Immunology of the lung

review

The immunology of asthma

Bart N Lambrecht1–3 & Hamida Hammad1,2

Asthma is a common disease that affects 300 million people worldwide. Given the large number of eosinophils in the airways
of people with mild asthma, and verified by data from murine models, asthma was long considered the hallmark T helper type 2
(TH2) disease of the airways. It is now known that some asthmatic inflammation is neutrophilic, controlled by the T H17 subset
of helper T cells, and that some eosinophilic inflammation is controlled by type 2 innate lymphoid cells (ILC2 cells) acting
together with basophils. Here we discuss results from in-depth molecular studies of mouse models in light of the results from the
first clinical trials targeting key cytokines in humans and describe the extraordinary heterogeneity of asthma.
© 2015 Nature America, Inc. All rights reserved.

Asthma is a chronic inflammatory disease of the conducting airways
in which many cells of the innate and adaptive immune systems act
together with epithelial cells to cause bronchial hyper-reactivity
(BHR) (the tendency of smooth muscle cells in people with asthma
to react to nonspecific stimuli such as cold air and exercise), mucus
overproduction, airway wall remodeling and airway narrowing.
In susceptible patients, this leads to repeated periods of shortness of
breath, wheezing and chest tightness. The disease is very common in
affluent societies, in which almost 1 in 10 children and 1 in 12 adults
is affected, which results in substantial morbidity and annual health-
care expenditure. Worldwide, up to 300 million people are affected.
The total cost of the disease, both in direct medical costs and indirect
costs caused by loss of productivity, is estimated to exceed $18 billion
annually in the USA. In many patients, the disease can be controlled
by a combination of an inhaled corticosteroid (which acts to suppress
the inflammation) and a short- or long-acting β2-adrenergic agonist
(which acts to open the constricting bronchial smooth muscle), but
npg
at a young age are likely to develop asthma1, and large studies have
found that up to half of patients with atopic eczema developed asthma
later in life2. In up to 80% of cases, patients with allergic asthma have
concurrent allergic rhinitis. The ‘united airways disease’ hypothesis
proposes that allergic rhinitis and asthma are manifestations of
the same underlying disease process and that each influences the
severity of the other.
Nonallergic (intrinsic) asthma often develops later in life and, per
its definition, has neither IgE reactivity to allergens in the serum
nor any obvious involvement of the adaptive immune system such
as type 2 helper T cells (TH2 cells). This form of the disease is more
common in women, is often associated with chronic rhinosinusitis
and nasal polyps, as well as obesity, and is difficult to treat, often
requiring long-term treatment with systemic steroids. The field of
clinical asthma diagnosis and treatment has undergone great concep-
tual shifts through the advent of genome-wide expression studies and
the first clinical trials using targeted therapies with biological agents.

in some 5–10% of patients, the disease is refractory to corticosteroid
treatment and often leads to hospital admissions caused by respiratory
viral infection with rhinovirus.
Traditionally, two forms of asthma have been defined in the clinic.
Most children and roughly 50% of adults have allergic asthma, in
which the disease coincides with allergic sensitization defined by
the presence of serum immunoglobulin E (IgE) antibodies and/or a
positive skin-prick test to the (lipo)proteins of common inhaled or
ingested allergens such as house dust mite (HDM), animal dander,
fungal spores, plant or tree pollen, or peanuts. In children, the disease
starts with allergic sensitization, often accompanied by eczema in the
first year of life. These children later develop allergic rhinitis and can
progress to asthma. This stepwise increase of symptoms has been
called the ‘atopic march’. In particular, children with multiple allergies
As with many chronic inflammatory diseases, clinicians now realize
that the division of asthma into only two clinical forms has been an
oversimplification. Different asthma phenotypes, each with a distinct
pathophysiology, are now being defined as asthma endotypes. The
endotypes differ in terms of genetic susceptibility, environmental risk
factors, age of onset, clinical presentation, prognosis and response to
standard and new therapies3–5. Asthma is therefore increasingly seen
as a syndrome rather than a single disease5,6. In people with asthma
who smoke, there is also considerable clinical overlap with chronic
obstructive pulmonary disease, whose immunological basis has been
reviewed7. In this Review, we will focus on the underlying immuno-
logical basis of the various asthma endotypes, integrating results from
human studies targeting particular pathways with results from animal
studies in which a great deal of molecular detail has been gathered.

Eosinophilic asthma as a TH2 disorder

1VIB Inflammation Research Center, Ghent University, Ghent, Belgium. Since the development of the field of pulmonary immunology, asthma
2Department of Respiratory Medicine, University Hospital Ghent, Ghent,

Belgium. 3Department of Pulmonary Medicine, Erasmus MC, Rotterdam,

the Netherlands. Correspondence should be addressed to B.N.L.
(bart.lambrecht@ugent.be) or H.H. (hamida.hammad@ugent.be).
Received 1 October; accepted 7 November; published online 18 December 2014;
doi:10.1038/ni.3049
has been seen as the hallmark TH2 disorder of the lungs. This was
supported by the early findings that asthmatic airway inflammation
measured in bronchoalveolar lavage (BAL) fluid, bronchial biopsies or
induced sputum is often eosinophilic in nature, regardless of whether
the patient is allergic or not8–11. In initial studies of people with mild

nature immunology  VOLUME 16  NUMBER 1  JANUARY 2015 45

 review

Figure 1  Overview of functions of TH2 cells

and ILC2 cells in asthma. TH2 cells and ILC2
cells share many features, such as expression
of the transcription factor GATA-3, which drives
the production of TH2 cytokines, and expression Airway remodeling
Epithelial Chemokine Goblet cell
of the chemokine receptors CCR4, CCR8 and Tissue repair
damage induction metaplasia
CRTH2. Through the production of IL-5, they
control eosinophil development in the bone
marrow. Via IL-13, they can cause goblet cell ECP IL-4 Amphiregulin
metaplasia and bronchial hyperreactivity and MBP
LTC4 IL-13
Charcot-Leyden
prime the vessel wall for upregulation of the crystals LTD4
adhesion molecule VCAM-1 and ICAM-1, thus IL-4
priming eosinophil exit. TH2 cells make more IL-5, IL-13
IL-5
IL-4. Both cell types have been found to Eosinophil
TH2 & ILC2
produce IL-9 (not shown here), although this (GATA-3+)
CCR4
could be a separate population of TH9 cells.
Survival IL-25R
ECP, eosinophil cationic protein; MBP, major Activation Bronchial
basic protein; VLA-4, integrin a4b1; VCAM-1, IL-33R
MBP
hyperreactivity
vascular cell adhesion molecule 1. ECP
IL-5 IL-4 LTC4
IL-13 LTD4
TNF
to moderate asthma, increased numbers of
CD4+ cells that produce interleukin 4 (IL-4) Chemotaxis
and IL-5 were found in BAL fluid and
© 2015 Nature America, Inc. All rights reserved.

