the clinic. Most children and roughly 50% of adults have allergic asthma, in which the disease coincides with allergic sensitization defined by the presence of serum immunoglobulin E (IgE) antibodies and/or a positive skin-prick test to the (lipo)proteins of common inhaled or ingested allergens such as house dust mite (HDM), animal dander, fungal spores, plant or tree pollen, or peanuts. In children, the disease starts with allergic sensitization, often accompanied by eczema in the first year of life. These children later develop allergic rhinitis and can progress to asthma. This stepwise increase of symptoms has been called the ‘atopic march’. In particular, children with multiple allergies at a young age are likely to develop asthma 1 , and large studies have found that up to half of patients with atopic eczema developed asthma later in life 2 . In up to 80% of cases, patients with allergic asthma have concurrent allergic rhinitis. The ‘united airways disease’ hypothesis proposes that allergic rhinitis and asthma are manifestations of the same underlying disease process and that each influences the severity of the other. Nonallergic (intrinsic) asthma often develops later in life and, per its definition, has neither IgE reactivity to allergens in the serum nor any obvious involvement of the adaptive immune system such as type 2 helper T cells (T H 2 cells). This form of the disease is more common in women, is often associated with chronic rhinosinusitis and nasal polyps, as well as obesity, and is difficult to treat, often requiring long-term treatment with systemic steroids. The field of clinical asthma diagnosis and treatment has undergone great concep- tual shifts through the advent of genome-wide expression studies and the first clinical trials using targeted therapies with biological agents. As with many chronic inflammatory diseases, clinicians now realize that the division of asthma into only two clinical forms has been an oversimplification. Different asthma phenotypes, each with a distinct pathophysiology, are now being defined as asthma endotypes. The endotypes differ in terms of genetic susceptibility, environmental risk factors, age of onset, clinical presentation, prognosis and response to standard and new therapies 3–5 . Asthma is therefore increasingly seen as a syndrome rather than a single disease 5,6 . In people with asthma who smoke, there is also considerable clinical overlap with chronic obstructive pulmonary disease, whose immunological basis has been reviewed 7 . In this Review, we will focus on the underlying immuno- logical basis of the various asthma endotypes, integrating results from human studies targeting particular pathways with results from animal studies in which a great deal of molecular detail has been gathered. Eosinophilic asthma as a T H 2 disorder Since the development of the field of pulmonary immunology, asthma has been seen as the hallmark T H 2 disorder of the lungs. This was supported by the early findings that asthmatic airway inflammation measured in bronchoalveolar lavage (BAL) fluid, bronchial biopsies or induced sputum is often eosinophilic in nature, regardless of whether the patient is allergic or not 8–11 . In initial studies of people with mild 1 VIB Inflammation Research Center, Ghent University, Ghent, Belgium. 2 Department of Respiratory Medicine, University Hospital Ghent, Ghent, Belgium. 3 Department of Pulmonary Medicine, Erasmus MC, Rotterdam, the Netherlands. Correspondence should be addressed to B.N.L. ([email protected]) or H.H. ([email protected]). Received 1 October; accepted 7 November; published online 18 December 2014; doi:10.1038/ni.3049 The immunology of asthma Bart N Lambrecht 1–3 & Hamida Hammad 1,2 Asthma is a common disease that affects 300 million people worldwide. Given the large number of eosinophils in the airways of people with mild asthma, and verified by data from murine models, asthma was long considered the hallmark T helper type 2 (T H 2) disease of the airways. It is now known that some asthmatic inflammation is neutrophilic, controlled by the T H 17 subset of helper T cells, and that some eosinophilic inflammation is controlled by type 2 innate lymphoid cells (ILC2 cells) acting together with basophils. Here we discuss results from in-depth molecular studies of mouse models in light of the results from the first clinical trials targeting key cytokines in humans and describe the extraordinary heterogeneity of asthma. npg © 2015 Nature America, Inc. All rights reserved.
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nature immunology VOLUME 16 NUMBER 1 JANUARY 2015 45
I m m u n o l o g y o f t h e l u n g r e v i e w
Asthma is a chronic inflammatory disease of the conducting airways in which many cells of the innate and adaptive immune systems act together with epithelial cells to cause bronchial hyper-reactivity (BHR) (the tendency of smooth muscle cells in people with asthma to react to nonspecific stimuli such as cold air and exercise), mucus overproduction, airway wall remodeling and airway narrowing. In susceptible patients, this leads to repeated periods of shortness of breath, wheezing and chest tightness. The disease is very common in affluent societies, in which almost 1 in 10 children and 1 in 12 adults is affected, which results in substantial morbidity and annual health-care expenditure. Worldwide, up to 300 million people are affected. The total cost of the disease, both in direct medical costs and indirect costs caused by loss of productivity, is estimated to exceed $18 billion annually in the USA. In many patients, the disease can be controlled by a combination of an inhaled corticosteroid (which acts to suppress the inflammation) and a short- or long-acting β2-adrenergic agonist (which acts to open the constricting bronchial smooth muscle), but in some 5–10% of patients, the disease is refractory to corticosteroid treatment and often leads to hospital admissions caused by respiratory viral infection with rhinovirus.
Traditionally, two forms of asthma have been defined in the clinic. Most children and roughly 50% of adults have allergic asthma, in which the disease coincides with allergic sensitization defined by the presence of serum immunoglobulin E (IgE) antibodies and/or a positive skin-prick test to the (lipo)proteins of common inhaled or ingested allergens such as house dust mite (HDM), animal dander, fungal spores, plant or tree pollen, or peanuts. In children, the disease starts with allergic sensitization, often accompanied by eczema in the first year of life. These children later develop allergic rhinitis and can progress to asthma. This stepwise increase of symptoms has been called the ‘atopic march’. In particular, children with multiple allergies
at a young age are likely to develop asthma1, and large studies have found that up to half of patients with atopic eczema developed asthma later in life2. In up to 80% of cases, patients with allergic asthma have concurrent allergic rhinitis. The ‘united airways disease’ hypothesis proposes that allergic rhinitis and asthma are manifestations of the same underlying disease process and that each influences the severity of the other.
