International Journal of

Molecular Sciences

Review
dIvergEnt: How IgE Axis Contributes to the
Continuum of Allergic Asthma and
Anti-IgE Therapies
Óscar Palomares 1 , Silvia Sánchez-Ramón 2,3 , Ignacio Dávila 4 , Luis Prieto 5 ,
Luis Pérez de Llano 6 , Marta Lleonart 7 , Christian Domingo 8, * and Antonio Nieto 9
1 Department of Biochemistry and Molecular Biology, School of Chemistry, Complutense University of
Madrid, 28040 Madrid, Spain; oscar.palomares@quim.ucm.es
2 Department of Clinical Immunology and Health Research Institute of the Hospital Clínico San
Carlos (IdISSC), Hospital Clínico San Carlos, 28040 Madrid, Spain; ssramon@salud.madrid.org
3 Department of Microbiology I, Complutense University School of Medicine, 28040 Madrid, Spain
4 Allergy Service, University Hospital of Salamanca and Institute for Biomedical Research of
Salamanca (IBSAL), Biomedical and Diagnosis Science Department, Salamanca University School of
Medicine, 37008 Salamanca, Spain; idg@usal.es
5 Department of Allergy and Immunology, University of Valencia and Dr. Peset University Hospital,
46017 Valencia, Spain; prieto_jes@gva.es
6 Neumology Service, Hospital Universitario Lucus Augusti, 27003 Lugo, Spain; eremos26@hotmail.com
7 Novartis Farmacéutica, 08013 Barcelona, Spain; marta.lleonart@novartis.com
8 Pulmonary Service, Corporació Sanitària Parc Taulí, Department of Medicine, Universitat Autònoma de
Barcelona (UAB), 08193 Barcelona, Spain
9 Pediatric Pulmonology & Allergy Unit, Children’s Hospital La Fe, 46026 Valencia, Spain; nieto_ant@gva.es
* Correspondence: CDomingo@tauli.cat; Tel.: +34-937-231-010

Received: 28 March 2017; Accepted: 15 June 2017; Published: 21 June 2017

Abstract: Asthma is an airway disease characterised by chronic inflammation with intermittent or

permanent symptoms including wheezing, shortness of breath, chest tightness, and cough, which
vary in terms of their occurrence, frequency, and intensity. The most common associated feature
in the airways of patients with asthma is airway inflammation. In recent decades, efforts have
been made to characterise the heterogeneous clinical nature of asthma. The interest in improving
the definitions of asthma phenotypes and endotypes is growing, although these classifications do
not always correlate with prognosis nor are always appropriate therapeutic approaches. Attempts
have been made to identify the most relevant molecular and cellular biomarkers underlying the
immunopathophysiological mechanisms of the disease. For almost 50 years, immunoglobulin E
(IgE) has been identified as a central factor in allergic asthma, due to its allergen-specific nature.
Many of the mechanisms of the inflammatory cascade underlying allergic asthma have already been
elucidated, and IgE has been shown to play a fundamental role in the triggering, development, and
chronicity of the inflammatory responses within the disease. Blocking IgE with monoclonal antibodies
such as omalizumab have demonstrated their efficacy, effectiveness, and safety in treating allergic
asthma. A better understanding of the multiple contributions of IgE to the inflammatory continuum
of asthma could contribute to the development of novel therapeutic strategies for the disease.

Keywords: allergy; asthma; immunoglobulin E (IgE); biomarkers; immunological mechanisms;

immunomodulation; biological treatment; anti-IgE; omalizumab

1. Introduction
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

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Int. J. Mol. Sci. 2017, 18, 1328 2 of 14

inflammation [1,2]. The term asthma encompasses a syndromic definition including different clinical
phenotypes and pathophysiological pathways, yielding a complex clinical scenario with several
disease variant classifications [3,4]. Many subtypes of asthma have been described on the basis
of different clinical phenotype definitions associated with different triggers [4–7]. 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 [3,8]. 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 [9–12], 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 [14,15]. 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 [17–19]. 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.

Table 1. Summary of human immunoglobin and their main function.