Kim Caesar/Nature Publishing Group

mucosal biopsies, correlating with the degree VLA-4
ICAM-1 VCAM-1
of airway eosinophilia12. Subsequent unsu-
VCAM-1
pervised clustering algorithms have shown
that the various asthma endotypes fall into IL-5
Vessel wall priming
TH2hi and TH2lo clusters on the basis of the for inflammatory cell
presence or absence of the cytokines IL-4, recruitment

IL-5 and IL-13 and eosinophils in blood and

Bone marrow mobilization Formation of perivascular
tissue4,13. The presence of serum IgE (atopy) of eosinophil precursors and peribronchial infiltrates
is the prototypical hallmark of adaptive TH2
immunity, driven by IL-4-induced class
switching of the immunoglobulins synthesized by B cells. Although IL-13, is able to improve lung function and reduce the frequency of
it is very easy to measure, the presence of high serum titers of IgE is a exacerbation in people with moderate to severe asthma with high
poor predictor of whether there is TH2 signature gene expression in levels of eosinophils in the blood24. In a phase 2 trial, blocking IL-13
the tissues and whether the patient will develop asthma. There may in humans with lebrikizumab (Genentech) also improved lung-
be better surrogate biomarkers of the TH2hi endotype of asthma, such function parameters, particularly in the TH2hi endotype25.
as levels of serum IL-25 and periostin that correlate well with tissue Eosinophilia in lung tissue is driven by IL-5, which supports the
eosinophilia14. development of eosinophils in the bone marrow, and by the recruit-
In mouse models of asthma driven by inhalation of the model anti- ment of eosinophils to the lung mucosa and interstitium via pro-
npg

gen ovalbumin (OVA) after intraperitoneal sensitization to OVA in duction of eotactic chemokines such as eotaxins 1, 2 and 3 (CCL11,
alum, the genetic or antibody-mediated depletion of CD4 + T cells CCL24 and CCL26, respectively). Eosinophil-derived products such
abolishes key features of asthma, whereas the adoptive transfer of TH2- as eosinophil peroxidase cause BHR directly and activate adaptive
polarized CD4+ T cells from mice with transgenic expression of an immunity through effects on dendritic cells (DCs)26–28. Eosinophils
OVA peptide–specific T cell antigen receptor (TCR) leads to the induc- can also present antigen directly to primed effector T cells29. Studies
tion of asthma features15–18. Conversely, asthma is suppressed by the of mice genetically modified to lack eosinophils have shown that
transfer of CD4+ type 1 helper T cells (TH1 cells) or administration of these cells also contribute to airway wall remodeling and subepithelial
IL-12, which induces the TH1 response19. Together with the early data membrane thickening via the release of transforming growth factor-β
from people with asthma, the case for CD4+ TH2 cells as controllers of (TGF-β), although this has not been seen in all asthma models30,31.
the disease was therefore verified (Fig. 1). Mice that lack the key TH2 Similar to neutrophils, eosinophils upon activation undergo cytolysis
cytokines IL-4, IL-5 or IL-13 all had substantial reductions in asthma and release extracellular DNA traps that contain eosinophilic granules.
features in the OVA model20. In the mouse, IL-4 is necessary for the As these granules maintain the capacity for ligand-induced secretion,
development of adaptive TH2 immunity and IgG1 and IgE antibodies the formation of DNA traps could lead to high local concentrations of
to OVA, and for priming the vessel wall for eosinophil extravasation; eosinophilic toxins such as eosinophil-derived neurotoxin, cationic
therefore, the OVA model relies heavily on IL-4 (refs. 20,21). IL-13 was proteins (eosinophil peroxidase) and major basic protein, which can
found to be necessary and sufficient for mounting BHR and for goblet damage structural cells of lungs32,33 (Fig. 1).
cell metaplasia, the process by which epithelial cells transdifferentiate The elimination of eosinophils from humans through the use of
and begin producing thick mucus containing the mucins MUC5AC antibody to IL-5 (mepolizumab; GlaxoSmithKline) led to a reduc-
and MUC5B, which clog the airway lumen22,23 (Fig. 1). tion in exacerbation frequency in a subset of patients with high lev-
In humans, treatment with an antibody to the α-chain of the recep- els of circulating eosinophils in blood and frequent exacerbations,
tor for IL-4 (dupilumab; Regeneron Pharmaceuticals), which effec- even in those receiving inhaled steroids34. As exacerbations often
tively blocks downstream signaling via the receptors for IL-4 and require systemic steroids that have serious side effects, blocking IL-5

46 VOLUME 16  NUMBER 1  JANUARY 2015  nature immunology

 review

Figure 2  Relative roles of TH2 cells and

ILC2 cells in two forms of eosinophilic asthma. Allergens Pollutants, microbes,
In atopic asthma (left), eosinophilic airway glycolipids
inflammation and BHR are driven by adaptive Goblet cells
Alternatively
TH2 cells that are stimulated by DCs to produce activated
IL-5, IL-13 and IL-4, the latter driving IgE Airway macrophages
synthesis. In nonatopic or intrinsic asthma epithelium
Ym1
(right), which is not dependent on adaptive IL-33
IL-33
immunity, ILC2 cells produce IL-5 and IL-13 IL-25
DCs IL-25
TSLP IL-33
and thus cause eosinophilia and BHR. As there TSLP
NKT cells
is no specific allergen involved and as ILC2
cells produce little IL-4, there is no associated MHCII TSLPR
IgE response from B cells. Modified from ref. TCR
Mast cells Naive
185. MHCII, MHC class II; TSLPR, receptor for T cell ILC2 IL-33R
TSLP; NKT cells, natural killer T cells. IL-25R GATA-3
PGD2
RORα
IL
-9
can therefore reduce the use of oral steroids35. CRTH2
In people with asthma in whom IL-5 was TH2
blocked, there was a considerable reduction in GATA-3
the deposition of extracellular matrix compo- IL-9R
nents tenascin, lumican and procollagen III,

Kim Caesar/Nature Publishing Group

13

-5
IL
Lipoxin A4

-5

IL
L-
possibly leading to less airway remodeling36.

