Seminars in Immunology 46 (2019) 101333

Contents lists available at ScienceDirect

Seminars in Immunology
journal homepage: www.elsevier.com/locate/ysmim

Review

Immunologic mechanisms in asthma T

a,b a,c,d a,c
Tadech Boonpiyathad , Zeynep Celebi Sözener , Pattraporn Satitsuksanoa ,
Cezmi A. Akdisa,c,*
a
Swiss Institute of Allergy and Asthma Research (SIAF), University of Zurich, Davos, Switzerland
b
Allergy and Clinical Immunology, Department of Medicine, Phramongkutklao Hospital, Bangkok, Thailand
c
Christine Kühne-Center for Allergy Research and Education (CK-CARE), Davos, Switzerland
d
Ankara University School of Medicine, Department of Chest Diseases Division of Clinical Immunology and Allergic Diseases, Ankara, Turkey

A R T I C LE I N FO A B S T R A C T

Keywords: Asthma is a chronic airway disease, which affects more than 300 million people. The pathogenesis of asthma
Asthma exhibits marked heterogeneity with many phenotypes defining visible characteristics and endotypes defining
Allergic molecular mechanisms. With the evolution of novel biological therapies, patients, who do not-respond to con-
Nonallergic ventional asthma therapy require novel biologic medications, such as anti-IgE, anti-IL-5 and anti-IL4/IL13 to
Eosinophilic
control asthma symptoms. It is increasingly important for physicians to understand immunopathology of asthma
Neutrophilic
Phenotype
and to characterize asthma phenotypes. Asthma is associated with immune system activation, airway hyperre-
Immunopathology sponsiveness (AHR), epithelial cell activation, mucus overproduction and airway remodeling. Both innate and
Mechanism adaptive immunity play roles in immunologic mechanisms of asthma. Type 2 asthma with eosinophilia is a
common phenotype in asthma. It occurs with and without visible allergy. The type 2 endotype comprises; T
helper type 2 (Th2) cells, type 2 innate lymphoid cells (ILC2), IgE-secreting B cells and eosinophils. Eosinophilic
nonallergic asthma is ILC2 predominated, which produces IL-5 to recruit eosinophil into the mucosal airway.
The second major subgroup of asthma is non-type 2 asthma, which contains heterogeneous group of endoypes
and phenotypes, such as exercise-induced asthma, obesity induced asthma, etc. Neutrophilic asthma is not in-
duced by allergens but can be induced by infections, cigarette smoke and pollution. IL-17 which is produced by
Th17 cells and type 3 ILCs, can stimulate neutrophilic airway inflammation. Macrophages, dendritic cells and
NKT cells are all capable of producing cytokines that are known to contribute in allergic and nonallergic asthma.
Bronchial epithelial cell activation and release of cytokines, such as IL-33, IL-25 and TSLP play a major role in
asthma. Especially, allergens or environmental exposure to toxic agents, such as pollutants, diesel exhaust,
detergents may affect the epithelial barrier leading to asthma development. In this review, we focus on the
immunologic mechanism of heterogenous asthma phenotypes.

1. Introduction
Asthma is a common chronic airway disease characterized by
variable airflow limitation secondary to airway narrowing, airway wall
thickening and increased mucus [1]. Airway narrowing results from
chronic airway inflammation secondary to plasma extravasation and
influx of the inflammatory cells such as eosinophils, neutrophils, lym-
phocytes, macrophages and mast cells. Airway hyperresponsiveness
(AHR) is an important physiologic feature of asthma. AHR is an ex-
aggerated response of the airways to a nonspecific stimuli, that would
produce little or no effect in healthy ones. Although asthma is often
defined as a reversible airway obstruction, it can evolve into irrever-
sible lung function impairment [2]. Increasing mucus production in the
airway lumen is one of the possible cause of the persistent airflow ob-
struction. Another mechanism of persistent airflow obstruction is
airway remodeling including pathologies such as goblet cell hyper-
plasia, excessive subepithelial collagen deposition, decreased epithelial
and cartilage integrity, airway smooth muscle hyperplasia and in-
creased vascularity [3].
Currently, asthma is considered as an umbrella diagnosis that con-
sists several variable clinical presentations (phenotypes) and distinct
pathophysiological mechanisms (endotypes) [4–6]. Allergic asthma is
the most common asthma phenotype with an early onset, sensitization
to an allergen, IgE related Th2-mediated background [7–9]. Type 2
immune response involves, Th2 cells, IgE-producing B cells, group 2
innate lymphoid cells (ILC2) and a small fraction of IL-4-producing NK

⁎
Corresponding author at: Swiss Institute of Allergy and Asthma Research (SIAF), Obere Str. 22 CH-7270, Davos Platz, Switzerland.
E-mail address: akdisac@siaf.uzh.ch (C.A. Akdis).

https://doi.org/10.1016/j.smim.2019.101333
Received 21 October 2019; Accepted 21 October 2019
Available online 06 November 2019
1044-5323/ © 2019 Elsevier Ltd. All rights reserved.
T. Boonpiyathad, et al. Seminars in Immunology 46 (2019) 101333

Fig. 1. Cellular compartments and pathways participates in immune mechanisms of allergic and nonallergic asthma. Airway epithelial cells contribute to type 2 and
non-type 2 inflammation, due to allergic or nonallergic (e.g. cigarette smoking and pollution) exposure. Epithelial cells secrete IL-25, IL-33 and thymic stromal
lymphopoietin (TSLP) together with dendritic cells, macrophages and NKT cells. These cytokines stimulate type 2 immune response via activated Th2 cells and ILC2.
IgE is involved in the early inflammatory process as a cause of allergic asthma. IL-5-secreting Th2 and ILC2 stimulates eosinophil-mediated inflammation. Th9
produces IL-9 which induce airway eosinophilic and allergic inflammation. Increasing numbers of CRTH2 expression on Th, Tc and Treg cells are found in the
immunopathology of allergic asthma. IL-1β and IL-23 secreted by epithelial cells induce neutrophilic inflammation stimulated by Th17 and ILC3.

cells and NK-T cells, basophils, eosinophils, mast cells and their major
cytokines. There is a complex network between type 2 cytokines (IL-4,
IL-5, IL-9 and IL-13) which are mainly secreted from type 2 immune
cells and alarmins (IL-25, IL-33 and TSLP) which are released from
tissue cells, particularly epithelial cells. Nonallergic or intrinsic asthma
includes a subset of patients with non-Th2 inflammation [2,10]. The
major mechanism leading to a non-type 2 response is thought to result
from an irregular innate immune response, including intrinsic neu-
trophil abnormalities and activation of the IL-17-mediated pathway.
The immunologic mechanisms of asthma are shown in Fig. 1. The
molecular and cellular mechanisms of asthma have been well-char-
acterized, however, not fully understood. Therefore, this review aims to
summarize the heterogenous asthma mechanisms and to highlight new
findings of the research that have helped to better understand and
manage asthma over the last few years
2. Allergic asthma
Allergic asthma is considered as the most common type of asthma,
which usually induced by sensitization to environmental allergens [11].
These environmental aeroallergens are house dust mites (HDM), grass,
weed and tree pollens, fungal spores, animal dander, etc. After sensi-
tization, symptoms of allergic asthma usually occur due to the sub-
sequent exposures to the allergens. A recent study indicated that dif-
ferent types of aeroallergens and specific sensitization profiles are
related to different clinical manifestations of allergic respiratory dis-
eases (rhinitis with/without asthma), different clinical symptoms, and
different levels of severity [12,13]. Initiation of immune response, often
begins with the activation and differentiation of allergen-specific Th2
cells, and triggered by allergens. Later on, immunoglobulin E (IgE) is
produced against allergens. IgE dependent mast cells are activated and
eosinophils recruit into the lungs, and eventually persistent airway in-
flammation and asthma symptoms occur [14].
2.1. Th2 cells
Th2 cells mediate these functions by producing various cytokines
such as IL-4, IL-5, and IL-13. They are considered as important mole-
cules for management of allergic asthma. IL-4 is a cytokine that induces
differentiation of naïve T cells to Th2 cells [15]. IL-5 is responsible for
the maturation and release of eosinophils in the bone marrow [16]. IL-
13 induces proliferation of IgE-producing B cells and endothelial cells
[17]. Recent developments revealed that the induction of allergen-re-
active Th2 cells requires a two-step procedure including initial exposure
or “sensitization” and reactivation with second exposure. T cell induc-
tion with an allergen is a complicated process that requires numerous
interactions between several cell types in the lungs and lymph nodes.
Another Th2 cytokine, IL-31 and IL-31R concentrations are also in-
creased in the serum of allergic asthma patients together with stem cell
factor [18]. Indeed, IL-33 is demonstrated to induce the expression of
Th2 cytokine and activation of basophils and eosinophils [12]. Che-
mokine receptors such as CCR4, CCR8, CXCR4 and CCR3 are expressed
on Th2 cells. CCR4 regulates chemotaxis of Th2 cells and its ligands
CCL17 and CCL22, are increased in the patients with allergic asthma.
CCR8 can induce eosinophilia and AHR and may be elevate in Th2 cells
in the lungs and airways of allergic asthmatics [13]. CXCR4 which is
participated in Th2 cell migration into the lungs and treatment of al-
lergic mice with selective CXCR4 inhibitors, significantly reduces AHR
and inflammatory responses [14].
2.2. Type 2 innate lymphoid cells
Type 2 innate lymphoid cells (ILC2s) are derived from common
lymphoid progenitor and belong to the lymphoid lineage. These cells
produce type 2 cytokines such as IL-4, IL-5, IL-9, and IL-13. ILC2s and
IL-33-ST2 receptor pathway play an important role in the development
of allergic diseases and asthma [15]. ILC2s under the control of the
transcription factors RORα and GATA3 [15]. In a mice model, lack of T

2
T. Boonpiyathad, et al.
and B cells, activated ILC2s can induce eosinophilia and AHR [16]. A
recent study indicated that induced Tregs (iTregs) suppress the pro-
duction of ILC2-driven, pro-inflammatory cytokines IL-5 and IL-13. The
suppression of Tregs is blocked by preventing direct cellular contact or
by inhibiting the ICOS-ICOS-ligand (ICOSL) pathway [15,17]. There-
fore, the regulation of ILC2 function is very important via the interac-
tion of ICOS-ICOSL [15]. In other words, both paths are very important
in the regulation of ILC2 function [18]. In addition, the decrease in
cytokine production from ILC2s is controlled by IL-10 and TGF-β.