Name Subclasses Form Location Main Function

Opsonization and immune exclusion by
Monomer, dimer Mucosal tissue and binding to noxious antigens and preventing the
IgA 2
and polymer blood adherence of microorganisms to the surface
epithelium [23]
Transmembrane antigen receptor of unexposed
Surface of mature B
IgD 1 Monomer antigen to complement the functions of IgM
cells and blood
[24,25]
To mediate the signalling response to
IgE 1 Monomer Blood
pathogens [26]
To bind to antigens to mediate the signalling
IgG 4 Monomer Blood
response to antigens [27]
Monomer and Surface of mature B
IgM 1 Initial response to infections [28]
pentamer cells and blood
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Int. J. Mol. Sci. 2017, 18, 1328 3 of 13

2. The Iceberg Model of Allergic Asthma: Immunological Pathways beyond Visible Clinical
2. The Iceberg Model of Allergic Asthma: Immunological Pathways beyond Visible Clinical
Symptoms
Symptoms
If we compare asthma with an iceberg, clinical symptoms such as cough, wheezing, breathlessness,
If we compare asthma with an iceberg, clinical symptoms such as cough, wheezing,
and chest tightness, which can be directly observed by clinicians, would be the equivalent to the tip of
breathlessness, and chest tightness, which can be directly observed by clinicians, would be the
the iceberg. However, to explain the complex process of asthma that triggers clinical symptoms we
equivalent to the tip of the iceberg. However, to explain the complex process of asthma that triggers
need clinical
to explore the iceberg
symptoms in depth
we need (Figure
to explore 1).
the iceberg in depth (Figure 1).

Figure 1. The Iceberg model of allergic asthma. Allergic asthma is characterised by a visible part of
Figure 1. The Iceberg model of allergic asthma. Allergic asthma is characterised by a visible part of
the disease; however, many pathophysiological changes of this complex process occur in the depths.
the disease;
Changeshowever, many
at the level of pathophysiological changes of
lymphatic nodes, peripheral this complex
blood, processappear
and submucosa occur in thethe
from depths.
Changes at the level
beginning of theof lymphatic
disease nodes,beperipheral
and should addressed blood,
in orderand submucosa
to minimise the appear
impact andfrom the beginning
persistency of of
the disease
symptoms.and should be addressed
The influence in orderacross
of IgE is present to minimise
all levelsthe impact
of the andFurther
iceberg. persistency
detailsofcan
symptoms.
be found The
influence
in theoftext.
IgEECP:
is present across
eosinophil all levels
cationic of the
protein, iceberg.
FcεRI: FurtherIgE
high affinity details canFcεRII:
receptor, be foundlowin the text.
affinity IgE ECP:
receptor,
eosinophil GM-CSF:
cationic granulocyte-macrophage
protein, FcεRI: high affinitycolony-stimulating
IgE receptor, FcεRII:factor,
lowIFNγ: interferon
affinity gamma, GM-CSF:
IgE receptor, IgE:
immunoglobulin E, IL:colony-stimulating
granulocyte-macrophage interleukin, ILC: innate lymphoid
factor, IFNγ: cells, LTC4: gamma,
interferon leukotriene IgE:C4,immunoglobulin
MBP: major
basic protein, MCP: monocyte chemotactic protein, MRP: myeloid
E, IL: interleukin, ILC: innate lymphoid cells, LTC4: leukotriene C4, MBP: major basic protein, related proteins, PAF:MCP:
platelet-activating factor, TGFβ: transforming growth factor beta, Th: T helper
monocyte chemotactic protein, MRP: myeloid related proteins, PAF: platelet-activating factor, TGFβ: cells, TLR: toll-like
receptors, TNFα: tumor necrosis factor alpha, Treg: regulatory T cells, TSLP: thymic stromal
transforming growth factor beta, Th: T helper cells, TLR: toll-like receptors, TNFα: tumor necrosis
lymphopoietin.
factor alpha, Treg: regulatory T cells, TSLP: thymic stromal lymphopoietin.

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
Int. J. Mol. Sci. 2017, 18, 1328 4 of 14

exacerbations. Some patients show persistent symptoms over time. As previously mentioned, most
asthmatic children present an allergic component [29,30], 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 [32–35]. 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 [35,37–39]. 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 [40–42].

3. The Role of Immunoglobulin E (IgE) in Allergic Asthma

The understanding of the immunological mechanisms underlying allergic asthma has advanced
significantly in recent decades. Today, it is accepted that there are two consecutive, well-defined stages:
the sensitization phase and the re-exposure phase. The re-exposure phase comprises two types of
event: early acute and late-phase reactions. Perpetuation of the inflammation may also contribute to
the chronic phase, which is associated with more severe clinical manifestations of asthma, including
frequent exacerbations as well as irreversible airway damage.