Nonallergic (intrinsic) asthma often develops later in life and, per its definition, has neither IgE reactivity to allergens in the serum nor any obvious involvement of the adaptive immune system such as type 2 helper T cells (TH2 cells). This form of the disease is more common in women, is often associated with chronic rhinosinusitis and nasal polyps, as well as obesity, and is difficult to treat, often requiring long-term treatment with systemic steroids. The field of clinical asthma diagnosis and treatment has undergone great concep-tual shifts through the advent of genome-wide expression studies and the first clinical trials using targeted therapies with biological agents. As with many chronic inflammatory diseases, clinicians now realize that the division of asthma into only two clinical forms has been an oversimplification. Different asthma phenotypes, each with a distinct pathophysiology, are now being defined as asthma endotypes. The endotypes differ in terms of genetic susceptibility, environmental risk factors, age of onset, clinical presentation, prognosis and response to standard and new therapies3–5. Asthma is therefore increasingly seen as a syndrome rather than a single disease5,6. In people with asthma who smoke, there is also considerable clinical overlap with chronic obstructive pulmonary disease, whose immunological basis has been reviewed7. In this Review, we will focus on the underlying immuno-logical basis of the various asthma endotypes, integrating results from human studies targeting particular pathways with results from animal studies in which a great deal of molecular detail has been gathered.
Eosinophilic asthma as a TH2 disorderSince the development of the field of pulmonary immunology, asthma has been seen as the hallmark TH2 disorder of the lungs. This was supported by the early findings that asthmatic airway inflammation measured in bronchoalveolar lavage (BAL) fluid, bronchial biopsies or induced sputum is often eosinophilic in nature, regardless of whether the patient is allergic or not8–11. In initial studies of people with mild
1VIB Inflammation Research Center, Ghent University, Ghent, Belgium. 2Department of Respiratory Medicine, University Hospital Ghent, Ghent, Belgium. 3Department of Pulmonary Medicine, Erasmus MC, Rotterdam, the Netherlands. Correspondence should be addressed to B.N.L. ([email protected]) or H.H. ([email protected]).
Received 1 October; accepted 7 November; published online 18 December 2014; doi:10.1038/ni.3049
TheimmunologyofasthmaBart N Lambrecht1–3 & Hamida Hammad1,2
Asthma is a common disease that affects 300 million people worldwide. Given the large number of eosinophils in the airways of people with mild asthma, and verified by data from murine models, asthma was long considered the hallmark T helper type 2 (TH2) disease of the airways. It is now known that some asthmatic inflammation is neutrophilic, controlled by the TH17 subset of helper T cells, and that some eosinophilic inflammation is controlled by type 2 innate lymphoid cells (ILC2 cells) acting together with basophils. Here we discuss results from in-depth molecular studies of mouse models in light of the results from the first clinical trials targeting key cytokines in humans and describe the extraordinary heterogeneity of asthma.
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to moderate asthma, increased numbers of CD4+ cells that produce interleukin 4 (IL-4) and IL-5 were found in BAL fluid and mucosal biopsies, correlating with the degree of airway eosinophilia12. Subsequent unsu-pervised clustering algorithms have shown that the various asthma endotypes fall into TH2hi and TH2lo clusters on the basis of the presence or absence of the cytokines IL-4, IL-5 and IL-13 and eosinophils in blood and tissue4,13. The presence of serum IgE (atopy) is the prototypical hallmark of adaptive TH2 immunity, driven by IL-4-induced class switching of the immunoglobulins synthesized by B cells. Although it is very easy to measure, the presence of high serum titers of IgE is a poor predictor of whether there is TH2 signature gene expression in the tissues and whether the patient will develop asthma. There may be better surrogate biomarkers of the TH2hi endotype of asthma, such as levels of serum IL-25 and periostin that correlate well with tissue eosinophilia14.
In mouse models of asthma driven by inhalation of the model anti-gen ovalbumin (OVA) after intraperitoneal sensitization to OVA in alum, the genetic or antibody-mediated depletion of CD4+ T cells abolishes key features of asthma, whereas the adoptive transfer of TH2-polarized CD4+ T cells from mice with transgenic expression of an OVA peptide–specific T cell antigen receptor (TCR) leads to the induc-tion of asthma features15–18. Conversely, asthma is suppressed by the transfer of CD4+ type 1 helper T cells (TH1 cells) or administration of IL-12, which induces the TH1 response19. Together with the early data from people with asthma, the case for CD4+ TH2 cells as controllers of the disease was therefore verified (Fig. 1). Mice that lack the key TH2 cytokines IL-4, IL-5 or IL-13 all had substantial reductions in asthma features in the OVA model20. In the mouse, IL-4 is necessary for the development of adaptive TH2 immunity and IgG1 and IgE antibodies to OVA, and for priming the vessel wall for eosinophil extravasation; therefore, the OVA model relies heavily on IL-4 (refs. 20,21). IL-13 was found to be necessary and sufficient for mounting BHR and for goblet cell metaplasia, the process by which epithelial cells transdifferentiate and begin producing thick mucus containing the mucins MUC5AC and MUC5B, which clog the airway lumen22,23 (Fig. 1).
In humans, treatment with an antibody to the α-chain of the recep-tor for IL-4 (dupilumab; Regeneron Pharmaceuticals), which effec-tively blocks downstream signaling via the receptors for IL-4 and
IL-13, is able to improve lung function and reduce the frequency of exacerbation in people with moderate to severe asthma with high levels of eosinophils in the blood24. In a phase 2 trial, blocking IL-13 in humans with lebrikizumab (Genentech) also improved lung- function parameters, particularly in the TH2hi endotype25.
Eosinophilia in lung tissue is driven by IL-5, which supports the development of eosinophils in the bone marrow, and by the recruit-ment of eosinophils to the lung mucosa and interstitium via pro-duction of eotactic chemokines such as eotaxins 1, 2 and 3 (CCL11, CCL24 and CCL26, respectively). Eosinophil-derived products such as eosinophil peroxidase cause BHR directly and activate adaptive immunity through effects on dendritic cells (DCs)26–28. Eosinophils can also present antigen directly to primed effector T cells29. Studies of mice genetically modified to lack eosinophils have shown that these cells also contribute to airway wall remodeling and subepithelial membrane thickening via the release of transforming growth factor-β (TGF-β), although this has not been seen in all asthma models30,31. Similar to neutrophils, eosinophils upon activation undergo cytolysis and release extracellular DNA traps that contain eosinophilic granules. As these granules maintain the capacity for ligand-induced secretion, the formation of DNA traps could lead to high local concentrations of eosinophilic toxins such as eosinophil-derived neurotoxin, cationic proteins (eosinophil peroxidase) and major basic protein, which can damage structural cells of lungs32,33 (Fig. 1).