,I
-4
IL-9
IL
New drugs that target eosinophils currently
© 2015 Nature America, Inc. All rights reserved.

3
IL

-1
under phase 3 clinical development include

-1

IL
3
Eosinophils
an antibody to the receptor for IL-5 (ben-
Bronchial hyperreactivity
ralizumab; AstraZeneca/MedImmune) that B cells

effects depletion of eosinophils for months

after a single injection37.
Allergic eosinophilic airway inflammation Nonallergic eosinophilic airway inflammation

ILCs in eosinophilic asthma

In studies in humans, blockade of the receptor for IL-4 or of IL-5 has
led to a favorable clinical response in patients with high eosinophil
counts regardless of whether these patients were atopic or not. In
mice, administration of allergens such as HDM or Alternaria alternata
spores also led to airway eosinophilia in mice deficient in the RAG
recombinase, which do not produce mature T cells or B cells. Such
findings suggest that in both species, there are ways of generating type
2 cytokines and eosinophilia without involvement of the adaptive
immune system (Fig. 2). Innate lymphoid cells (ILCs) were initially
classified as non-T, non-B effector cells in many disease models of
TH2 immunity38–40. Published reviews have described the nomen-
npg
endogenous IL-33, which activates ILC2 cells and causes pulmonary
eosinophilia45. Subsequent data have linked ILC2 cells to the patho-
genesis of allergic airway inflammation; for example, protease-
containing allergens (papain and A. alternata) might activate ILC2
cells indirectly through an effect on lung epithelial cells44,46. The
proteolytic injury induces the release of IL-33, which in turn acti-
vates ILC2 cells to induce lung eosinophilia and BHR. Another way
in which ILC2 cells can be activated in the lungs following allergen
exposure is through expression of the cysteine leukotriene receptor
CysLT1R47. LTD4, the main ligand for CysLT1R, can be induced after
a single exposure to proteolytic allergens and has been found to regu-

clature of the distinctive forms of ILCs, some of which produce
interferon-γ (IFN-γ) (group 1 ILCs, which include traditional natu-
ral killer cells and ILC1 cells), TH2 cytokines (group 2 ILCs formerly
known as ‘nuocytes’ or ‘natural helper cells’, now referred to as ‘ILC2
cells’), and IL-17 and/or IL-22, or are involved in the formation of
lymphoid tissues (group 3 ILCs, which include ILC3 cells and lym-
phoid tissue–inducer cells)41. In many ways, ILC2 cells resemble TH2
cells (Fig. 1). ILC2 cells lack antigen-specific receptors, but like TH2
cells they react to the epithelium-derived cytokines IL-25, IL-33 and
thymic stromal lymphopoietin (TSLP)38–40. ILC2 cells that produce
TH2 cytokines (IL-13, IL-5 and IL-9) were initially described in the
gut of mice infected with helminths, where they contribute to tissue
eosinophilia and to mucus production, crucial for worm expulsion42.
ILC2 cells develop from common lymphoid progenitors in response to
IL-7 and IL-33 and depend on the transcription factors GATA-3 and
RORα. The activation of ILC2 cells is further induced by IL-25 and IL-33,
produced mainly by epithelial cells in response to injury and stimula-
tion via pattern-recognition receptors. The administration of either
cytokine to the airways of mice induces the population expansion of
ILC2 cells that produce IL-5 and IL-13 in the lungs and BAL fluid43,44.
Intratracheal administration of chitin or infection with the intesti-
nal nematode Strongyloides venezuelensis triggers the production of
late the activation and proliferation of ILC2 cells47. Such data indicate
that ILC2 cells can be activated very early after allergen exposure and
that their production of IL-5 and IL-13 could cause some features of
allergic asthma in a T cell–independent manner (Figs. 1 and 2). In
addition to their role in allergy, ILC2 cells also contribute to BHR
development in response to respiratory viruses such as influenza virus
and rhinovirus in adult mice and neonatal mice, respectively48,49. In
the context of infection with influenza virus, ILC2 cells that produce
IL-5 also contribute to the accumulation of eosinophils in the lungs
after viral clearance50. A role for ILC2 cells in viral infections might
help to explain how viral exposure can cause or exacerbate asthma
symptoms in some people.
Because many of the initial reports discussed above used RAG-
deficient mice, in which the contribution of ILC2 cells might be over-
rated due to their lack of a functional adaptive immune system, the
relative contributions of ILC2 cells versus that of TH2 cells in asthma
has remained unclear. Several groups have addressed this question in
mice with an intact adaptive immune system. ILC2 cells have been
found to represent more than half of the cells producing TH2 cytokines
in the lungs of mice subjected to OVA- and HDM-induced asthma51.
Due to a lack of RORα expression in the hematopoietic compart-
ment, mice that lack ILC2 cells develop less-severe lung inflammation