Therefore, ILC2s play a pivotal role in the initiation, enhancement, and
steroid resistance of allergic airway inflammation [18].
2.3. Th9 cells
Th9 cells produce IL-9 which have the potential to induce eosino-
philic inflammation, mucus hypersecretion and hyperreactivity in the
airways [21]. Airway inflammation induced by Th9 cells, is strongly
stimulated by OX40 signaling in T cells [22]. OX40 activates the ubi-
quitin ligase TRAF6, which triggered the induction of NF-kB-inducing
kinase (NIK) in CD4+ T cells and the non-canonical NF-kB pathway
which subsequently lead to Th9 differentiation [23]. Moreover, mTOR
complex 2 controls Th9 differentiation during allergic airway in-
flammation [24]. Patients with allergic asthma have higher Th9 cells
and IL-9 concentrations in their circulation [25,26]. IL-9, impairs IFN-γ
production and synergistically promotes IL-4-induced IgE secretion
[25]. IL-9 plays a role in steroid-resistant asthma but anti-IL-9 mono-
clonal antibody has not been found beneficial in controlling asthma
symptoms and reducing asthma exacerbation [27].
2.4. Dendritic cells
Airway dendritic cells (DCs) play a crucial role in providing capacity
to integrate signals from exposure to allergens and translate them di-
rectly into allergen-specific T cell responses [28]. Regulation of DC
activation is a key mediated immune response to allergens. Activation
of DCs can be triggered by direct interaction with the foreign allergen;
however, it is recognized that functional activation of DCs is critically
influenced by interactions with other cells of innate immune system
[29]. The DC lineage consists of conventional DCs (cDC) and plasma-
cytoid DCs (pDC). Lung DCs are heterogeneous cell population which
comprises two different cDCs; type 1 (cDC1s) and type 2 cDCs (cDC2s).
Compared to other DC subsets, cDC1s have less capacity to take up
allergens and are associated with tolerogenic function [30]. cDC1s can
induce the differentiation of Tregs when expose to HDM through re-
tinoic acid (RA) and peroxisome proliferator-activated receptor-gamma
(PPARγ) induction [31].
cDC2s are important for induction of Th2 and Th17 cell differ-
entiation in HDM-induced asthma [32]. HDM can be recognized by
innate receptors on the cell membrane of DCs, including C-type lectin
receptors, such as Dectin-2 [33]. Dectin-1−/− mice did not develop
eosinophilic inflammation and also did not show an induction of Th2 or
Th17 cytokines in an HDM-mediated asthma model [34]. In addition,
cDC2s express OX-40 ligand (OX-40 L) which is essential for Th2 cell
differentiation [35]. OX-40 L and CCL17 are higher on cDCs of patients
with asthma than healthy controls [36]. Allergen inhalation induces
only DC2s to migrate to bronchial tissue and causes an increase of IL-
25-receptor on both cDCs and pDCs [37]. In an allergic reaction, IgE-
bound antigens are rapidly introduced into antigen-specific CD4+ T
cells by DCs. Moreover, TSLP-stimulated cDCs of allergic asthmatic
patients produce IL-9 that leads to polorization of Th9 [38]. ADAM10 is
a glycosylated type I membrane protein that expressed on DCs and
involved in the development of Th2 immune response [39]. Further-
more, cDC1 has been shown to induce Th2 differentiation after ex-
posure to live-attenuated viral particles, this indicates that, in asth-
matics, cDC1s shift towards a phenotype that promotes Th2 during viral
infections [40].
3
Seminars in Immunology 46 (2019) 101333
2.5. Natural killer T cells
Natural killer T cells represents an important innate T cell subset.
They involve cell-cell interaction and down-stream modulation of DCs.
Invariant natural killer T (iNKT) cells, a sub group of NKT cells, are
suggested to modulate Th1/Th2 balance via the engagement of en-
dogeneous or exogeneous ligands to Toll-like receptor 4 (TLR4) in iNKT
cells. iNKT cells and mucosal-associated invariant T (MAIT) cells re-
spond rapidly to antigens bound to CD1d and MR1 molecules, respec-
tively, and immediately exert effector functions by producing various
cytokines and granules [31]. Sixty percent of CD4+ T cells in the
bronchoalveolar lavage from severe asthmatic patients are iNKT cells
[41]. The number of iNKT cells were significantly increased in per-
ipheral blood and sputum of patients with severe asthma, too [42,43].
Th2-like iNKT cells might be involved in development of asthma ex-
acerbation. MAIT cells exist in the lungs and contribute to produce Th2
cytokines but several reports have indicated the different roles for these
cells in asthma [44].
Signaling via TLR4 in innate immune cells results in the generation
of type 1 cytokines and consequently the development of Th1/Th17 cell
immunity [45]. Polymorphism of the components that involved in TLR4
signaling might be correlated with asthma, allergy and AHR [46]. It was
demonstrated that the presence of TLR4 and MyD88 molecules are
necessary for development of allergic responses. [47]. TLR4 has been
shown to be essential for the induction of airway inflammation by fungi
derived allergens and that, they bind to TLR4 on epithelial airway cells
and macrophages supporting inflammatory signals and Th2 cell de-
velopment [48]. On the other hand, MyD88 is known to be critical for
induction of experimental asthma induced by Alternaria extract [49].
MyD88 is shared by all TLRs except TLR3 as well as IL-33 which also
plays a role in inducing Th2 responses [50]. TLR4 ligands regulate iNKT
cell functions in pulmonary diseases.
2.6. Eosinophils
Eosinophils are effector cells of the innate immune system and they
contain cytotoxic granules. By degranulation of eosinophils, numerous
toxic proteins such as eosinophil-derived neurotoxin (EDN), eosinophil
cationic protein (ECP), eosinophil peroxidase (EPO), major basic pro-
tein (MBP), cytokine-mediated activation (IL-5) and lipid mediators,
such as cysteinyl leukotrienes (cysLTs) are released [51]. Beside blood
eosinophilia, tissue eosinophilia is also considered as an important
feature of allergic inflammation and asthma. Eosinophils tend to ac-
cumulate at sites of allergic inflammation and contribute to the devel-
opment of bronchial asthma [52]. They may have a role in airway re-
modeling via producing transforming growth factor (TGF)-β and cysLTs
and they induce AHR with MBP production [53]. CysLTs may involve in
the accumulation of eosinophils in the airways of asthmatics. Inhalation
of LTE4 stimulates the accumulation of eosinophils in asthmatic airways
[54]. LTD4 induces transendothelial migration of eosinophils and re-
lease of specific granule proteins primarily through β2 integrin and the
cysLT1 receptor [55]. Development and maintenance of the eosino-
philic inflammation in the airways is contribution of cysLTs, together
with the Th2 network. Two independent studies showed that serum IL-
5, EDN, and ECP were modulated following benralizumab treatment.
The decrease seen in eosinophil count after benralizumab, results in a
significant reduction also in EDN and ECP concentrations. This in-
dicates that cytotoxic granule proteins are not released after the re-
duction of eosinophils. [56]. The eosinophil recruitment is likely with
the adhesion of eosinophils to endothelial cells, through the α4 in-
tegrin/vascular cell adhesion molecule (VCAM)-1 [57]. VCAM-1 is
upregulated by IL-4 and IL-13 in endothelial cells. The interaction of
eosinophils with VCAM-1 induces eosinophil activation [57]. Eotaxin
and its receptor, CCR3, are expressed higher in the airways of asthmatic
patients than the controls [58]. Basophils may be particularly important
in eosinophilic asthma. Increasing sputum basophil number in the
T. Boonpiyathad, et al.
patients with eosinophilic asthma was reported [59,60].
2.7. Mast cells
Mast cells are essential in the development of asthma and may have
substantial effects on smooth muscles, mucous hyper-secretion and
tissue remodeling, particularly in the airways, by releasing proteases
such as tryptase and growth factors [61]. Mast cells express high levels
of IL-33 receptor ST2 and have been shown to be activated by IL-33. IL-
33 stimulates mast cells to produce Th2 cytokines, particularly IL-13 via
5-/12-Lipoxygenase cascade [62]. Number of mast cells are increased in
allergic and non-allergic asthma but the accumulation of mast cells is
more evidenced for the allergic asthmatics [63]. Moreover, mast cells
are more active in bronchial mucosa of the allergic patients than non-
allergic ones [64].
They are the major cellular sources of PGD2. Mast cell numbers and
PGD2 concentrations are increased in the airways of patients with se-
vere asthma [65]. D prostanoid (DP) and chemoattractant receptor-
homologous molecule (CRTH2), receptors for PGD2, are expressed on
Th2 cells. Recently, the role of CRTH2 in the pathogenesis of asthma
has been highlighted. It was demonstrated that CRTH2 expression on T
cells (Th2, Tc and Treg), ILC2s and eosinophils is higher in eosinophilic
allergic asthma than nonallergic asthma and healthy controls [66].
Moreover, CRTH2+ Treg cells have been shown to have defective
suppressor functions and decreased numbers of CRTH2+ Treg cells in
patients with allergic asthma are found to be correlated with improved
asthma control [66].