The elimination of eosinophils from humans through the use of antibody to IL-5 (mepolizumab; GlaxoSmithKline) led to a reduc-tion in exacerbation frequency in a subset of patients with high lev-els of circulating eosinophils in blood and frequent exacerbations, even in those receiving inhaled steroids34. As exacerbations often require systemic steroids that have serious side effects, blocking IL-5
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Figure 1 Overview of functions of TH2 cells and ILC2 cells in asthma. TH2 cells and ILC2 cells share many features, such as expression of the transcription factor GATA-3, which drives the production of TH2 cytokines, and expression of the chemokine receptors CCR4, CCR8 and CRTH2. Through the production of IL-5, they control eosinophil development in the bone marrow. Via IL-13, they can cause goblet cell metaplasia and bronchial hyperreactivity and prime the vessel wall for upregulation of the adhesion molecule VCAM-1 and ICAM-1, thus priming eosinophil exit. TH2 cells make more IL-4. Both cell types have been found to produce IL-9 (not shown here), although this could be a separate population of TH9 cells. ECP, eosinophil cationic protein; MBP, major basic protein; VLA-4, integrin α4β1; VCAM-1, vascular cell adhesion molecule 1.
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endogenous IL-33, which activates ILC2 cells and causes pulmonary eosinophilia45. Subsequent data have linked ILC2 cells to the patho-genesis of allergic airway inflammation; for example, protease- containing allergens (papain and A. alternata) might activate ILC2 cells indirectly through an effect on lung epithelial cells44,46. The proteolytic injury induces the release of IL-33, which in turn acti-vates ILC2 cells to induce lung eosinophilia and BHR. Another way in which ILC2 cells can be activated in the lungs following allergen exposure is through expression of the cysteine leukotriene receptor CysLT1R47. LTD4, the main ligand for CysLT1R, can be induced after a single exposure to proteolytic allergens and has been found to regu-late the activation and proliferation of ILC2 cells47. Such data indicate that ILC2 cells can be activated very early after allergen exposure and that their production of IL-5 and IL-13 could cause some features of allergic asthma in a T cell–independent manner (Figs. 1 and 2). In addition to their role in allergy, ILC2 cells also contribute to BHR development in response to respiratory viruses such as influenza virus and rhinovirus in adult mice and neonatal mice, respectively48,49. In the context of infection with influenza virus, ILC2 cells that produce IL-5 also contribute to the accumulation of eosinophils in the lungs after viral clearance50. A role for ILC2 cells in viral infections might help to explain how viral exposure can cause or exacerbate asthma symptoms in some people.
Because many of the initial reports discussed above used RAG- deficient mice, in which the contribution of ILC2 cells might be over-rated due to their lack of a functional adaptive immune system, the relative contributions of ILC2 cells versus that of TH2 cells in asthma has remained unclear. Several groups have addressed this question in mice with an intact adaptive immune system. ILC2 cells have been found to represent more than half of the cells producing TH2 cytokines in the lungs of mice subjected to OVA- and HDM-induced asthma51. Due to a lack of RORα expression in the hematopoietic compart-ment, mice that lack ILC2 cells develop less-severe lung inflammation
can therefore reduce the use of oral steroids35. In people with asthma in whom IL-5 was blocked, there was a considerable reduction in the deposition of extracellular matrix compo-nents tenascin, lumican and procollagen III, possibly leading to less airway remodeling36. New drugs that target eosinophils currently under phase 3 clinical development include an antibody to the receptor for IL-5 (ben-ralizumab; AstraZeneca/MedImmune) that effects depletion of eosinophils for months after a single injection37.
ILCs in eosinophilic asthmaIn studies in humans, blockade of the receptor for IL-4 or of IL-5 has led to a favorable clinical response in patients with high eosinophil counts regardless of whether these patients were atopic or not. In mice, administration of allergens such as HDM or Alternaria alternata spores also led to airway eosinophilia in mice deficient in the RAG recombinase, which do not produce mature T cells or B cells. Such findings suggest that in both species, there are ways of generating type 2 cytokines and eosinophilia without involvement of the adaptive immune system (Fig. 2). Innate lymphoid cells (ILCs) were initially classified as non-T, non-B effector cells in many disease models of TH2 immunity38–40. Published reviews have described the nomen-clature of the distinctive forms of ILCs, some of which produce interferon-γ (IFN-γ) (group 1 ILCs, which include traditional natu-ral killer cells and ILC1 cells), TH2 cytokines (group 2 ILCs formerly known as ‘nuocytes’ or ‘natural helper cells’, now referred to as ‘ILC2 cells’), and IL-17 and/or IL-22, or are involved in the formation of lymphoid tissues (group 3 ILCs, which include ILC3 cells and lym-phoid tissue–inducer cells)41. In many ways, ILC2 cells resemble TH2 cells (Fig. 1). ILC2 cells lack antigen-specific receptors, but like TH2 cells they react to the epithelium-derived cytokines IL-25, IL-33 and thymic stromal lymphopoietin (TSLP)38–40. ILC2 cells that produce TH2 cytokines (IL-13, IL-5 and IL-9) were initially described in the gut of mice infected with helminths, where they contribute to tissue eosinophilia and to mucus production, crucial for worm expulsion42. ILC2 cells develop from common lymphoid progenitors in response to IL-7 and IL-33 and depend on the transcription factors GATA-3 and RORα. The activation of ILC2 cells is further induced by IL-25 and IL-33, produced mainly by epithelial cells in response to injury and stimula-tion via pattern-recognition receptors. The administration of either cytokine to the airways of mice induces the population expansion of ILC2 cells that produce IL-5 and IL-13 in the lungs and BAL fluid43,44. Intratracheal administration of chitin or infection with the intesti-nal nematode Strongyloides venezuelensis triggers the production of
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Figure 2 Relative roles of TH2 cells and ILC2 cells in two forms of eosinophilic asthma. In atopic asthma (left), eosinophilic airway inflammation and BHR are driven by adaptive TH2 cells that are stimulated by DCs to produce IL-5, IL-13 and IL-4, the latter driving IgE synthesis. In nonatopic or intrinsic asthma (right), which is not dependent on adaptive immunity, ILC2 cells produce IL-5 and IL-13 and thus cause eosinophilia and BHR. As there is no specific allergen involved and as ILC2 cells produce little IL-4, there is no associated IgE response from B cells. Modified from ref. 185. MHCII, MHC class II; TSLPR, receptor for TSLP; NKT cells, natural killer T cells.