nature immunology  VOLUME 16  NUMBER 1  JANUARY 2015 47

 review
than their wild-type littermates do after intranasal administration
of papain or HDMs52–54. The precise signals involved in the recruit-
ment of ILC2 cells to the lungs after allergen exposure are not very
clear, but microarray data suggest that the same chemokine recep-
tors that attract TH2 cells (CCR4 and CCR8), the prostaglandin D2
receptor CRTH2 and CysLTR1 might be involved47,55. Production
of the CCR4 ligands CCL17 and CCL22, depends on signaling via
STAT6 in epithelial cells, and STAT6-deficient mice fail to recruit
ILC2 cells to the airways56. The signals that dampen the recruitment
and activation of ILC2 cells are only starting to be investigated. The
resolvin lipoxin A4 has been shown to suppress IL-13 production by
ILC2 cells, which indicates that the function of ILC2 cells in asthma
could be regulated by anti-inflammatory lipid mediators57 (Fig. 2).
Similarly, the uptake of apoptotic cells by lung epithelial cells (a proc-
ess dependent on the small GTPase Rac) suppresses the production of
IL-33 and in this way suppresses activation of ILC2 cells58. Some
parasites have also evolved strategies to suppress the activation
of ILC2 cells. Soluble excretory and secretory products of
Heligmosomoides polygyrus block the recruitment of ILC2 cells in
response to airway allergen exposure by blocking the epithelial
production of IL-33 (ref. 59).
© 2015 Nature America, Inc. All rights reserved.
Although ILC2 cells can contribute to TH2 cell–mediated lung
inflammation, the method of action by which this occurs remains
unclear. Chitin is a common constituent of the wall of arthropods
and helminths and is a well-known trigger for the recruitment of
ILC2 cells to the lungs. After exposure to chitin, the IL-13 secreted
by ILC2 cells is crucial for inducing the alternative activation of
macrophages, whereas IL-5 controls early airway eosinophilia 60. In
addition to those effects on cells of the innate immune system, ILC2
cells can also directly or indirectly influence the adaptive immune
system through the release of cytokines. ILC2 cells may provide an
early source of IL-13 that polarizes naive CD4+ T cells to become TH2
cells. Although most TH2 priming occurs via IL-4, the experimental
inhaled allergen papain is IL-4 independent but requires IL-13 from
ILC2 cells to induce adaptive CD4+ T cells via migratory antigen-
presenting DCs54. ILC2 cells have also been shown to express major
histocompatibility complex (MHC) class II and costimulatory
molecules, suggesting that they may themselves act as antigen-
presenting cells, activating CD4+ T cells during the sensitization
npg
phase or during the effector phase. Despite their low expression of
MHC class II, human ILC2 cells are able to drive the proliferation
of HDM-specific CD4+ T cells ex vivo61. Mouse ILC2 cells are able
to endocytose soluble OVA, but they are not able to induce OVA-
specific naive CD4+ T cell proliferation unless antigen-derived
peptides are added to the coculture. Although ILC2 cells can induce
some degree of T cell proliferation under some circumstances and
with soluble peptide antigen ex vivo, whether they also process and
present antigens in vivo remains to be addressed. Also, gut ILC2 cells
have considerable expression of MHC class II, whereas expression is
much lower on lung ILC2 cells, which raises the question of whether
ILC2 cells are antigen-presenting cells relevant to asthma.
Such studies have begun to shed light on the relative contribution
of ILC2 and TH2 cells in allergy. However, to pinpoint the exact role
of each cell population in the disease, there is an urgent need for new
tools that would allow the specific depletion of ILC2 cells at different
stages of the response (sensitization versus effector phase). Crossing
Cd4-Cre mice (which express Cre recombinase from the T cell–
specific Cd4 promoter) to mice in which a loxP-flanked gene encoding
the diphtheria toxin receptor is inserted into the locus encoding the
inducible costimulator ICOS produces progeny in which it is possible
to deplete mice of ILC2 cells while sparing CD4+ TH2 cells61. With this
48 VOLUME 16  NUMBER 1  JANUARY 2015  nature immunology
model, it will be essential to investigate which of the allergic asthma
features are governed by ILC2 cells. Given the fact that depletion of
CD4+ T cells in chronic experimental asthma affects mainly airway
eosinophilia without affecting the development of airway remodeling,
one possibility would be that ILC2 cells control airway remodeling18.
In support of this concept, just like CD4+ TH2 cells, ILC2 cells have
been shown to produce the TGF-β-like molecule amphiregulin, which
contributes to airway remodeling by acting on fibroblasts and epi-
thelial repair processes62,63. Alternatively, they might be the driving
force of the alternative activation of macrophages, which contribute
to airway wall remodeling by promoting collagen synthesis60.
Despite the rapid increase in knowledge about ILC2 cells in experi-
mental models of type 2 immunity, still very little is understood about
the clinical relevance of ILC2 cells in human asthma. ILC2 cells may
have a predominant role in a subset of people with severe, nonatopic
asthma who have high eosinophil counts in the blood and lungs and
have a TH2 signature in the tissues, which would explain why they
respond favorably to blockade of the IL-4 receptor or IL-5 (Fig. 2).
This subform of the TH2hi endotype cluster of asthma often occurs
with chronic rhinosinusitis and nasal polyps and does not respond
well to steroids. A subset of these patients also seem to have a colo-
nization of the nasal sinuses and airways with filamentous fungi that
might represent a chronic trigger for the innate immune system64. In
patients with rhinosinusitis, there is an increase in GATA-3+CRTH2+
ILC2 cells in the nasal tissues65,66. The production of IL-5 and IL-13
is not as well suppressed by steroids in ILC2 cells as it is in CD4+
T cells. TSLP can induce this state of steroid refractoriness in ILC2
cells by inducing phosphorylation of the transcription factor STAT5
and by upregulating the prosurvival factor Bcl-xL67. If ILC2 cells
are driving disease in this subset of patients, it would explain the
steroid refractoriness. The ILC2 cells could be stimulated by chronic
epithelial activation induced, for example, by environmental pollut-
ants, irritants, chronic airway mycosis or repetitive viral infections
driving the expression of IL-25, IL-33 and TSLP (Fig. 2).
Neutrophilic asthma as a TH17 disorder
Although asthma is classically associated with eosinophilia and TH2
cytokines, some patients show a neutrophil-predominant disease
with an absence of TH2 cytokines. In particular, patients with late-
onset and more severe forms of asthma seem to have neutrophilic
inflammation with less reversible airway obstruction and a mixed
TH1 and TH17 cytokine milieu68–70. The role of IL-17 and TH17 cells
in allergic asthma has not been fully elucidated, with IL-17 sometimes
favoring and sometimes protecting mice from the disease. These dis-
crepancies can been explained by the timing of the neutralization or
administration of IL-17, as a protective role for IL-17A in asthma has
been observed only during the challenge phase71,72. Similar results
have been obtained for IL-22, another cytokine produced by TH17
cells73. Another study showed that high exposure to diesel exhaust
particles is associated with both exacerbated asthma symptoms and
increased serum concentrations of IL-17A in children with atopic
asthma74. Severe forms of asthma are characterized by increased
airway remodeling. In some experimental asthma models driven by
HDMs or ozone, IL-17A contributes to remodeling by promoting
fibroblast proliferation75 and by counteracting the anti-inflammatory
role of regulatory T cells76. In mice and humans, IL-17 can also cause
direct contraction of bronchial smooth muscle cells and thus cause
BHR in the absence of neutrophilic inflammation77. It remains to
be conclusively shown where in asthmatic airways the IL-17A and
IL-17F are produced. In addition to conventional TCRαβ+CD4+
T cells, TCRγδ+ T cells, invariant natural killer T cells and ILC3 cells