2.8. Immunoglobulin E
IgE antibodies are responsible for the “early phase” of an allergic
reaction and considered to have a minor role in the “late phase” reac-
tion [67]. The biological role of IgE is complex and related to its ability
to influence the functions of several immune and structural cells that
involved the pathogenesis of chronic allergic inflammation via specific
receptors, such as high-affinity (FcεRI) and low-affinity CD23 (or
FcεRII) receptors [67]. FcεRI is expressed by mast cells, basophils, DCs,
airway smooth muscle cells, epithelial cells, endothelial cells, and eo-
sinophils. IgE facilitates antigen presentation by DCs. The allergen
captured by DCs, binds to FCεRI receptors and is then presented to
memory Th2 cells [68]. Cross linked IgE on DCs, leads to 1000-fold
increase in activation of T cells and production of CCL28 (chemokine
attracts Th2 lymphocytes) [69]. Moreover, FcεRI activation blocks, or
at least reduces, intracellular signals involved in the production of type
I IFN that are degraded by the anti-viral response [70].
CD23 expression on B cells is a major part of the adaptive immune
response to inhaled HDM allergen to induce allergen-specific Th2 re-
sponse [71]. IgE has a direct effect on eosinophil functions such as
activation, release of eosinophil peroxidase, increase expression of in-
tegrin and release of TNF-α [67]. IgE directly activates airway smooth
muscles to produce IL-4, IL-5, IL-13, TNF-α, TSLP and chemokines
(CCL5, CCL11, CXCL8, CXCL10) These causes contraction and pro-
liferation of the airway smooth muscles, leading to airway remodeling
[72]. CD23 which also expressed on airway epithelial cells involved in
the transport of IgE-allergen complexes across the polarized airway
mucosal barrier [73]. IgE+ memory B cells and plasmablasts were
elevated in allergic patients and correlated with Th2 cell numbers [74].
2.9. Epithelial cells
Airway epithelium forms the first line of defense against airborne
pathogens and prevents organism from infectious particles. Airway
epithelial damage following exposure to environmental factors causes
inflammation. Subsequent to the histological changes in the airway
mucosal epithelium, functional abnormalities occur. Such changes are
believed to have a significant association with the pathophysiology of
4
Seminars in Immunology 46 (2019) 101333
asthma. Barrier functions of the lung epithelium is mainly provided by
tight junctions (TJ). These heteromeric protein complexes form the
sealing interface between adjacent epithelial cells [75].
Bronchial epithelial cells release significantly greater amounts of IL-
8, GM-CSF, RANTES, and sICAM-1 in asthmatic patients than in non-
allergic controls [76]. When the epithelial barrier is damaged, epithelial
cytokines such as TSLP, IL-25, and IL-33 are released [77]. IL-25 and IL-
33 activate ILC2s directly to produce Th2-cytokines [78]. Viral infec-
tions like rhinovirus, can also induce IL-33 and promotes type 2 in-
flammatory pattern [79]. IL-4 and IL-13 cause barrier dysfunction in
human airway epithelial cells [80]. IL-13-producing ILC2s significantly
impair the epithelial barrier of human bronchial epithelial cells [81].
Meanwhile, CPG-DNA administration enhances the tight junction in-
tegrity of the bronchial epithelial barrier [82]. Moreover, CD11c+ DCs
stimulated by TSLP can activate CRTH2+ Th2 effector memory cells
and they undergo further Th2 polarization to amplify their roles in
allergic inflammation [83]. In addition, TSLP is a hematopoietic B cell
proliferation and differentiation factor [84]. TSLP also directly promote
naive CD4+ and CD8+ T cells to develop into Th2 cells [85]. TSLP
further enhances GATA3 expression in human ILC2s and induces them
to produce IL-4 and other Th2 cytokines [86]. TSLP can significantly
enhances eosinophilic inflammation, promotes activity and chemotaxis
of eosinophils by delaying the eosinophil apoptosis, upregulating the
expression of adhesion molecule CD18, intercellular adhesion mole-
cule-1 and down-regulating the L-selectin [87,88]. Periostin is an ex-
tracellular matrix protein which secreted by activated airway epithelial
cells. It recognizes as a biomarker of type 2 inflammation [89]. Peri-
ostin gene expression is up-regulated in bronchial epithelial cells by IL-
13 and IL-4 [90]. Periostin acts on fibroblasts to promote airway re-
modeling, enhance mucus secretion and recruit eosinophils [91].
3. Nonallergic asthma
3.1. Neutrophilic asthma
Many of the immunopathologic features of nonallergic asthma are
similar to those observed in allergic asthma [92]. Patients with non-
allergic asthma have a high expression of RANTES and GM-CSF re-
ceptor alpha in mucosa and bronchoalveolar lavage [93]. In the sputum
of non-eosinophilic asthmatics, three signature genes related to innate
immunity: IL-1β, alkaline phosphatase tissue-nonspecific isozyme
(ALPL) and CXCR2 were identified. [94]. While type 2 immune re-
sponse cells mainly involve in the development of eosinophilic allergic
asthma, other Th cell subsets like Th1 and Th17 cells which produced
IL-17, IL-21 and IL-22 are dominant in neutrophilic asthma. IL-17 is
responsible for the recruitment of neutrophils into the lungs. Activation
of the neutrophils can be either directly through CXCL8 production or
indirectly by production of IL-6, G-CSF, GM-CSF, IL-8, CXCL1 and
CXCL5 from airway epithelial cells [4]. IL-17 is often associated with
neutrophilic inflammation and AHR. IL-17A and IL-17 F are upregu-
lated in the lungs of asthmatic patients and this is correlated with se-
verity of asthma and steroid-resistant [95]. Moreover, IL-17–related
cytokine levels were increased in bronchial/nasal mucosa of patients
with exacerbation prone neutrophilic asthma [96]. Also, IL-17A and
IFN-γ have significantly increased in patients with steroid-resistant
asthma [97]. DCs play an important role to bridge innate and adaptive
immunity, and they trigger Th17 cell differentiation by providing an-
tigenic, costimulatory and cytokine signals. IL-6, IL-23 and TGF-β are
required for Th17 differentiation and are responsible for upregulation
of the transcription factor ROR??t as well as IL-23 receptor in T cells
[98]. IL-23 is crucial for maintaining the Th17 cell functionally in ac-
tive state [99]. Another mechanism in neutrophilic airway inflamma-
tion is based on inflammasome activation. The nucleotide-binding oli-
gomerization domain-like receptor family, pyrin domain containing 3
(NLRP3) inflammasome, an intracellular multiprotein complex, facil-
itates the autoactivation of proinflammatory cysteine protease caspase-
T. Boonpiyathad, et al.
1 [100]. Then the activated caspase-1 cleaves pro-IL-1β and pro-IL-18
into their mature forms. Active IL-1β was found to promote Th17 cell-
dependent inflammation [101]. NLRP3 is activated by serum amyloid A
(SAA) protein, which is produced upon exposure of airway epithelial
cells to microbes and can be detected at high levels in both serum and
induced sputum of asthmatic patients [102]. NLRP3 activation can be
triggered by danger-associated molecular patterns (DAMP) that gener-
ated in epithelial damage caused by oxidative stress such as air pollu-
tion and cigarette smoke. Gene expression of NLRP3, IL-1β and caspase-
1 is detected at high levels in sputum, and IL-1β levels correlate with
sputum IL-8 levels in patients with neutrophilic asthma [103]. In neu-
trophilic asthma, the ability of alveolar macrophages to phagocytize
apoptotic cells is significantly impaired compared to eosinophilic
asthma [104].
Th1 cells and Th1 related cytokines such as IFN-γ and TNF-α, are
increased in patients with severe neutrophilic asthma [105]. High levels
of IFN-γ and low levels of secretory leukocyte protease inhibitor (SLPI)
are found in patients with severe asthma [106]. High IFN-γ levels in the
airways, promote AHR through the suppression of SLPI. In mouse ex-
periments it was shown that, high IFN-γ levels in the airways induces
neutrophilic lung inflammation, emphysema and AHR [107]. TNF-α is
mainly produced by macrophages and mast cells and it promotes neu-
trophil chemotaxis [108]. Administration of inhaled recombinant TNF-
α, to healthy controls results in AHR and airway neutrophilia [109].
AHR may result from the direct effect of TNF-α on the airway smooth
muscle or indirectly the release of cysteinyl leukotrienes C4 and D4
[110]. The efficacy of anti-TNF-α treatment in moderate to severe
asthma is questionable.
Type-3 innate lymphoid cells (ILC3) and IL-17 secreting ILCs are
potentially important in neutrophilic asthma. ILC3s, Th17 cells, M1
macrophages and neutrophils are associated with steroid-resistant and
obesity-related asthma [111]. In the lungs of obese mice, increased IL-
17A producing CCR6+ ILC3s were found to be associated with AHR and
neutrophilic inflammation. [112]. These study also demonstrated that,
IL-1β produced by M1 macrophages increased in both lungs and adi-
pose tissue of obese mice, and stimulates ILC3s to produce IL-17A
[112]. IL-17+ ILC3 and ILC2 levels were found to be increased in mice
on high-fat diet following HDM challenge and decreased using anti-
CD90 antibody [113]. M1-mediated inflammation in adipose tissue
enhances M2-mediated inflammation in the asthmatic lung [114]. Gene
signatures of ILC3 are enriched in total RNA of patients with adult-onset
asthma [115].
IL-6 is secreted by non-leukocytes such as endothelial cells, fibro-
blasts, astrocytes, epithelial cells. IL-6 levels are also affected by viral
infections and obesity and increase in intrinsic asthma compared to
allergic asthma [104,105]. IL-6 levels in sputum are inversely corre-
lated with the predictive percentage of FEV1 [106]. In addition, in-
creased levels of IL-6 in serum are correlated with impaired lung
function in obese asthmatic patients [107].
Environmental stimuli such as diesel exhaust particles and cigarette
smoke can trigger Th17-mediated airway inflammation in asthmatic
patients [116]. Along with asthma inflammation, cigarette smoke can
induce a change in the phenotype of asthma through the predominance
of activated macrophages and neutrophils in sputum, airways and lung
parenchyma. In addition, cigarette smoke activates macrophages and
they produce oxygen species (ROS), matrix metalloproteinase (MMP)
and cytokines that prolonged survival of neutrophils in the lung tissue
(e.g. IL-8) [117]. Activated macrophages are also stimulate Th1 and
Th17, that can promote bronchial epithelial cells and goblet cell acti-
vation to enhance airway inflammation, mucus production and airway
remodeling [117]. Exposure to fungal cell-wall beta-glucans, increases
the levels of IL-17A and IL-13 and contributes to severe steroid-resistant
asthma [118].