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than their wild-type littermates do after intranasal administration of papain or HDMs52–54. The precise signals involved in the recruit-ment of ILC2 cells to the lungs after allergen exposure are not very clear, but microarray data suggest that the same chemokine recep-tors that attract TH2 cells (CCR4 and CCR8), the prostaglandin D2 receptor CRTH2 and CysLTR1 might be involved47,55. Production of the CCR4 ligands CCL17 and CCL22, depends on signaling via STAT6 in epithelial cells, and STAT6-deficient mice fail to recruit ILC2 cells to the airways56. The signals that dampen the recruitment and activation of ILC2 cells are only starting to be investigated. The resolvin lipoxin A4 has been shown to suppress IL-13 production by ILC2 cells, which indicates that the function of ILC2 cells in asthma could be regulated by anti-inflammatory lipid mediators57 (Fig. 2). Similarly, the uptake of apoptotic cells by lung epithelial cells (a proc-ess dependent on the small GTPase Rac) suppresses the production of IL-33 and in this way suppresses activation of ILC2 cells58. Some parasites have also evolved strategies to suppress the activation of ILC2 cells. Soluble excretory and secretory products of Heligmosomoides polygyrus block the recruitment of ILC2 cells in response to airway allergen exposure by blocking the epithelial production of IL-33 (ref. 59).
Although ILC2 cells can contribute to TH2 cell–mediated lung inflammation, the method of action by which this occurs remains unclear. Chitin is a common constituent of the wall of arthropods and helminths and is a well-known trigger for the recruitment of ILC2 cells to the lungs. After exposure to chitin, the IL-13 secreted by ILC2 cells is crucial for inducing the alternative activation of macrophages, whereas IL-5 controls early airway eosinophilia60. In addition to those effects on cells of the innate immune system, ILC2 cells can also directly or indirectly influence the adaptive immune system through the release of cytokines. ILC2 cells may provide an early source of IL-13 that polarizes naive CD4+ T cells to become TH2 cells. Although most TH2 priming occurs via IL-4, the experimental inhaled allergen papain is IL-4 independent but requires IL-13 from ILC2 cells to induce adaptive CD4+ T cells via migratory antigen- presenting DCs54. ILC2 cells have also been shown to express major histocompatibility complex (MHC) class II and costimulatory molecules, suggesting that they may themselves act as antigen- presenting cells, activating CD4+ T cells during the sensitization phase or during the effector phase. Despite their low expression of MHC class II, human ILC2 cells are able to drive the proliferation of HDM-specific CD4+ T cells ex vivo61. Mouse ILC2 cells are able to endocytose soluble OVA, but they are not able to induce OVA- specific naive CD4+ T cell proliferation unless antigen-derived peptides are added to the coculture. Although ILC2 cells can induce some degree of T cell proliferation under some circumstances and with soluble peptide antigen ex vivo, whether they also process and present antigens in vivo remains to be addressed. Also, gut ILC2 cells have considerable expression of MHC class II, whereas expression is much lower on lung ILC2 cells, which raises the question of whether ILC2 cells are antigen-presenting cells relevant to asthma.
Such studies have begun to shed light on the relative contribution of ILC2 and TH2 cells in allergy. However, to pinpoint the exact role of each cell population in the disease, there is an urgent need for new tools that would allow the specific depletion of ILC2 cells at different stages of the response (sensitization versus effector phase). Crossing Cd4-Cre mice (which express Cre recombinase from the T cell– specific Cd4 promoter) to mice in which a loxP-flanked gene encoding the diphtheria toxin receptor is inserted into the locus encoding the inducible costimulator ICOS produces progeny in which it is possible to deplete mice of ILC2 cells while sparing CD4+ TH2 cells61. With this
model, it will be essential to investigate which of the allergic asthma features are governed by ILC2 cells. Given the fact that depletion of CD4+ T cells in chronic experimental asthma affects mainly airway eosinophilia without affecting the development of airway remodeling, one possibility would be that ILC2 cells control airway remodeling18. In support of this concept, just like CD4+ TH2 cells, ILC2 cells have been shown to produce the TGF-β-like molecule amphiregulin, which contributes to airway remodeling by acting on fibroblasts and epi-thelial repair processes62,63. Alternatively, they might be the driving force of the alternative activation of macrophages, which contribute to airway wall remodeling by promoting collagen synthesis60.
Despite the rapid increase in knowledge about ILC2 cells in experi-mental models of type 2 immunity, still very little is understood about the clinical relevance of ILC2 cells in human asthma. ILC2 cells may have a predominant role in a subset of people with severe, nonatopic asthma who have high eosinophil counts in the blood and lungs and have a TH2 signature in the tissues, which would explain why they respond favorably to blockade of the IL-4 receptor or IL-5 (Fig. 2). This subform of the TH2hi endotype cluster of asthma often occurs with chronic rhinosinusitis and nasal polyps and does not respond well to steroids. A subset of these patients also seem to have a colo-nization of the nasal sinuses and airways with filamentous fungi that might represent a chronic trigger for the innate immune system64. In patients with rhinosinusitis, there is an increase in GATA-3+CRTH2+ ILC2 cells in the nasal tissues65,66. The production of IL-5 and IL-13 is not as well suppressed by steroids in ILC2 cells as it is in CD4+ T cells. TSLP can induce this state of steroid refractoriness in ILC2 cells by inducing phosphorylation of the transcription factor STAT5 and by upregulating the prosurvival factor Bcl-xL
67. If ILC2 cells are driving disease in this subset of patients, it would explain the steroid refractoriness. The ILC2 cells could be stimulated by chronic epithelial activation induced, for example, by environmental pollut-ants, irritants, chronic airway mycosis or repetitive viral infections driving the expression of IL-25, IL-33 and TSLP (Fig. 2).