3.1. The Sensitization Phase

The immune allergic response begins with sensitization (Figure 1). This phase occurs when the
patient is first exposed to an allergen. At this stage, there are no clinical symptoms. Dendritic cells
(DC), which are the main allergen-presenting cells (APC) located in the respiratory tract, capture
the allergen and process it while migrating to the nearest lymph node. The processed allergen is
then presented to naïve CD4+ T lymphocytes in the context of major histocompatibility complex
(MHC)-class II-associated peptides. These T cells are activated and differentiated into allergen-specific
T helper type 2 (Th2) cells (a process which is partially dependent on interleukin IL-4) [43,44].
Allergen-specific Th2 cells collaborate in the activation and isotype-switching of B cells to produce high
levels of allergen-specific IgE antibodies. Once IgE is released into the circulation, it binds through its
Cε3 domain to high affinity IgE receptor (FcεRI) and CD23 located on the surface of effector cells, such
as mast cells (MC) and basophils and other relevant cells in the pathophysiology of asthma, such as
DC, monocytes, and smooth muscle cells (SMC).
During this phase, a pool of memory allergen-specific Th2 and B cells that will play an important
role in the subsequent phases is generated. Innate non-hematopoietic immunity is also present
during the sensitization phase, especially with the involvement of the epithelial cells. Classically, the
bronchial epithelium has been considered a merely physical barrier protecting the internal milieu
against foreign aggressions. Today, it is known that it is able to respond to several external stimuli
(allergens, viruses, proteases), triggering the production of Th2-promoting cytokines, such as thymic
stromal lymphopoietin, IL-25 or IL-33 [45], which activate DC, favouring the generation of type 2
responses and the further production of IgE. Other cells, such as basophils, natural killer T cells or type
2 innate lymphoid cells are also important in the sensitization phase, producing different cytokines
(such as IL-4) and amplifying Th2 responses.
B cells can also act as APCs, triggering Th2 differentiation and generating IgE-specific antibodies.
Memory B cells differentiate into short-lived plasma cells or to allergen-specific long-lived plasma cells,
which remain in the bone marrow. The IgE repertoire of a given patient can include specific low-affinity
IgE that can also trigger the sensitization phase [46]. Recently, a study has used high-throughput
DNA sequencing of Ig heavy chain rearrangements to identify clonal lineages of B cells containing
members expressing IgE [47]. The results demonstrate that the primary source of IgE in humans is the
secondary isotype switching of IgG1-expressing B cells. Thus, this suggests that IgE is derived from
antigen-experienced B cells rather than from naive B cells with low-affinity, non-mutated antibodies.
Int. J. Mol. Sci. 2017, 18, 1328 5 of 14

These data provide a basis from which to evaluate allergen-specific lineages with IgE members that
are responsible for human allergic disease [47].

3.2. The Re-Exposure Phase

3.2.1. The Acute Reaction

Upon re-exposure, the causative allergen cross-links to at least two IgE molecules bound to FcεRI
on MC or basophils, with a subsequent release of diverse preformed mediators (histamine, heparin,
TNF-α) and newly synthesised lipid mediators (prostaglandins and leukotrienes). At this point, an
IgE-mediated type I early hypersensitivity reaction can occur within minutes of allergen exposure.
These events may cause responses at a local level, such as bronchoconstriction, vasodilation, and/or
airway mucus secretion. These pathophysiological events trigger the allergy-associated symptoms of
nasal congestion, wheezing, sneezing, cough, conjunctivitis, runny nose, dyspnoea, and chest tightness.

3.2.2. The Late-Phase Response

Usually preceded by a clinically evident early-phase reaction, the late-phase response may
produce delayed and more persistent effects. It has been described in approximately 50% of adult
allergic asthmatic patients upon allergen challenge [48,49]. The late-phase reaction occurs after the
activation of memory allergen-specific Th2 cells by APC (DC and B cells) through a process partially
dependent on IgE-facilitated presentation and due to the accumulation of MC-derived mediators in
the exposed local tissues. Activated allergen-specific Th2 cells and MC produce different mediators,
cytokines, and chemokines that drive the infiltration and activation of inflammatory cells such as
eosinophils, memory Th2 cells, neutrophils, or basophils to the lung parenchyma.
Memory allergen-specific Th2 cells previously activated by IgE-facilitated presentation produce a
plethora of cytokines (IL-5, IL-13, IL-4 or IL-9), chemokines, and adhesion molecules that contribute to
the recruitment of eosinophils and to the activation of effector cells, which release a series of mediators
and toxic proteins (eosinophilic cationic protein, major basic protein, leukotrienes, etc.). These are
responsible for the typical pathophysiological findings of the late phases of allergic asthma: increased
vascular permeability, bronchial oedema, bronchospasm, and hypercrinia/dyscrinia.
Then, inflammatory cells (eosinophils) infiltrate the airways. This process is mainly mediated
by chemokines and IL-5 produced by allergen-specific memory Th2 cells. Th2 cells and Th2-derived
cytokines also contribute to the local production of IgE by B cells, airway muscle contraction, and
increased vascular permeability favouring inflammation and exacerbated mucus production by goblet
cells, all of which leads to bronchial hyperresponsiveness and obstruction, characteristic of the late
severe phases of allergic asthma. Other cells that can also contribute to the exacerbation of these
phenomena include epithelial cells, type 2 innate lymphoid cells producing Th2 cytokines, natural
killer T cells, and Th1 or Th17 cells.

