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Chronic inﬂammation and asthma
Article in Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis · September 2009

DOI: 10.1016/j.mrfmmm.2009.09.005 · Source: PubMed
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Published as: Mutat Res. 2010 August 07; 690(1-2): 24–39.
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Chronic inflammation and asthma
Jenna R. Murdoch and Clare M. Lloyd⁎

Leukocyte Biology Section, National Heart and Lung Institute, Faculty of Medicine, Imperial
College London, London SW7 2AZ, UK.
Abstract
Allergic asthma is a complex and chronic inflammatory disorder which is associated with airway
hyper-responsiveness and tissue remodelling of the airway structure. Although originally thought
to be a Th2-driven inflammatory response to inhaled innocuous allergen, the immune response in
asthma is now considered highly heterogeneous. There are now various in vivo systems which
have been designed to examine the pathways leading to the development of this chronic immune
response and reflect, in part this heterogeneity. Furthermore, the emergence of endogenous
immunoregulatory pathways and active pro-resolving mediators hold great potential for future
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therapeutic intervention. In this review, the key cellular and molecular mediators relating to
chronic allergic airway disease are discussed, as well as emerging players in the regulation of
chronic allergic inflammation.
Keywords
Asthma; Chronic allergic airway inflammation; Remodelling
1 Asthma
Allergic asthma is a heterogeneous disorder of the conducting airways involving chronic
airway inflammation, declining airway function and tissue remodelling. The prevalence of
asthma has rapidly increased over the last few decades to epidemic proportions and there are
now an estimated 300 million sufferers worldwide, a total that is expected to rise
dramatically over the next 15–20 years [1]. Asthma is associated with enormous healthcare
expenditures and, despite the advances in effective therapy, the consequential economic
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burden associated with disease control and morbidity continues to escalate [2].
Asthma is thought to arise from the complex interplay of genetic susceptibility and
environmental influences, such as timing and dose of allergen and co-exposure to infection
[3]. This culminates in an inappropriate inflammatory response led by the T-helper type
(Th)-2 lymphocytes to normally harmless airborne allergens [4] (summarised in Fig. 1).
Although no specific gene or environmental factor solely accounts for asthma, the genetic
predisposition to mount a local mucosal immunoglobulin (Ig) type E (IgE) response, known
as atopy, is one of the strongest risk factors for developing the disease [3,5]. The majority of
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Corresponding author. Tel.: +44 0207 5943102; fax: +44 0207 5943119. c.lloyd@imperial.ac.uk.
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incorporating any publisher-supplied amendments or retractions issued subsequently. The published journal article, guaranteed to be
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Murdoch and Lloyd Page 2
asthma is associated with atopy [6], however there are also clinically defined variant forms
of the disorder which are independent of atopy, i.e. do not mount an IgE response to
environmental allergens [7]. Th2 associated inflammation and IgE production are also
features of non-atopic or intrinsic asthma, although what drives this process remains
unknown [8]. Indeed, asthma is now considered a heterogeneous disorder comprised of
distinct endotypes [9,10]. This review will provide an overview of the immunopathological
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mechanisms underlying the various clinical features of asthma as well as some important
remaining questions in asthma research.
1.1 Airway hyper-responsiveness

Clinically, asthma presents as a physiological dysfunction of the lung characterised by
breathlessness, wheeze and a variable airflow obstruction [11]. This accounts for the
dramatic increase in responsiveness of the conducting airways known as airway hyper-
responsiveness (AHR) [12]. AHR, considered the hallmark of the asthma phenotype, is
defined as the ease with which the airways narrow in response to a bronchoconstrictive
challenge and manifests as a combination of increased sensitivity and reactivity for a given
stimulus [13]. AHR is a fundamental abnormality in asthma however at present there is no
clear or consistent association between immunological and structural features of asthma and
the increased responsiveness of the airways. Rapid bronchiolar constriction and reversal
with bronchodilators suggests that ASM is involved. Increased ASM is seen in kids and
removal of ASM by thermoplasty, improves AHR demonstrating a contribution of ASM to
AHR [14]. Airway wall thickening due to remodelling is associated with increased AHR
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[15]. However, Niimi et al. demonstrated an inverse relationship between AHR and airway
wall thickness [16]. This is discussed fully in recent review [17]. Recent studies have
demonstrated a variety of cellular inflammatory phenotypes associated with asthma. An
eosinophilic or neutrophilic infiltrate is a common feature of allergic airway inflammation
and this has been correlated clinically with AHR although similar results were not found in
murine studies. Increased presence of mast cells [18] and Th2 [19] cells also correlates with
AHR. Understanding the mechanisms underlying this response is of great importance.
2 Immunopathogenesis of chronic asthma

2.1 Acute episodes, persistent inflammation and airway remodelling
Inflammation is a response of the immune system to injury which is beneficial to the host
under normal circumstances. However, an aberrant immune response to non-pathogenic
stimuli in the asthmatic airway leads to a chronic inflammatory response relevant to the
pathogenesis of the disease [20]. Episodes of acute inflammatory reactions are often
accompanied by an underlying chronic inflammation even in the absence of continuous
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allergen exposure [11]. The complex interplay between the multi-cellular inflammatory
infiltrate and parenchymal lung tissue cells is orchestrated by a broad network of self-
amplifying bioactive mediators, including cytokines, antibodies and growth factors [21].
Inflammatory leukocyte recruitment is directed by small inflammatory soluble molecules
known as chemokines [21,22]. Inappropriate immune activation is thought to be, in part,
responsible for the chronicity of allergic asthma, however there is now increasing evidence
that dysregulation of endogenous immune regulating processes are, in part, also responsible
for the development of this disease [23].
The immune system has classically been divided into two major arms: innate and adaptive.
The evolutionarily primitive innate immune system forms an immunosurveillance network
in the periphery to initiate an immediate beneficial response to foreign agents [24]. Adaptive
immune lymphocytes re-circulate within the blood and lymphatic system and have the
ability to mount an antigen-specific immune response accompanied by development of long

lasting memory to subsequent challenges by the same antigen [25]. The potency of the
adaptive immune systems lies in its ability to generate billions of different antigen receptors
from multiple gene segments [26]. The innate and adaptive immune systems are closely
interlinked since the innate immune response defines the phenotype of subsequent antigen-
specific adaptive immunity [25]. Optimal immune function relies on contributions from both
divisions in equilibrium with immunoregulatory components [27]. Allergic inflammation is
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mediated by cells from both the innate, adaptive and surrounding tissue cells. Recently,
however, the distinctions between innate and adaptive immunity have become blurred.
Indeed, certain leukocytes populations such as γδT cells and NKT cells do not fit either
convention [28]. An overview of the various immune leukocytes involved in the allergic
airway is discussed below.
3 Allergic sensitisation
3.1 Th2 priming by DCs
It was long enigmatic how sensitisation to natural allergens occurred since, unlike pathogen-
associated antigens, not all allergens are intrinsically immunogenic. One of the earliest steps
in the establishment of allergic sensitisation is the generation of an antigen-specific T cell
response to an allergen [29]. Th2 responses are typical of allergic asthma; however, T cells
do not react directly to inhaled antigens and require critical instructions provided the innate
immune system. Dendritic cells (DCs) are considered the most powerful antigen-presenting
cells (APCs) and form an innate immune network within the lung tissue [30]. They express a
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variety of evolutionarily ancient germline-encoded receptor families, known as pattern-

recognition receptors (PRRs) which enable constant monitoring of the airways. PRRs
recognise a broad range of invariant structures such as microbial components, known as
pathogen-associated molecular patterns (PAMPs) which enable the immune system to detect
pathogens and promote elimination [31]. Many allergens are contaminated with agonists of
PRR enabling them to induce DC “maturation”. This involves up-regulation of co-
stimulatory molecules and acquisition of the capacity to migrate to the draining lymph
nodes, enabling them to interact with an effectively prime an antigen-specific effector T cell
response [32–34]. Recently, generation of allergic Th2 responses to allergen have been
demonstrated via PRR such as Toll-like receptors (TLRs) suggesting that this may be a
critical component of sensitisation to some allergens [35]. However, not all allergens are
intrinsically immunogenic or have PRR agonistic potential. Danger signals or damage-
associated molecular patters (DAMPs) in the absence of infection can also influence
dendritic cell activation [32,36]. Many allergens contain enzymatic activity which liberate
DAMPs in the lung microenvironment [37]. Indeed, Hammad et al. have shown that
triggering of epithelial expressed TLR-4, a receptor that recognises conserved components
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of microbes, helps drive the development of allergic reactions to a common household

antigen [38]. In addition, the release of Uric acid by dying cells can induce Th2 polarisation
and atopic asthma via triggering of NALP3 inflammasome in DCs [39].
There is now compelling evidence in support of the crucial role played by DC in

determining the functional outcome of T cells responses following allergen exposure and
inception of atopic asthma [30]. In addition to T cell priming, it is now well established that
DCs are also essential for maintenance of the Th2 response towards aeroallergens [40]. It is
important to note that, in addition to conventional DCs (cDCs), an additional DC subset
known as plasmacytoid (pDC) are present in the lung [41]. Interestingly, transfer of allergen
loaded pDC suppressed inflammation in allergen sensitised and challenged mice, whereas
depletion of pDC abrogated this tolerance [34], and as such pDCs are thought to have a
regulatory influence in the airway. Manipulation of DC function can have profound effects
on the allergic inflammatory response highlighting these cells as potential targets for
therapeutic intervention. This has been excellently reviewed elsewhere [42].

Activation of Th2 cells by APCs leads to the production of cytokines such as IL-4. The
presence of an IL-4 rich cytokine milieu promotes co-stimulatory interactions between T
cells and B cells initiating class switching and secretory plasma B cell affinity maturation to
produce IgE [43] (Fig. 2). However, priming an allergen-specific Th2 response from naïve
CD4+T cells is dependent on exogenous IL-4 in the surrounding milieu [44]. The nature of
the cells that produce ‘early’ IL-4 required for this differentiation remains unknown.
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Interestingly, basophils are potential candidate responsible for early production of this
cytokine [45]. Furthermore, recent investigations have elegantly demonstrated the
importance of allergen presentation by basophils to the development of allergic sensitisation
in vivo, and the ability of basophils to initiate Th2 differentiation in the absence of DCs in
vitro [46–48]. This information offers a new paradigm for the initiation of Th2 immunity
which will no doubt lead to exciting developments about their function in disease and
potential as a therapeutic target. Chronic inflammatory conditions encountered in vivo are
thought to promote antigen-presenting capabilities in a variety of different cell types. Indeed
many immune cells associated with the asthmatic phenotype demonstrate APC capabilities
including γδT cells [49], eosinophils [50,51] and lung structural cells [52]. During chronic
inflammation, it is thought the interface between T cells and non-professional APCs in the
asthmatic lung and serves to further propagate inflammatory response [53].
The pulmonary epithelium is the first point of contact for inhaled environmental allergens
and is increasingly implicated as a central player in the Th2 cell sensitisation process [54].
The relationship between the pulmonary innate immune system and surrounding tissue is
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essential to the proximal events leading to Th2 mediated allergen sensitivity and there is
now a growing appreciation of the contribution of innate immune system to asthma [55,56].
Indeed, many products of asthma susceptibility genes have been linked to the innate immune
system [4]. Epithelial cells influence DC function through direct cell–cell interaction and via
the release of mediators [55]. Allergens such as house dust mite (HDM), can directly or
indirectly interact with the innate immune functions of airway epithelial cells and DCs
[38,57]. Many allergens possess epithelial modulatory activity and increase the permeability
of this barrier [58]. Indeed, inhaled allergens can directly stimulate epithelial cells to
produce a range of mediators such as thymic stromal lymphopoietin (TSLP) [59], IL-33
[60,61], and IL-25 [62]. These mediators can direct a polarised Th2 cell effector response
and further perpetuate the salient features of asthma [63].
4 The inflammatory cascade—multi-cellular and fundamental to the

pathogenesis of asthma
4.1 Inflammatory infiltrates
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By virtue of their capacity to release a wide range of pro-inflammatory mediators, affinity

for IgE and strategic proximity to blood vessels, mucosal surfaces and smooth muscle, mast
cells have long been considered a key effector cell of asthma pathogenesis. Once
synthesised, IgE antibodies circulate in the blood before binding to the high affinity Fcɛ
antibody receptor (FcɛR)-I, present on tissue mast cells and peripheral blood basophils, or
the lower affinity FcɛRII, found on a wide variety of leukocytes [64]. Mast cells are
strategically located in both the airway epithelium and deeper layers of the mucosa [65]. In
the asthmatic airways, the majority of IgE is bound by FcɛR1 on mast cells making them
highly responsive to inhaled antigen [66]. Cross-linking of receptor bound IgE aggregations
on the surface of these cells triggers a complex network of intracellular signalling events
[66]. Leading to degranulation and discharge of preformed mediators such as proteases and
vaso-active histamines, synthesis of lipid derived eicosanoids, leukotrienes (LTs) and
prostaglandins (PGs), and the transcription of cytokines [67]. These mediators cause the
early phase asthmatic reaction (EAR) which is directly responsible for AHR and is

characterised by mucus secretion and vasodilatation prior to the recruitment of inflammatory

cells [68]. The EAR lasts 30–60 min and followed 4–6 h later by the late phase asthmatic
reaction (LAR) featuring excessive Th2 driven eosinophilic inflammation.
The importance of mast cells in atopic asthma became somewhat overshadowed by

developments in the understanding of Th2 cell biology in asthma. However, recent
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developments in the field of mast cell biology have led to a resurgence of interest [69,70].
Mast cells can provide an early source of pro-inflammatory mediators such as IL-4, which
can influence the proximal events during allergen-specific effector T cell sensitisation [67],
and IL-5 which promotes eosinophil recruitment and activation [71]. Interestingly, the
airway smooth muscle (ASM) bundles are infiltrated with mast cells in asthmatics [72]. The
ASM is responsible for airway constriction and provides recruitment and survival factors for
mast cells [72]. Interestingly microlocalisation of mast cells to ASM is absent in non-
asthmatics eosinophilic bronchitis patients [73], which share many clinical manifestations
with asthma such as eosinophilia and cough, yet demonstrate normal airway responsiveness
[74]. This has led to the idea that selective mast cell microlocalisation within the lung
structure may be a key factor in determining the declining lung function seen in asthmatics
[73].
Granulocytic eosinophils typically predominate the atopic allergic inflammatory infiltrate

[75], and the degree of eosinophilia has been correlated with disease severity in some
asthmatic patients [76]. Eosinophils are found in both the lung tissue and the
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bronchoalveolar lavage (BAL) fluid of asthmatic patients [75,77], and are, in large, recruited
from the bone marrow as CD34+ precursors following the release of prostaglandins,
cysteinyl leukotrienes, cytokines and chemokines such as monocyte chemotactic protein
(MCP)-1/CCL2, MIP3α/CCL20 and Regulated upon Activation, Normal T cell Expressed
and Secreted (RANTES)/CCL5 from the asthmatic airway [78]. Selective recruitment of
eosinophils to the airways is driven by Th2 mediated induction of the eotaxin family of
chemoattractants (eotaxin-1/CCL11, eotaxin-2/CCL24 and eotaxin-3/CCL26) acting through
the CCR3 chemokine receptor [79]. Eotaxin production is largely produced by epithelial
cells in response to Th2 derived cytokines such as IL-13 and IL-5 [80]. A number of
cytokines can prime eosinophil maturation including IL-3, and graulocyte–monocyte colony
stimulating factor (GM-CSF) [78]. In particular, IL-5 is important for eosinophil recruitment
[81], as well as the differentiation, proliferation and maturation of eosinophils [78].
Once recruited, primed eosinophils degranulate to release their cationic proteins including
major basic protein (MBP) and eosinophil peroxidise (EPO) [82]. This capacity is thought to
extend from the traditional role of eosinophils in protecting the host against parasitic worms
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[83]. These products are toxic to the lung microenvironment and, in addition to superoxide
production, cause damage to the surrounding tissue microenvironment [78]. Inflammatory
mediator release including Th2 cytokines (IL-4 and IL-13), and lipid eicosanoids
(prostaglandins, leukotrienes and lipoxins), from eosinophils also contribute to the clinical
symptoms of asthma through their potent effects on airway vascular tissue and smooth
muscle reactivity [84]. Together, these products promote pathophysiological hallmarks of
asthma [78]. Once established, the repetitive cycle of tissue damage and inflammatory-cell
recruitment becomes chronic even in the absence of sustained allergen, the chronic
inflammation persists [85]. Recent studies have also identified an immune modulatory role
for eosinophils including antigen presentation function, attributing eosinophils the ability to
direct effector the lymphocyte response [86]. In addition, eosinophils also possess the ability
to synthesise, store and secrete the immunoregulatory IL-10 [87] and the Th1 cytokine IFN-
γ which may skew the pathogenic Th2 response [88]. The importance of this during allergic
asthma requires further attention.