can be a source of copious IL-17, and the relative contribution of
all of these might differ in various asthma endotypes. The cytokine
production by TH17 cells is notoriously resistant to inhibition by ster-
oids, which explains why neutrophil-rich inflammation driven by
TH17 cells is the pathological correlate of steroid-resistant asthma.
A clinical trial with a antibody that neutralizes the human receptor for
IL-17 (brodalumab; Amgen/AstraZeneca), which blocks the activity
of IL-17A, IL-17F and IL-25, has shown minimal effects on outcome
measures of asthma in mild to moderate disease78. It is possible that
subgroups of patients, particularly those with large numbers of spu-
tum neutrophils or with a high degree of lung function reversibility,
would respond more favorably70. There is also a complex interaction
between TH17 cell–driven asthma and tumor-necrosis factor (TNF).
Lung and systemic levels of TNF are increased in patients with severe
steroid-resistant asthma, although some studies have not confirmed
this70,79. In an adoptive transfer model of TH17 OVA-specific T cells,
neutralization of TNF led to reduced neutrophilic influx in the lung
tissue and airspaces, associated with amelioration of lung function
parameters such as lung compliance but not airway hyper-resistance 70.
In clinical trials, the results of TNF blockade have also been vari-
able79–81. It is still unclear if TNF blockade in IL-17-rich neutrophilic
© 2015 Nature America, Inc. All rights reserved.
asthma would also improve steroid responsiveness.
Overlap syndromes
The view of eosinophilic asthma as an exclusive T H2 disorder and
neutrophilic asthma as an exclusive TH17 disorder is probably an
oversimplification seen only at the extremes of a continuous spec-
trum. In many cases, there is considerable overlap in the types of
cytokines found in an asthma endotype, related to severity of disease.
This has been nicely demonstrated in a model of fungal mycosis in
mice, which at extremely high challenge levels exhibit immunophe-
notype switching from a predominant TH2 response to TH1 and/or
TH17 response(s)82. Some asthma features are induced by CD4+
T cells that produce both TH17 cytokines and TH2 cytokines. In mice,
these IL-4+ TH17 cells induce more severe disease when transferred83.
Another study has shown that the chitinase-like protein Ym1, tradi-
tionally produced by alternatively activated macrophages elicited by
IL-4 and IL-13, drives the production of IL-17 by γδ T cells and thus
contributes to lung neutrophilia and damage in a TH2 setting84. IL-4+
npg
CD4+ TH17 cells have also been identified in humans, and the amount
of IL-17 released by such T cells in BAL fluid correlates with increased
BHR and airway obstruction85.
It is also important to consider the contribution of the T H1 cell–
derived cytokine IFN-γ in eosinophilic and neutrophilic asthma.
Simultaneous transfer of OVA-specific TH1-polarized cells plus TH2-
polarized cells into mice is able to exacerbate bronchial hyper-reactiv-
ity in which IFN-γ acts together with IL-13 to cause smooth muscle
contraction and activation of cells of the innate immune system and
IFN-γ itself promotes the homing of TH2 cells to the lungs86–89. IL-18
drives the activation of TH1 cells that produce IL-13 and cause severe
BHR90. The airways of asthmatics contain increased amounts of IFN-
γ-producing CD4+ T cells, and there is a rise in the serum levels of this
cytokine during acute attacks of asthma91,92. However, no studies of
humans have assessed the therapeutic effect of IFN-γ blockade.
TH9 cells in asthma
IL-9 was initially thought to be a TH2-specific cytokine induced by IL-2,
IL-4 and TGF-β93. TH9 cells have been identified as a distinct helper
T cell subset94, and other studies have shown that additional stimuli
such TSLP, signaling via receptors of the Notch family or ligation of
the receptor OX40 (refs. 95–97) also contribute to the differentiation
nature immunology  VOLUME 16  NUMBER 1  JANUARY 2015 49
review
of TH9 cells. Studies addressing the molecular pathways involved in
IL-9 production have found that binding of the transcription factors
Smad2, Smad3, STAT5, IRF4 and PU.1 to the Il9 promoter are essen-
tial for TH9 differentiation and IL-9 production98–101. This process
is influenced by the inhibitory SOCS proteins, and deficiency in CIS,
a member of the SOCS family, causes increased TH2 differentiation
and exacerbated asthma features100. IL-9 is a mast cell growth factor
that promotes IL-4-driven antibody production by B cells102 and can
also induce goblet cell metaplasia. IL-9 has high expression in the lungs
of patients with asthma103, and in mice, the neutralization of IL-9
with antibodies has been shown to ameliorate OVA- and Aspergillus
fumigatus–induced asthma symptoms101,104. In a chronic asthma
model, antibody to IL-9 blocked the development of airway remod-
eling by reducing mast cell numbers102. Although T cells were initially
considered as the main source of IL-9, experiments with fate-mapping
reporter mice have shown that following papain administration, ILC2
cells produce greater amounts of IL-9 than do T cells105. IL-9 derived
from ILC2 cells has been shown to be an autocrine amplifier of ILC2
cell function by promoting their survival106. The relative contribu-
tions of IL-9 derived from TH9 cells and that derived from ILC2 cells
in allergic asthma remains to be addressed. Trials have been initiated
to target IL-9 in patients with asthma (MEDI-528; MedImmune), but
they have produced disappointing clinical results107.
Regulatory T cells in asthma
For many years, it was postulated that inflammatory responses in
asthma would develop because patients had a deficiency in natural or
induced regulatory T cells (Treg cells). In mice, the usual outcome of
the inhalation of harmless antigens such as OVA is tolerance, a process
mediated by Foxp3+ induced Treg cells (iTreg cells)108. Indeed, mice
that lack the intronic Foxp3 enhancer CNS1 show a paucity of iTreg
cells and develop strong TH2 responses at mucosal sites, including the
lungs109. iTreg cells are also found in the airways of mice with asthma,
where they have high expression of neuropilin 1 (ref. 110). Adoptive-
transfer studies of mice have revealed that Treg cells suppress asthma
features through IL-10 and TGF-β, two cytokines able to suppress
pulmonary DC activation111, and through direct interactions with
endothelial cells, thus preventing angiogenesis112. Another possible
mechanism involves IL-35 production by ICOS+ Treg cells that have
the potential to suppress IL-17-induced BHR in mice113.
In healthy humans, immune responses to allergens can be consid-
ered active peripheral tolerance driven mainly by IL-10 and TGF-β.
The precise role of Treg cells in patients with allergic diseases has been
much debated. In severe asthmatics, the number of Treg cells present
in the blood and sputum is lower, and their suppressive activities
are impaired compared with those of cells from healthy subjects114.
Moreover, the percentage of Treg cells is also decreased in the BAL
fluid of pediatric patients with asthma115. In adult patients, the data
are more controversial, with some reports showing that the number of
Treg cells in the lungs is increased116 or and other showing that number
is decreased117. Despite such discrepancies, all studies agree that
Treg cells are functionally impaired in people with asthma.
Interestingly, this defect in Treg cell function in allergic patients seems
to affect only the regulation of TH2 responses. In the blood of HDM-
sensitized children, a population of Treg cells coexpressing the tran-
scription factors Foxp3 and GATA-3 could suppress the production
TH1 cytokines but not that of TH2 cytokines by peripheral blood
mononuclear cells. This suggests that Treg cells in allergic patients
might promote allergen-specific TH2 responses instead of control-
ling them. In the mouse, a similar Treg cell population unable to sup-
press TH2 responses has been reported. These Treg cells express the
 review