3.2.3. The Chronic Phase

The late response can evolve into a chronic inflammatory response, which may be induced by
repetitive exposure to the specific allergen that stimulates allergen-specific Th2 cells and MC, which in
turn promote more eosinophilia and additional IgE production. This chronic phase typically involves
the presence not only of large numbers of innate and adaptive immune cells at the affected site, but
also the presence of changes in the extracellular space and alterations in the number, phenotype, and
function of structural cells in the affected tissues. In this regard, apart from its indirect effect on the
perpetuation of the inflammation, IgE may also play an important role in the airway remodelling, as
evidenced by recent studies which have suggested a direct effect of this immunoglobulin in airway
structural changes [50,51]. Persistent inflammation may promote the generation of airway remodelling,
leading to a progressive loss of lung function and fixed airway obstruction.
Int. J. Mol. Sci. 2017, 18, 1328 6 of 14

Int. J. Mol. Sci. 2017, 18, 1328 6 of 13

4. Immunopathophysiology ofof
4. Immunopathophysiology IgE
IgEininthe
theAsthma Continuum
Asthma Continuum
Although the development
Although the development of allergic reactions
of allergic is characterised
reactions is characterisedbybya awide
wideheterogeneity,
heterogeneity,IgE
IgEplays
a crucial
playsrole in bridging
a crucial innate and
role in bridging adaptive
innate immunopathological
and adaptive immunopathologicalevents in the
events in continuum
the continuumof allergic
of
allergic asthma, from allergic sensitization to clinical early and late phases, and its evolution
asthma, from allergic sensitization to clinical early and late phases, and its evolution into a chronic into a
chronic condition, by acting on different immune cells and modifying their
condition, by acting on different immune cells and modifying their functions (Figure 2). functions (Figure 2).

Figure
Figure 2. A2.continuum
A continuum scenario
scenario ininthe
theimmunoglobulin
immunoglobulin EE(IgE) (IgE)role in in
role allergic asthma.
allergic The The
asthma. IgE has
IgEahas a
central role in the continuum cascade of allergic reaction and participates in all phases: the
central role in the continuum cascade of allergic reaction and participates in all phases: the sensitivity sensitivity
phasephase reaction,
reaction, the early
the early clinical
clinical phase,phase,
the the
latelate clinical
clinical phase,
phase, andand
thethe final
final chronicconsequences.
chronic consequences. ILC2:
ILC2: type 2 innate lymphoid cells, Th: T helper cells, Treg: regulatory T cells.
type 2 innate lymphoid cells, Th: T helper cells, Treg: regulatory T cells.
IgE exerts important immunomodulatory effects by binding to its high-affinity and low-affinity
IgE exertsThe
receptors. important
FcεRII isimmunomodulatory
constitutively expressed effects by binding
in different to its high-affinity
cells, helping to perpetuateand low-affinity
the allergic
receptors. TheWhen
response. FcεRII IgEis links
constitutively expressed
to its receptors on thein different
effector cells,
cells, evenhelping to perpetuate
in the absence the allergic
of an allergen,
there is
response. an induction
When IgE links of to
theitsreceptor
receptorsexpression, a cytokinergic
on the effector effect,inand
cells, even thea absence
stabilization
of anof allergen,
the
receptors [52]. This increases the viability of MC and can induce the cascade
there is an induction of the receptor expression, a cytokinergic effect, and a stabilization of the of proinflammatory
cytokines
receptors [52].inThis
contact with thethe
increases allergen [52,53].
viability MC have
of MC and acan central role the
induce in the initiation
cascade of of the allergic
proinflammatory
immune response, providing signals that induce and/or maintain IgE synthesis as well as Th2
cytokines in contact with the allergen [52,53]. MC have a central role in the initiation of the allergic
lymphocyte differentiation [54]. Recent findings have also indicated that MC have
immune response, providing signals that induce and/or maintain IgE synthesis as well as Th2
immunomodulatory properties [55]. An ongoing IgE-dependent activation of MC may contribute to
lymphocyte differentiation
the increase in vascular[54]. Recentinfiltration
damage, findings have also indicated
by inflammatory thatand
cells, MCto have
the immunomodulatory
increase in the
properties [55].and
migration An maturation
ongoing IgE-dependent
of DC [56,57]. Theactivation of MCmay
consequence maybe contribute
an increase to in
theBHR
increase in vascular
and airway
damage, infiltration
remodelling which byappears
inflammatory cells,associated
to be strongly and to the withincrease in the migration
the persistence of asthma. and maturation of
DC [56,57]. ForThe consequence
their may be an
part, Th2 cytokines haveincrease in BHR and
been considered as airway
central remodelling
mediators in whichallergicappears
asthma, to be
operating through mechanisms other
strongly associated with the persistence of asthma. than those classically implicated in allergic responses [58].
For their part, Th2 cytokines have been considered as central mediators in allergicand
Cytokines act on the bronchial epithelium, the mucosa and bronchial SMC, producing BHR asthma,
clinical manifestations of asthma. In some patients, this process becomes chronic, with IgE and MC
operating through mechanisms other than those classically implicated in allergic responses [58].
as the initial drivers of the long-term pathophysiological changes and tissue remodelling associated
Cytokines act on the bronchial epithelium, the mucosa and bronchial SMC, producing BHR and clinical
with chronic allergic reactions [59].
manifestations of asthma. In some patients, this process becomes chronic, with IgE and MC as the
So, with the emerging knowledge on the role of IgE as a key factor in the pathophysiological
initialprocess
drivers
of of the long-term
allergic asthma, its pathophysiological
therapeutic potential andchanges andneed
relevance tissue remodelling
to be reassessed. 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.
Int. J. Mol. Sci. 2017, 18, 1328 7 of 14