Basophils are the least abundant granulocyte in the allergic airways and share many of their
recruitment mechanisms with eosinophils thus often considered to be an accompaniment of
T cell dependent allergic eosinophilia [89]. Lack of distinct functional markers has hindered
understanding of their contribution to asthma pathogenesis, however basophils do express
FcɛRI and contribute to the local symptoms of inflammation and AHR through
degranulation and release of eicosanoids and histamines [90], and potentially via release of
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cytokines such as IL-4 [45], and APC function [46–48], which has led to a new appreciation
of their role during both initiation and amplification of the allergic Th2 effector response
[90].
The link between asthma and eosinophilic inflammation is long established [75]. Although
eosinophilia is the most characteristic type of inflammation in asthma, this is neither an
exclusive feature nor the only type of inflammation observed [91] and eosinophilic asthma is
now considered a distinct phenotype of asthma associated pathologically, by thickening of
the basement membrane, and pharmacologically, by corticosteroid responsiveness [92].
Elevated numbers of neutrophils and neutrophil-derived products without significant
eosinophilia has been reported in the airways of asthmatics [93]. In particular, this has been
associated with cases of severe asthma [10,94], asthma exacerbations [95] and particular
asthma phenotypes such as non-atopic asthma [96]. It is important to note that neutrophilic
asthma and eosinophilic asthma are not mutually exclusive and substantial overlap has been
reported between each [92,97]. Indeed, recent studies have yielded new insights about the
clinical and pathological correlates of eosinophilic and neutrophilic inflammation in asthma
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[98], and it is now recognised that non-eosinophilic asthma represents a sizeable subgroup
of asthmatics [99]. This has reinforced the concept that asthma is a heterogeneous disorder
which has several specific endotypes [9], that are associated with distinct clinical
phenotypes and different inflammatory responses [97]. Importantly, this bears important
considerations for response to therapy exemplified in non-eosinophilic asthmatics which
demonstrate a poor response to inhaled corticosteroids, the mainstay of asthma therapy
[100].
4.2 The Th2 lymphocyte response in the immunopathogenesis of asthma

One of the fundamental immunopathological features of allergic inflammation is the
development of an allergen-specific effector Th2 response [20] and accompanying long-
lived memory cells that continue to survey the airways for specific inhaled antigens [29].
Functional differentiation of Th effector subsets from naïve CD4+αβT cells involves the
activation or repression of whole sets of genes resulting in differential expression of lineage
defining transcription factors, effector mediator profiles and phenotypically distinguishing
chemokine receptor expression which enables the subset to create a self-sustaining loop
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[101]. Until recently, differentiation into the mutually exclusive Th1 and Th2 effector cell
subsets represented the sole paradigm of functional naïve CD4+T cell diversification
[101,102]. Currently, several different effector fates for naïve CD4+Th cells have been
identified and, in contrast to original thinking that Th effector differentiation was a terminal
event [103,104], recent reports demonstrating functional plasticity within the Th2 subset
suggests that this may not be the case [105]. Novel developments in the field of Th
differentiation are likely to yield important information regarding our future understanding
of the heterogeneity of chronic T cells in the design of therapeutics for chronic inflammatory
disorders such as asthma.
Allergen-specific Th2 effector cells migrate to the lungs and enable the airways to recognise
and respond to environmental allergens [106–108]. An increase in effector Th2 lymphocytes
and their mediators has been reported in the bronchial mucosa and BAL fluid of asthmatic
patients [107]. Elevated Th2 numbers also correlate with disease severity [107,109] and
there is now overwhelming experimental and clinical evidence supporting the critical

importance of Th2 cells during allergic sensitisation and propagation [106,108].

Phenotypically, Th2 cells are defined by expression of T1/ST2 [110,111] and the chemokine
receptors CCR3 [112], CCR4 [113] and CCR8 [114]. The chemoattractant ligands for these
Th2 associated receptors include eotaxin-1/CCL11, RANTES/CCL5, Thymus and
Activation Regulated Chemokine (TARC)/CCL17 and Macrophage Derived Chemokine
(MDC)/CCL22 are upregulated in the allergic airway [115,116]. The potential of Th2 cells
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to promote allergic immunopathology is amplified by production of a range of mediators

including IL-4, IL-5, IL-9, IL-13 and IL-25 which together promote the salient feature of
asthma such as IgE production, AHR, inflammation and tissue remodelling [117,118]. IL-4
and IL-13 are involved in the class switching of B cells to IgE synthesis [119], and favor
mucus secretion and fibrosis [120,121]. Th2 cytokines also activate secondary effector cells
in asthma including the recruitment of mast cells (IL-4, IL-9 and IL-13) [67] and basophils
(IL-3 and IL-4) [90], whilst IL-5 supports growth, differentiation, and activation of
eosinophils [78].
IL-25, also known as IL-17E, is a product of activated Th2 cells and innate cells such as
mast cells. Evidence suggests that IL-25 enhances antigen induced Th2 cytokine production
and eosinophil recruitment to the airways [122]. IL-25 mediated enhancement of antigen
induced eosinophil recruitment can be inhibited by the depletion of CD4+T cells suggesting
this mediator promotes allergic airway inflammation by a CD4+T cell dependent mechanism
[122]. Although originally thought to be a Th2 derived cytokines, the Th cell source of IL-9
in the allergic airway requires clarification in light of the recent identification of an IL-9
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producing Th9 subset [105,123]. An overview of the main immunopathological features

mediated by the Th2 response in the allergic airway is given in Fig. 3.
4.3 Emerging T lymphocytes in the immunopathogenesis of asthma

Although the asthmatic response is considered to be dominated by Th2 lymphocytes, it is
now clear that there are assorted layers of complex underlying T cell mediated responses
present in the allergic lung [124], and it is now thought that asthma may not solely be
controlled by the Th2 subset [125]. The immunopathological potential of these different
lymphocyte types and the potential synergy between them must be considered when
studying complicated inflammatory diseases such as asthma. This is discussed further
below.
Th1 cells preferentially produce the mediators IFN-γ, IL-2, TNF-α and lymphotoxin,
activate potent microbicidal activity from macrophages and antagonise the development of
Th2 responses [113,126,127]. IFN-γ producing Th1 cells have been documented in the
airways and serum of asthmatic patients however their contribution to asthma pathogenesis
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is not clear [107,128]. T-bet, the Th1 defining transcription factor is under expressed in the
asthmatic airway [129] and T-bet−/− mice have severe defects in Th1 cell differentiation and
susceptibility to Th2 biased asthma-like disease [130], suggesting a regulatory contribution.
Moreover, addition of Th1 related cytokines has been demonstrated to inhibit allergic airway
inflammation by inhibiting the Th2 response in vivo [131–133]. Conversely, introduction of
Th1 cells into a murine asthma model was reported to worsen airway inflammation
suggesting they may cause further lung immunopathology [134].
An IL-17 producing effector fate for naïve CD4+Th cells in the presence of TGF-β with
either IL-6 or IL-21 has recently been described [135,136]. These “Th17” cells express the
IL-23 receptor (IL-23R) [137,138], are characterised by production of IL-17 (IL-17A),
IL-17F and IL-22 [135,139,140], and are now acknowledged as a distinct lineage from Th1
and Th2 cells [141–143]. IL-17 acts on a broad range of leukocytes and has been found at
elevated levels in the airways of asthmatics however the functional relevance to this to the
asthmatic disease state remains unclear [144,145]. IL-17 is thought to be critically involved

in the proximal events during allergen sensitivity [146]. Conversely, it has been
demonstrated that IL-17 has a negative effect on the established allergic airway disease
[146] and an inhibitory influence on the production of pro-asthmatic mediators from
fibroblasts [147]. To date, studies on Th17 cells in the allergic lung have used models of
Th2 adjuvant driven allergic pathology; however, the effect of Th2 skewing adjuvant
compounds on the development and maintenance of Th17 responses is not known. Chronic
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asthmatics can develop steroid resistance which is difficult to treat [148]. Th17 cells, but not
Th2 cells, have been demonstrated to be mediate steroid resistant asthma in vivo [149].
Much more research is required to further understanding of the biology of this Th lineage
and fully address their role in chronic inflammatory diseases such as asthma.
Allergen-specific CD8+T cells have also been observed in asthmatic patients [108,150,151].
Exploration of whether CD8+T cells contribute to or suppress the allergic phenotype in vivo
has been inconclusive. Reduced AHR, eosinophilic inflammation and IL-13 production has
been reported mice deficient in CD8+T cells, restorable upon reconstitution of these cells
[152,153]. Conversely, depletion of CD8+T cells during allergic sensitisation enhanced Th2
responses suggesting their involvement in asthma pathogenesis may be stage dependent
[154]. This pro-allergic capability has been related to their ability to produce significant
amounts of IL-5, the critical effector in asthmatic eosinophilia [155,156]. Indeed, transfer of
IL-5 producing CD8+T cells induced eosinophilic inflammation in the lung following
allergen challenge [157]. Allergen-specific CD8 T cells have also shown suppressive
activity in vivo through production of Th1 skewing IL-12 [158]. This information suggests
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CD8+T cells have the potential to modulate the course and outcome of allergic disease.
4.4 Non-classical lymphocytes in the immunopathogenesis of asthma

Although most immune cells are classified as either innate or adaptive, unique non-classical
lymphocytes such as γδT cells [159], NK cells [160], and NKT cells [161], possess
characteristics of both the innate and adaptive immune system. Despite the established role
of allergen-specific antibodies [64], and effector and memory αβT cell responses [162] in
allergic immunopathology, the importance of non-classical innate-like lymphocytes in the
allergic airway has recently been the focus of asthma research [163,164]. Natural killer (NK)
cells are normally present in the lung and express a variety of receptors which enable a
primary immunosurveillance function [160]. Increased numbers of NK cells and NK cell
activity have been observed in patients with asthma but little is known of their role in the
allergic airway allergens [165,166]. The contribution of NK cells to allergic airway disease
has been studied in vivo using OVA sensitisation/challenge systems [167]. Depletion of NK
cells before immunisation or during challenge was reported to inhibit pulmonary
eosinophilia, T cell infiltration and associated inflammatory mediators suggesting a
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pathological contribution to both development and maintenance of allergic airway disease

[167].
4.5 iNKT cells

Natural killer T cells (NKT cells) are innate lymphocytes expressing a highly conserved
TCR and innate-like receptors characteristic of NK cells [168]. iNKT cells are selected and
restricted by the non-classical MHC I-like CD1d molecule [169] recognising endogenous
and exogenous glycolipids such as α-galactosyl ceramide (αGC) [170]. Direct activation of
NKT cells by glycolipids results in the production of large amounts of Th1 and Th2
cytokines such as IFN-γ and IL-4 [161]. This function attributes them potent immune
immunopotentiating effects prior to development of adaptive immune [171,172]. iNKT cells
are found in the lungs and increase in response to allergen challenge; however, the role of
iNKT cells in the allergic lung has been controversial [171,173]. In vivo murine studies have
demonstrated a contributing role to allergic AHR and airway inflammation independent of

allergen priming [164,174,175]. Rapid Th2 cytokine release is thought to promote the
development of allergic Th2 responses. In addition, a subset of iNKT cells preferentially
producing IL-13 and expressing the receptor for pro-allergic cytokine IL-25 has recently
been demonstrated and may potentiate IL-25 induced propagation of allergic airway
inflammation [176]. Jin et al., used an allergic model of OVA sensitisation/challenge model
to demonstrate that Vγ1+AHR-promoting γδT cells and iNKT cells synergise in the
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development of AHR and that they depend on each other for this function [177]. In addition
to in vivo studies indicating a role for NKT cells in the development of allergen-induced
AHR, Akbari et al., reported that greater than 60% of CD4+T cells in the airways of
moderate–severe asthmatic patients were NKT cells [171]. Subsequently, studies
demonstrating that NKT cells were a minority population [173]. In support of these findings,
Thomas et al. found similarly low numbers of invariant natural killer T cells in subjects with
asthma not receiving corticosteroids [178]. The start differences in these studies have since
been attributed to the difficulty in detection and analysis of these cells [179,180]. Further
work is required to clarify understanding of iNKT cells in allergic asthma.
4.6 γδT cells

Although both conventional αβ and γδT cells arise from thymic progenitors, γδT cells share
many of their signatory properties with innate leukocytes residing predominately in the
alveoli epithelium, lamina propria, smooth muscle layers and around blood vessels walls
where they make frequent contact with the more numerous resident leukocytes [181,182].
An increase in pulmonary γδT cells has been observed in asthmatic patients, in particular
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during symptoms of acute asthma exacerbations [183–185]. Although their role in the
allergic airway is not yet clear, a great deal of recent interest has focussed on their ability to
modulate adaptive immune responses, specifically their role in normal airway function and
lung homeostasis [181,186]. Recently, an important role for γδT as regulators of normal
airway tone has recently emerged [187] Increased AHR in allergen sensitised and
challenged γδT cell deficient (TCRδ−/−) or depleted mice has been observed [188,189].
Additionally, non-sensitised γδT cell deficient mice receiving allergen challenge
demonstrated increased AHR with no accompanying overt inflammatory changes [188].
Interestingly, negative regulation of AHR by γδT cells was found to be independent of
αβTh2 driven inflammation and eosinophilia [188]. How γδT cells exert their effects on
airway tone is not defined at present. γδT cells do not appear to recognise allergen directly
[190], and the regulation of airway responsiveness by γδT cells is not antigen specific [177].
Potential targets including direct interaction with ASM, mast cells or neuronal components
that regulate airway tone have been suggested [188]. The release of mediators triggered by a
stress reaction or modulation through epithelial repair or innate leukocytes has also been
proposed. Early studies by McMenamin et al. demonstrated suppression of the allergic
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αβTh2 driven response by an anti-inflammatory γδT cell population elicited in response to

repeated exposure to aerosolised antigen [191]. However, there are now several contrasting
studies which support the notion that γδT cells potentiate the activation of allergic Th2
inflammatory responses [163,188,192,193]. The conflicting opinions on whether γδT cells
are anti- or pro-inflammatory in allergic inflammation have in part been resolved by
consideration of the differences in in vivo systems and experimental programmes [186].
5 Regulation and resolution of allergic inflammation

The majority of research into asthma has focussed on elucidating the pro-inflammatory
pathways underlying disease pathogenesis and consequently many of the current therapeutic
targets focus on blocking the initiating or amplifying components [194]. Paradoxically, the
necessity of appropriate termination and resolution of inflammation has comparatively
recently been recognised [195]. This has led to the concept that chronic inflammation may
arise as a result of a lack of specific ‘stop’ signals for inflammatory responses. Coupled with

continued presence of allergens, this might explain the chronic nature of allergic disease.
Natural resolution of inflammation is a dynamic process which requires the removal of
stimulus, down regulation of mediators and elimination of dead cells [195]. Dysregulation or
failure of this process prevents a return to homeostasis and can contribute to the
pathogenesis and progression of chronic inflammatory disorders such as asthma [196].
Many of the endogenous, pro-resolving and anti-inflammatory mechanisms which co-
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ordinate the resolution process have begun to be defined and are thought to originate from
the inflammatory response [197,197].
5.1 Regulatory processes