Various studies have demonstrated that, exposure of bronchial
epithelial cells to nitrogen dioxide (NO2), ozone (O3), and diesel ex-
haust particles (DEPs) results in significant synthesis and release of
5
Seminars in Immunology 46 (2019) 101333
proinflammatory mediators, including eicosanoids, cytokines, and ad-
hesion molecules. Exposure to NO2 and O3 results in a significant re-
lease of LTC4 and a variety of cytokines, including IL-8, TNF-α, ICAM-1
and GM-CSF from the cultures [119,120]. In non-allergic inflammatory
response, bronchial airway epithelial cells can produce IL-1β, TGF-β
and IL-6, which recruit neutrophils via stimulation of IL-17 release from
Th17 cells. Cigarette smoke and ambient pollution have an adverse
effect on airway epithelial cells. A recent study showed that, epithelial
cell genes which are mostly related to cell growth and transcription
regulation, are significantly irregular in associated with smoking and
PM2.5, [121]. Moreover, cigarette smoke induces MMP-1 release from
bronchial epithelial cells [122].
TJ, mucin, and inflammasome-related molecules are expressed dif-
ferently in distinct inflammatory phenotypes of asthma, Zo-1 and
Cldn18 were found to be downregulated in all phenotypes, while in-
creased Cldn4 expression was characteristic for neutrophilic airway
inflammation [123]. Mucins Clca1 (Gob5) and Muc5ac were also up-
regulated in neutrophilic asthma phenotype. Moreover,increased ex-
pression of inflammasome-related molecules such as Nlrp3, Nlrc4,
Casp-1, and IL-1beta for neutrophilic asthma have been identified
[123].
3.2. Eosinophilic nonallergic asthma
Some patients with eosinophilic asthma are not allergic [124]. In-
deed, late-onset eosinophilic asthma which is frequently associated
with chronic rhinosinusitis and nasal polyps is often severe and non-
allergic [125]. In this phenotype, despite high doses of inhaled, and
systemic corticosteroids, lung and blood eosinophilia persists. ILC2s
play a vital role in eosinophilic non-allergic asthma. The number of
ILC2s increased in the lungs and peripheral blood of the asthmatic
patients who have chronic rhinosinusitis with nasal polyps and have an
increased eosinophil count [126]. ILC2s can produce high amounts of
IL-5, that might be explain this severe eosinophilic inflammation in the
absence of classical Th2-mediated allergic response in late-onset eosi-
nophilic asthma. Lipoxin A4, a natural pro-resolving ligand for ALX/
FPR2 receptors, significantly increases NK cell-mediated eosinophil
apoptosis and decreases IL-13-secreting ILC2s [127]. Through, lipoxin
A4 decreases eosinophilic inflammation. In severe asthma, lipoxin A4
concentrations have been shown to decrease and this may clarify eo-
sinophilia and chronic airway inflammation that characterize the dis-
ease. In an asthma genome study, ILC2 related genes, ROR-α and IL-33
receptor complex (ST2), were found to be associated with development
of asthma [128]. In mouse asthma model induced by Alternaria, ILC2s
together with IL-33, IL-5 and IL-13 are sufficient to drive eosinophilia
and AHR [129]. Moreover, ILC2s together with NKT cells, IL13 and IL-
33 can induce AHR in mice exposed to glycolipid antigens [130]. TSLP
confers, partial ILC2 resistance to corticosteroid through STAT5 sig-
naling [131]. A recent study has shown that, glucocorticoid therapy
may reduce ILC2 activation in patients with asthma via MEK/JAK-STAT
signaling pathways [132].
GM-CSF plays an important role in eosinophil activation after mi-
gration process, even without IL-5. GM-CSF induces eosinophil super-
oxide anion generation and the release of specific granule proteins in
vitro, when incubated with VCAM-1 or intercellular cell adhesion mo-
lecule (ICAM)-1 [133]. Even in the absence of IL-5, Th2 network,
containing a cascade of VCAM-1/CC chemokines/GM-CSF, is likely the
primary pathway for maintaining eosinophilic infiltration and activa-
tion in asthma [134].
4. Conclusion
In this review, authors have described the immunologic mechanisms
in asthma (Table 1). Asthma is a heterogeneous disease, comprising
distinct phenotypic spectrums of patient populations. The current
availability of biotherapeutic agents has provided individualized
T. Boonpiyathad, et al.
Table 1
Asthma phenotypes and cellular mechanism.
Asthma phenotype Clinical
Allergic Early-onset, children, often associated with allergic rhinitis, positive skin prick test to
aeroallergens or presence of allergen-specific Ig E, Eosiniphilic or noneosinophilic,
eosinophilic inflammation in sputum ( > 3% of the total cell count), allergen induced
exacerbate
Neutrophilic nonallergic Late-onset asthma, adult, corticosteroid resistant, absent of eosinophilia, paucigranulocytic/
neutrophilic, cigarette smoke, pollution and viral induced exacerbate
Eosinophilic nonallergic Late-onset eosinophilic asthma, associated with chronic rhinosinusitis and nasal polyps,
eosinophilia and eosinophilic inflammation in sputum ( > 3% of the total cell count)
treatment for patients who do not respond to conventional asthma
therapy. Novel developing medications, such as, anti-CRTH2 receptor,
anti-endothelin receptor, anti-TSLP, anti-IL-8, anti-IL-17 and the cur-
rent ones which are targeting the downstream allergy mediators, such
as IgE, IL-5 and IL-4/IL-13 have been studied for administration in
different asthma phenotypes. To get the greatest benefit from these
agents, all asthmatic patients should undergo an aeroallergen skin prick
test or allergen-specific IgE measurement to assess allergic status, and
complete blood counts to assess eosinophil levels. These biomarkers are
both non-invasive and useful to provide accurate clinical information
about the underlying asthma phenotype. The knowledge of molecular
process involved in disease pathogenesis will be further investigated to
bring novel therapeutic options for asthmatic patient.
Acknowledgments
The authors' laboratories are supported by the Swiss National
Foundation grant 320030_140772 and Christine Kühne - Center for
Allergy Research and Education (CK-CARE), European 7th frame work
projects MeDALL: Mechanisms of the Development of Allergy (No:
261357) and PREDICTA: Post-Infectious Immune Reprogramming and
Its Association with Persistence and Chronicity of Respiratory Allergic
Diseases (No: 260895).
References
[1] M. Schatz, L. Rosenwasser, The allergic asthma phenotype, J. Allergy Clin.
Immunol. Pract. 2 (6) (2014) 645–648 quiz 649.
[2] R.M. Dunn, P.J. Busse, M.E. Wechsler, Asthma in the elderly and late-onset adult
asthma, Allergy 73 (2) (2018) 284–294.
[3] Y.C. Wang, M.S. Jaakkola, T.K. Lajunen, C.H. Lai, J.J.K. Jaakkola, Asthma-COPD
Overlap Syndrome among subjects with newly diagnosed adult-onset asthma,
Allergy 73 (7) (2018) 1554–1557.
[4] I. Agache, C.A. Akdis, Endotypes of allergic diseases and asthma: an important step
in building blocks for the future of precision medicine, Allergol. Int. 65 (3) (2016)
243–252.
[5] H.T. Tan, S. Hagner, F. Ruchti, U. Radzikowska, G. Tan, C. Altunbulakli,
A. Eljaszewicz, M. Moniuszko, M. Akdis, C.A. Akdis, H. Garn, M. Sokolowska,
Tight junction, mucin, and inflammasome-related molecules are differentially
expressed in eosinophilic, mixed, and neutrophilic experimental asthma in mice,
Allergy (2018).
[6] A. Muraro, R.F. Lemanske Jr., M. Castells, M.J. Torres, D. Khan, H.U. Simon,
C. Bindslev-Jensen, W. Burks, L.K. Poulsen, H.A. Sampson, M. Worm, K.C. Nadeau,
Precision medicine in allergic disease-food allergy, drug allergy, and anaphylaxis-
PRACTALL document of the European Academy of Allergy and Clinical
Immunology and the American Academy of Allergy, Asthma and Immunology,
Allergy 72 (7) (2017) 1006–1021.
6
Seminars in Immunology 46 (2019) 101333
Inflammatory response
Epithelial cells secreted IL-25, IL-33 and TSLP
DC2 express IL-4, OX-40 L, CCL17 and PGE2
TLR4
NKT cells secreted type 2 cytokines
Th2 secreted IL-4, IL-5, IL-13 and IL-31
ILC2 secreted type 2 cytokines
Th9 secreted IL-9
IgE class-switched B cells
Mast cells secreted proteas and PGD2
Eosinophils secreted IL-4, IL-5, IL-13, granule proteins
(EDN, ECP, EPO, MBP) and cysteinyl leukotriens
Epithelial cells secreted IL-β and IL-23
DCs secreted IL-6, IL-23 and TGF-β
Th17 secreted IL-17
Th1secreted IFN-γ and TNF-α
ILC3s secreted IL-17
Monocyte and NKT cells secreted IL-8
Epithelial cells secreted IL-25, IL-33 and TSLP
ILC2 secreted IL-5 and Lipoxin A4
NKT cells
GM-CSF
[7] J. Genuneit, A.M. Seibold, C.J. Apfelbacher, G.N. Konstantinou, J.J. Koplin, S. La
Grutta, K. Logan, M.R. Perkin, C. Flohr, E.I.G.o.E, Task Force’ overview of sys-
tematic reviews in allergy epidemiology’ of the, overview of systematic reviews in
allergy epidemiology, Allergy 72 (6) (2017) 849–856.
[8] M. Odling, N. Andersson, S. Ekstrom, E. Melen, A. Bergstrom, I. Kull,
Characterization of asthma in the adolescent population, Allergy 73 (8) (2018)
1744–1746.