Sensitization Challenge

Direct cDC Indirect cDC

activation activation

hi
CD11c monocytic
cells
TSLP, GM-CSF, IL-33, IL-25, IgE-mediated allergen
IL-1α, ATP, uric acid presentation
CCL2 CD11b+ cDC IL-13
CCL20 migration
β-defensins ILC2 TH2 TH2 PGD2
TH2 TH2
CCL17 Histamine
CCL22
Mast cell
Basophils
T H2
Recruitment and reactivation
TH2
Activation of cells of of TH2 cells
innate immune
system TH2
Recruitment of TH2

Kim Caesar/Nature Publishing Group

pre-cDCs
TH2

CD4 T H2
OX40L, Jagged1, IgE synthesis
IL-6, IL-23, LTC4 by B cells
Lack of IL-12 TH2
© 2015 Nature America, Inc. All rights reserved.

TFH
TH2 ILC2

Allergen presentation by
non professional APCs
TH2 and TH17 polarization

Figure 3  Epithelial cell–DC interactions during the sensitization and challenge phase of experimental asthma. Both lung cDCs and epithelial cells
express pattern-recognition receptors and can be activated directly by allergens. In response to allergens, lung epithelial cells produce chemokines
(CCL2 and CCL20) that attract immature pre-cDCs. Activated epithelial cells produce ‘instructive’ cytokines (for example, IL-1α, GM-CSF, IL-25,
IL-33 and TSLP) and danger signals (ATP and uric acid) that favor the maturation of CD11b + cDCs (which depend on the transcription factor IRF4
for maturation and migration). Activated lung CD11b + cDCs then migrate to the draining mediastinal lymph nodes, where they induce T H2 and TH17
responses. Migration is stimulated by IL-13 derived from ILC2 cells. Some helper T cells start producing IL-21 and adopt a follicular helper T cell (T FH)
fate to induce class switching to IgE in B lymphocytes. In the lymph nodes, DCs receive help from basophils to sustain T H2 responses. CD11chi DCs also
have a predominant role during the TH2 effector phase of asthma, when the lungs are repeatedly exposed to allergens (right). During allergen challenge,
poorly migratory CD11chi monocytic DCs and/or macrophages could locally restimulate effector function in lung-resident lymphocytes or they could
recruit effector TH2 cells through the production of CCL17 and CCL22. IgE-mediated allergen recognition enhances T H2 responses to inhaled
allergens, at least in humans.

inhibitory molecule TIGIT and produce fibrinogen-like protein 2, become clear that airway epithelial cells are crucial in controlling DC
which allows them to selectively spare TH2 responses while efficiently activation127. Many allergens, such as A. fumigatus spores, cockroach
npg

inhibiting TH1 and TH17 responses118. Whether this TIGIT+ popula-
tion and the GATA-3+Foxp3+ T cells identified in allergic children
are related or not remains to be addressed.
Epithelial cell–DC interactions in response to allergens
Whatever the endotype of asthma, the various T cells or ILCs that
control airway inflammation need to be activated. For T cell responses
of all kinds, this involves the activation of antigen-presenting DCs that
recognize the allergen and present it to T cells in the lymph nodes
that drain the lungs (Fig. 3). Various studies have shown that DCs are
necessary and sufficient for inducing TH2 and TH17 adaptive immu-
nity to inhaled allergens in mice that have not encountered the aller-
gens previously119. There are different subtypes of DCs in the lungs,
broadly categorized as conventional DCs (cDCs) and plasmacytoid
DCs (pDCs). Among cDCs, CD11b+CD172 (SIRP1α)+ cDCs that
depend on the transcription factor IRF4 are necessary and sufficient
to induce allergic sensitization120–122, whereas CD103+XCR1+ cDCs
that depend on the transcription factors IRF8 and BATF3 induce
tolerance to inhaled allergens123,124. pDCs also induce tolerance to
inhaled antigens by inducing Foxp3+ Treg cell responses to inhaled
antigens125,126. There has been much progress in understanding of
the process of allergic sensitization by DCs. From such studies it has
or HDMs, have protease activity. Proteases (such as papain or Der
p 1) act on epithelial cells to decrease barrier function by cleaving
tight junction proteins and induce an innate cytokine response via
stimulation of protease-activated receptors. A. fumigatus protease
activity leads to the formation of fibrinogen-cleavage products in
the fluid lining the lungs that activate Toll-like receptor 4 (TLR4)
and in this way stimulate airway epithelial cells to produce IL-33
and TSLP, which activate DCs, ILC2 cells and basophils128. Cat dan-
der and HDM extracts contain allergens (Fel d 1 and Der p 1) that
directly stimulate TLR4 on epithelial cells to produce IL-1α, IL25,
IL-33, TSLP and the cytokine GM-CSF129–131. After the inhalation
of allergens, there is also the release of endogenous ‘danger signals’
such as uric acid, ATP and HMGB1 (refs. 132–134). Allergens such
as HDMs can also be immunogenic by triggering C-type lectin recep-
tors such as dectin-1 or dectin-2 on lung epithelial cells or DCs, which
could contribute to mixed TH2 and TH17 immunity135,136. The epithe-
lial cytokines induced by allergens or proteases induce TH2 immunity
by activating CD11b+ cDCs (causing their migration and upregula-
tion of costimulatory molecules such as OX40L) and by activating
ILC2 cells and basophils that could be an important source of polar-
izing IL-4 and/or IL-13 for priming TH2 immunity and avoiding tol-
erance to inhaled allergens54,130,137–139 (Fig. 3). When there is too