The removal of apoptotic cells at the termination of inflammation (termed efferocytosis)
promotes a return to homeostasis. In addition to cell clearance, efferocytosis results in
collateral release of anti-inflammatory mediators such as IL-10 which contribute to
restorations of tissue homeostasis and growth factors which may additionally aid
maintenance of lung tissue integrity [198]. An increase in apoptotic cells has been observed
in the asthmatic lung and it has been proposed that efferocytosis may be impaired in such
situations [199,200]. Therapeutic approaches to promote clearance of inflammatory cells
from inflamed sites may reduce host damage during inflammatory disease such as asthma.
Altered chemokine production is a feature of allergic airway inflammation and responsible

for inflammatory leukocyte recruitment and retention within the lungs [115]. As
inflammation resolves, chemokines need to be removed from the microenvironment to halt
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further leukocyte recruitment. The “silent” chemokine receptor D6 plays an important role
in scavenging inflammatory, but not constitutive chemokines [201]. D6 knockout mice fail
to resolve acute inflammatory responses, suggesting that D6 has important roles in
resolution [202]. Infiltrating leukocytes can also upregulate selected chemokine receptors as
they undergo apoptosis, in order to sequester chemokines and so prevent further leukocyte
recruitment [203].
A novel genus of local acting anti-inflammatory lipid mediators with pro-resolving and
protective properties, coined resolvins and protectins, are produced from omega-3 fatty acids
(EPA and DHA) [197,204] and are actively synthesised during resolution of inflammation.
These molecules function to stop granulocyte infiltration, prevent pro-inflammatory
chemokine release and activation of inflammatory cells whilst stimulating clearance of
inflammatory cells controlling the duration and magnitude of inflammation. Resolvin E1
(RvE1) acts as an anti-inflammatory and pro-resolution lipid mediator of allergic airway
inflammation [205,206]. These recent studies have revealed important connections between
lipid biology and immunology. Further understanding of these pathways is likely to expand
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therapeutic intervention possibilities.
5.2 Regulatory T cells

CD4+ regulatory T lymphocytes (Tregs) play a key role in control of inflammatory
responses [207]. These cells can be naturally occurring (nTreg), selected by high avidity
interactions in the thymus, or induced (iTreg) extrathymically from naïve conventional
CD4+T cells under subimmunogenic antigen presentation, during chronic inflammation and
during homeostasis [208]. Tregs constitutively express high levels of the IL-2 receptor-α
chain (CD25) and are maintained by TGF-β. The transcription factor, Forkhead box
protein-3 (FoxP3) is important to generation of CD4+CD25+FoxP3+Tregs and also used as
an identification marker [209,210]. An important role for CD4+CD25+FoxP3+Tregs to
immune regulation of a variety of chronic inflammatory disease scenarios including asthma
has been noted [211]. Treg function is thought to be impaired in allergic patients since
CD4+CD25+FoxP3+Tregs from non-allergic donors but not allergic donors suppressed

proliferation and Th2 cytokine secretion by CD4+CD25−T cells [212]. A direct link between
CD4+CD25+FoxP3+Tregs and suppression of AHR in asthma has now been demonstrated in
vivo [213]. In a chronic model of allergic airway disease, transfer of antigen-specific Tregs
suppressed features of established allergic airway inflammation and prevented the
development of airway remodelling [214]. These data suggest that exploiting the regulatory
properties of CD4+CD25+FoxP3+Tregs in vivo could regulate asthmatic disease. Tregs elicit
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regulatory function by a variety of mechanisms including modulation of APC function [215]

and induction of a state of non-responsiveness or ‘anergy’ in effector cells through secretion
of immunosuppressive cytokines known as “bystander suppression” [216].
5.3 Regulatory cytokines

IL-10 is an important homeostatic cytokine in the airways [217] and has been reported to
modulate many effector functions that are associated with allergic asthma including Th2
activation, IgE production [218], eosinophil and mast cell function [219–221] and inhibition
of mast cell function [222,223]. Furthermore, diminishing IL-10 can break tolerance to
allergens suggesting a role in regulation of responses to allergens [217]. Allergen-specific
IL-10 producing Tregs were found to be significantly lower than healthy controls,
suggesting that a defect in IL-10 production may contribute to the asthmatic phenotype
[224]. In vivo, resolution of allergic airway inflammation by CD4+CD25+Tregs has recently
been shown to be IL-10 dependent [225].
Although considered to be a pro-fibrotic cytokine, TGF-β also has potent anti-inflammatory

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activity, can inhibit T cell proliferation and differentiation and impair Ig synthesis and
secretion [226]. TGF-β expression is upregulated in the lungs of asthmatic patients [227],
and active TGF-β signalling is increased in allergen-induced airways disease in mouse
[228], suggesting that TGF-β may play an important role in the inflammatory process. The
implication that TGF-β may regulate the allergic inflammatory response in the airways has
been investigated in vivo [229–231]. However, the pleiotropic nature of the cytokine
however has consequently made it most difficult to dissect the pro or anti-inflammatory
effects.
Exploiting the body's own endogenous counter-regulatory mechanisms offers therapeutic

potential for common inflammatory diseases such as asthma. Further progress in this area is
likely to prove important in the discovery of new and safe targets.
6 Airway remodelling
Chronic inflammation is often accompanied by remodelling of the tissues and there is
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evidence of structural alterations to the airway architecture in asthmatics [232], which is

collectively known as remodelling [233,234]. Airway calibre is determined dynamically by
the constricting forces of ASM and elasticity and hysteresis of the parenchyma [235].
Remodelling changes contribute a thickening of the airway wall [236], and reduction of the
airway diameter [237] which is believed to result in fixed airflow obstruction, persistent
AHR and a poor short-term treatment response [238]. Remodelling changes include a
thickened reticular basement membrane, dysregulated extracellular matrix (ECM) protein
deposition and increased vasculature [239]. The remodelled lung also features striking
increase in ASM mass with evidence for both hyperplasic and hypertrophic changes
[240,241], in addition to recruitment of ASM progenitors [18,242]. Furthermore, the
remodelled lung features compromised epithelial barrier function [243,244], and is
accompanied by mucus gland hyperplasia [233]. A summary of these changes is depicted
schematically in Fig. 4.

There is an increasing recognition that alterations to ECM composition play an important

role in the remodelling process [245]. Mesenchyme derived myofibroblasts which have both
fibroblast and ASM-like properties and a highly proliferative, contractile and secretory
phenotype, are normally responsible for tissue repair after injury [246]. However,
subepithelial myofibroblasts are increased in asthma and this has been correlated to
basement membrane thickness in asthmatic patients [247,248]. Although they are considered
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key participants in airway remodelling [246], the mechanisms underlying myofibroblast

induction are not fully understood. It has been proposed that fibroblast-like progenitors
(fibrocytes) migrate to the allergic lung contributing to the myofibroblasts response [249]. In
addition, ASM and fibroblasts can also develop a myofibroblasts-like phenotype in the
remodelled lung [250–252]. Collectively, these processes are critical to the generation and
regulation of ECM during airway remodelling [253–255]. Interestingly, loss of epithelial
characteristics and subsequent acquisition of mesenchymal characteristics giving rise to
fibroblasts and myofibroblasts has also been postulated [256]. This is known as epithelial–
mesenchymal transition (EMT) [256]. The extent to which EMT occurs in the allergic lung
has been the subject of active investigation [257,258]. Epithelial to mesenchymal cross talk
propagates chronic allergic inflammation and provides the optimal environment for
development of remodelling [11,259]. This interaction between epithelium and underlying
mesenchyme in the asthmatic lung is thought to represent a reactivation of the
developmental epithelial–mesenchymal-trophic unit (EMTU) associated with
morphogenesis during foetal lung development [259]. It is proposed that allergen-induced
epithelial damage and Th2 mediated inflammatory insult cooperate to promote functional
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disturbance of the EMTU [260].
6.1 Transforming growth factor-β: a key player in airway remodelling

The pleiotropic mediator TGF-β is produced by both immune leukocytes and structural cells
and has potent pro-fibrotic activity [261]. TGF-β is upregulated in the airways of asthmatics
[227], and is considered the master regulator of remodelling [262]. The TGF-β receptor is
widely expressed and receptor-ligand signalling promotes ECM synthesis and myofibroblast
transformation from ASM and fibroblasts [246,263]. TGF-β also propagates remodelling
through a variety of other means including the induction of inflammatory mediators by
structural cells (Fig. 3) [264], and has a direct effect on ASM contractility which can
influence airway responsiveness [265,266]. In vitro studies have observed constitutive
activation of the TGF-β signalling pathways in the allergic airways [227,228]. The
importance of TGF-β as a pro-remodelling cytokine has also been illustrated in vivo using
mouse models of asthma [267]. McMillan et al. demonstrated a reduction in peri-bronchiolar
ECM deposition and decreased ASM proliferation following TGF-β blockade during
established disease in a mouse asthma model [267]. TGF-β induced remodelling was also
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evaluated in mice lacking the TGF-β signalling component Smad-3. Following induction of
allergic airway disease decreases in airway fibrosis were associated with a reduction in
myofibroblasts without associated changes in inflammation [268]. Furthermore,
overexpression of TGF-β in the lung induced severe fibrosis with characteristic remodelling
ECM deposition [262,269].
In addition to TGF-β, additional mediators such as growth factors and proteinases released
from inflammatory and structural cells in the airway create a complex environment that
contributes to airway remodelling. Increased platelet derived growth factor derived growth
factor (PDGF) is found in the asthmatic lung and promotes proliferation of fibroblasts and
ASM [270,271]. Increased angiogenesis, and the pro-angiogenic cytokine Vascular
Endothelial Growth Factor (VEGF) and its receptors have been noted in the asthmatic
airway [272,273]. Furthermore, dysregulated production of extracellular matrix
metalloproteinase (MMPs) family members has been reported in the asthmatic airway [274].

These proteinases are responsible for the degradation of the extracellular matrix during
tissue remodelling [275].
6.2 Other important contributors to airway remodelling

There is now substantial evidence recognising the importance of eosinophils in airway
remodelling [276]. Indeed, many eosinophil products are capable of influencing the
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differentiation, proliferation and function of lung structural cells [78,277]. Allergen

sensitised mice can be induced to develop remodelling when exposed to prolonged allergen
challenge regimens [251]. Sensitised Δdbl-GATA mice, which are devoid of eosinophils,
subjected to a prolonged allergen challenge regimen, were significantly protected from
remodelling [278]. Production of the pro-fibrotic mediator TGF-β by eosinophils is
frequently observed in the lungs of asthmatics [279,280], and this is thought to be the
predominant mechanism by which eosinophils fuel the development of remodelling [281].
This is supported experimentally, whereby IL-5−/− mice, which have significantly reduced
allergen-induced airway eosinophilia, are protected from TGF-β dependent remodelling
[282,283], and clinically following anti-IL-5 treatment in asthmatic patients which reduced
ECM deposition [280]. Additionally, eosinophils contribute to remodelling indirectly
through TNF-β mediated induction of additional fibrotic factors such as plasminogen
activator inhibitor-1 (PAI-1) and MMPs [284]. Neutrophils can deliver multiple granule
products and reactive oxygen intermediates which promote inflammation and have tissue
damaging potential which may contribute to airway remodelling [285,286]. Mast cells have
a hyperplastic effect on ASM mass and induce collagen secretion from surrounding
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fibroblasts and myofibroblasts which may contribute to airway remodelling [287,288]. ASM
derived chemokines can further recruit mast cells and promote their degranulation
establishing a positive feedback loop in the allergic lung [289,290]. Furthermore, mast cells
are a source of pro-fibrotic TGF-β [68] and have also been shown to produce matrix active
MMPs in the allergic lung [291].
7 Airway inflammation and remodelling: parallel or sequential events

It has generally been accepted that remodelling occurs as a consequence of prolonged cycles
of damage and repair as a consequence of Th2 led immunopathology. However, despite the
progress that has been made regarding airway remodelling, several critical questions remain
unresolved. This has been excellently reviewed elsewhere [117,233,292]. One particular
controversy is whether chronic inflammation and remodelling progress as parallel or
sequential events. Reports of allergen-induced structural changes in the airway prior to
symptomatic asthma [293], imply that remodelling occurs early. Furthermore, remodelling
in established asthma is poorly responsive to current therapies, such as inhalation of
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corticosteroids and administration of beta(2)-agonists, anti-leukotrienes [294], and cannot

account for the heterogeneity of human asthma phenotypes. More recent theories propose
that dysregulated injury/repair processes stemming from the susceptibility of the bronchial
epithelia to components of the inhaled environment might precede, or occur in parallel with
airway inflammation. This hypothesis is strongly supported by paediatric studies [295,296],
and the concept that the EMTU is abnormally sensitive to environmental factors due to a
genetic or prenatal environmental basis and as a result becomes abnormally activated [297].
This may help explain why the prolonged use of anti-inflammatory therapy does not always
correlate with the natural history of asthma. Improvements to in vivo systems in which to
study remodelling will be imperative to the understanding of this question.
7.1 Future considerations for airway remodelling

Airway remodelling is a complex and dynamic process that is now considered to be
fundamental to the chronicity of the asthmatic disorder [298]. Although the function

implications of these structural changes are only beginning to be understood, it is thought

that remodelling can have serious repercussions for the response to therapy and can
contribute to airway obstruction [15,299]. Indeed, a correlation between airway wall
thickening and a decline in airway function of asthmatic patients has been reported [300].
Current asthma therapies such as inhaled corticosteroids are directed towards reducing
inflammation and have only a partial effect on remodelling [301]. This has profound
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problems for the future of disease management [302]. Controversially, associations between
airway remodelling and asthma severity have been inconsistent and it cannot be excluded
that thickening of the airway wall provides functional protection against airway narrowing
in asthma [233]. A better understanding of the mechanisms underlying airway remodelling,
its reversibility/prevention and its complex relationship with airway inflammation is a
prerequisite for developing therapeutic.
8 Future challenges and prospects for asthma therapy

In vitro and in vivo asthma models and clinical studies have disclosed much information
regarding asthma pathogenesis including many targets amenable to therapeutic intervention.
However, there is still no cure for asthma and progress in the development of effective new
compounds for asthma therapy has been comparatively slow. The cornerstones of current
asthma therapy (β(2)-agonists and inhaled corticosteroids) provide symptomatic relief and
some physiological improvements for most asthma sufferers [148,303]. Whilst this approach
has been reasonably effective, incidences of steroid resistant asthma is a major drawback
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and the side effects of steroid therapy can lead to poor patient compliance [304].
Furthermore, asthma symptoms return as soon as corticosteroid therapy is withdrawn [305].
Consequently, there is a need for more tailored and specific therapies that target the local
pathways involved in asthma pathogenesis.
Several recent and important discoveries in Th cell biology, self-limitation of inflammation

and immune regulation carry therapeutic potential as strategy for asthma treatment.
Understanding and optimising the body's own endogenous regulatory and pro-resolving
local inhibitory mechanisms system offers a potentially safe and effective approach for
tailored development of asthma therapy, in particular acute inflammatory events and steroid
refractory allergic inflammation which is otherwise difficult to treat. The immune system
comprises complex, multi-cellular layers that are tightly regulated and function with the
surrounding microenvironment to maintain homeostasis and provide host defence. Cells
with regulatory potential such as CD4+CD25+FoxP3Tregs and γδT cells are also an
attractive target for asthma therapy. To harness the therapeutic potential of the immune
system, a variety of factors need to be considered including mode of activation, migration
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and function. By identifying and understanding these interactions it will be possible to

further define their benefit to allergic airway responses without losing the ability to fight
infection. This knowledge is essential for development of immune modulatory intervention
strategies and fine tuning the host response to maximise the protective and minimise the
destructive aspects of the host allergic response. Consideration must also be given to the
contribution of different Th cell subsets and the complicated and largely undefined
relationship between them. Further understanding of these components will be vital to
identification of potential mechanisms to tip the balance between regulatory and pro-allergic
immune responses. Furthermore, understanding of regulatory pathways and the relationship
between inflammation and remodelling may aid the development of new strategies for the
chronically remodelled lung environment which is refractory to anti-inflammatory
treatments and also the development of structural alterations seen in childhood which occur
independent of inflammation or prior to overt symptoms.