[9] M.W. Su, W.C. Lin, C.H. Tsai, B.L. Chiang, Y.H. Yang, Y.T. Lin, L.C. Wang, J.H. Lee,
C.C. Chou, Y.F. Wu, Y.L. Yeh, Y.L. Lee, Childhood asthma clusters reveal neu-
trophil-predominant phenotype with distinct gene expression, Allergy 73 (10)
(2018) 2024–2032.
[10] L. Worth, S. Michel, V.D. Gaertner, M. Kabesch, M. Schieck, Asthma- and IgE-
associated polymorphisms affect expression of TH 17 genes, Allergy 73 (6) (2018)
1342–1347.
[11] S.T. Holgate, S. Wenzel, D.S. Postma, S.T. Weiss, H. Renz, P.D. Sly, Asthma, Nat.
Rev. Dis. Primers 1 (2015) 15025.
[12] A. Valero, S. Quirce, I. Davila, J. Delgado, J. Dominguez-Ortega, Allergic re-
spiratory disease: different allergens, different symptoms, Allergy 72 (9) (2017)
1306–1316.
[13] J. Bousquet, S. Arnavielhe, A. Bedbrook, J. Fonseca, M. Morais Almeida, A. Todo
Bom, et al., The Allergic Rhinitis and its Impact on Asthma (ARIA) score of allergic
rhinitis using mobile technology correlates with quality of life: the MASK study,
Allergy 73 (2) (2018) 505–510.
[14] S.R. Del Giacco, A. Bakirtas, E. Bel, A. Custovic, Z. Diamant, E. Hamelmann,
E. Heffler, O. Kalayci, S. Saglani, S. Sergejeva, S. Seys, A. Simpson, L. Bjermer,
Allergy in severe asthma, Allergy 72 (2) (2017) 207–220.
[15] D. Russkamp, A. Aguilar-Pimentel, F. Alessandrini, V. Gailus-Durner, H. Fuchs,
C. Ohnmacht, A. Chaker, M.H. de Angelis, M. Ollert, C.B. Schmidt-Weber, S. Blank,
IL-4 receptor alpha blockade prevents sensitization and alters acute and long-
lasting effects of allergen-specific immunotherapy of murine allergic asthma,
Allergy (2019).
[16] M. Hassani, L. Koenderman, Immunological and hematological effects of IL-
5(Ralpha)-targeted therapy: an overview, Allergy 73 (10) (2018) 1979–1988.
[17] Y. Mitamura, S. Nunomura, Y. Nanri, M. Ogawa, T. Yoshihara, M. Masuoka,
G. Tsuji, T. Nakahara, A. Hashimoto-Hachiya, S.J. Conway, M. Furue, K. Izuhara,
The IL-13/periostin/IL-24 pathway causes epidermal barrier dysfunction in al-
lergic skin inflammation, Allergy 73 (9) (2018) 1881–1891.
[18] Z. Lei, G. Liu, Q. Huang, M. Lv, R. Zu, G.M. Zhang, Z.H. Feng, B. Huang, SCF and
IL-31 rather than IL-17 and BAFF are potential indicators in patients with allergic
asthma, Allergy 63 (3) (2008) 327–332.
[21] T. Ohtomo, O. Kaminuma, J. Yamada, N. Kitamura, A. Abe, N. Kobayashi,
M. Suko, A. Mori, Eosinophils are required for the induction of bronchial hy-
perresponsiveness in a Th transfer model of BALB/c background, Int. Arch. Allergy
Immunol. 152 (Suppl. 1) (2010) 79–82.
[22] X. Xiao, Y. Fan, J. Li, X. Zhang, X. Lou, Y. Dou, X. Shi, P. Lan, Y. Xiao, L. Minze,
X.C. Li, Guidance of super-enhancers in regulation of IL-9 induction and airway
inflammation, J. Exp. Med. 215 (2) (2018) 559–574.
[23] X. Xiao, S. Balasubramanian, W. Liu, X. Chu, H. Wang, E.J. Taparowsky, Y.X. Fu,
Y. Choi, M.C. Walsh, X.C. Li, OX40 signaling favors the induction of T(H)9 cells
and airway inflammation, Nat. Immunol. 13 (10) (2012) 981–990.
[24] H. Chen, L. Zhang, P. Wang, H. Su, W. Wang, Z. Chu, L. Zhang, X. Zhang, Y. Zhao,
mTORC2 controls Th9 polarization and allergic airway inflammation, Allergy 72
(10) (2017) 1510–1520.
[25] L. Jia, Y. Wang, J. Li, S. Li, Y. Zhang, J. Shen, W. Tan, C. Wu, Detection of IL-9
producing T cells in the PBMCs of allergic asthmatic patients, BMC Immunol. 18
(1) (2017) 38.
T. Boonpiyathad, et al.
[26] D. Hoppenot, K. Malakauskas, S. Lavinskiene, I. Bajoriuniene, V. Kalinauskaite,
R. Sakalauskas, Peripheral blood Th9 cells and eosinophil apoptosis in asthma
patients, Medicina Kaunas (Kaunas) 51 (1) (2015) 10–17.
[27] M. Saeki, O. Kaminuma, T. Nishimura, N. Kitamura, A. Mori, T. Hiroi, Th9 cells
induce steroid-resistant bronchial hyperresponsiveness in mice, Allergol. Int. 66S
(2017) S35–S40.
[28] M.A. Gill, The role of dendritic cells in asthma, J. Allergy Clin. Immunol. 129 (4)
(2012) 889–901.
[29] H. Vroman, R.W. Hendriks, M. Kool, Dendritic cell subsets in asthma: impaired
tolerance or exaggerated inflammation? Front. Immunol. 8 (2017) 941.
[30] M. Plantinga, M. Guilliams, M. Vanheerswynghels, K. Deswarte, F. Branco-
Madeira, W. Toussaint, L. Vanhoutte, K. Neyt, N. Killeen, B. Malissen, H. Hammad,
B.N. Lambrecht, Conventional and monocyte-derived CD11b(+) dendritic cells
initiate and maintain T helper 2 cell-mediated immunity to house dust mite al-
lergen, Immunity 38 (2) (2013) 322–335.
[31] A. Khare, N. Krishnamoorthy, T.B. Oriss, M. Fei, P. Ray, A. Ray, Cutting edge:
inhaled antigen upregulates retinaldehyde dehydrogenase in lung CD103+ but
not plasmacytoid dendritic cells to induce Foxp3 de novo in CD4+ T cells and
promote airway tolerance, J. Immunol. 191 (1) (2013) 25–29.
[32] A. Norimoto, K. Hirose, A. Iwata, T. Tamachi, M. Yokota, K. Takahashi, S. Saijo,
Y. Iwakura, H. Nakajima, Dectin-2 promotes house dust mite-induced T helper
type 2 and type 17 cell differentiation and allergic airway inflammation in mice,
Am. J. Respir. Cell Mol. Biol. 51 (2) (2014) 201–209.
[33] N.A. Barrett, A. Maekawa, O.M. Rahman, K.F. Austen, Y. Kanaoka, Dectin-2 re-
cognition of house dust mite triggers cysteinyl leukotriene generation by dendritic
cells, J. Immunol. 182 (2) (2009) 1119–1128.
[34] T. Ito, K. Hirose, A. Norimoto, T. Tamachi, M. Yokota, A. Saku, H. Takatori,
S. Saijo, Y. Iwakura, H. Nakajima, Dectin-1 plays an important role in house dust
mite-induced allergic airway inflammation through the activation of CD11b+
dendritic cells, J. Immunol. 198 (1) (2017) 61–70.
[35] J. Han, A. Dakhama, Y. Jia, M. Wang, W. Zeng, K. Takeda, Y. Shiraishi,
M. Okamoto, S.F. Ziegler, E.W. Gelfand, Responsiveness to respiratory syncytial
virus in neonates is mediated through thymic stromal lymphopoietin and OX40
ligand, J. Allergy Clin. Immunol. 130 (5) (2012) 1175–1186 e9.
[36] B. Bleck, A. Kazeros, K. Bakal, L. Garcia-Medina, A. Adams, M. Liu, R.A. Lee,
D.B. Tse, A. Chiu, G. Grunig, J.P. Egan 3rd, J. Reibman, Coexpression of type 2
immune targets in sputum-derived epithelial and dendritic cells from asthmatic
subjects, J. Allergy Clin. Immunol. 136 (3) (2015) 619–627 e5.
[37] D. Tworek, S.G. Smith, B.M. Salter, A.J. Baatjes, T. Scime, R. Watson, C. Obminski,
G.M. Gauvreau, P.M. O’Byrne, IL-25 receptor expression on airway dendritic cells
after allergen challenge in subjects with asthma, Am. J. Respir. Crit. Care Med. 193
(9) (2016) 957–964.
[38] A. Froidure, C. Shen, D. Gras, J. Van Snick, P. Chanez, C. Pilette, Myeloid dendritic
cells are primed in allergic asthma for thymic stromal lymphopoietin-mediated
induction of Th2 and Th9 responses, Allergy 69 (8) (2014) 1068–1076.
[39] S.R. Damle, R.K. Martin, C.L. Cockburn, J.C. Lownik, J.A. Carlyon, A.D. Smith,
D.H. Conrad, ADAM10 and Notch1 on murine dendritic cells control the devel-
opment of type 2 immunity and IgE production, Allergy 73 (1) (2018) 125–136.
[40] C. Pilette, M.R. Jacobson, C. Ratajczak, B. Detry, G. Banfield, J. VanSnick,
S.R. Durham, K.T. Nouri-Aria, Aberrant dendritic cell function conditions Th2-cell
polarization in allergic rhinitis, Allergy 68 (3) (2013) 312–321.
[41] C. Iwamura, T. Nakayama, Role of CD1d- and MR1-Restricted t cells in asthma,
Front. Immunol. 9 (2018) 1942.