Neutrophilic asthma as a TH17 disorderAlthough asthma is classically associated with eosinophilia and TH2 cytokines, some patients show a neutrophil-predominant disease with an absence of TH2 cytokines. In particular, patients with late-onset and more severe forms of asthma seem to have neutrophilic inflammation with less reversible airway obstruction and a mixed TH1 and TH17 cytokine milieu68–70. The role of IL-17 and TH17 cells in allergic asthma has not been fully elucidated, with IL-17 sometimes favoring and sometimes protecting mice from the disease. These dis-crepancies can been explained by the timing of the neutralization or administration of IL-17, as a protective role for IL-17A in asthma has been observed only during the challenge phase71,72. Similar results have been obtained for IL-22, another cytokine produced by TH17 cells73. Another study showed that high exposure to diesel exhaust particles is associated with both exacerbated asthma symptoms and increased serum concentrations of IL-17A in children with atopic asthma74. Severe forms of asthma are characterized by increased airway remodeling. In some experimental asthma models driven by HDMs or ozone, IL-17A contributes to remodeling by promoting fibroblast proliferation75 and by counteracting the anti-inflammatory role of regulatory T cells76. In mice and humans, IL-17 can also cause direct contraction of bronchial smooth muscle cells and thus cause BHR in the absence of neutrophilic inflammation77. It remains to be conclusively shown where in asthmatic airways the IL-17A and IL-17F are produced. In addition to conventional TCRαβ+CD4+ T cells, TCRγδ+ T cells, invariant natural killer T cells and ILC3 cells
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can be a source of copious IL-17, and the relative contribution of all of these might differ in various asthma endotypes. The cytokine production by TH17 cells is notoriously resistant to inhibition by ster-oids, which explains why neutrophil-rich inflammation driven by TH17 cells is the pathological correlate of steroid-resistant asthma. A clinical trial with a antibody that neutralizes the human receptor for IL-17 (brodalumab; Amgen/AstraZeneca), which blocks the activity of IL-17A, IL-17F and IL-25, has shown minimal effects on outcome measures of asthma in mild to moderate disease78. It is possible that subgroups of patients, particularly those with large numbers of spu-tum neutrophils or with a high degree of lung function reversibility, would respond more favorably70. There is also a complex interaction between TH17 cell–driven asthma and tumor-necrosis factor (TNF). Lung and systemic levels of TNF are increased in patients with severe steroid-resistant asthma, although some studies have not confirmed this70,79. In an adoptive transfer model of TH17 OVA-specific T cells, neutralization of TNF led to reduced neutrophilic influx in the lung tissue and airspaces, associated with amelioration of lung function parameters such as lung compliance but not airway hyper-resistance 70. In clinical trials, the results of TNF blockade have also been vari-able79–81. It is still unclear if TNF blockade in IL-17-rich neutrophilic asthma would also improve steroid responsiveness.
Overlap syndromesThe view of eosinophilic asthma as an exclusive TH2 disorder and neutrophilic asthma as an exclusive TH17 disorder is probably an oversimplification seen only at the extremes of a continuous spec-trum. In many cases, there is considerable overlap in the types of cytokines found in an asthma endotype, related to severity of disease. This has been nicely demonstrated in a model of fungal mycosis in mice, which at extremely high challenge levels exhibit immunophe-notype switching from a predominant TH2 response to TH1 and/or TH17 response(s)82. Some asthma features are induced by CD4+ T cells that produce both TH17 cytokines and TH2 cytokines. In mice, these IL-4+ TH17 cells induce more severe disease when transferred83. Another study has shown that the chitinase-like protein Ym1, tradi-tionally produced by alternatively activated macrophages elicited by IL-4 and IL-13, drives the production of IL-17 by γδ T cells and thus contributes to lung neutrophilia and damage in a TH2 setting84. IL-4+ CD4+ TH17 cells have also been identified in humans, and the amount of IL-17 released by such T cells in BAL fluid correlates with increased BHR and airway obstruction85.
It is also important to consider the contribution of the TH1 cell–derived cytokine IFN-γ in eosinophilic and neutrophilic asthma. Simultaneous transfer of OVA-specific TH1-polarized cells plus TH2-polarized cells into mice is able to exacerbate bronchial hyper-reactiv-ity in which IFN-γ acts together with IL-13 to cause smooth muscle contraction and activation of cells of the innate immune system and IFN-γ itself promotes the homing of TH2 cells to the lungs86–89. IL-18 drives the activation of TH1 cells that produce IL-13 and cause severe BHR90. The airways of asthmatics contain increased amounts of IFN-γ-producing CD4+ T cells, and there is a rise in the serum levels of this cytokine during acute attacks of asthma91,92. However, no studies of humans have assessed the therapeutic effect of IFN-γ blockade.
TH9 cells in asthmaIL-9 was initially thought to be a TH2-specific cytokine induced by IL-2, IL-4 and TGF-β93. TH9 cells have been identified as a distinct helper T cell subset94, and other studies have shown that additional stimuli such TSLP, signaling via receptors of the Notch family or ligation of the receptor OX40 (refs. 95–97) also contribute to the differentiation
of TH9 cells. Studies addressing the molecular pathways involved in IL-9 production have found that binding of the transcription factors Smad2, Smad3, STAT5, IRF4 and PU.1 to the Il9 promoter are essen-tial for TH9 differentiation and IL-9 production98–101. This process is influenced by the inhibitory SOCS proteins, and deficiency in CIS, a member of the SOCS family, causes increased TH2 differentiation and exacerbated asthma features100. IL-9 is a mast cell growth factor that promotes IL-4-driven antibody production by B cells102 and can also induce goblet cell metaplasia. IL-9 has high expression in the lungs of patients with asthma103, and in mice, the neutralization of IL-9 with antibodies has been shown to ameliorate OVA- and Aspergillus fumigatus–induced asthma symptoms101,104. In a chronic asthma model, antibody to IL-9 blocked the development of airway remod-eling by reducing mast cell numbers102. Although T cells were initially considered as the main source of IL-9, experiments with fate-mapping reporter mice have shown that following papain administration, ILC2 cells produce greater amounts of IL-9 than do T cells105. IL-9 derived from ILC2 cells has been shown to be an autocrine amplifier of ILC2 cell function by promoting their survival106. The relative contribu-tions of IL-9 derived from TH9 cells and that derived from ILC2 cells in allergic asthma remains to be addressed. Trials have been initiated to target IL-9 in patients with asthma (MEDI-528; MedImmune), but they have produced disappointing clinical results107.