8.1 A new perspective on asthma pathogenesis

Asthma is an extremely complex disease. It is now clear that asthma is not solely determined
by a Th2 response but instead reflects a constantly changing immune response that features
complex counter regulatory and effector networks between the microenvironment of
structural cells in the context of the cellular leukocytes. Innate-like lymphocytes represent a
common pathway through which a number of potential mechanisms operate during
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inflammatory regulation. Identifying defects in this pathway could facilitate the diagnosis of
asthma, and could be used to monitor asthma control and hence be useful in clinical
decision-making.
The conceptual lines between innate and adaptive immunity have been clearly drawn in
current dogma of the immune system. Adaptive immunity is thought to develop during the
lifetime of an individual, mediated by selectable receptors. In contrast innate immunity is
common to an entire species and hardly modified by an individual's history. As more
becomes known of the plasticity within the innate and adaptive immune system, current
theoretical concepts must be constantly re-evaluated. With this, the lines between innate and
adaptive pathways become less distinct. Current understanding of the interface between
innate and adaptive immunity, leukocytes which share properties with both arms of the
immune system, and the immune modulatory potential of structural cells in the airways is
continually growing. Arguably, deeper understanding of these relationships will no doubt
continue to add an extra twist to the already complicated immune network and regulatory
pathways underlying chronic inflammatory disease.
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Conflict of interest statement

The authors have no conflicting interest.
Acknowledgments
CML is a Wellcome Senior Fellow (Wellcome Trust 057704) and JRM is supported by a Foundation Studentship
from the National Heart and Lung Institute at Imperial College.
References
[1]. Holgate S.T. Polosa R. Treatment strategies for allergy and asthma. Nat. Rev. Immunol.
2008;8:218–230. [PubMed: 18274559]
[2]. Bahadori K. Doyle-Waters M.M. Marra C. Lynd L. Alasaly K. Swiston J. FitzGerald J.M.
Economic burden of asthma: a systematic review. BMC Pulm. Med. 2009;9:24. [PubMed:
19454036]
Sponsored Document
[3]. Nelson H.S. The importance of allergens in the development of asthma and the persistence of
symptoms. Dis. Mon. 2001;47:5–15. [PubMed: 11182682]
[4]. Holgate S.T. Davies D.E. Powell R.M. Howarth P.H. Haitchi H.M. Holloway J.W. Local genetic
and environmental factors in asthma disease pathogenesis: chronicity and persistence
mechanisms. Eur. Respir. J. 2007;29:793–803. [PubMed: 17400878]
[5]. Karjalainen J. Hulkkonen J. Nieminen M.M. Huhtala H. Aromaa A. Klaukka T. Hurme M.
Interleukin-10 gene promoter region polymorphism is associated with eosinophil count and
circulating immunoglobulin E in adult asthma. Clin. Exp. Allergy 2003;33:78–83. [PubMed:
12534553]
[6]. Pearce N. Pekkanen J. Beasley R. How much asthma is really attributable to atopy? Thorax
1999;54:268–272. [PubMed: 10325905]
[7]. Macfarlane A.J. Kon O.M. Smith S.J. Zeibecoglou K. Khan L.N. Barata L.T. McEuen A.R.
Buckley M.G. Walls A.F. Meng Q. Humbert M. Barnes N.C. Robinson D.S. Ying S. Kay A.B.
Basophils, eosinophils, and mast cells in atopic and nonatopic asthma and in late-phase allergic
reactions in the lung and skin. J. Allergy Clin. Immunol. 2000;105:99–107. [PubMed: 10629459]

[8]. Humbert M. Menz G. Ying S. Corrigan C.J. Robinson D.S. Durham S.R. Kay A.B. The
immunopathology of extrinsic (atopic) and intrinsic (non-atopic) asthma: more similarities than
differences. Immunol. Today 1999;20:528–533. [PubMed: 10529782]
[9]. Anderson G.P. Endotyping asthma: new insights into key pathogenic mechanisms in a complex,
heterogeneous disease. Lancet 2008;372:1107–1119. [PubMed: 18805339]
[10]. Wenzel S.E. Schwartz L.B. Langmack E.L. Halliday J.L. Trudeau J.B. Gibbs R.L. Chu H.W.
Sponsored Document
Evidence that severe asthma can be divided pathologically into two inflammatory subtypes with
distinct physiologic and clinical characteristics. Am. J. Respir. Crit. Care Med. 1999;160:1001–
1008. [PubMed: 10471631]
[11]. Bousquet J. Jeffery P.K. Busse W.W. Johnson M. Vignola A.M. Asthma. From
bronchoconstriction to airways inflammation and remodelling. Am. J. Respir. Crit. Care Med.
2000;161:1720–1745. [PubMed: 10806180]
[12]. Hargreave F.E. Dolovich J. O’Byrne P.M. Ramsdale E.H. Daniel E.E. The origin of airway
hyperresponsiveness. J. Allergy Clin. Immunol. 1986;78:825–832. [PubMed: 3537079]
[13]. Juniper E.F. Frith P.A. Hargreave F.E. Airway responsiveness to histamine and methacholine:
relationship to minimum treatment to control symptoms of asthma. Thorax 1981;36:575–579.
[PubMed: 7031972]
[14]. Cox G. Miller J.D. McWilliams A. FitzGerald J.M. Lam S. Bronchial thermoplasty for asthma.
Am. J. Respir. Crit. Care Med. 2006;173:965–969. [PubMed: 16456145]
[15]. Boulet L.P. Turcotte H. Laviolette M. Naud F. Bernier M.C. Martel S. Chakir J. Airway
hyperresponsiveness, inflammation, and subepithelial collagen deposition in recently diagnosed
versus long-standing mild asthma. Influence of inhaled corticosteroids. Am. J. Respir. Crit. Care
Med. 2000;162:1308–1313. [PubMed: 11029336]
Sponsored Document
[16]. Niimi A. Matsumoto H. Takemura M. Ueda T. Chin K. Mishima M. Relationship of airway wall
thickness to airway sensitivity and airway reactivity in asthma. Am. J. Respir. Crit. Care Med.
2003;168:983–988. [PubMed: 12829452]
[17]. McParland B.E. Macklem P.T. Pare P.D. Airway wall remodeling: friend or foe? J. Appl.
Physiol. 2003;95:426–434. [PubMed: 12794101]
[18]. Siddiqui S. Hollins F. Saha S. Brightling C.E. Inflammatory cell microlocalisation and airway
dysfunction: cause and effect? Eur. Respir. J. 2007;30:1043–1056. [PubMed: 18055703]
[19]. Kearley J. Buckland K.F. Mathie S.A. Lloyd C.M. Resolution of allergic inflammation and AHR
is dependent upon disruption of the T1/ST2-IL-33 pathway. Am. J. Respir. Crit. Care Med.
2009;179:772–781. [PubMed: 19179489]
[20]. Holgate S.T. Pathogenesis of asthma. Clin. Exp. Allergy 2008;38:872–897. [PubMed: 18498538]
[21]. Kay A.B. Mediators of hypersensitivity and inflammatory cells in the pathogenesis of bronchial
asthma. Eur. J. Respir. Dis. Suppl. 1983;129:1–44. [PubMed: 6418559]
[22]. Lloyd C.M. Rankin S.M. Chemokines in allergic airway disease. Curr. Opin. Pharmacol.
2003;3:443–448. [PubMed: 12901955]
[23]. Robinson D.S. Regulatory T cells and asthma. Clin. Exp. Allergy 2009;39:1314–1323. [PubMed:
Sponsored Document
19538496]
[24]. Janeway C.A. Medzhitov R. Innate immune recognition. Annu. Rev. Immunol. 2002;20:197–
216. [PubMed: 11861602]
[25]. Janeway C.A. Bottomly K. Signals and signs for lymphocyte responses. Cell 1994;76:275–285.
[PubMed: 7904901]
[26]. von B.H. Aifantis I. Gounari F. Azogui O. Haughn L. Apostolou I. Jaeckel E. Grassi F. Klein L.
Thymic selection revisited: how essential is it? Immunol. Rev. 2003;191:62–78. [PubMed:
12614352]
[27]. Medzhitov R. Janeway C.A. Innate immune induction of the adaptive immune response. Cold
Spring Harb. Symp. Quant. Biol. 1999;64:429–435. [PubMed: 11232318]
[28]. Lanier L.L. Sun J.C. Do the terms innate and adaptive immunity create conceptual barriers? Nat.
Rev. Immunol. 2009;9:302–303. [PubMed: 19396937]
[29]. Herrick C.A. Bottomly K. To respond or not to respond: T cells in allergic asthma. Nat. Rev.
Immunol. 2003;3:405–412. [PubMed: 12766762]

[30]. Lambrecht B.N. Hammad H. Lung dendritic cells: targets for therapy in allergic disease. Handb.
Exp. Pharmacol. 2009;188:99–114. [PubMed: 19031023]
[31]. Gordon S. Pattern recognition receptors: doubling up for the innate immune response. Cell
2002;111:927–930. [PubMed: 12507420]
[32]. Willart M.A. Lambrecht B.N. The danger within: endogenous danger signals, atopy and asthma.
Clin. Exp. Allergy 2009;39:12–19. [PubMed: 19016800]
Sponsored Document
[33]. de Heer H.J. Hammad H. Kool M. Lambrecht B.N. Dendritic cell subsets and immune regulation
in the lung. Semin. Immunol. 2005;17:295–303. [PubMed: 15967679]
[34]. de Heer H.J. Hammad H. Soullie T. Hijdra D. Vos N. Willart M.A. Hoogsteden H.C. Lambrecht
B.N. Essential role of lung plasmacytoid dendritic cells in preventing asthmatic reactions to
harmless inhaled antigen. J. Exp. Med. 2004;200:89–98. [PubMed: 15238608]
[35]. Eisenbarth S.C. Piggott D.A. Huleatt J.W. Visintin I. Herrick C.A. Bottomly K.
Lipopolysaccharide-enhanced, toll-like receptor 4-dependent T helper cell type 2 responses to
inhaled antigen. J. Exp. Med. 2002;196:1645–1651. [PubMed: 12486107]
[36]. Ibrahim M.A. Chain B.M. Katz D.R. The injured cell: the role of the dendritic cell system as a
sentinel receptor pathway. Immunol. Today 1995;16:181–186. [PubMed: 7734045]
[37]. Cates E.C. Fattouh R. Johnson J.R. Llop-Guevara A. Jordana M. Modeling responses to
respiratory house dust mite exposure. Contrib. Microbiol. 2007;14:42–67. [PubMed: 17684332]
[38]. Hammad H. Chieppa M. Perros F. Willart M.A. Germain R.N. Lambrecht B.N. House dust mite
allergen induces asthma via Toll-like receptor 4 triggering of airway structural cells. Nat. Med.
2009;15:410–416. [PubMed: 19330007]
[39]. Kool M. Petrilli V. De S.T. Rolaz A. Hammad H. van N.M. Bergen I.M. Castillo R. Lambrecht
Sponsored Document
B.N. Tschopp J. Cutting edge: alum adjuvant stimulates inflammatory dendritic cells through
activation of the NALP3 inflammasome. J. Immunol. 2008;181:3755–3759. [PubMed:
18768827]
[40]. Lambrecht B.N. Salomon B. Klatzmann D. Pauwels R.A. Dendritic cells are required for the
development of chronic eosinophilic airway inflammation in response to inhaled antigen in
sensitized mice. J. Immunol. 1998;160:4090–4097. [PubMed: 9558120]
[41]. Akbari O. DeKruyff R.H. Umetsu D.T. Pulmonary dendritic cells producing IL-10 mediate
tolerance induced by respiratory exposure to antigen. Nat. Immunol. 2001;2:725–731. [PubMed:
11477409]
[42]. Hammad H. Lambrecht B.N. Recent progress in the biology of airway dendritic cells and
implications for understanding the regulation of asthmatic inflammation. J. Allergy Clin.
Immunol. 2006;118:331–336. [PubMed: 16890754]
[43]. Geha R.S. Jabara H.H. Brodeur S.R. The regulation of immunoglobulin E class-switch
recombination. Nat. Rev. Immunol. 2003;3:721–732. [PubMed: 12949496]
[44]. Seder R.A. Paul W.E. Acquisition of lymphokine-producing phenotype by CD4+ T cells. Annu.
Rev. Immunol. 1994;12:635–673. [PubMed: 7912089]
[45]. Yoshimoto T. Tsutsui H. Tominaga K. Hoshino K. Okamura H. Akira S. Paul W.E. Nakanishi K.
Sponsored Document
IL-18, although antiallergic when administered with IL-12, stimulates IL-4 and histamine release
by basophils. Proc. Natl. Acad. Sci. U.S.A. 1999;96:13962–13966. [PubMed: 10570181]
[46]. Yoshimoto T. Yasuda K. Tanaka H. Nakahira M. Imai Y. Fujimori Y. Nakanishi K. Basophils
contribute to T(H)2-IgE responses in vivo via IL-4 production and presentation of peptide-MHC
class II complexes to CD4+ T cells. Nat. Immunol. 2009;10:706–712. [PubMed: 19465908]
[47]. Perrigoue J.G. Saenz S.A. Siracusa M.C. Allenspach E.J. Taylor B.C. Giacomin P.R. Nair M.G.
Du Y. Zaph C. Van R.N. Comeau M.R. Pearce E.J. Laufer T.M. Artis D. MHC class II-
dependent basophil-CD4+ T cell interactions promote T(H)2 cytokine-dependent immunity. Nat.
Immunol. 2009;10:697–705. [PubMed: 19465906]
[48]. Sokol C.L. Chu N.Q. Yu S. Nish S.A. Laufer T.M. Medzhitov R. Basophils function as antigen-
presenting cells for an allergen-induced T helper type 2 response. Nat. Immunol. 2009;10:713–
720. [PubMed: 19465907]
[49]. Cheng L. Cui Y. Shao H. Han G. Zhu L. Huang Y. O’Brien R.L. Born W.K. Kaplan H.J. Sun D.
Mouse gammadelta T cells are capable of expressing MHC class II molecules, and of functioning
as antigen-presenting cells. J. Neuroimmunol. 2008;203:3–11. [PubMed: 18774183]

[50]. Kovacsovics-Bankowski M. Clark K. Benacerraf B. Rock K.L. Efficient major histocompatibility

complex class I presentation of exogenous antigen upon phagocytosis by macrophages. Proc.
Natl. Acad. Sci. U.S.A. 1993;90:4942–4946. [PubMed: 8506338]
[51]. Shi G.P. Bryant R.A. Riese R. Verhelst S. Driessen C. Li Z. Bromme D. Ploegh H.L. Chapman
H.A. Role for cathepsin F in invariant chain processing and major histocompatibility complex
class II peptide loading by macrophages. J. Exp. Med. 2000;191:1177–1186. [PubMed:
Sponsored Document
10748235]
[52]. Kundig T.M. Bachmann M.F. DiPaolo C. Simard J.J. Battegay M. Lother H. Gessner A. Kuhlcke
K. Ohashi P.S. Hengartner H. Fibroblasts as efficient antigen-presenting cells in lymphoid
organs. Science 1995;268:1343–1347. [PubMed: 7761853]
[53]. Elsner J. Kapp A. Regulation and modulation of eosinophil effector functions. Allergy
1999;54:15–26. [PubMed: 10195355]
[54]. Folkerts G. Nijkamp F.P. Airway epithelium: more than just a barrier! Trends Pharmacol. Sci.
1998;19:334–341. [PubMed: 9745362]
[55]. Hammad H. Lambrecht B.N. Dendritic cells and epithelial cells: linking innate and adaptive
immunity in asthma. Nat. Rev. Immunol. 2008;8:193–204. [PubMed: 18301423]
[56]. Suarez C.J. Parker N.J. Finn P.W. Innate immune mechanism in allergic asthma. Curr. Allergy
Asthma Rep. 2008;8:451–459. [PubMed: 18682113]
[57]. Kauffman H. Tamm M. Timmerman J.A. Borger P. House dust mite major allergens Der p 1 and
Der p 5 activate human airway-derived epithelial cells by protease-dependent and protease-
independent mechanisms. Clin. Mol. Allergy 2006;4:5. [PubMed: 16569217]
[58]. Kalsheker N.A. Deam S. Chambers L. Sreedharan S. Brocklehurst K. Lomas D.A. The house
Sponsored Document
dust mite allergen Der p1 catalytically inactivates alpha 1-antitrypsin by specific reactive centre
loop cleavage: a mechanism that promotes airway inflammation and asthma. Biochem. Biophys.
Res. Commun. 1996;221:59–61. [PubMed: 8660343]
[59]. Sebastian K. Borowski A. Kuepper M. Friedrich K. Signal transduction around thymic stromal
lymphopoietin (TSLP) in atopic asthma. Cell Commun. Signal. 2008;6:5. [PubMed: 18724870]
[60]. Kondo Y. Yoshimoto T. Yasuda K. Futatsugi-Yumikura S. Morimoto M. Hayashi N. Hoshino T.
Fujimoto J. Nakanishi K. Administration of IL-33 induces airway hyperresponsiveness and
goblet cell hyperplasia in the lungs in the absence of adaptive immune system 649. Int. Immunol.
2008;20:791–800. [PubMed: 18448455]
[61]. Kurowska-Stolarska M. Kewin P. Murphy G. Russo R.C. Stolarski B. Garcia C.C. Komai-Koma
M. Pitman N. Li Y. McKenzie A.N.J. Teixeira M.M. Liew F.Y. Xu D. IL-33 induces antigen-
specific IL-5+ T cells and promotes allergic-induced airway inflammation independent of IL-4
650. J. Immunol. 2008;181:4780–4790. [PubMed: 18802081]
[62]. Angkasekwinai P. Park H. Wang Y.H. Wang Y.H. Chang S.H. Corry D.B. Liu Y.J. Zhu Z. Dong
C. Interleukin 25 promotes the initiation of proallergic type 2 responses 659. J. Exp. Med.
2007;204:1509–1517. [PubMed: 17562814]
[63]. Lloyd C.M. Dust mites’ dirty dealings in the lung. Nat. Med. 2009;15:366–367. [PubMed:
Sponsored Document
19350005]
[64]. Gould H.J. Sutton B.J. Beavil A.J. Beavil R.L. McCloskey N. Coker H.A. Fear D. Smurthwaite
L. The biology of IGE and the basis of allergic disease. Annu. Rev. Immunol. 2003;21:579–628.
[PubMed: 12500981]
[65]. Yu M. Tsai M. Tam S.Y. Jones C. Zehnder J. Galli S.J. Mast cells can promote the development
of multiple features of chronic asthma in mice. J. Clin. Invest. 2007;116(6):1633–1641.
[PubMed: 16710480]
[66]. Robinson D.S. The role of the mast cell in asthma: induction of airway hyperresponsiveness by
interaction with smooth muscle? J. Allergy Clin. Immunol. 2004;114:58–65. [PubMed:
15241345]
[67]. Bradding P. Walls A.F. Holgate S.T. The role of the mast cell in the pathophysiology of asthma.
J. Allergy Clin. Immunol. 2006;117:1277–1284. [PubMed: 16750987]
[68]. Williams C.M. Galli S.J. The diverse potential effector and immunoregulatory roles of mast cells
in allergic disease. J. Allergy Clin. Immunol. 2000;105:847–859. [PubMed: 10808163]

