Asthma is one of the world´s most common chronic airway diseases, characterised by recurrent symptoms associated with variable airflow obstruction, bronchial hyperresponsiveness (BHR), and inflammation [1
]. The term asthma encompasses a syndromic definition including different clinical phenotypes and pathophysiological pathways, yielding a complex clinical scenario with several disease variant classifications [3
]. Many subtypes of asthma have been described on the basis of different clinical phenotype definitions associated with different triggers [4
]. For its part, the endotype classification includes different etiological and pathophysiological mechanisms, thus allowing identifiable gene-expression profiles and biomarkers for the design of new therapeutic strategies [3
]. Wenzel [4
] emphasised that although several endotype classifications of asthma have been proposed, none have been met with wide-ranging agreement.
The prevalence of allergic diseases has increased all over the world in recent decades [9
], and in fact these conditions have become a real pandemic phenomenon [13
]. On average, around 10–12% of children under the age of 6 or 7 years, 14% of adolescents aged between 7 and 14 years, and 5% of the global population suffer from asthma, and more than 250,000 annual deaths are attributed to the disease [14
]. Up to 90% of childhood asthma is allergic, and children with allergies have a 30% increased risk of developing asthma [16
]. After following a cohort of 1041 children with mild-moderate asthma, the Childhood Asthma Management Program (CAMP) reported that asthma appears to be periodic in 39% of cases and persistent in 55%, and that no effect of earlier anti-inflammatory treatment was noted [17
]. The CAMP study emphasised that children are exposed to a wide variety of environmental factors which are known to trigger symptoms, despite attempts to modify the environment in their homes [20
Asthma affects patients of all ages and represents a serious public health problem with a high socioeconomic impact. In Europe, annual care costs (direct and indirect) of persistent asthma in the whole of the European population aged from 15 to 64 years exceed EUR 19 billion [21
]. Therefore, in order to achieve prompt control, there is an urgent need to determine the factors directly associated with the disease. The search for new therapeutic options should focus on clearly stated key molecules.
Most cases of asthma are due to an immunoglobulin E (IgE)-mediated reaction after sensitization to inhaled allergens. IgE belongs to the Ig family (Table 1
), proteins that bind to the specific antigens which are used by the immune system to protect an organism against pathogens. Allergic asthma is associated with increased levels of circulating total and specific IgE, with a clear involvement both at the onset of the disease and during its chronic phase. Thus, IgE has emerged as the most promising target for the management of the allergic form of the condition [22
]. In this review, we discuss the central role of IgE-mediated pathophysiological and inflammatory mechanisms in all the phases of allergic asthma.
2. The Iceberg Model of Allergic Asthma: Immunological Pathways beyond Visible Clinical Symptoms
If we compare asthma with an iceberg, clinical symptoms such as cough, wheezing, breathlessness, and chest tightness, which can be directly observed by clinicians, would be the equivalent to the tip of the iceberg. However, to explain the complex process of asthma that triggers clinical symptoms we need to explore the iceberg in depth (Figure 1
A patient with allergic asthma may clinically manifest the aforementioned symptoms after exposure to a specific environmental allergen to which he or she is sensitised, and may suffer later exacerbations. Some patients show persistent symptoms over time. As previously mentioned, most asthmatic children present an allergic component [29
], and the presence of allergen-specific IgE has been shown to predict later asthma development [31
]; this allergic phenomenon correlates with asthma severity in different age ranges and populations [32
]. Allergic sensitization is identified in 86% of adults with asthma onset before the age of 6 years and in 49% of young adults aged between 22 and 40 years [36
]. Asthma severity, poor asthma control, and recurrent exacerbations all correlate with high serum IgE levels [35
]. Hospitalisations and deterioration in lung function have also been associated with high total serum IgE [35
]. Several studies of IgE-mediated persistent severe allergic asthma suggest that the disease is better controlled under a treatment that targets the IgE pathway [40
4. Immunopathophysiology of IgE in the Asthma Continuum
Although the development of allergic reactions is characterised by a wide heterogeneity, IgE plays a crucial role in bridging innate and adaptive immunopathological events in the continuum of allergic asthma, from allergic sensitization to clinical early and late phases, and its evolution into a chronic condition, by acting on different immune cells and modifying their functions (Figure 2
IgE exerts important immunomodulatory effects by binding to its high-affinity and low-affinity receptors. The FcεRII is constitutively expressed in different cells, helping to perpetuate the allergic response. When IgE links to its receptors on the effector cells, even in the absence of an allergen, there is an induction of the receptor expression, a cytokinergic effect, and a stabilization of the receptors [52
]. This increases the viability of MC and can induce the cascade of proinflammatory cytokines in contact with the allergen [52
]. MC have a central role in the initiation of the allergic immune response, providing signals that induce and/or maintain IgE synthesis as well as Th2 lymphocyte differentiation [54
]. Recent findings have also indicated that MC have immunomodulatory properties [55
]. An ongoing IgE-dependent activation of MC may contribute to the increase in vascular damage, infiltration by inflammatory cells, and to the increase in the migration and maturation of DC [56
]. The consequence may be an increase in BHR and airway remodelling which appears to be strongly associated with the persistence of asthma.
For their part, Th2 cytokines have been considered as central mediators in allergic asthma, operating through mechanisms other than those classically implicated in allergic responses [58
]. Cytokines act on the bronchial epithelium, the mucosa and bronchial SMC, producing BHR and clinical manifestations of asthma. In some patients, this process becomes chronic, with IgE and MC as the initial drivers of the long-term pathophysiological changes and tissue remodelling associated with chronic allergic reactions [59
So, with the emerging knowledge on the role of IgE as a key factor in the pathophysiological process of allergic asthma, its therapeutic potential and relevance need to be reassessed.