Regulatory T cells in asthmaFor many years, it was postulated that inflammatory responses in asthma would develop because patients had a deficiency in natural or induced regulatory T cells (Treg cells). In mice, the usual outcome of the inhalation of harmless antigens such as OVA is tolerance, a process mediated by Foxp3+ induced Treg cells (iTreg cells)108. Indeed, mice that lack the intronic Foxp3 enhancer CNS1 show a paucity of iTreg cells and develop strong TH2 responses at mucosal sites, including the lungs109. iTreg cells are also found in the airways of mice with asthma, where they have high expression of neuropilin 1 (ref. 110). Adoptive-transfer studies of mice have revealed that Treg cells suppress asthma features through IL-10 and TGF-β, two cytokines able to suppress pulmonary DC activation111, and through direct interactions with endothelial cells, thus preventing angiogenesis112. Another possible mechanism involves IL-35 production by ICOS+ Treg cells that have the potential to suppress IL-17-induced BHR in mice113.
In healthy humans, immune responses to allergens can be consid-ered active peripheral tolerance driven mainly by IL-10 and TGF-β. The precise role of Treg cells in patients with allergic diseases has been much debated. In severe asthmatics, the number of Treg cells present in the blood and sputum is lower, and their suppressive activities are impaired compared with those of cells from healthy subjects114. Moreover, the percentage of Treg cells is also decreased in the BAL fluid of pediatric patients with asthma115. In adult patients, the data are more controversial, with some reports showing that the number of Treg cells in the lungs is increased116 or and other showing that number is decreased117. Despite such discrepancies, all studies agree that Treg cells are functionally impaired in people with asthma. Interestingly, this defect in Treg cell function in allergic patients seems to affect only the regulation of TH2 responses. In the blood of HDM- sensitized children, a population of Treg cells coexpressing the tran-scription factors Foxp3 and GATA-3 could suppress the production TH1 cytokines but not that of TH2 cytokines by peripheral blood mononuclear cells. This suggests that Treg cells in allergic patients might promote allergen-specific TH2 responses instead of control-ling them. In the mouse, a similar Treg cell population unable to sup-press TH2 responses has been reported. These Treg cells express the
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inhibitory molecule TIGIT and produce fibrinogen-like protein 2, which allows them to selectively spare TH2 responses while efficiently inhibiting TH1 and TH17 responses118. Whether this TIGIT+ popula-tion and the GATA-3+Foxp3+ T cells identified in allergic children are related or not remains to be addressed.
Epithelial cell–DC interactions in response to allergensWhatever the endotype of asthma, the various T cells or ILCs that control airway inflammation need to be activated. For T cell responses of all kinds, this involves the activation of antigen-presenting DCs that recognize the allergen and present it to T cells in the lymph nodes that drain the lungs (Fig. 3). Various studies have shown that DCs are necessary and sufficient for inducing TH2 and TH17 adaptive immu-nity to inhaled allergens in mice that have not encountered the aller-gens previously119. There are different subtypes of DCs in the lungs, broadly categorized as conventional DCs (cDCs) and plasmacytoid DCs (pDCs). Among cDCs, CD11b+CD172 (SIRP1α)+ cDCs that depend on the transcription factor IRF4 are necessary and sufficient to induce allergic sensitization120–122, whereas CD103+XCR1+ cDCs that depend on the transcription factors IRF8 and BATF3 induce tolerance to inhaled allergens123,124. pDCs also induce tolerance to inhaled antigens by inducing Foxp3+ Treg cell responses to inhaled antigens125,126. There has been much progress in understanding of the process of allergic sensitization by DCs. From such studies it has
become clear that airway epithelial cells are crucial in controlling DC activation127. Many allergens, such as A. fumigatus spores, cockroach or HDMs, have protease activity. Proteases (such as papain or Der p 1) act on epithelial cells to decrease barrier function by cleaving tight junction proteins and induce an innate cytokine response via stimulation of protease-activated receptors. A. fumigatus protease activity leads to the formation of fibrinogen-cleavage products in the fluid lining the lungs that activate Toll-like receptor 4 (TLR4) and in this way stimulate airway epithelial cells to produce IL-33 and TSLP, which activate DCs, ILC2 cells and basophils128. Cat dan-der and HDM extracts contain allergens (Fel d 1 and Der p 1) that directly stimulate TLR4 on epithelial cells to produce IL-1α, IL25, IL-33, TSLP and the cytokine GM-CSF129–131. After the inhalation of allergens, there is also the release of endogenous ‘danger signals’ such as uric acid, ATP and HMGB1 (refs. 132–134). Allergens such as HDMs can also be immunogenic by triggering C-type lectin recep-tors such as dectin-1 or dectin-2 on lung epithelial cells or DCs, which could contribute to mixed TH2 and TH17 immunity135,136. The epithe-lial cytokines induced by allergens or proteases induce TH2 immunity by activating CD11b+ cDCs (causing their migration and upregula-tion of costimulatory molecules such as OX40L) and by activating ILC2 cells and basophils that could be an important source of polar-izing IL-4 and/or IL-13 for priming TH2 immunity and avoiding tol-erance to inhaled allergens54,130,137–139 (Fig. 3). When there is too
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Figure 3 Epithelial cell–DC interactions during the sensitization and challenge phase of experimental asthma. Both lung cDCs and epithelial cells express pattern-recognition receptors and can be activated directly by allergens. In response to allergens, lung epithelial cells produce chemokines (CCL2 and CCL20) that attract immature pre-cDCs. Activated epithelial cells produce ‘instructive’ cytokines (for example, IL-1α, GM-CSF, IL-25, IL-33 and TSLP) and danger signals (ATP and uric acid) that favor the maturation of CD11b+ cDCs (which depend on the transcription factor IRF4 for maturation and migration). Activated lung CD11b+ cDCs then migrate to the draining mediastinal lymph nodes, where they induce TH2 and TH17 responses. Migration is stimulated by IL-13 derived from ILC2 cells. Some helper T cells start producing IL-21 and adopt a follicular helper T cell (TFH) fate to induce class switching to IgE in B lymphocytes. In the lymph nodes, DCs receive help from basophils to sustain TH2 responses. CD11chi DCs also have a predominant role during the TH2 effector phase of asthma, when the lungs are repeatedly exposed to allergens (right). During allergen challenge, poorly migratory CD11chi monocytic DCs and/or macrophages could locally restimulate effector function in lung-resident lymphocytes or they could recruit effector TH2 cells through the production of CCL17 and CCL22. IgE-mediated allergen recognition enhances TH2 responses to inhaled allergens, at least in humans.