[69]. Polosa R. Renaissance of the effector role of the mast cell in bronchial asthma. Ann. Ital. Med.
Int. 1995;10:126–133. [PubMed: 7619653]
[70]. Sutcliffe A. Kaur D. Page S. Woodman L. Armour C.L. Baraket M. Bradding P. Hughes J.M.
Brightling C.E. Mast cell migration to Th2 stimulated airway smooth muscle from asthmatics.
Thorax 2007;61(8):657–662. [PubMed: 16601090]
[71]. Lorentz A. Schwengberg S. Mierke C. Manns M.P. Bischoff S.C. Human intestinal mast cells
Sponsored Document
produce IL-5 in vitro upon IgE receptor cross-linking and in vivo in the course of intestinal
inflammatory disease. Eur. J. Immunol. 1999;29:1496–1503. [PubMed: 10359103]
[72]. Brightling C.E. Bradding P. Symon F.A. Holgate S.T. Wardlaw A.J. Pavord I.D. Mast-cell
infiltration of airway smooth muscle in asthma 541. N. Engl. J. Med. 2002;346:1699–1705.
[PubMed: 12037149]
[73]. Brightling C.E. Cough due to asthma and nonasthmatic eosinophilic bronchitis. Lung. 2009 Epub
ahead of print.
[74]. Brightling C.E. Symon F.A. Birring S.S. Bradding P. Wardlaw A.J. Pavord I.D. Comparison of
airway immunopathology of eosinophilic bronchitis and asthma. Thorax 2003;58:528–532.
[PubMed: 12775868]
[75]. Kay A.B. The role of eosinophils in the pathogenesis of asthma. Trends Mol. Med. 2005;11:148–
152. [PubMed: 15823751]
[76]. Bousquet J. Relating inflammatory changes in asthma to clinical status. Respir. Med.
2000;94(Suppl. F):S32–S33. [PubMed: 11059966]
[77]. Lemiere C. The use of sputum eosinophils in the evaluation of occupational asthma. Curr. Opin.
Allergy Clin. Immunol. 2004;4:81–85. [PubMed: 15021058]
Sponsored Document
[78]. Trivedi S.G. Lloyd C.M. Eosinophils in the pathogenesis of allergic airways disease. Cell. Mol.
Life Sci. 2007;64:1269–1289. [PubMed: 17364144]
[79]. Gutierrez-Ramos J.C. Lloyd C. Gonzalo J.A. Eotaxin: from an eosinophilic chemokine to a major
regulator of allergic reactions. Immunol. Today 1999;20:500–504. [PubMed: 10529777]
[80]. Zimmermann N. Hershey G.K. Foster P.S. Rothenberg M.E. Chemokines in asthma: cooperative
interaction between chemokines and IL-13. J. Allergy Clin. Immunol. 2003;111:227–242.
[PubMed: 12589338]
[81]. Foster P.S. Mould A.W. Yang M. Mackenzie J. Mattes J. Hogan S.P. Mahalingam S. Mckenzie
A.N. Rothenberg M.E. Young I.G. Matthaei K.I. Webb D.C. Elemental signals regulating
eosinophil accumulation in the lung. Immunol. Rev. 2001;179:173–181. [PubMed: 11292021]
[82]. Kariyawasam H.H. Robinson D.S. The eosinophil: the cell and its weapons, the cytokines, its
locations. Semin. Respir. Crit. Care Med. 2006;27:117–127. [PubMed: 16612762]
[83]. Anthony R.M. Rutitzky L.I. Urban J.F. Stadecker M.J. Gause W.C. Protective immune
mechanisms in helminth infection. Nat. Rev. Immunol. 2007;7:975–987. [PubMed: 18007680]
[84]. Frigas E. Gleich G.J. The eosinophil and the pathophysiology of asthma. J. Allergy Clin.
Immunol. 1986;77:527–537. [PubMed: 3514730]
Sponsored Document
[85]. Maddox L. Schwartz D.A. The pathophysiology of asthma. Annu. Rev. Med. 2002;53:477–498.
[PubMed: 11818486]
[86]. Shi H.Z. Eosinophils function as antigen-presenting cells. J. Leukoc. Biol. 2004;76:520–527.
[PubMed: 15218055]
[87]. Nakajima H. Gleich G.J. Kita H. Constitutive production of IL-4 and IL-10 and stimulated
production of IL-8 by normal peripheral blood eosinophils. J. Immunol. 1996;156:4859–4866.
[PubMed: 8648135]
[88]. Lamkhioued B. Gounni A.S. Aldebert D. Delaporte E. Prin L. Capron A. Capron M. Synthesis of
type 1 (IFN gamma) and type 2 (IL-4, IL-5, and IL-10) cytokines by human eosinophils. Ann.
N.Y. Acad. Sci. 1996;796:203–208. [PubMed: 8906227]
[89]. Gangur V. Birmingham N.P. Thanesvorakul S. Joseph S. CCR3 and CXCR3 as drug targets for
allergy: principles and potential. Curr. Drug Targets Inflamm. Allergy 2003;2:53–62. [PubMed:
14561176]
[90]. Falcone F.H. Haas H. Gibbs B.F. The human basophil: a new appreciation of its role in immune
responses. Blood 2000;96:4028–4038. [PubMed: 11110670]

[91]. Hargreave F.E. Quantitative sputum cell counts as a marker of airway inflammation in clinical
practice. Curr. Opin. Allergy Clin. Immunol. 2007;7:102–106. [PubMed: 17218819]
[92]. Fahy J.V. Eosinophilic and neutrophilic inflammation in asthma: insights from clinical studies.
Proc. Am. Thorac. Soc. 2009;6:256–259. [PubMed: 19387026]
[93]. Drews A.C. Pizzichini M.M. Pizzichini E. Pereira M.U. Pitrez P.M. Jones M.H. Sly P.D. Stein
R.T. Neutrophilic airway inflammation is a main feature of induced sputum in nonatopic
Sponsored Document
asthmatic children. Allergy. 2009 Epub ahead of print.

[94]. Jatakanon A. Lim S. Barnes P.J. Changes in sputum eosinophils predict loss of asthma control.
Am. J. Respir. Crit. Care Med. 2000;161:64–72. [PubMed: 10619799]
[95]. Fahy J.V. Kim K.W. Liu J. Boushey H.A. Prominent neutrophilic inflammation in sputum from
subjects with asthma exacerbation. J. Allergy Clin. Immunol. 1995;95:843–852. [PubMed:
7722165]
[96]. Amin K. Ludviksdottir D. Janson C. Nettelbladt O. Bjornsson E. Roomans G.M. Boman G.
Seveus L. Venge P. Inflammation and structural changes in the airways of patients with atopic
and nonatopic asthma. BHR Group. Am. J. Respir. Crit. Care Med. 2000;162:2295–2301.
[PubMed: 11112154]
[97]. Simpson J.L. Scott R. Boyle M.J. Gibson P.G. Inflammatory subtypes in asthma: assessment and
identification using induced sputum. Respirology 2006;11:54–61. [PubMed: 16423202]
[98]. Green R.H. Brightling C.E. Bradding P. The reclassification of asthma based on subphenotypes.
Curr. Opin. Allergy Clin. Immunol. 2007;7:43–50. [PubMed: 17218810]
[99]. Haldar P. Pavord I.D. Noneosinophilic asthma: a distinct clinical and pathologic phenotype. J.
Sponsored Document
[100]. Pavord I.D. Brightling C.E. Woltmann G. Wardlaw A.J. Non-eosinophilic corticosteroid
unresponsive asthma. Lancet 1999;353:2213–2214. [PubMed: 10392993]
[101]. Mosmann T.R. Coffman R.L. TH1 and TH2 cells: different patterns of lymphokine secretion
lead to different functional properties. Annu. Rev. Immunol. 1989;7:145–173. [PubMed:
2523712]
[102]. Mosmann T.R. Coffman R.L. Heterogeneity of cytokine secretion patterns and functions of
helper T cells. Adv. Immunol. 1989;46:111–147. [PubMed: 2528896]
[103]. Grogan J.L. Mohrs M. Harmon B. Lacy D.A. Sedat J.W. Locksley R.M. Early transcription and
silencing of cytokine genes underlie polarization of T helper cell subsets. Immunity
2001;14:205–215. [PubMed: 11290331]
[104]. Murphy E. Shibuya K. Hosken N. Openshaw P. Maino V. Davis K. Murphy K. O’Garra A.
Reversibility of T helper 1 and 2 populations is lost after long-term stimulation. J. Exp. Med.
1996;183:901–913. [PubMed: 8642294]
[105]. Veldhoen M. Uyttenhove C. van S.J. Helmby H. Westendorf A. Buer J. Martin B. Wilhelm C.
Stockinger B. Transforming growth factor-beta ‘reprograms’ the differentiation of T helper 2
cells and promotes an interleukin 9-producing subset. Nat. Immunol. 2008;9:1341–1346.
[PubMed: 18931678]
Sponsored Document
[106]. Robinson D.S. Hamid Q. Ying S. Tsicopoulos A. Barkans J. Bentley A.M. Corrigan C. Durham
S.R. Kay A.B. Predominant TH2-like bronchoalveolar T-lymphocyte population in atopic
asthma. N. Engl. J. Med. 1992;326:298–304. [PubMed: 1530827]
[107]. Corrigan C.J. Kay A.B. Asthma. Role of T-lymphocytes and lymphokines. Br. Med. Bull.
1992;48:72–84. [PubMed: 1352170]
[108]. Del Prete G.F. De C.M. D’Elios M.M. Maestrelli P. Ricci M. Fabbri L. Romagnani S. Allergen
exposure induces the activation of allergen-specific Th2 cells in the airway mucosa of patients
with allergic respiratory disorders. Eur. J. Immunol. 1993;23:1445–1449. [PubMed: 8100770]
[109]. Walker C. Kaegi M.K. Braun P. Blaser K. Activated T cells and eosinophilia in bronchoalveolar
lavages from subjects with asthma correlated with disease severity. J. Allergy Clin. Immunol.
1991;88:935–942. [PubMed: 1744364]
[110]. Xu D. Chan W.L. Leung B.P. Huang F. Wheeler R. Piedrafita D. Robinson J.H. Liew F.Y.
Selective expression of a stable cell surface molecule on type 2 but not type 1 helper T cells. J.
Exp. Med. 1998;187:787–794. [PubMed: 9480988]

[111]. Lohning M. Stroehmann A. Coyle A.J. Grogan J.L. Lin S. Gutierrez-Ramos J.C. Levinson D.
Radbruch A. Kamradt T. T1/ST2 is preferentially expressed on murine Th2 cells, independent of
interleukin 4, interleukin 5, and interleukin 10, and important for Th2 effector function. Proc.
Natl. Acad. Sci. U.S.A. 1998;95:6930–6935. [PubMed: 9618516]
[112]. Sallusto F. Mackay C.R. Lanzavecchia A. Selective expression of the eotaxin receptor CCR3 by
human T helper 2 cells. Science 1997;277:2005–2007. [PubMed: 9302298]
Sponsored Document
[113]. Sallusto F. Lanzavecchia A. Mackay C.R. Chemokines and chemokine receptors in T-cell
priming and Th1/Th2-mediated responses. Immunol. Today 1998;19:568–574. [PubMed:
9864948]
[114]. D’Ambrosio D. Iellem A. Bonecchi R. Mazzeo D. Sozzani S. Mantovani A. Sinigaglia F.
Selective up-regulation of chemokine receptors CCR4 and CCR8 upon activation of polarized
human type 2 Th cells. J. Immunol. 1998;161:5111–5115. [PubMed: 9820476]
[115]. Lloyd C. Chemokines in allergic lung inflammation. Immunology 2002;105:144–154.
[PubMed: 11872089]
[116]. Lloyd C.M. Delaney T. Nguyen T. Tian J. Martinez A. Coyle A.J. Gutierrez-Ramos J.C. CC
chemokine receptor (CCR)3/eotaxin is followed by CCR4/monocyte-derived chemokine in
mediating pulmonary T helper lymphocyte type 2 recruitment after serial antigen challenge in
vivo. J. Exp. Med. 2000;191:265–274. [PubMed: 10637271]
[117]. Davies D.E. Wicks J. Powell R.M. Puddicombe S.M. Holgate S.T. Airway remodeling in
asthma: new insights. J. Allergy Clin. Immunol. 2003;111:215–225. [PubMed: 12589337]
[118]. McGee H.S. Agrawal D.K. TH2 cells in the pathogenesis of airway remodeling: regulatory T
cells a plausible panacea for asthma. Immunol. Res. 2006;35:219–232. [PubMed: 17172648]
Sponsored Document
[119]. Finkelman F.D. Holmes J. Katona I.M. Urban J.F. Beckmann M.P. Park L.S. Schooley K.A.
Coffman R.L. Mosmann T.R. Paul W.E. Lymphokine control of in vivo immunoglobulin isotype
selection. Annu. Rev. Immunol. 1990;8:303–333. [PubMed: 1693082]
[120]. Kumar R.K. Herbert C. Webb D.C. Li L. Foster P.S. Effects of anticytokine therapy in a mouse
model of chronic asthma. Am. J. Respir. Crit. Care Med. 2004;170:1043–1048. [PubMed:
15306533]
[121]. Fattouh R. Jordana M. TGF-beta, eosinophils and IL-13 in allergic airway remodeling: a critical
appraisal with therapeutic considerations. Inflamm. Allergy Drug Targets 2008;7:224–236.
[PubMed: 19075788]
[122]. Tamachi T. Maezawa Y. Ikeda K. Kagami S. Hatano M. Seto Y. Suto A. Suzuki K. Watanabe
N. Saito Y. Tokuhisa T. Iwamoto I. Nakajima H. IL-25 enhances allergic airway inflammation
by amplifying a TH2 cell-dependent pathway in mice. J. Allergy Clin. Immunol. 2006;118:606–
614. [PubMed: 16950278]
[123]. Dardalhon V. Awasthi A. Kwon H. Galileos G. Gao W. Sobel R.A. Mitsdoerffer M. Strom T.B.
Elyaman W. Ho I.C. Khoury S. Oukka M. Kuchroo V.K. IL-4 inhibits TGF-beta-induced
Foxp3+ T cells and, together with TGF-beta, generates IL-9+ IL-10+ Foxp3(−) effector T cells.
Nat. Immunol. 2008;9:1347–1355. [PubMed: 18997793]
Sponsored Document
[124]. Afshar R. Medoff B.D. Luster A.D. Allergic asthma: a tale of many T cells. Clin. Exp. Allergy
2008;38:1847–1857. [PubMed: 19037961]
[125]. Salvi S.S. Babu K.S. Holgate S.T. Is asthma really due to a polarized T cell response toward a
helper T cell type 2 phenotype? Am. J. Respir. Crit. Care Med. 2001;164:1343–1346. [PubMed:
11704578]
[126]. Bonecchi R. Bianchi G. Bordignon P.P. D’Ambrosio D. Lang R. Borsatti A. Sozzani S.
Allavena P. Gray P.A. Mantovani A. Sinigaglia F. Differential expression of chemokine
receptors and chemotactic responsiveness of type 1 T helper cells (Th1s) and Th2s. J. Exp. Med.
1998;187:129–134. [PubMed: 9419219]
[127]. Loetscher P. Uguccioni M. Bordoli L. Baggiolini M. Moser B. Chizzolini C. Dayer J.M. CCR5
is characteristic of Th1 lymphocytes. Nature 1998;391:344–345. [PubMed: 9450746]
[128]. Krug N. Erpenbeck V.J. Balke K. Petschallies J. Tschernig T. Hohlfeld J.M. Fabel H. Cytokine
profile of bronchoalveolar lavage-derived CD4(+), CD8(+), and gammadelta T cells in people
with asthma after segmental allergen challenge. Am. J. Respir. Cell. Mol. Biol. 2001;25:125–
131. [PubMed: 11472985]