[42] Y.I. Koh, J.U. Shim, Association between sputum natural killer T cells and eosi-
nophilic airway inflammation in human asthma, Int. Arch. Allergy Immunol. 153
(3) (2010) 239–248.
[43] J.C. Carpio-Pedroza, G. Vaughan, B.E. del Rio-Navarro, J.M. del Rio-Chivardi,
A. Vergara-Castaneda, L.A. Jimenez-Zamudio, A. Morales-Flores, G. Rodriguez-
Moreno, K. Ruiz-Tovar, S. Fonseca-Coronado, L.M. Goncalves Rossi, A. Escobar-
Gutierrez, Participation of CD161(+) and invariant natural killer T cells in pe-
diatric asthma exacerbations, Allergy Asthma Proc. 34 (1) (2013) 84–92.
[44] Y. Endo, K. Hirahara, T. Iinuma, K. Shinoda, D.J. Tumes, H.K. Asou, N. Matsugae,
K. Obata-Ninomiya, H. Yamamoto, S. Motohashi, K. Oboki, S. Nakae, H. Saito,
Y. Okamoto, T. Nakayama, The interleukin-33-p38 kinase axis confers memory T
helper 2 cell pathogenicity in the airway, Immunity 42 (2) (2015) 294–308.
[45] A. Zakeri, M. Russo, Dual role of toll-like receptors in human and experimental
asthma models, Front. Immunol. 9 (2018) 1027.
[46] D. Vercelli, Discovering susceptibility genes for asthma and allergy, Nat. Rev.
Immunol. 8 (3) (2008) 169–182.
[47] A. Trompette, S. Divanovic, A. Visintin, C. Blanchard, R.S. Hegde, R. Madan,
P.S. Thorne, M. Wills-Karp, T.L. Gioannini, J.P. Weiss, C.L. Karp, Allergenicity
resulting from functional mimicry of a Toll-like receptor complex protein, Nature
457 (7229) (2009) 585–588.
[48] V.O. Millien, W. Lu, J. Shaw, X. Yuan, G. Mak, L. Roberts, L.Z. Song, J.M. Knight,
C.J. Creighton, A. Luong, F. Kheradmand, D.B. Corry, Cleavage of fibrinogen by
proteinases elicits allergic responses through Toll-like receptor 4, Science 341
(6147) (2013) 792–796.
[49] O. Denis, M. Vincent, X. Havaux, S. De Prins, G. Treutens, K. Huygen, Induction of
the specific allergic immune response is independent of proteases from the fungus
Alternaria alternata, Eur. J. Immunol. 43 (4) (2013) 907–917.
[50] H.J. McSorley, N.F. Blair, K.A. Smith, A.N. McKenzie, R.M. Maizels, Blockade of IL-
33 release and suppression of type 2 innate lymphoid cell responses by helminth
secreted products in airway allergy, Mucosal Immunol. 7 (5) (2014) 1068–1078.
[51] K. Nakagome, M. Nagata, Involvement and possible role of eosinophils in asthma
exacerbation, Front. Immunol. 9 (2018) 2220.
[52] M. Terl, V. Sedlak, P. Cap, R. Dvorakova, V. Kasak, T. Koci, B. Novotna,
7
Seminars in Immunology 46 (2019) 101333
E. Seberova, P. Panzner, V. Zindr, Asthma management: a new phenotype-based
approach using presence of eosinophilia and allergy, Allergy 72 (9) (2017)
1279–1287.
[53] D.T. Wong, A. Elovic, K. Matossian, N. Nagura, J. McBride, M.Y. Chou,
J.R. Gordon, T.H. Rand, S.J. Galli, P.F. Weller, Eosinophils from patients with
blood eosinophilia express transforming growth factor beta 1, Blood 78 (10)
(1991) 2702–2707.
[54] L.A. Laitinen, A. Laitinen, T. Haahtela, V. Vilkka, B.W. Spur, T.H. Lee, Leukotriene
E4 and granulocytic infiltration into asthmatic airways, Lancet 341 (8851) (1993)
989–990.
[55] K. Saito, M. Nagata, I. Kikuchi, Y. Sakamoto, Leukotriene D4 and eosinophil
transendothelial migration, superoxide generation, and degranulation via beta2
integrin, Ann. Allergy Asthma Immunol. 93 (6) (2004) 594–600.
[56] T.H. Pham, G. Damera, P. Newbold, K. Ranade, Reductions in eosinophil bio-
markers by benralizumab in patients with asthma, Respir. Med. 111 (2016) 21–29.
[57] M. Nagata, J.B. Sedgwick, R. Vrtis, W.W. Busse, Endothelial cells upregulate eo-
sinophil superoxide generation via VCAM-1 expression, Clin. Exp. Allergy 29 (4)
(1999) 550–561.
[58] S. Ying, D.S. Robinson, Q. Meng, J. Rottman, R. Kennedy, D.J. Ringler,
C.R. Mackay, B.L. Daugherty, M.S. Springer, S.R. Durham, T.J. Williams, A.B. Kay,
Enhanced expression of eotaxin and CCR3 mRNA and protein in atopic asthma.
Association with airway hyperresponsiveness and predominant co-localization of
eotaxin mRNA to bronchial epithelial and endothelial cells, Eur. J. Immunol. 27
(12) (1997) 3507–3516.
[59] Y. Suzuki, K. Wakahara, T. Nishio, S. Ito, Y. Hasegawa, Airway basophils are in-
creased and activated in eosinophilic asthma, Allergy 72 (10) (2017) 1532–1539.
[60] C.R. Brooks, C.J. van Dalen, I.F. Hermans, P.G. Gibson, J.L. Simpson, J. Douwes,
Sputum basophils are increased in eosinophilic asthma compared with non-eosi-
nophilic asthma phenotypes, Allergy 72 (10) (2017) 1583–1586.
[61] K. Amin, The role of mast cells in allergic inflammation, Respir. Med. 106 (1)
(2012) 9–14.
[62] M. Ro, A.J. Lee, J.H. Kim, 5-/12-Lipoxygenase-linked cascade contributes to the
IL-33-induced synthesis of IL-13 in mast cells, thus promoting asthma develop-
ment, Allergy 73 (2) (2018) 350–360.
[63] K. Amin, D. Ludviksdottir, C. Janson, O. Nettelbladt, E. Bjornsson, G.M. Roomans,
G. Boman, L. Seveus, P. Venge, Inflammation and structural changes in the air-
ways of patients with atopic and nonatopic asthma. BHR Group, Am. J. Respir.
Crit. Care Med. 162 (6) (2000) 2295–2301.
[64] P. Bradding, C. Brightling, Mast cell infiltration of airway smooth muscle in
asthma, Respir. Med. 101 (5) (2007) 1045 author reply 1046-7.
[65] M.L. Fajt, S.L. Gelhaus, B. Freeman, C.E. Uvalle, J.B. Trudeau, F. Holguin,
S.E. Wenzel, Prostaglandin D(2) pathway upregulation: relation to asthma se-
verity, control, and TH2 inflammation, J. Allergy Clin. Immunol. 131 (6) (2013)
1504–1512.
[66] T. Boonpiyathad, G. Capova, H.W. Duchna, A.L. Croxford, H. Farine, A. Dreher,
M. Clozel, J. Schreiber, P. Kubena, N. Lunjani, D. Mirer, B. Ruckert,
P. Satitsuksanoa, G. Tan, P.M.A. Groenen, M. Akdis, D.S. Strasser, E.D. Renner,
C.A. Akdis, Impact of high altitude therapy on Type-2 immune responses in asthma
patients, Allergy (2019).
[67] A. Matucci, A. Vultaggio, E. Maggi, I. Kasujee, Is IgE or eosinophils the key player
in allergic asthma pathogenesis? Are we asking the right question? Respir. Res. 19
(1) (2018) 113.
[68] J.T. Schroeder, A.P. Bieneman, K.L. Chichester, R.G. Hamilton, H. Xiao, S.S. Saini,
M.C. Liu, Decreases in human dendritic cell-dependent T(H)2-like responses after
acute in vivo IgE neutralization, J. Allergy Clin. Immunol. 125 (4) (2010)
896–901 e6.
[69] S.H. Khan, M.H. Grayson, Cross-linking IgE augments human conventional den-
dritic cell production of CC chemokine ligand 28, J. Allergy Clin. Immunol. 125
(1) (2010) 265–267.
[70] J.P. Lynch, S.B. Mazzone, M.J. Rogers, J.J. Arikkatt, Z. Loh, A.L. Pritchard,
J.W. Upham, S. Phipps, The plasmacytoid dendritic cell: at the cross-roads in
asthma, Eur. Respir. J. 43 (1) (2014) 264–275.
[71] M. Dullaers, M.J. Schuijs, M. Willart, K. Fierens, J. Van Moorleghem, H. Hammad,
B.N. Lambrecht, House dust mite-driven asthma and allergen-specific T cells de-
pend on B cells when the amount of inhaled allergen is limiting, J. Allergy Clin.
Immunol. 140 (1) (2017) 76–88 e7.
[72] D.S. Ferreira, R.M. Carvalho-Pinto, M.G. Gregorio, R. Annoni, A.M. Teles,
M. Buttignol, B.B. Araujo-Paulino, E.H. Katayama, B.L. Oliveira, H.S. Del Frari,
A. Cukier, M. Dolhnikoff, R. Stelmach, K.F. Rabe, T. Mauad, Airway pathology in
severe asthma is related to airflow obstruction but not symptom control, Allergy
73 (3) (2018) 635–643.
[73] S. Palaniyandi, E. Tomei, Z. Li, D.H. Conrad, X. Zhu, CD23-dependent transcytosis
of IgE and immune complex across the polarized human respiratory epithelial
cells, J. Immunol. 186 (6) (2011) 3484–3496.
[74] J.J. Heeringa, L. Rijvers, N.J. Arends, G.J. Driessen, S.G. Pasmans, J.J.M. van
Dongen, J.C. de Jongste, M.C. van Zelm, IgE-expressing memory B cells and
plasmablasts are increased in blood of children with asthma, food allergy, and
atopic dermatitis, Allergy 73 (6) (2018) 1331–1336.