50 VOLUME 16  NUMBER 1  JANUARY 2015  nature immunology


much endotoxin in the inhaled allergen fraction, however, TH1
immunity ensues. Many of the human genome-wide association
studies of asthma and atopy have found single-nucleotide polymor-
phisms in genes encoding molecules that control epithelial barrier
function (for example, filaggrin) and control the production or
responsiveness to epithelial cytokines, such as TSLP and IL1RL1
(which encodes the receptor for IL-33); this indicates a crucial
role for epithelial cells in asthma. Also, many of the environmental
risk factors for atopy and asthma, such as cigarette smoking, viral
infections and air pollution, seem to converge on the epithelial
cell–DC interaction127.
It has become increasingly clear that DCs and epithelial cells have
an important role not only in sensitization to allergens but also in
ongoing asthma (Fig. 3). There is an increase in the abundance of
activated DCs in the airways of people with asthma and in mice with
ongoing inflammation, and these form clusters with activated T cells
around the airways and blood vessels in the lung140,141. Depletion
of CD11chi cells during ongoing allergen challenge suppresses the
salient features of asthma142,143. The monocyte-derived DCs that
accumulate in the airways have some features of macrophages, such
as the expression of the Fc receptors CD64 and FcεRI, and are poorly
© 2015 Nature America, Inc. All rights reserved.
migratory. They also express the chitinase-like protein Ym1, like alter-
natively activated macrophages143. Their main function is the local
recruitment of effector T cells via the production of chemokines, and
thus they compartmentalize ongoing inflammation to the airways120.
In ongoing disease, epithelial cells continue to fuel airway inflam-
mation by activating incoming monocytes to adopt an immunogenic
phenotype and by producing chemokines and cytokines that activate
eosinophils, neutrophils and other cells of the innate immune system.
Epithelial cells that go through repeated cycles of injury and repair
also contribute substantially to the process of airway wall remodeling
via release of repair cytokines127. Such concepts are slowly making
their way to clinical testing. AMG 157 (Amgen) is a human antibody
to TSLP that has been shown to block the late asthmatic response and
bronchoconstriction in response to allergen challenge in humans,
and reduces eosinophil counts144. Human antibodies to GM-CSF and
IL-1α have been developed for rheumatoid disease, but results for
asthma have not yet been reported.
npg
IgE effects on mast cell, basophil or DCs?
IgE has the lowest concentration of all antibodies, and IgE is mainly
known for its role in allergic disease, in which it has the potential
to activate mast cells and basophils when crosslinked on the high-
affinity IgE receptor FcεRI. In mast cells and basophils, this receptor
complex is composed of FcεRIα and FcεRIβ and a dimer of FcεRIγ
chains (FcεRI(αβγ2)). The expression of FcεRI is heavily influ-
enced by serum concentrations of IgE and also by the TH2 cytokine
IL-4. The presence of antigen-specific IgE in the serum of patients
with asthma leads to the immediate suggestion that mast cells
and basophils, armed with high-affinity IgE receptors, have an
important role in the disease. However, studies of mast cell–deficient
mice have produced conflicting results. In models of mild asthma
without the systemic adjuvant alum, mast cells have an important
proinflammatory role that is stimulated by IFN-γ145,146; in mod-
els using alum or strong HDMs, mast cells are redundant147,148. In
humans, the lack of clinical efficacy of antihistamines on the symp-
toms and signs of asthma has always been taken as evidence that mast
cells do not serve a big role in asthma. However, mast cells can infil-
trate the bronchial smooth muscle layer and contribute to BHR149,
possibly driven by the mast cell growth factor IL-9 and release of
leukotrienes. In the TH2hi endotype of asthma, increased numbers
nature immunology  VOLUME 16  NUMBER 1  JANUARY 2015 51
review
of mast cells have also been found between airway epithelial cells.
Bronchial epithelial cells exposed to IL-13 produce the mast cell
growth factor SCF, which might explain the increase in intraepithe-
lial mast cells150.
Increased numbers of basophils have been found in the blood and
tissues of patients with asthma and mice exposed to HDMs. Basophils
are an important source of IL-4 that could contribute to TH2-type
sensitization in trans by acting together with DCs151,152. In response to
inhalation of papain, there is even cooperation between IL-33-activated
basophils and ILC2 cells, in which basophil-derived IL-4 boosts the ter-
minal differentiation and activation of ILC2 cells148 (Fig. 3). However,
although they are proposed to have antigen-presenting function,
basophils are not proficient at stimulating naive CD4 + T cells,
and mice genetically modified to lack basophils (Mcpt8-Cre mice)
develop normal asthma features in response to OVA in alum153.
Basophils could also have an important role in the effector and recall
response to allergens by producing lipid mediators and cytokines that
prime the vessel wall for extravasation and stimulate CD4+ effector
cells directly154, and they could be involved in tissue remodeling.
Basophils are armed with the high-affinity IgE receptor and, just
like mast cells, could react immediately when there is reexposure to
relevant allergen.
Maybe the strongest indication of a role of the IgE in asthma is the
clinical efficacy of anti-IgE strategies in human asthma. The drug
omalizumab (Xolair; Genentech/Novartis) is a humanized mono-
clonal antibody that binds to the constant domain of IgE, inhibit-
ing its interaction with the high-affinity receptor FcεRI, and has
proven efficacy in a subset of patients. Before this drug shows clini-
cal effects in patients, it must be administered for a few weeks, which
suggests that the drug does not work by inhibiting the early degranu-
lation of mast cells or basophils. Upon prolonged treatment, there is
also a reduction in TH2 cytokine production in lung tissues, which
suggests that it affects the generation of effector TH2 responses155.
Monocytes and circulating DCs of allergic humans express FcεRI(αγ2)
without FcεRIβ156,157. The targeting of allergens to FcεRI via IgE leads
to an improvement of 1000-fold in the activation of CD4+ T cells
in vitro, most probably because FcεRI targets antigens to the MHC
class II–rich endosomal compartment of DCs where peptides are
loaded158. Ligation of FcεRI on DCs also leads to the production of
CCL28, a chemokine that selectively attracts TH2 cells159. The effect of
triggering FcεRI on DCs has been studied in vivo only recently. DCs
in mice carrying a transgene expressing human FcεRI under control of
the promoter of the gene encoding mouse integrin CD11c are at least
50 times more potent in presenting OVA antigen to CD4+ T cells when
antigen-specific IgE is present160. Moreover, the presence of IgE on
DCs primes naive T cells for TH2 differentiation, and recall responses
to OVA antigen are stronger in vivo. Although mouse cDCs do not
express FcεRIα, mouse DCs recruited in response to viral lung infec-
tion or HDM exposure express FcεRIα in combination with FcεRIγ,
which leading to the expression of functional FcεRI(αγ2)120,151,161.
In mice, triggering of this receptor also leads to production of CCL28
and to IL-13 production in T cells.
Although triggering via FcεRI can lead to cellular activation
dependent on the transcription factor NF-κB in DCs, it can also lead
to the production of IL-10 and the tryptophan catabolizing enzyme
indoleamine deoxygenase, which suggests that FcεRIα expression on
DCs might also contribute to the inhibition of inflammation162. In
support of that, a study of mice that express human FcεRIα on DCs
has demonstrated that ligation of IgE on DCs by relevant allergen
suppresses the production of inflammatory chemokines that attract
mast cells and suppresses asthma in mice163.
 review