[129]. Zheng W. Flavell R.A. The transcription factor GATA-3 is necessary and sufficient for Th2
cytokine gene expression in CD4 T cells. Cell 1997;89:587–596. [PubMed: 9160750]
[130]. Finotto S. Neurath M.F. Glickman J.N. Qin S. Lehr H.A. Green F.H. Ackerman K. Haley K.
Galle P.R. Szabo S.J. Drazen J.M. De Sanctis G.T. Glimcher L.H. Development of spontaneous
airway changes consistent with human asthma in mice lacking T-bet. Science 2002;295:336–338.
[PubMed: 11786643]
Sponsored Document
[131]. Gavett S.H. Chen X. Finkelman F. Wills-Karp M. Depletion of murine CD4+ T lymphocytes
prevents antigen-induced airway hyperreactivity and pulmonary eosinophilia. Am. J. Respir.
Cell. Mol. Biol. 1994;10:587–593. [PubMed: 8003337]
[132]. Wiley R. Palmer K. Gajewska B. Stampfli M. Alvarez D. Coyle A. Gutierrez-Ramos J. Jordana
M. Expression of the Th1 chemokine IFN-gamma-inducible protein 10 in the airway alters
mucosal allergic sensitization in mice. J. Immunol. 2001;166:2750–2759. [PubMed: 11160341]
[133]. Patel M. Xu D. Kewin P. Choo-Kang B. McSharry C. Thomson N.C. Liew F.Y. TLR2 agonist
ameliorates established allergic airway inflammation by promoting Th1 response and not via
regulatory T cells. J. Immunol. 2005;174:7558–7563. [PubMed: 15944255]
[134]. Hansen G. Berry G. DeKruyff R.H. Umetsu D.T. Allergen-specific Th1 cells fail to
counterbalance Th2 cell-induced airway hyperreactivity but cause severe airway inflammation. J.
Clin. Invest. 1999;103:175–183. [PubMed: 9916129]
[135]. Mangan P.R. Harrington L.E. O’Quinn D.B. Helms W.S. Bullard D.C. Elson C.O. Hatton R.D.
Wahl S.M. Schoeb T.R. Weaver C.T. Transforming growth factor-beta induces development of
the T(H)17 lineage. Nature 2006;441:231–234. [PubMed: 16648837]
[136]. Veldhoen M. Hocking R.J. Atkins C.J. Locksley R.M. Stockinger B. TGFbeta in the context of
an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells.
Sponsored Document
Immunity 2006;24:179–189. [PubMed: 16473830]

[137]. Manel N. Unutmaz D. Littman D.R. The differentiation of human T(H)-17 cells requires
transforming growth factor-beta and induction of the nuclear receptor RORgammat. Nat.
Immunol. 2008;9:641–649. [PubMed: 18454151]
[138]. Bettelli E. Carrier Y. Gao W. Korn T. Strom T.B. Oukka M. Weiner H.L. Kuchroo V.K.
Reciprocal developmental pathways for the generation of pathogenic effector TH17 and
regulatory T cells. Nature 2006;441:235–238. [PubMed: 16648838]
[139]. Wilson N.J. Boniface K. Chan J.R. McKenzie B.S. Blumenschein W.M. Mattson J.D. Basham
B. Smith K. Chen T. Morel F. Lecron J.C. Kastelein R.A. Cua D.J. McClanahan T.K. Bowman
E.P. de Waal M.R. Development, cytokine profile and function of human interleukin 17-
producing helper T cells. Nat. Immunol. 2007;8:950–957. [PubMed: 17676044]
[140]. Zhou L. Ivanov I.I. Spolski R. Min R. Shenderov K. Egawa T. Levy D.E. Leonard W.J. Littman
D.R. IL-6 programs T(H)-17 cell differentiation by promoting sequential engagement of the
IL-21 and IL-23 pathways. Nat. Immunol. 2007;8:967–974. [PubMed: 17581537]
[141]. Aarvak T. Chabaud M. Miossec P. Natvig J.B. IL-17 is produced by some proinflammatory
Th1/Th0 cells but not by Th2 cells. J. Immunol. 1999;162:1246–1251. [PubMed: 9973376]
Sponsored Document
[142]. Harrington L.E. Hatton R.D. Mangan P.R. Turner H. Murphy T.L. Murphy K.M. Weaver C.T.
Interleukin 17-producing CD4+ effector T cells develop via a lineage distinct from the T helper
type 1 and 2 lineages. Nat. Immunol. 2005;6:1123–1132. [PubMed: 16200070]
[143]. Park H. Li Z. Yang X.O. Chang S.H. Nurieva R. Wang Y.H. Wang Y. Hood L. Zhu Z. Tian Q.
Dong C. A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin
17. Nat. Immunol. 2005;6:1133–1141. [PubMed: 16200068]
[144]. Barczyk A. Pierzchala W. Sozanska E. Interleukin-17 in sputum correlates with airway
hyperresponsiveness to methacholine. Respir. Med. 2003;97:726–733. [PubMed: 12814161]
[145]. Molet S. Hamid Q. Davoine F. Nutku E. Taha R. Page N. Olivenstein R. Elias J. Chakir J. IL-17
is increased in asthmatic airways and induces human bronchial fibroblasts to produce cytokines.
J. Allergy Clin. Immunol. 2001;108:430–438. [PubMed: 11544464]
[146]. Schnyder-Candrian S. Togbe D. Couillin I. Mercier I. Brombacher F. Quesniaux V. Fossiez F.
Ryffel B. Schnyder B. Interleukin-17 is a negative regulator of established allergic asthma. J.
Exp. Med. 2006;203:2715–2725. [PubMed: 17101734]

[147]. Schnyder B. Schnyder-Candrian S. Pansky A. Schmitz M.L. Heim M. Ryffel B. Moser R. IL-17
reduces TNF-induced Rantes and VCAM-1 expression. Cytokine 2005;31:191–202. [PubMed:
15975820]
[148]. Szefler S.J. Martin R.J. King T.S. Boushey H.A. Cherniack R.M. Chinchilli V.M. Craig T.J.
Dolovich M. Drazen J.M. Fagan J.K. Fahy J.V. Fish J.E. Ford J.G. Israel E. Kiley J. Kraft M.
Lazarus S.C. Lemanske R.F. Mauger E. Peters S.P. Sorkness C.A. Significant variability in
Sponsored Document
response to inhaled corticosteroids for persistent asthma. J. Allergy Clin. Immunol.

2002;109:410–418. [PubMed: 11897984]
[149]. McKinley L. Alcorn J.F. Peterson A. Dupont R.B. Kapadia S. Logar A. Henry A. Irvin C.G.
Piganelli J.D. Ray A. Kolls J.K. TH17 cells mediate steroid-resistant airway inflammation and
airway hyperresponsiveness in mice. J. Immunol. 2008;181:4089–4097. [PubMed: 18768865]
[150]. O'Sullivan S. Cormican L. Faul J.L. Ichinohe S. Johnston S.L. Burke C.M. Poulter L.W.
Activated, cytotoxic CD8(+) T lymphocytes contribute to the pathology of asthma death. Am. J.
Respir. Crit. Care Med. 2001;164:560–564. [PubMed: 11520715]
[151]. Ying S. Humbert M. Barkans J. Corrigan C.J. Pfister R. Menz G. Larche M. Robinson D.S.
Durham S.R. Kay A.B. Expression of IL-4 and IL-5 mRNA and protein product by CD4+ and
CD8+ T cells, eosinophils, and mast cells in bronchial biopsies obtained from atopic and
nonatopic (intrinsic) asthmatics. J. Immunol. 1997;158:3539–3544. [PubMed: 9120316]
[152]. Miyahara N. Takeda K. Kodama T. Joetham A. Taube C. Park J.W. Miyahara S. Balhorn A.
Dakhama A. Gelfand E.W. Contribution of antigen-primed CD8+ T cells to the development of
airway hyperresponsiveness and inflammation is associated with IL-13. J. Immunol.
2004;172:2549–2558. [PubMed: 14764728]
[153]. Hamelmann E. Oshiba A. Paluh J. Bradley K. Loader J. Potter T.A. Larsen G.L. Gelfand E.W.
Sponsored Document
Requirement for CD8+ T cells in the development of airway hyperresponsiveness in a marine

model of airway sensitization. J. Exp. Med. 1996;183:1719–1729. [PubMed: 8666929]
[154]. Stock P. Kallinich T. Akbari O. Quarcoo D. Gerhold K. Wahn U. Umetsu D.T. Hamelmann E.
CD8(+) T cells regulate immune responses in a murine model of allergen-induced sensitization
and airway inflammation. Eur. J. Immunol. 2004;34:1817–1827. [PubMed: 15214030]
[155]. Coyle A.J. Le G.G. Bertrand C. Tsuyuki S. Heusser C.H. Kopf M. Anderson G.P. Interleukin-4
is required for the induction of lung Th2 mucosal immunity. Am. J. Respir. Cell. Mol. Biol.
1995;13:54–59. [PubMed: 7598937]
[156]. Coyle A.J. Tsuyuki S. Th2 cells and cytokine networks in allergic inflammation of the lung.
Mediat. Inflamm. 1995;4:239–247.
[157]. Sawicka E. Noble A. Walker C. Kemeny D.M. Tc2 cells respond to soluble antigen in the
respiratory tract and induce lung eosinophilia and bronchial hyperresponsiveness. Eur. J.
Immunol. 2004;34:2599–2608. [PubMed: 15307192]
[158]. Wells J.W. Cowled C.J. Giorgini A. Kemeny D.M. Noble A. Regulation of allergic airway
inflammation by class I-restricted allergen presentation and CD8 T-cell infiltration. J. Allergy
Clin. Immunol. 2007;119:226–234. [PubMed: 17208606]
Sponsored Document
[159]. Born W.K. Jin N. Aydintug M.K. Wands J.M. French J.D. Roark C.L. O’Brien R.L.
Gammadelta T lymphocytes-selectable cells within the innate system? J. Clin. Immunol.
2007;27:133–144. [PubMed: 17333410]
[160]. Pardoll D.M. Immunology. Stress, NK receptors, and immune surveillance. Science
2001;294:534–536. [PubMed: 11567108]
[161]. Taniguchi M. Seino K. Nakayama T. The NKT cell system: bridging innate and acquired
immunity. Nat. Immunol. 2003;4:1164–1165. [PubMed: 14639465]
[162]. Larche M. Robinson D.S. Kay A.B. The role of T lymphocytes in the pathogenesis of asthma. J.
[163]. Zuany-Amorim C. Ruffie C. Haile S. Vargaftig B.B. Pereira P. Pretolani M. Requirement for
gammadelta T cells in allergic airway inflammation. Science 1998;280:1265–1267. [PubMed:
9596580]
[164]. Akbari O. Stock P. Meyer E. Kronenberg M. Sidobre S. Nakayama T. Taniguchi M. Grusby
M.J. DeKruyff R.H. Umetsu D.T. Essential role of NKT cells producing IL-4 and IL-13 in the

development of allergen-induced airway hyperreactivity. Nat. Med. 2003;9:582–588. [PubMed:

12669034]
[165]. Weissler J.C. Nicod L.P. Lipscomb M.F. Toews G.B. Natural killer cell function in human lung
is compartmentalized. Am. Rev. Respir. Dis. 1987;135:941–949. [PubMed: 3565942]
[166]. Timonen T. Stenius-Aarniala B. Natural killer cell activity in asthma. Clin. Exp. Immunol.
1985;59:85–90. [PubMed: 3971600]
Sponsored Document
[167]. Korsgren M. Persson C.G. Sundler F. Bjerke T. Hansson T. Chambers B.J. Hong S. Van K.L.
Ljunggren H.G. Korsgren O. Natural killer cells determine development of allergen-induced
eosinophilic airway inflammation in mice. J. Exp. Med. 1999;189:553–562. [PubMed: 9927517]
[168]. Seino K. Taniguchi M. Functionally distinct NKT cell subsets and subtypes. J. Exp. Med.
2005;202:1623–1626. [PubMed: 16365145]
[169]. Bendelac A. Selection and adaptation of cells expressing major histocompatibility complex
class I-specific receptors of the natural killer complex. J. Exp. Med. 1997;186:349–351.
[PubMed: 9265075]
[170]. Tsuji M. Glycolipids and phospholipids as natural CD1d-binding NKT cell ligands. Cell. Mol.
Life Sci. 2006;63:1889–1898. [PubMed: 16794785]
[171]. Akbari O. Faul J.L. Hoyte E.G. Berry G.J. Wahlstrom J. Kronenberg M. DeKruyff R.H. Umetsu
D.T. CD4+ invariant T-cell-receptor+ natural killer T cells in bronchial asthma. N. Engl. J. Med.
2006;354:1117–1129. [PubMed: 16540612]
[172]. Bendelac A. Savage P.B. Teyton L. The biology of NKT cells. Annu. Rev. Immunol.
2007;25:297–336. [PubMed: 17150027]
[173]. Vijayanand P. Seumois G. Pickard C. Powell R.M. Angco G. Sammut D. Gadola S.D.
Sponsored Document
Friedmann P.S. Djukanovic R. Invariant natural killer T cells in asthma and chronic obstructive
pulmonary disease. N. Engl. J. Med. 2007;356:1410–1422. [PubMed: 17409322]
[174]. Lisbonne M. Diem S. de Castro K.A. Lefort J. Araujo L.M. Hachem P. Fourneau J.M. Sidobre
S. Kronenberg M. Taniguchi M. Van E.P. Dy M. Askenase P. Russo M. Vargaftig B.B. Herbelin
A. Leite-de-Moraes M.C. Cutting edge: invariant V alpha 14 NKT cells are required for allergen-
induced airway inflammation and hyperreactivity in an experimental asthma model. J. Immunol.
2003;171:1637–1641. [PubMed: 12902459]
[175]. Bilenki L. Yang J. Fan Y. Wang S. Yang X. Natural killer T cells contribute to airway
eosinophilic inflammation induced by ragweed through enhanced IL-4 and eotaxin production.
Eur. J. Immunol. 2004;34:345–354. [PubMed: 14768039]
[176]. Terashima A. Watarai H. Inoue S. Sekine E. Nakagawa R. Hase K. Iwamura C. Nakajima H.
Nakayama T. Taniguchi M. A novel subset of mouse NKT cells bearing the IL-17 receptor B
responds to IL-25 and contributes to airway hyperreactivity. J. Exp. Med. 2008;205:2727–2733.
[PubMed: 19015310]
[177]. Jin N. Miyahara N. Roark C.L. French J.D. Aydintug M.K. Matsuda J.L. Gapin L. O’Brien R.L.
Gelfand E.W. Born W.K. Airway hyperresponsiveness through synergy of gammadelta} T cells
and NKT cells. J. Immunol. 2007;179:2961–2968. [PubMed: 17709511]
Sponsored Document
[178]. Thomas S.Y. Lilly C.M. Luster A.D. Invariant natural killer T cells in bronchial asthma. N.
Engl. J. Med. 2006;354:2613–2616. [PubMed: 16775244]
[179]. Hamzaoui A. Rouhou S.C. Grairi H. Abid H. Ammar J. Chelbi H. Hamzaoui K. NKT cells in
the induced sputum of severe asthmatics. Mediat. Inflamm. 2006;2006:71214.
[180]. Sen Y. Yongyi B. Yuling H. Luokun X. Li H. Jie X. Tao D. Gang Z. Junyan L. Chunsong H.
Zhang X. Youxin J. Feili G. Boquan J. Jinquan T. V alpha 24-invariant NKT cells from patients
with allergic asthma express CCR9 at high frequency and induce Th2 bias of CD3+ T cells upon
CD226 engagement. J. Immunol. 2005;175:4914–4926. [PubMed: 16210593]
[181]. Wands J.M. Roark C.L. Aydintug M.K. Jin N. Hahn Y.S. Cook L. Yin X. Dal P.J. Lahn M.
Hyde D.M. Gelfand E.W. Mason R.J. O’Brien R.L. Born W.K. Distribution and leukocyte
contacts of gammadelta T cells in the lung. J. Leukoc. Biol. 2005;78:1086–1096. [PubMed:
16204632]
[182]. Haas W. Pereira P. Tonegawa S. Gamma/delta cells. Annu. Rev. Immunol. 1993;11:637–685.
[PubMed: 8476575]

[183]. Spinozzi F. Agea E. Bistoni O. Forenza N. Monaco A. Bassotti G. Nicoletti I. Riccardi C.