[75] O.H. Wittekindt, Tight junctions in pulmonary epithelia during lung inflammation,
Pflugers Arch. 469 (1) (2017) 135–147.
[76] N.V. Chemuturi, P. Hayden, M. Klausner, M.D. Donovan, Comparison of human
tracheal/bronchial epithelial cell culture and bovine nasal respiratory explants for
nasal drug transport studies, J. Pharm. Sci. 94 (9) (2005) 1976–1985.
[77] P. Licona-Limon, L.K. Kim, N.W. Palm, R.A. Flavell, TH2, allergy and group 2
innate lymphoid cells, Nat. Immunol. 14 (6) (2013) 536–542.
[78] F. Roan, K. Obata-Ninomiya, S.F. Ziegler, Epithelial cell-derived cytokines: more
T. Boonpiyathad, et al.
than just signaling the alarm, J. Clin. Invest. 129 (4) (2019) 1441–1451.
[79] D.J. Jackson, H. Makrinioti, B.M. Rana, B.W. Shamji, M.B. Trujillo-Torralbo,
J. Footitt, D.-R. Jerico, A.G. Telcian, A. Nikonova, J. Zhu, J. Aniscenko,
L. Gogsadze, E. Bakhsoliani, S. Traub, J. Dhariwal, J. Porter, D. Hunt, T. Hunt,
T. Hunt, L.A. Stanciu, M. Khaitov, N.W. Bartlett, M.R. Edwards, O.M. Kon,
P. Mallia, N.G. Papadopoulos, C.A. Akdis, J. Westwick, M.J. Edwards,
D.J. Cousins, R.P. Walton, S.L. Johnston, IL-33-dependent type 2 inflammation
during rhinovirus-induced asthma exacerbations in vivo, Am. J. Respir. Crit. Care
Med. 190 (12) (2014) 1373–1382.
[80] B. Saatian, F. Rezaee, S. Desando, J. Emo, T. Chapman, S. Knowlden, S.N. Georas,
Interleukin-4 and interleukin-13 cause barrier dysfunction in human airway epi-
thelial cells, Tissue Barriers 1 (2) (2013) e24333.
[81] K. Sugita, C.A. Steer, I. Martinez-Gonzalez, C. Altunbulakli, H. Morita, F. Castro-
Giner, T. Kubo, P. Wawrzyniak, B. Ruckert, K. Sudo, S. Nakae, K. Matsumoto,
L. O’Mahony, M. Akdis, F. Takei, C.A. Akdis, Type 2 innate lymphoid cells disrupt
bronchial epithelial barrier integrity by targeting tight junctions through IL-13 in
asthmatic patients, J. Allergy Clin. Immunol. 141 (1) (2018) 300–310 e11.
[82] T. Kubo, P. Wawrzyniak, H. Morita, K. Sugita, K. Wanke, J.I. Kast, C. Altunbulakli,
B. Ruckert, B. Jakiela, M. Sanak, M. Akdis, C.A. Akdis, CpG-DNA enhances the
tight junction integrity of the bronchial epithelial cell barrier, J. Allergy Clin.
Immunol. 136 (5) (2015) 1413–1416 e1-8.
[83] Y.H. Wang, T. Ito, Y.H. Wang, B. Homey, N. Watanabe, R. Martin, C.J. Barnes,
B.W. McIntyre, M. Gilliet, R. Kumar, Z. Yao, Y.J. Liu, Maintenance and polariza-
tion of human TH2 central memory T cells by thymic stromal lymphopoietin-ac-
tivated dendritic cells, Immunity 24 (6) (2006) 827–838.
[84] R.J. Ray, C. Furlonger, D.E. Williams, C.J. Paige, Characterization of thymic
stromal-derived lymphopoietin (TSLP) in murine B cell development in vitro, Eur.
J. Immunol. 26 (1) (1996) 10–16.
[85] M. Kitajima, H.C. Lee, T. Nakayama, S.F. Ziegler, TSLP enhances the function of
helper type 2 cells, Eur. J. Immunol. 41 (7) (2011) 1862–1871.
[86] J. Mjosberg, J. Bernink, K. Golebski, J.J. Karrich, C.P. Peters, B. Blom, et al., The
transcription factor GATA3 is essential for the function of human type 2 innate
lymphoid cells, Immunity 37 (4) (2012) 649–659.
[87] A. Cianferoni, J. Spergel, The importance of TSLP in allergic disease and its role as
a potential therapeutic target, Expert Rev. Clin. Immunol. 10 (11) (2014)
1463–1474.
[88] C.K. Wong, S. Hu, P.F. Cheung, C.W. Lam, Thymic stromal lymphopoietin induces
chemotactic and prosurvival effects in eosinophils: implications in allergic in-
flammation, Am. J. Respir. Cell Mol. Biol. 43 (3) (2010) 305–315.
[89] A. James, C. Janson, A. Malinovschi, C. Holweg, K. Alving, J. Ono, S. Ohta, A. Ek,
R. Middelveld, B. Dahlen, B. Forsberg, K. Izuhara, S.E. Dahlen, Serum periostin
relates to type-2 inflammation and lung function in asthma: data from the large
population-based cohort Swedish GA(2)LEN, Allergy 72 (11) (2017) 1753–1760.
[90] J.M. Lopez-Guisa, C. Powers, D. File, E. Cochrane, N. Jimenez, J.S. Debley, Airway
epithelial cells from asthmatic children differentially express proremodeling fac-
tors, J. Allergy Clin. Immunol. 129 (4) (2012) 990–997 e6.
[91] K. Izuhara, S.J. Conway, B.B. Moore, H. Matsumoto, C.T. Holweg, J.G. Matthews,
J.R. Arron, Roles of periostin in respiratory disorders, Am. J. Respir. Crit. Care
Med. 193 (9) (2016) 949–956.
[92] S.P. Peters, Asthma phenotypes: nonallergic (intrinsic) asthma, J. Allergy Clin.
Immunol. Pract. 2 (6) (2014) 650–652.
[93] N. Novak, T. Bieber, Allergic and nonallergic forms of atopic diseases, J. Allergy
Clin. Immunol. 112 (2) (2003) 252–262.
[94] K.J. Baines, J.L. Simpson, L.G. Wood, R.J. Scott, N.L. Fibbens, H. Powell,
D.C. Cowan, D.R. Taylor, J.O. Cowan, P.G. Gibson, Sputum gene expression sig-
nature of 6 biomarkers discriminates asthma inflammatory phenotypes, J. Allergy
Clin. Immunol. 133 (4) (2014) 997–1007.
[95] W. Al-Ramli, D. Prefontaine, F. Chouiali, J.G. Martin, R. Olivenstein, C. Lemiere,
Q. Hamid, T(H)17-associated cytokines (IL-17A and IL-17F) in severe asthma, J.
Allergy Clin. Immunol. 123 (5) (2009) 1185–1187.
[96] F.L.M. Ricciardolo, V. Sorbello, A. Folino, F. Gallo, G.M. Massaglia, G. Favata,
S. Conticello, D. Vallese, F. Gani, M. Malerba, G. Folkerts, G. Rolla, M. Profita,
T. Mauad, A. Di Stefano, G. Ciprandi, Identification of IL-17F/frequent exacerbator
endotype in asthma, J. Allergy Clin. Immunol. 140 (2) (2017) 395–406.
[97] E.S. Chambers, A.M. Nanzer, P.E. Pfeffer, D.F. Richards, P.M. Timms,
A.R. Martineau, C.J. Griffiths, C.J. Corrigan, C.M. Hawrylowicz, Distinct en-
dotypes of steroid-resistant asthma characterized by IL-17A(high) and IFN-gamma
(high) immunophenotypes: potential benefits of calcitriol, J. Allergy Clin.
Immunol. 136 (3) (2015) 628–637 e4.
[98] G. Huang, Y. Wang, H. Chi, Regulation of TH17 cell differentiation by innate
immune signals, Cell. Mol. Immunol. 9 (4) (2012) 287–295.
[99] M.J. McGeachy, Y. Chen, C.M. Tato, A. Laurence, B. Joyce-Shaikh,
W.M. Blumenschein, T.K. McClanahan, J.J. O’Shea, D.J. Cua, The interleukin 23
receptor is essential for the terminal differentiation of interleukin 17-producing
effector T helper cells in vivo, Nat. Immunol. 10 (3) (2009) 314–324.
[100] T.H. Lee, H.J. Song, C.S. Park, Role of inflammasome activation in development
and exacerbation of asthma, Asia Pac. Allergy 4 (4) (2014) 187–196.
[101] G.J. Martinez, R.I. Nurieva, X.O. Yang, C. Dong, Regulation and function of
proinflammatory TH17 cells, Ann. N. Y. Acad. Sci. 1143 (2008) 188–211.
[102] F. Ozseker, S. Buyukozturk, B. Depboylu, D. Yilmazbayhan, E. Karayigit,
A. Gelincik, S. Genc, B. Colakoglu, M. Dal, H. Issever, Serum amyloid A (SAA) in
induced sputum of asthmatics: a new look to an old marker, Int.
Immunopharmacol. 6 (10) (2006) 1569–1576.
[103] J.L. Simpson, S. Phipps, K.J. Baines, K.M. Oreo, L. Gunawardhana, P.G. Gibson,
Elevated expression of the NLRP3 inflammasome in neutrophilic asthma, Eur.
Respir. J. 43 (4) (2014) 1067–1076.
8
Seminars in Immunology 46 (2019) 101333
[104] J.L. Simpson, P.G. Gibson, I.A. Yang, J. Upham, A. James, P.N. Reynolds, S. Hodge,
A.S.R. Group, Impaired macrophage phagocytosis in non-eosinophilic asthma,
Clin. Exp. Allergy 43 (1) (2013) 29–35.
[105] M.A. Berry, B. Hargadon, M. Shelley, D. Parker, D.E. Shaw, R.H. Green,
P. Bradding, C.E. Brightling, A.J. Wardlaw, I.D. Pavord, Evidence of a role of
tumor necrosis factor alpha in refractory asthma, N. Engl. J. Med. 354 (7) (2006)
697–708.