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 [61–63]. 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 [64,65]. 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 [67,68].
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 [67,69,70]. Table 2 summarises some
conceptual aspects that distinguish between the approaches of blocking Th2 cytokines and the IgE,
which are not mutually exclusive.

Table 2. Physiological differences between immunoglobulin E (IgE) and T helper type 2 lymphocytes
(Th2) cytokines.

IgE Th2 Cytokines

Type I (and also IV) hypersensitivity Type IV hypersensitivity (IVb)
Recognition and specific memory for the involved
No memory
allergens (e.g., venoms, environmental irritants)
Control in the effector arm of the allergy Chemical messengers
Local and systemic effects Local effects
Mean half-life 2.5 days (months when linked to its
Mean half-life, minutes
receptor)
Central axis of Th2 response Redundancy in asthma
Beneficial physiological role: response against Beneficial physiological role: tissue repair and
helminthes response against extracellular organisms
Examples of hypersensitivity reaction: allergic Examples of hypersensitivity reaction: chronic
rhinitis, asthma, systemic anaphylaxis asthma, chronic allergic rhinitis

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 [72–74].
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
Int. J. Mol. Sci. 2017, 18, 1328 8 of 14

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 [77,78]. This latter feature may have a clinical impact on
viral-induced asthma exacerbations, which are very frequent in children [77–80]. 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 [81–87]. 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.

6. Conclusions
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 [88–92]. 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.

Acknowledgments: The authors wish to thank Emili González-Pérez and Mònica Giménez (TFS Develop) for
their assistance in writing this manuscript. An unrestricted grant was provided by Novartis Farmacéutica. for
literature search, preparation of tables and assistance in the editing of the manuscript, which was carried out by
TFS Develop.
Author Contributions: Óscar Palomares, Silvia Sánchez-Ramón and Antonio Nieto conceived and designed the
structure of the review and contributed to the writing, critical and editorial review of the manuscript. Ignacio
Dávila, Luis Prieto, Luis Pérez de Llano, Christian Domingo and Marta Lleonart contributed to the writing, critical
and editorial review of the manuscript. All the authors read and approved the final version of the manuscript.
Conflicts of Interest: Silvia Sánchez-Ramón, Ignacio Dávila and Oscar Palomares have received speaker fees
from Novartis Farmacéutica and participate in the ExIgE group sponsored by Novartis Farmacéutica. Ignacio
Dávila has additionally participated in advisory boards from Novartis Farmacéutica. Marta Lleonart is employee
of Novartis Farmacéutica. The rest of authors do not have any competing interest regarding this manuscript.
Int. J. Mol. Sci. 2017, 18, 1328 9 of 14

Abbreviations
APC Allergen-presenting cells
BHR Bronchial hyperresponsiveness
FcεRI High affinity IgE receptor
FcεRII Low affinity IgE receptor
FEV1 Forced expiratory volume in 1 second
FVC Forced vital capacity
IgE Immunoglobulin E
IL Interleukin
IS Immune system
MC Mast cells
SMC Smooth muscle cells
Th2 T helper type 2 lymphocytes

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