Grignani F. Bertotto A. Increased allergen-specific, steroid-sensitive gamma delta T cells in
bronchoalveolar lavage fluid from patients with asthma. Ann. Intern. Med. 1996;124:223–227.
[PubMed: 8533997]
[184]. Pawankar R. Gammadelta T cells in allergic airway diseases. Clin. Exp. Allergy 2000;30:318–
323. [PubMed: 10691888]
Sponsored Document
[185]. Molfino N.A. Doherty P.J. Suurmann I.L. Yang S.X. Kesten S. Chapman K.R. Slutsky A.S.
Analysis of the T cell receptor Vgamma region gene repertoire in bronchoalveolar lavage (BAL)
and peripheral blood of atopic asthmatics and healthy subjects. Clin. Exp. Immunol.
1996;104:144–153. [PubMed: 8603519]
[186]. Lahn M. The role of gammadelta T cells in the airways. J. Mol. Med. 2000;78:409–425.
[PubMed: 11097110]
[187]. Born W.K. Lahn M. Takeda K. Kanehiro A. O’Brien R.L. Gelfand E.W. Role of gammadelta T
cells in protecting normal airway function. Respir. Res. 2000;1:151–158. [PubMed: 11667979]
[188]. Lahn M. Kanehiro A. Takeda K. Joetham A. Schwarze J. Kohler G. O’Brien R. Gelfand E.W.
Born W. Negative regulation of airway responsiveness that is dependent on gammadelta T cells
and independent of alphabeta T cells. Nat. Med. 1999;5:1150–1156. [PubMed: 10502818]
[189]. Lahn M. Kanehiro A. Takeda K. Terry J. Hahn Y.S. Aydintug M.K. Konowal A. Ikuta K.
O’Brien R.L. Gelfand E.W. Born W.K. MHC class I-dependent Vgamma4+ pulmonary T cells
regulate alpha beta T cell-independent airway responsiveness. Proc. Natl. Acad. Sci. U.S.A.
2002;99:8850–8855. [PubMed: 12070351]
[190]. Hahn Y.S. Taube C. Jin N. Takeda K. Park J.W. Wands J.M. Aydintug M.K. Roark C.L. Lahn
M. O’Brien R.L. Gelfand E.W. Born W.K. V gamma 4+ gamma delta T cells regulate airway
Sponsored Document
hyperreactivity to methacholine in ovalbumin-sensitized and challenged mice. J. Immunol.

2003;171:3170–3178. [PubMed: 12960345]
[191]. McMenamin C. Pimm C. McKersey M. Holt P.G. Regulation of IgE responses to inhaled
antigen in mice by antigen-specific gamma delta T cells. Science 1994;265:1869–1871.
[PubMed: 7916481]
[192]. Svensson L. Lilliehook B. Larsson R. Bucht A. Gammadelta T cells contribute to the systemic
immunoglobulin E response and local B-cell reactivity in allergic eosinophilic airway
inflammation. Immunology 2003;108:98–108. [PubMed: 12519308]
[193]. Schramm C.M. Puddington L. Yiamouyiannis C.A. Lingenheld E.G. Whiteley H.E. Wolyniec
W.W. Noonan T.C. Thrall R.S. Proinflammatory roles of T-cell receptor (TCR)gammadelta and
TCRalphabeta lymphocytes in a murine model of asthma. Am. J. Respir. Cell. Mol. Biol.
2000;22:218–225. [PubMed: 10657943]
[194]. Fang C. Corrigan C.J. Ying S. The treatment targets of asthma: from laboratory to clinic.
Inflamm. Allergy Drug Targets 2008;7:119–128. [PubMed: 18691142]
[195]. Serhan C.N. Savill J. Resolution of inflammation: the beginning programs the end. Nat.
Immunol. 2005;6:1191–1197. [PubMed: 16369558]
Sponsored Document
[196]. Haslett C. Introduction—the paradox of inflammation. Semin. Cell Biol. 1995;6:315–316.

[PubMed: 8748138]
[197]. Bannenberg G.L. Chiang N. Ariel A. Arita M. Tjonahen E. Gotlinger K.H. Hong S. Serhan C.N.
Molecular circuits of resolution: formation and actions of resolvins and protectins. J. Immunol.
2005;174:4345–4355. [PubMed: 15778399]
[198]. Vandivier R.W. Henson P.M. Douglas I.S. Burying the dead: the impact of failed apoptotic cell
removal (efferocytosis) on chronic inflammatory lung disease. Chest 2006;129:1673–1682.
[PubMed: 16778289]
[199]. Savill J. Apoptosis in resolution of inflammation. J. Leukoc. Biol. 1997;61:375–380. [PubMed:
9103222]
[200]. Henson P.M. Possible roles for apoptosis and apoptotic cell recognition in inflammation and
fibrosis. Am. J. Respir. Cell. Mol. Biol. 2003;29:S70–S76. [PubMed: 14503559]
[201]. Fra A.M. Locati M. Otero K. Sironi M. Signorelli P. Massardi M.L. Gobbi M. Vecchi A.
Sozzani S. Mantovani A. Cutting edge: scavenging of inflammatory CC chemokines by the

promiscuous putatively silent chemokine receptor D6. J. Immunol. 2003;170:2279–2282.

[PubMed: 12594248]
[202]. Jamieson T. Cook D.N. Nibbs R.J. Rot A. Nixon C. McLean P. Alcami A. Lira S.A. Wiekowski
M. Graham G.J. The chemokine receptor D6 limits the inflammatory response in vivo. Nat.
Immunol. 2005;6:403–411. [PubMed: 15750596]
[203]. Ariel A. Fredman G. Sun Y.P. Kantarci A. Van Dyke T.E. Luster A.D. Serhan C.N. Apoptotic
Sponsored Document
neutrophils and T cells sequester chemokines during immune response resolution through
modulation of CCR5 expression. Nat. Immunol. 2006;7:1209–1216. [PubMed: 17013391]
[204]. Serhan C.N. Chiang N. Van Dyke T.E. Resolving inflammation: dual anti-inflammatory and
pro-resolution lipid mediators. Nat. Rev. Immunol. 2008;8:349–361. [PubMed: 18437155]
[205]. Haworth O. Cernadas M. Yang R. Serhan C.N. Levy B.D. Resolvin E1 regulates interleukin 23,
interferon-gamma and lipoxin A4 to promote the resolution of allergic airway inflammation. Nat.
Immunol. 2008;9:873–879. [PubMed: 18568027]
[206]. Bonnans C. Levy B.D. Lipid mediators as agonists for the resolution of acute lung inflammation
and injury. Am. J. Respir. Cell. Mol. Biol. 2007;36:201–205. [PubMed: 16990613]
[207]. O’Garra A. Vieira P.L. Vieira P. Goldfeld A.E. IL-10-producing and naturally occurring CD4+
Tregs: limiting collateral damage. J. Clin. Invest. 2004;114:1372–1378. [PubMed: 15545984]
[208]. Curotto de Lafaille M.A. Lafaille J.J. Natural and adaptive foxp3+ regulatory T cells: more of
the same or a division of labor? Immunity 2009;30:626–635. [PubMed: 19464985]
[209]. Fontenot J.D. Gavin M.A. Rudensky A.Y. Foxp3 programs the development and function of
CD4+CD25+ regulatory T cells. Nat. Immunol. 2003;4:330–336. [PubMed: 12612578]
[210]. Khattri R. Cox T. Yasayko S.A. Ramsdell F. An essential role for Scurfin in CD4+CD25+ T
Sponsored Document
regulatory cells. Nat. Immunol. 2003;4:337–342. [PubMed: 12612581]

[211]. Groux H. O’Garra A. Bigler M. Rouleau M. Antonenko S. de Vries J.E. Roncarolo M.G. A
CD4+ T-cell subset inhibits antigen-specific T-cell responses and prevents colitis. Nature
1997;389:737–742. [PubMed: 9338786]
[212]. Ling E.M. Smith T. Nguyen X.D. Pridgeon C. Dallman P.M. Arbery J. Carr V.A. Robinson
D.S. Relation of CD4+CD25+ regulatory T-cell suppression of allergen-driven T-cell activation
to atopic status and expression of allergic disease. The Lancet 2004;363:608–615.
[213]. Joetham A. Takeda K. Taube C. Miyahara N. Matsubara S. Koya T. Rha Y.H. Dakhama A.
Gelfand E.W. Naturally occurring lung CD4(+)CD25(+) T cell regulation of airway allergic
responses depends on IL-10 induction of TGF-beta. J. Immunol. 2007;178:1433–1442. [PubMed:
17237391]
[214]. Kearley J. Robinson D.S. Lloyd C.M. CD4+CD25+ regulatory T cells reverse established
allergic airway inflammation and prevent airway remodeling. J. Allergy Clin. Immunol.
2008;122:617–624. [PubMed: 18672278]
[215]. Read S. Greenwald R. Izcue A. Robinson N. Mandelbrot D. Francisco L. Sharpe A.H. Powrie F.
Blockade of CTLA-4 on CD4+CD25+ regulatory T cells abrogates their function in vivo. J.
Immunol. 2006;177:4376–4383. [PubMed: 16982872]
Sponsored Document
[216]. Wilczynski J.R. Radwan M. Kalinka J. The characterization and role of regulatory T cells in
immune reactions. Front. Biosci. 2008;13:2266–2274. [PubMed: 17981708]
[217]. Borish L. Aarons A. Rumbyrt J. Cvietusa P. Negri J. Wenzel S. Interleukin-10 regulation in
normal subjects and patients with asthma. J. Allergy Clin. Immunol. 1996;97:1288–1296.
[PubMed: 8648025]
[218]. Nouri-Aria K.T. Wachholz P.A. Francis J.N. Jacobson M.R. Walker S.M. Wilcock L.K. Staple
S.Q. Aalberse R.C. Till S.J. Durham S.R. Grass pollen immunotherapy induces mucosal and
peripheral IL-10 responses and blocking IgG activity. J. Immunol. 2004;172:3252–3259.
[PubMed: 14978133]
[219]. Arock M. Zuany-Amorim C. Singer M. Benhamou M. Pretolani M. Interleukin-10 inhibits
cytokine generation from mast cells. Eur. J. Immunol. 1996;26:166–170. [PubMed: 8566061]
[220]. Royer B. Varadaradjalou S. Saas P. Guillosson J.J. Kantelip J.P. Arock M. Inhibition of IgE-
induced activation of human mast cells by IL-10. Clin. Exp. Allergy 2001;31:694–704. [PubMed:
11422128]

[221]. Takanaski S. Nonaka R. Xing Z. O’Byrne P. Dolovich J. Jordana M. Interleukin 10 inhibits

lipopolysaccharide-induced survival and cytokine production by human peripheral blood
eosinophils. J. Exp. Med. 1994;180:711–715. [PubMed: 8046346]
[222]. Moore K.W. O’Garra A. Malefyt R.W. Vieira P. Mosmann T.R. Interleukin-10. Annu. Rev.
Immunol. 1993;11:165–190. [PubMed: 8386517]
[223]. Waal Malefyt R. Haanen J. Spits H. Roncarolo M.G. te Velde A. Figdor C. Johnson K.
Sponsored Document
Kastelein R. Yssel H. de Vries J.E. Interleukin 10 (IL-10) and viral IL-10 strongly reduce
antigen-specific human T cell proliferation by diminishing the antigen-presenting capacity of
monocytes via downregulation of class II major histocompatibility complex expression. J. Exp.
Med. 1991;174:915–924. [PubMed: 1655948]
[224]. Akdis M. Verhagen J. Taylor A. Karamloo F. Karagiannidis C. Crameri R. Thunberg S. Deniz
G. Valenta R. Fiebig H. Kegel C. Disch R. Schmidt-Weber C.B. Blaser K. Akdis C.A. Immune
responses in healthy and allergic individuals are characterized by a fine balance between
allergen-specific T regulatory 1 and T helper 2 cells. J. Exp. Med. 2004;199:1567–1575.
[PubMed: 15173208]
[225]. Kearley J. Barker J.E. Robinson D.S. Lloyd C.M. Resolution of airway inflammation and
hyperreactivity after in vivo transfer of CD4+CD25+ regulatory T cells is interleukin 10
dependent. J. Exp. Med. 2005;202:1539–1547. [PubMed: 16314435]
[226]. Letterio J.J. Roberts A.B. Regulation of immune responses by TGF-beta. Annu. Rev. Immunol.
1998;16:137–161. [PubMed: 9597127]
[227]. Vignola A.M. Chanez P. Chiappara G. Merendino A. Pace E. Rizzo A. la Rocca A.M. Bellia V.
Bonsignore G. Bousquet J. Transforming growth factor-beta expression in mucosal biopsies in
asthma and chronic bronchitis. Am. J. Respir. Crit. Care Med. 1997;156:591–599. [PubMed:
Sponsored Document
9279245]
[228]. Rosendahl A. Checchin D. Fehniger T.E. ten D.P. Heldin C.H. Sideras P. Activation of the
TGF-beta/activin-Smad2 pathway during allergic airway inflammation. Am. J. Respir. Cell. Mol.
Biol. 2001;25:60–68. [PubMed: 11472976]
[229]. Nakao A. Miike S. Hatano M. Okumura K. Tokuhisa T. Ra C. Iwamoto I. Blockade of
transforming growth factor beta/Smad signaling in T cells by overexpression of Smad7 enhances
antigen-induced airway inflammation and airway reactivity. J. Exp. Med. 2000;192:151–158.
[PubMed: 10899902]
[230]. Schramm C. Herz U. Podlech J. Protschka M. Finotto S. Reddehase M.J. Kohler H. Galle P.R.
Lohse A.W. Blessing M. TGF-beta regulates airway responses via T cells. J. Immunol.
2003;170:1313–1319. [PubMed: 12538691]
[231]. Scherf W. Burdach S. Hansen G. Reduced expression of transforming growth factor beta 1
exacerbates pathology in an experimental asthma model. Eur. J. Immunol. 2005;35:198–206.
[PubMed: 15593298]
[232]. Bousquet J. Vignola A.M. Chanez P. Campbell A.M. Bonsignore G. Michel F.B. Airways
remodelling in asthma: no doubt, no more? Int. Arch. Allergy Immunol. 1995;107:211–214.
Sponsored Document
[PubMed: 7613133]
[233]. Lloyd C.M. Robinson D.S. Allergen-induced airway remodelling. Eur. Respir. J. 2007;29:1020–
1032. [PubMed: 17470623]
[234]. Vignola A.M. Chanez P. Siena L. Chiappara G. Bonsignore G. Bousquet J. Airways
remodelling in asthma. Pulm. Pharmacol. Ther. 1998;11:359–367.
[235]. Jeffery P.K. Morphology of the airway wall in asthma and in chronic obstructive pulmonary
disease. Am. Rev. Respir. Dis. 1991;143:1152–1158. [PubMed: 2024827]
[236]. Hogaboam C.M. Blease K. Mehrad B. Steinhauser M.L. Standiford T.J. Kunkel S.L. Lukacs
N.W. Chronic airway hyperreactivity, goblet cell hyperplasia, and peribronchial fibrosis during
allergic airway disease induced by Aspergillus fumigatus. Am. J. Pathol. 2000;156:723–732.
[PubMed: 10666400]
[237]. Kuwano K. Bosken C.H. Pare P.D. Bai T.R. Wiggs B.R. Hogg J.C. Small airways dimensions
in asthma and in chronic obstructive pulmonary disease. Am. Rev. Respir. Dis. 1993;148:1220–
1225. [PubMed: 8239157]