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much endotoxin in the inhaled allergen fraction, however, TH1 immunity ensues. Many of the human genome-wide association studies of asthma and atopy have found single-nucleotide polymor-phisms in genes encoding molecules that control epithelial barrier function (for example, filaggrin) and control the production or responsiveness to epithelial cytokines, such as TSLP and IL1RL1 (which encodes the receptor for IL-33); this indicates a crucial role for epithelial cells in asthma. Also, many of the environmental risk factors for atopy and asthma, such as cigarette smoking, viral infections and air pollution, seem to converge on the epithelial cell–DC interaction127.
It has become increasingly clear that DCs and epithelial cells have an important role not only in sensitization to allergens but also in ongoing asthma (Fig. 3). There is an increase in the abundance of activated DCs in the airways of people with asthma and in mice with ongoing inflammation, and these form clusters with activated T cells around the airways and blood vessels in the lung140,141. Depletion of CD11chi cells during ongoing allergen challenge suppresses the salient features of asthma142,143. The monocyte-derived DCs that accumulate in the airways have some features of macrophages, such as the expression of the Fc receptors CD64 and FcεRI, and are poorly migratory. They also express the chitinase-like protein Ym1, like alter-natively activated macrophages143. Their main function is the local recruitment of effector T cells via the production of chemokines, and thus they compartmentalize ongoing inflammation to the airways120. In ongoing disease, epithelial cells continue to fuel airway inflam-mation by activating incoming monocytes to adopt an immunogenic phenotype and by producing chemokines and cytokines that activate eosinophils, neutrophils and other cells of the innate immune system. Epithelial cells that go through repeated cycles of injury and repair also contribute substantially to the process of airway wall remodeling via release of repair cytokines127. Such concepts are slowly making their way to clinical testing. AMG 157 (Amgen) is a human antibody to TSLP that has been shown to block the late asthmatic response and bronchoconstriction in response to allergen challenge in humans, and reduces eosinophil counts144. Human antibodies to GM-CSF and IL-1α have been developed for rheumatoid disease, but results for asthma have not yet been reported.
IgE effects on mast cell, basophil or DCs?IgE has the lowest concentration of all antibodies, and IgE is mainly known for its role in allergic disease, in which it has the potential to activate mast cells and basophils when crosslinked on the high-affinity IgE receptor FcεRI. In mast cells and basophils, this receptor complex is composed of FcεRIα and FcεRIβ and a dimer of FcεRIγ chains (FcεRI(αβγ2)). The expression of FcεRI is heavily influ-enced by serum concentrations of IgE and also by the TH2 cytokine IL-4. The presence of antigen-specific IgE in the serum of patients with asthma leads to the immediate suggestion that mast cells and basophils, armed with high-affinity IgE receptors, have an important role in the disease. However, studies of mast cell–deficient mice have produced conflicting results. In models of mild asthma without the systemic adjuvant alum, mast cells have an important proinflammatory role that is stimulated by IFN-γ145,146; in mod-els using alum or strong HDMs, mast cells are redundant147,148. In humans, the lack of clinical efficacy of antihistamines on the symp-toms and signs of asthma has always been taken as evidence that mast cells do not serve a big role in asthma. However, mast cells can infil-trate the bronchial smooth muscle layer and contribute to BHR149, possibly driven by the mast cell growth factor IL-9 and release of leukotrienes. In the TH2hi endotype of asthma, increased numbers
of mast cells have also been found between airway epithelial cells. Bronchial epithelial cells exposed to IL-13 produce the mast cell growth factor SCF, which might explain the increase in intraepithe-lial mast cells150.
Increased numbers of basophils have been found in the blood and tissues of patients with asthma and mice exposed to HDMs. Basophils are an important source of IL-4 that could contribute to TH2-type sensitization in trans by acting together with DCs151,152. In response to inhalation of papain, there is even cooperation between IL-33-activated basophils and ILC2 cells, in which basophil-derived IL-4 boosts the ter-minal differentiation and activation of ILC2 cells148 (Fig. 3). However, although they are proposed to have antigen-presenting function, basophils are not proficient at stimulating naive CD4+ T cells, and mice genetically modified to lack basophils (Mcpt8-Cre mice) develop normal asthma features in response to OVA in alum153. Basophils could also have an important role in the effector and recall response to allergens by producing lipid mediators and cytokines that prime the vessel wall for extravasation and stimulate CD4+ effector cells directly154, and they could be involved in tissue remodeling. Basophils are armed with the high-affinity IgE receptor and, just like mast cells, could react immediately when there is reexposure to relevant allergen.
Maybe the strongest indication of a role of the IgE in asthma is the clinical efficacy of anti-IgE strategies in human asthma. The drug omalizumab (Xolair; Genentech/Novartis) is a humanized mono-clonal antibody that binds to the constant domain of IgE, inhibit-ing its interaction with the high-affinity receptor FcεRI, and has proven efficacy in a subset of patients. Before this drug shows clini-cal effects in patients, it must be administered for a few weeks, which suggests that the drug does not work by inhibiting the early degranu-lation of mast cells or basophils. Upon prolonged treatment, there is also a reduction in TH2 cytokine production in lung tissues, which suggests that it affects the generation of effector TH2 responses155. Monocytes and circulating DCs of allergic humans express FcεRI(αγ2) without FcεRIβ156,157. The targeting of allergens to FcεRI via IgE leads to an improvement of 1000-fold in the activation of CD4+ T cells in vitro, most probably because FcεRI targets antigens to the MHC class II–rich endosomal compartment of DCs where peptides are loaded158. Ligation of FcεRI on DCs also leads to the production of CCL28, a chemokine that selectively attracts TH2 cells159. The effect of triggering FcεRI on DCs has been studied in vivo only recently. DCs in mice carrying a transgene expressing human FcεRI under control of the promoter of the gene encoding mouse integrin CD11c are at least 50 times more potent in presenting OVA antigen to CD4+ T cells when antigen-specific IgE is present160. Moreover, the presence of IgE on DCs primes naive T cells for TH2 differentiation, and recall responses to OVA antigen are stronger in vivo. Although mouse cDCs do not express FcεRIα, mouse DCs recruited in response to viral lung infec-tion or HDM exposure express FcεRIα in combination with FcεRIγ, which leading to the expression of functional FcεRI(αγ2)120,151,161. In mice, triggering of this receptor also leads to production of CCL28 and to IL-13 production in T cells.