Normal antiviral immunity to HRV Antiviral immunity to HRV in asthma

Interferon response IFN-α, IFN-β, Attachment to ICAM-1 Increased attachment

genes (ISG15) IFN-γ TLR3, TLR7, Mda5 triggering to ICAM-1

TGF-β Reduced IFN-α, Increased viral replication

Viral replication IFN-β, IFN-γ and shedding, cell death
CD103+ cDC
contained
CD8
pDC Ym1
Induction of protective CD11b+ cDC
adaptive immunity pDC
CCL2
CCL11 Alternatively TH2
IgE loaded TH17
activated
macrophage

Kim Caesar/Nature Publishing Group

TH2 TH17

Virus-induced asthma
exacerbation
TH17
TH2
Recruitment of
monocytic cells

Neutrophils
Eosinophils
© 2015 Nature America, Inc. All rights reserved.

Figure 4  Defective antiviral immunity in asthma. In the normal antiviral response to HRV (left), HRV attaches to epithelial cells by adhering to
ICAM-1. Following viral entry, TLRs and the cytosolic receptor Mda5 are triggered in lung epithelial cells to induce type I and type III interferon
responses. This leads to an antiviral state and controls viral replication, together with CD8 + T cell immunity generated by CD103+ cDCs. Other early
sources of type I interferons include pDCs and recruited monocytic cells. In asthma (right), ICAM-1 expression is upregulated, which leads to more entry
of virus. However, the induction of interferons is severely hampered. This could be intrinsic to asthma or might result from the suppressive functions
of eosinophils and alternatively activated macrophages, acting via Ym1 to suppress antiviral immunity in the epithelium. pDCs armed with IgE also fail
to produce type I interferons. The ensuing high viral load causes damage to the epithelium and thus causing locally present monocytic DCs and T H2 or
TH17 cells to cause airway inflammation rich in neutrophils and eosinophils.

Susceptibility to respiratory viral infection
In most patients with asthma, exacerbations are caused by relatively
mild respiratory viruses, such as human rhinovirus (HRV), respiratory
syncytial virus or adenovirus, or by influenza virus. In childhood,
HRV is associated with persistent wheezing, which is a strong
risk factor for asthma later in life164,165. Experimental infection
with HRV-16 in asthmatics causes neutrophilic inflammation
and steroid resistance166,167. In mice that express humanized integrin
ligand ICAM-1, infection with HRV can exacerbate disease168,169.
npg
suppresses antiviral immunity as a secondary effect. In support
of that proposal, triggering of FcεRI on pDCs by IgE crosslinking
interferes with the normal antiviral functions of pDCs and type I
interferon production178–180. When bronchial epithelial cells are
cultured with eosinophils, they are less able to produce type I and type III
interferons in response to HRV, via eosinophil-derived TGF-β181
(Fig. 4). The interference with antiviral immunity by type 2 immune
responses is probably an old adaptation response. Indeed, in the gut
immune system, a suppressive effect of helminth infection on antiviral

Experimental models of infection with Sendai virus have revealed that
respiratory viruses can induce an innate immune response that leads
to the activation of natural killer T cells and alternative activation of
macrophages that sustain airway pathology via IL-13 (ref. 170).
In some asthma endotypes, virus-induced exacerbations are a major
problem despite adequate control of disease. The increased suscepti-
bility to viruses could be caused by a primary defect in innate antiviral
immunity in some asthmatics, related to epithelial fragility and barrier
disruption, or to defects in the production of TLR7 or interferon171
(Fig. 4). In the lung, antiviral immunity relies heavily on produc-
tion of type I interferons (IFN-α and IFN-β) and type III interferons
(IFN-λ, IL-28A, IL-28B and IL-29) and inducing interferon-stimulated
genes, such as the gene expressing the the ubiquitin-like molecule
ISG15. When exposed to HRV-16, epithelial cells from adult and
pediatric patients with asthma produce less IFN-β and IFN-λ and
have a less pronounced interferon-induced gene signature, particu-
larly when the disease is poorly controlled172–174. It has been unclear
whether this also causes an increased viral load in the lower respiratory
tract, and whether defective interferon responses explain susceptibility
to all viruses175–177. An alternative explanation for the enhanced
susceptibility to viral infection is that allergic sensitization 178 or
the presence of TH2 cell–driven eosinophilic airway inflammation
immunity to norovirus has been described182. Alternative activation
of macrophages via IL-13 caused upregulation of the chitinase-like
protein Ym1, which suppresses antiviral immunity182. Chitinases and
chitinase-like proteins are strongly upregulated in mouse and human
asthma and could be functionally linked to the diminished antiviral
state of people with asthma or to more neutrophil-rich asthma84,183.
Whatever the cause of the defect, the first trials using inhaled inter-
ferons to treat viral exacerbations of asthma have been initiated 184.
It is also possible to target the function of chitinase-like proteins.
Conclusions
Clinicians have begun to realize that asthma is a heterogeneous disease
with many endotypes. Various aspects of innate or adaptive immunity
to allergens, environmental triggers or viruses are involved in caus-
ing sensitization to allergens, symptoms of asthma, exacerbations,
and response to therapies. There is extensive crosstalk between the
airway epithelium and cells of the immune system in the initiation
and perpetuation of the disease. The results from the first intervention
trials in humans with asthma reflect the heterogeneity of this disease.
No single drug will be effective for all patients, but some drugs might
be very effective in selected patients who are carefully identified on
the basis of underlying immunological processes.

52 VOLUME 16  NUMBER 1  JANUARY 2015  nature immunology


Acknowledgments
Supported by the European Union European Research Council (B.N.L.), the
European Union Framework Programme 7 (MedALL and EUBIOPRED to B.N.L.),
the University of Ghent Multidisciplinary Research Platform (Group-ID, to B.N.L.)
and Fonds Wetenschappelijk Onderzoek Vlaanderen (B.N.L. and H.H.).
COMPETING FINANCIAL INTERESTS
The authors declare no competing financial interests.
Reprints and permissions information is available online at http://www.nature.com/
reprints/index.html.
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