[106] M. Raundhal, C. Morse, A. Khare, T.B. Oriss, J. Milosevic, J. Trudeau, R. Huff,
J. Pilewski, F. Holguin, J. Kolls, S. Wenzel, P. Ray, A. Ray, High IFN-gamma and
low SLPI mark severe asthma in mice and humans, J. Clin. Invest. 125 (8) (2015)
3037–3050.
[107] B.J. Lee, H.G. Moon, T.S. Shin, S.G. Jeon, E.Y. Lee, Y.S. Gho, C.G. Lee, Z. Zhu,
J.A. Elias, Y.K. Kim, Protective effects of basic fibroblast growth factor in the
development of emphysema induced by interferon-gamma, Exp. Mol. Med. 43 (4)
(2011) 169–178.
[108] T. Nabe, Tumor necrosis factor alpha-mediated asthma? Int. Arch. Allergy
Immunol. 160 (2) (2013) 111–113.
[109] P.S. Thomas, D.H. Yates, P.J. Barnes, Tumor necrosis factor-alpha increases airway
responsiveness and sputum neutrophilia in normal human subjects, Am. J. Respir.
Crit. Care Med. 152 (1) (1995) 76–80.
[110] C. Brightling, M. Berry, Y. Amrani, Targeting TNF-alpha: a novel therapeutic ap-
proach for asthma, J. Allergy Clin. Immunol. 121 (1) (2008) 5–10 quiz 11-2.
[111] H.Y. Kim, D.T. Umetsu, R.H. Dekruyff, Innate lymphoid cells in asthma: Will they
take your breath away? Eur. J. Immunol. 46 (4) (2016) 795–806.
[112] H.Y. Kim, H.J. Lee, Y.J. Chang, M. Pichavant, S.A. Shore, K.A. Fitzgerald,
Y. Iwakura, E. Israel, K. Bolger, J. Faul, R.H. DeKruyff, D.T. Umetsu, Interleukin-
17-producing innate lymphoid cells and the NLRP3 inflammasome facilitate
obesity-associated airway hyperreactivity, Nat. Med. 20 (1) (2014) 54–61.
[113] L. Everaere, S. Ait-Yahia, O. Molendi-Coste, H. Vorng, S. Quemener, P. LeVu,
S. Fleury, E. Bouchaert, Y. Fan, C. Duez, P. de Nadai, B. Staels, D. Dombrowicz,
A. Tsicopoulos, Innate lymphoid cells contribute to allergic airway disease ex-
acerbation by obesity, J. Allergy Clin. Immunol. 138 (5) (2016) 1309–1318 e11.
[114] N. Sharma, M. Akkoyunlu, R.L. Rabin, Macrophages-common culprit in obesity
and asthma, Allergy 73 (6) (2018) 1196–1205.
[115] P.P. Hekking, M.J. Loza, S. Pavlidis, B. de Meulder, D. Lefaudeux, F. Baribaud,
C. Auffray, A.H. Wagener, P.I. Brinkman, R.I. Lutter, A.T. Bansal, A.R. Sousa,
S.A. Bates, Y. Pandis, L.J. Fleming, D.E. Shaw, S.J. Fowler, Y. Guo, A. Meiser,
K. Sun, J. Corfield, P.H. Howarth, E.H. Bel, I.M. Adcock, K.F. Chung,
R. Djukanovic, P.J. Sterk, U.B.S. Group, Pathway discovery using transcriptomic
profiles in adult-onset severe asthma, J. Allergy Clin. Immunol. 141 (4) (2018)
1280–1290.
[116] E.B. Brandt, M.B. Kovacic, G.B. Lee, A.M. Gibson, T.H. Acciani, T.D. Le Cras,
P.H. Ryan, A.L. Budelsky, G.K. Khurana Hershey, Diesel exhaust particle induction
of IL-17A contributes to severe asthma, J. Allergy Clin. Immunol. 132 (5) (2013)
1194–1204 e2.
[117] R. Polosa, N.C. Thomson, Smoking and asthma: dangerous liaisons, Eur. Respir. J.
41 (3) (2013) 716–726.
[118] Z. Zhang, J.M. Biagini Myers, E.B. Brandt, P.H. Ryan, M. Lindsey, R.A. Mintz-Cole,
et al., Beta-Glucan exacerbates allergic asthma independent of fungal sensitization
and promotes steroid-resistant TH2/TH17 responses, J. Allergy Clin. Immunol.
139 (1) (2017) 54–65 e8.
[119] J.L. Devalia, R.J. Sapsford, D.R. Cundell, C. Rusznak, A.M. Campbell, R.J. Davies,
Human bronchial epithelial cell dysfunction following in vitro exposure to ni-
trogen dioxide, Eur. Respir. J. 6 (9) (1993) 1308–1316.
[120] C. Rusznak, J.L. Devalia, R.J. Sapsford, R.J. Davies, Ozone-induced mediator re-
lease from human bronchial epithelial cells in vitro and the influence of nedo-
cromil sodium, Eur. Respir. J. 9 (11) (1996) 2298–2305.
[121] S.L. O’Beirne, S.A. Shenoy, J. Salit, Y. Strulovici-Barel, R.J. Kaner, S. Visvanathan,
J.S. Fine, J.G. Mezey, R.G. Crystal, Ambient pollution-related reprogramming of
the human small airway epithelial transcriptome, Am. J. Respir. Crit. Care Med.
198 (11) (2018) 1413–1422.
[122] C. Mathis, C. Poussin, D. Weisensee, S. Gebel, A. Hengstermann, A. Sewer,
V. Belcastro, Y. Xiang, S. Ansari, S. Wagner, J. Hoeng, M.C. Peitsch, Human
bronchial epithelial cells exposed in vitro to cigarette smoke at the air-liquid in-
terface resemble bronchial epithelium from human smokers, Am. J. Physiol. Lung
Cell Mol. Physiol. 304 (7) (2013) L489–503.
[123] H.T. Tan, S. Hagner, F. Ruchti, U. Radzikowska, G. Tan, C. Altunbulakli,
A. Eljaszewicz, M. Moniuszko, M. Akdis, C.A. Akdis, H. Garn, M. Sokolowska,
Tight junction, mucin, and inflammasome-related molecules are differentially
expressed in eosinophilic, mixed, and neutrophilic experimental asthma in mice,
Allergy 74 (2) (2019) 294–307.
[124] I.D. Pavord, S. Korn, P. Howarth, E.R. Bleecker, R. Buhl, O.N. Keene, H. Ortega,
P. Chanez, Mepolizumab for severe eosinophilic asthma (DREAM): a multicentre,
double-blind, placebo-controlled trial, Lancet 380 (9842) (2012) 651–659.
[125] G.G. Brusselle, T. Maes, K.R. Bracke, Eosinophils in the spotlight: eosinophilic
airway inflammation in nonallergic asthma, Nat. Med. 19 (8) (2013) 977–979.
[126] J.M. Mjosberg, S. Trifari, N.K. Crellin, C.P. Peters, C.M. van Drunen, B. Piet,
W.J. Fokkens, T. Cupedo, H. Spits, Human IL-25- and IL-33-responsive type 2
innate lymphoid cells are defined by expression of CRTH2 and CD161, Nat.
Immunol. 12 (11) (2011) 1055–1062.
[127] C. Barnig, M. Cernadas, S. Dutile, X. Liu, M.A. Perrella, S. Kazani, M.E. Wechsler,
E. Israel, B.D. Levy, Lipoxin A4 regulates natural killer cell and type 2 innate
lymphoid cell activation in asthma, Sci. Transl. Med. 5 (174) (2013) 174ra26.
[128] M.F. Moffatt, I.G. Gut, F. Demenais, D.P. Strachan, E. Bouzigon, S. Heath, E. von
Mutius, M. Farrall, M. Lathrop, W. Cookson, G. Consortium, A large-scale, con-
sortium-based genomewide association study of asthma, N. Engl. J. Med. 363 (13)
T. Boonpiyathad, et al.
(2010) 1211–1221.
[129] K.R. Bartemes, K. Iijima, T. Kobayashi, G.M. Kephart, A.N. McKenzie, H. Kita, IL-
33-responsive lineage- CD25+ CD44(hi) lymphoid cells mediate innate type 2
immunity and allergic inflammation in the lungs, J. Immunol. 188 (3) (2012)
1503–1513.
[130] H.Y. Kim, Y.J. Chang, S. Subramanian, H.H. Lee, L.A. Albacker,
P. Matangkasombut, P.B. Savage, A.N. McKenzie, D.E. Smith, J.B. Rottman,
R.H. DeKruyff, D.T. Umetsu, Innate lymphoid cells responding to IL-33 mediate
airway hyperreactivity independently of adaptive immunity, J. Allergy Clin.
Immunol. 129 (1) (2012) 216–227 e1-6.
[131] T.A. Doherty, D.H. Broide, Airway innate lymphoid cells in the induction and
Seminars in Immunology 46 (2019) 101333
regulation of allergy, Allergol. Int. 68 (1) (2019) 9–16.
[132] Q.N. Yu, Y.B. Guo, X. Li, C.L. Li, W.P. Tan, X.L. Fan, Z.L. Qin, D. Chen, W.P. Wen,
S.G. Zheng, Q.L. Fu, ILC2 frequency and activity are inhibited by glucocorticoid
treatment via STAT pathway in patients with asthma, Allergy 73 (9) (2018)
1860–1870.
[133] M. Nagata, J.B. Sedgwick, H. Kita, W.W. Busse, Granulocyte macrophage colony-
stimulating factor augments ICAM-1 and VCAM-1 activation of eosinophil func-
tion, Am. J. Respir. Cell Mol. Biol. 19 (1) (1998) 158–166.
[134] K. Nakagome, M. Nagata, Pathogenesis of airway inflammation in bronchial
asthma, Auris Nasus Larynx 38 (5) (2011) 555–563.