Although triggering via FcεRI can lead to cellular activation dependent on the transcription factor NF-κB in DCs, it can also lead to the production of IL-10 and the tryptophan catabolizing enzyme indoleamine deoxygenase, which suggests that FcεRIα expression on DCs might also contribute to the inhibition of inflammation162. In support of that, a study of mice that express human FcεRIα on DCs has demonstrated that ligation of IgE on DCs by relevant allergen suppresses the production of inflammatory chemokines that attract mast cells and suppresses asthma in mice163.
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Susceptibility to respiratory viral infectionIn most patients with asthma, exacerbations are caused by relatively mild respiratory viruses, such as human rhinovirus (HRV), respiratory syncytial virus or adenovirus, or by influenza virus. In childhood, HRV is associated with persistent wheezing, which is a strong risk factor for asthma later in life164,165. Experimental infection with HRV-16 in asthmatics causes neutrophilic inflammation and steroid resistance166,167. In mice that express humanized integrin ligand ICAM-1, infection with HRV can exacerbate disease168,169. Experimental models of infection with Sendai virus have revealed that respiratory viruses can induce an innate immune response that leads to the activation of natural killer T cells and alternative activation of macrophages that sustain airway pathology via IL-13 (ref. 170).
In some asthma endotypes, virus-induced exacerbations are a major problem despite adequate control of disease. The increased suscepti-bility to viruses could be caused by a primary defect in innate antiviral immunity in some asthmatics, related to epithelial fragility and barrier disruption, or to defects in the production of TLR7 or interferon171 (Fig. 4). In the lung, antiviral immunity relies heavily on produc-tion of type I interferons (IFN-α and IFN-β) and type III interferons (IFN-λ, IL-28A, IL-28B and IL-29) and inducing interferon-stimulated genes, such as the gene expressing the the ubiquitin-like molecule ISG15. When exposed to HRV-16, epithelial cells from adult and pediatric patients with asthma produce less IFN-β and IFN-λ and have a less pronounced interferon-induced gene signature, particu-larly when the disease is poorly controlled172–174. It has been unclear whether this also causes an increased viral load in the lower respiratory tract, and whether defective interferon responses explain susceptibility to all viruses175–177. An alternative explanation for the enhanced susceptibility to viral infection is that allergic sensitization178 or the presence of TH2 cell–driven eosinophilic airway inflammation
suppresses antiviral immunity as a secondary effect. In support of that proposal, triggering of FcεRI on pDCs by IgE crosslinking interferes with the normal antiviral functions of pDCs and type I interferon production178–180. When bronchial epithelial cells are cultured with eosinophils, they are less able to produce type I and type III interferons in response to HRV, via eosinophil-derived TGF-β181 (Fig. 4). The interference with antiviral immunity by type 2 immune responses is probably an old adaptation response. Indeed, in the gut immune system, a suppressive effect of helminth infection on antiviral immunity to norovirus has been described182. Alternative activation of macrophages via IL-13 caused upregulation of the chitinase-like protein Ym1, which suppresses antiviral immunity182. Chitinases and chitinase-like proteins are strongly upregulated in mouse and human asthma and could be functionally linked to the diminished antiviral state of people with asthma or to more neutrophil-rich asthma84,183. Whatever the cause of the defect, the first trials using inhaled inter-ferons to treat viral exacerbations of asthma have been initiated184. It is also possible to target the function of chitinase-like proteins.
ConclusionsClinicians have begun to realize that asthma is a heterogeneous disease with many endotypes. Various aspects of innate or adaptive immunity to allergens, environmental triggers or viruses are involved in caus-ing sensitization to allergens, symptoms of asthma, exacerbations, and response to therapies. There is extensive crosstalk between the airway epithelium and cells of the immune system in the initiation and perpetuation of the disease. The results from the first intervention trials in humans with asthma reflect the heterogeneity of this disease. No single drug will be effective for all patients, but some drugs might be very effective in selected patients who are carefully identified on the basis of underlying immunological processes.
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Figure 4 Defective antiviral immunity in asthma. In the normal antiviral response to HRV (left), HRV attaches to epithelial cells by adhering to ICAM-1. Following viral entry, TLRs and the cytosolic receptor Mda5 are triggered in lung epithelial cells to induce type I and type III interferon responses. This leads to an antiviral state and controls viral replication, together with CD8+ T cell immunity generated by CD103+ cDCs. Other early sources of type I interferons include pDCs and recruited monocytic cells. In asthma (right), ICAM-1 expression is upregulated, which leads to more entry of virus. However, the induction of interferons is severely hampered. This could be intrinsic to asthma or might result from the suppressive functions of eosinophils and alternatively activated macrophages, acting via Ym1 to suppress antiviral immunity in the epithelium. pDCs armed with IgE also fail to produce type I interferons. The ensuing high viral load causes damage to the epithelium and thus causing locally present monocytic DCs and TH2 or TH17 cells to cause airway inflammation rich in neutrophils and eosinophils.
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AckNowLedgmeNtsSupported by the European Union European Research Council (B.N.L.), the European Union Framework Programme 7 (MedALL and EUBIOPRED to B.N.L.), the University of Ghent Multidisciplinary Research Platform (Group-ID, to B.N.L.) and Fonds Wetenschappelijk Onderzoek Vlaanderen (B.N.L. and H.H.).
comPetINg FINANcIAL INteRestsThe authors declare no competing financial interests.
reprintsandpermissionsinformationisavailableonlineathttp://www.nature.com/reprints/index.html.
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