5. Should IgE Blocking Be a Key Therapeutic Target for Allergic Asthma?
The idea that asthma is a chronic inflammatory airway disease has been the rationale for the treatment with anti-inflammatory agents, namely inhaled corticosteroids. However, assuming that inflammation is a consequence rather than the cause of the problem, treating allergic asthma with pleiotropic anti-inflammatory drugs alone would imply treating exclusively the tip of the iceberg. This approach has shown to be helpful to palliate symptoms, but this treatment does not modify the nature of the disease (Figure 1
In this scenario, a novel therapeutic approach to asthma and other allergic respiratory diseases focuses on interfering with the effects of IgE [60
]. Omalizumab is an anti-IgE humanised monoclonal antibody which inhibits IgE effector function by binding to free IgE at the same site as FcεRI, and thereby impedes IgE binding to FcεRI on effector cells, thus avoiding MC and basophil activation [61
]. Initial studies of omalizumab in patients with mild asthma showed that blocking IgE reduced the early bronchoconstriction response to inhaled allergens. Furthermore, omalizumab has been shown to decrease eosinophilia in blood [64
]. Omalizumab was approved for use in asthma and has been used for more than 10 years now, with extensive reports of evident clinical benefits in the literature [66
]. Moreover, omalizumab has helped to identify additional roles of IgE in allergic asthma beyond the suppression and blocking of the immediate allergic reaction [67
Biological modification of Th2-type cells has been also reported as an approach for specific patients in whom the appropriate Th2 immune pathway is predominant [67
]. Table 2
summarises some conceptual aspects that distinguish between the approaches of blocking Th2 cytokines and the IgE, which are not mutually exclusive.
Recent findings suggest that, under certain conditions, treatment with anti-cytokine monoclonal antibodies can potentiate the target cytokine rather than neutralise its activity [71
]. This is likely due to the formation of cytokine/anti-cytokine complexes, which might explain why targeting cytokines could be clinically inefficient if the employed doses of the monoclonal antibody are low enough to favour the formation of these immune complexes [71
]. It should be also borne in mind, in any case, that IgE blockade also indirectly inhibits the production of Th2 cytokines by memory allergen-specific Th2 cells and MC, thus contributing to inhibit acute early responses, reducing inflammation and maintaining homeostasis [72
The clinical and immunological benefits of blocking IgE include: (i) the prevention of IgE fixation to high-affinity receptors in MC and basophils, thus avoiding the release of mediators after allergen linkage; (ii) the reduction of basophils [75
] and MC survival; (iii) the decrease in local IgE production; (iv) the blockade of total circulating IgE and IgE located in the lymph nodes; (v) the disabling of IgE-facilitated allergen presentation (DC and Th2 lymphocytes) [76
]; (vi) the decrease in the release of IL-4 [72
] and IL-5 [73
] and consequently in their concentration levels; and (vii) an additional antiviral effect by upregulating the expression of interferons by plasmacytoid DC through a reduction of the crosslinking of IgE with the DC FcεRI [77
]. This latter feature may have a clinical impact on viral-induced asthma exacerbations, which are very frequent in children [77
]. Bearing all these aspects in mind, the final outcome of anti-IgE treatment is an attenuation of most of the acute and late responses, together with a lower risk of exacerbations observed in patients with allergic asthma. Thus, it appears that the modulation of IgE is of paramount importance for the successful treatment of allergic asthma.
Numerous clinical trials and real-life studies have demonstrated anti-IgE (omalizumab) as a successful treatment to reduce exacerbations, hospitalisations, visits to specialists, and medication use as well as to improve symptom control and quality of life in severe asthma patients [66
]. Other biologicals targeting type 2 cytokines or their receptors have been also recently approved or are under development as add on therapies for severe asthma, such as anti-IL5 monoclonal antibodies (mAbs), anti-IL5Rα, or anti-IL4Rα mAbs [81
]. As above discussed, due to the central role of IgE in the allergic inflammatory pathways, anti-IgE treatments have been also shown to partially impair the production of Th2 cytokines such as IL-5, IL-4, and IL-13. However, up to date, head-to-head comparative studies for all these biological agents have not been reported and future research will help to elucidate which severe asthma specific phenotypes/endotypes might better benefit from each specific biological treatment.
Allergic asthma is a heterogeneous airway disease triggered by the exposure of the patient to environmental allergens. Traditionally, asthma and allergic diseases have been broadly defined and treated with non-specific anti-inflammatory drugs and bronchodilators. With the recognition of allergic asthma as an allergen-specific disease with heterogeneous phenomena, together with the recent cluster analysis definition, and molecular and clinical phenotyping, a more targeted therapy may open up new avenues for the treatment of allergic asthma.
IgE plays a central role from the very start of the disease and throughout its continuum. Controlled clinical trials and real-life studies carried out over more than 10 years have demonstrated that IgE blocking shows a notable profile of effectiveness, efficacy, and safety in the treatment of moderate to severe allergic asthma [88
]. Blocking the IgE axis appears to have a series of effects beyond its expected mechanistic action, as new information concerning the roles of IgE in the pathophysiology of the allergic asthma comes to light. Future studies should assess the potential long-term disease-modifying effect of anti-IgE therapeutic strategies. Additional efforts should also be made to discover novel biomarkers and potential targets for improving the field of personalised and precise therapeutic strategies in order to prevent allergic asthma from becoming chronic.