[238]. Chiappara G. Gagliardo R. Siena A. Bonsignore M.R. Bousquet J. Bonsignore G. Vignola A.M.
Airway remodelling in the pathogenesis of asthma. Curr. Opin. Allergy Clin. Immunol.
2001;1:85–93. [PubMed: 11964675]
[239]. Boulet L.P. Laviolette M. Turcotte H. Cartier A. Dugas M. Malo J.L. Boutet M. Bronchial
subepithelial fibrosis correlates with airway responsiveness to methacholine. Chest 1997;112:45–
52. [PubMed: 9228356]
Sponsored Document
[240]. Woodruff P.G. Dolganov G.M. Ferrando R.E. Donnelly S. Hays S.R. Solberg O.D. Carter R.
Wong H.H. Cadbury P.S. Fahy J.V. Hyperplasia of smooth muscle in mild to moderate asthma
without changes in cell size or gene expression. Am. J. Respir. Crit. Care Med. 2004;169:1001–
1006. [PubMed: 14726423]
[241]. Ebina M. Takahashi T. Chiba T. Motomiya M. Cellular hypertrophy and hyperplasia of airway
smooth muscles underlying bronchial asthma. A 3-D morphometric study. Am. Rev. Respir. Dis.
1993;148:720–726. [PubMed: 8368645]
[242]. Kaur D. Saunders R. Berger P. Siddiqui S. Woodman L. Wardlaw A. Bradding P. Brightling
C.E. Airway smooth muscle and mast cell-derived CC chemokine ligand 19 mediate airway
smooth muscle migration in asthma. Am. J. Respir. Crit. Care Med. 2006;174(December 1 (11)):
1179–1188. [PubMed: 16959919]
[243]. Knight D.A. Stewart G.A. Thompson P.J. The respiratory epithelium and airway smooth muscle
homeostasis: its relevance to asthma. Clin. Exp. Allergy 1994;24:698–706. [PubMed: 7982119]
[244]. Jeffery P.K. Wardlaw A.J. Nelson F.C. Collins J.V. Kay A.B. Bronchial biopsies in asthma. An
ultrastructural, quantitative study and correlation with hyperreactivity. Am. Rev. Respir. Dis.
1989;140:1745–1753. [PubMed: 2690708]
[245]. Araujo B.B. Dolhnikoff M. Silva L.F.F. Elliot J. Lindeman J.H.N. Ferreira D.S. Mulder A.
Sponsored Document
Gomes H.A.P. Fernezlian S.M. James A. Mauad T. Extracellular matrix components and
regulators within the airway smooth muscle in asthma. Eur. Respir. J. 2008;32:61–69. [PubMed:
18321931]
[246]. Morishima Y. Nomura A. Uchida Y. Noguchi Y. Sakamoto T. Ishii Y. Goto Y. Masuyama K.
Zhang M.J. Hirano K. Mochizuki M. Ohtsuka M. Sekizawa K. Triggering the induction of
myofibroblast and fibrogenesis by airway epithelial shedding. Am. J. Respir. Cell. Mol. Biol.
2001;24:1–11. [PubMed: 11152644]
[247]. Brewster C.E. Howarth P.H. Djukanovic R. Wilson J. Holgate S.T. Roche W.R. Myofibroblasts
and subepithelial fibrosis in bronchial asthma. Am. J. Respir. Cell. Mol. Biol. 1990;3:507–511.
[PubMed: 2223105]
[248]. Zhang K. Rekhter M.D. Gordon D. Phan S.H. Myofibroblasts and their role in lung collagen
gene expression during pulmonary fibrosis. A combined immunohistochemical and in situ
hybridization study. Am. J. Pathol. 1994;145:114–125. [PubMed: 7518191]
[249]. Schmidt M. Sun G. Stacey M.A. Mori L. Mattoli S. Identification of circulating fibrocytes as
precursors of bronchial myofibroblasts in asthma. J. Immunol. 2003;171:380–389. [PubMed:
12817021]
Sponsored Document
[250]. Johnson J.R. Wiley R.E. Fattouh R. Swirski F.K. Gajewska B.U. Coyle A.J. Gutierrez-Ramos
J.C. Ellis R. Inman M.D. Jordana M. Continuous exposure to house dust mite elicits chronic
airway inflammation and structural remodeling. Am. J. Respir. Crit. Care Med. 2004;169:378–
385. [PubMed: 14597485]
[251]. McMillan S.J. Lloyd C.M. Prolonged allergen challenge in mice leads to persistent airway
remodelling. Clin. Exp. Allergy 2004;34:497–507. [PubMed: 15005746]
[252]. Nguyen T.T. Ward J.P. Hirst S.J. beta1-Integrins mediate enhancement of airway smooth
muscle proliferation by collagen and fibronectin. Am. J. Respir. Crit. Care Med. 2005;171:217–
223. [PubMed: 15502110]
[253]. Hashimoto S. Gon Y. Takeshita I. Matsumoto K. Maruoka S. Horie T. Transforming growth
Factor-beta1 induces phenotypic modulation of human lung fibroblasts to myofibroblast through
a c-Jun-NH2-terminal kinase-dependent pathway. Am. J. Respir. Crit. Care Med. 2001;163:152–
157. [PubMed: 11208641]
[254]. Richter A. Puddicombe S.M. Lordan J.L. Bucchieri F. Wilson S.J. Djukanovic R. Dent G.
Holgate S.T. Davies D.E. The contribution of interleukin (IL)-4 and IL-13 to the epithelial–

mesenchymal trophic unit in asthma. Am. J. Respir. Cell. Mol. Biol. 2001;25:385–391. [PubMed:
11588018]
[255]. Jeffery P.K. Remodeling in asthma and chronic obstructive lung disease. Am. J. Respir. Crit.
Care Med. 2001;164:S28–S38. [PubMed: 11734464]
[256]. Willis B.C. Borok Z. TGF-beta-induced EMT: mechanisms and implications for fibrotic lung
disease. Am. J. Physiol. Lung Cell. Mol. Physiol. 2007;293:L525–L534. [PubMed: 17631612]
Sponsored Document
[257]. Kalluri R. Neilson E.G. Epithelial–mesenchymal transition and its implications for fibrosis. J.
Clin. Invest. 2003;112:1776–1784. [PubMed: 14679171]
[258]. Lee J.M. Dedhar S. Kalluri R. Thompson E.W. The epithelial–mesenchymal transition: new
insights in signaling, development, and disease. J. Cell Biol. 2006;172:973–981. [PubMed:
16567498]
[259]. Holgate S.T. Holloway J. Wilson S. Bucchieri F. Puddicombe S. Davies D.E. Epithelial–
mesenchymal communication in the pathogenesis of chronic asthma. Proc. Am. Thorac. Soc.
2004;1:93–98. [PubMed: 16113419]
[260]. Holgate S.T. Lackie P.M. Howarth P.H. Roche W.R. Puddicombe S.M. Richter A. Wilson S.J.
Holloway J.W. Davies D.E. Invited lecture: activation of the epithelial mesenchymal trophic unit
in the pathogenesis of asthma. Int. Arch. Allergy Immunol. 2001;124:253–258. [PubMed:
11306984]
[261]. Dennler S. Goumans M.J. ten D.P. Transforming growth factor beta signal transduction. J.
Leukoc. Biol. 2002;71:731–740. [PubMed: 11994497]
[262]. Sime P.J. Xing Z. Graham F.L. Csaky K.G. Gauldie J. Adenovector-mediated gene transfer of
active transforming growth factor-beta1 induces prolonged severe fibrosis in rat lung. J. Clin.
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Invest. 1997;100:768–776. [PubMed: 9259574]

[263]. Gu L. Zhu Y.J. Yang X. Guo Z.J. Xu W.B. Tian X.L. Effect of TGF-beta/Smad signaling
pathway on lung myofibroblast differentiation. Acta Pharmacol. Sin. 2007;28:382–391.
[PubMed: 17303001]
[264]. Wenzel S.E. Trudeau J.B. Barnes S. Zhou X. Cundall M. Westcott J.Y. McCord K. Chu H.W.
TGF-beta and IL-13 synergistically increase eotaxin-1 production in human airway fibroblasts. J.
Immunol. 2002;169:4613–4619. [PubMed: 12370400]
[265]. Chen G. Khalil N. TGF-beta1 increases proliferation of airway smooth muscle cells by
phosphorylation of map kinases. Respir. Res. 2006;7:2. [PubMed: 16390551]
[266]. Goldsmith A.M. Bentley J.K. Zhou L. Jia Y. Bitar K.N. Fingar D.C. Hershenson M.B.
Transforming growth factor-beta induces airway smooth muscle hypertrophy. Am. J. Respir.
[267]. McMillan S.J. Xanthou G. Lloyd C.M. Manipulation of allergen-induced airway remodeling by
treatment with anti-TGF-beta antibody: effect on the Smad signaling pathway. J. Immunol.
2005;174:5774–5780. [PubMed: 15843580]
[268]. Le A.V. Cho J.Y. Miller M. McElwain S. Golgotiu K. Broide D.H. Inhibition of allergen-
induced airway remodeling in Smad 3-deficient mice. J. Immunol. 2007;178:7310–7316.
Sponsored Document
[PubMed: 17513781]
[269]. Kolb M. Bonniaud P. Galt T. Sime P.J. Kelly M.M. Margetts P.J. Gauldie J. Differences in the
fibrogenic response after transfer of active transforming growth factor-beta1 gene to lungs of
“fibrosis-prone” and “fibrosis-resistant” mouse strains. Am. J. Respir. Cell. Mol. Biol.
2002;27:141–150. [PubMed: 12151305]
[270]. Ross R. Platelet-derived growth factor. Lancet 1989;1:1179–1182. [PubMed: 2566744]
[271]. Heldin C.H. Structural and functional studies on platelet-derived growth factor. EMBO J.
1992;11:4251–4259. [PubMed: 1425569]
[272]. Lee C.G. Link H. Baluk P. Homer R.J. Chapoval S. Bhandari V. Kang M.J. Cohn L. Kim Y.K.
McDonald D.M. Elias J.A. Vascular endothelial growth factor (VEGF) induces remodeling and
enhances TH2-mediated sensitization and inflammation in the lung. Nat. Med. 2004;10:1095–
1103. [PubMed: 15378055]
[273]. Bhandari V. Choo-Wing R. Chapoval S.P. Lee C.G. Tang C. Kim Y.K. Ma B. Baluk P. Lin M.I.
McDonald D.M. Homer R.J. Sessa W.C. Elias J.A. Essential role of nitric oxide in VEGF-

induced, asthma-like angiogenic, inflammatory, mucus, and physiologic responses in the lung.
Proc. Natl. Acad. Sci. U.S.A. 2006;103:11021–11026. [PubMed: 16832062]
[274]. McMillan S.J. Kearley J. Campbell J.D. Zhu X.W. Larbi K.Y. Shipley J.M. Senior R.M.
Nourshargh S. Lloyd C.M. Matrix metalloproteinase-9 deficiency results in enhanced allergen-
induced airway inflammation. J. Immunol. 2004;172:2586–2594. [PubMed: 14764732]
[275]. Lee C.G. Homer R.J. Zhu Z. Lanone S. Wang X. Koteliansky V. Shipley J.M. Gotwals P. Noble
Sponsored Document
P. Chen Q. Senior R.M. Elias J.A. Interleukin-13 induces tissue fibrosis by selectively
stimulating and activating transforming growth factor beta(1). J. Exp. Med. 2001;194:809–821.
[PubMed: 11560996]
[276]. Kariyawasam H.H. Robinson D.S. The role of eosinophils in airway tissue remodelling in
asthma. Curr. Opin. Immunol. 2007;19:681–686. [PubMed: 17949963]
[277]. Rothenberg M.E. Hogan S.P. The eosinophil. Annu. Rev. Immunol. 2006;24:147–174.
[PubMed: 16551246]
[278]. Humbles A.A. Lloyd C.M. McMillan S.J. Friend D.S. Xanthou G. McKenna E.E. Ghiran S.
Gerard N.P. Yu C. Orkin S.H. Gerard C. A critical role for eosinophils in allergic airways
remodeling. Science 2004;305:1776–1779. [PubMed: 15375268]
[279]. Minshall E.M. Leung D.Y. Martin R.J. Song Y.L. Cameron L. Ernst P. Hamid Q. Eosinophil-
associated TGF-beta1 mRNA expression and airways fibrosis in bronchial asthma. Am. J. Respir.
[280]. Flood-Page P. Menzies-Gow A. Phipps S. Ying S. Wangoo A. Ludwig M.S. Barnes N.
Robinson D. Kay A.B. Anti-IL-5 treatment reduces deposition of ECM proteins in the bronchial
subepithelial basement membrane of mild atopic asthmatics. J. Clin. Invest. 2003;112:1029–
1036. [PubMed: 14523040]
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[281]. Kay A.B. Phipps S. Robinson D.S. A role for eosinophils in airway remodelling in asthma.
Trends Immunol. 2004;25:477–482. [PubMed: 15324740]
[282]. Cho J.Y. Miller M. Baek K.J. Han J.W. Nayar J. Lee S.Y. McElwain K. McElwain S. Friedman
S. Broide D.H. Inhibition of airway remodeling in IL-5-deficient mice. J. Clin. Invest.
2004;113:551–560. [PubMed: 14966564]
[283]. Tanaka H. Komai M. Nagao K. Ishizaki M. Kajiwara D. Takatsu K. Delespesse G. Nagai H.
Role of interleukin-5 and eosinophils in allergen-induced airway remodeling in mice. Am. J.
Respir. Cell. Mol. Biol. 2004;31:62–68. [PubMed: 14975941]
[284]. Hara I. Miyake H. Hara S. Arakawa S. Kamidono S. Significance of matrix metalloproteinases
and tissue inhibitors of metalloproteinase expression in the recurrence of superficial transitional
cell carcinoma of the bladder. J. Urol. 2001;165:1769–1772. [PubMed: 11342973]
[285]. Sampson A.P. The role of eosinophils and neutrophils in inflammation. Clin. Exp. Allergy
2000;30(Suppl. 1):22–27. [PubMed: 10849470]
[286]. Lavoie J.P. Maghni K. Desnoyers M. Taha R. Martin J.G. Hamid Q.A. Neutrophilic airway
inflammation in horses with heaves is characterized by a Th2-type cytokine profile. Am. J.
Respir. Crit. Care Med. 2001;164:1410–1413. [PubMed: 11704587]
Sponsored Document
[287]. Kaur D. Saunders R. Berger P. Siddiqui S. Woodman L. Wardlaw A. Bradding P. Brightling

C.E. Airway smooth muscle and mast cell-derived CC chemokine ligand 19 mediate airway
smooth muscle migration in asthma. Am. J. Respir. Crit. Care Med. 2006;174:1179–1188.
[PubMed: 16959919]
[288]. Plante S. Semlali A. Joubert P. Bissonnette E. Laviolette M. Hamid Q. Chakir J. Mast cells
regulate procollagen I (alpha 1) production by bronchial fibroblasts derived from subjects with
asthma through IL-4/IL-4 delta 2 ratio. J. Allergy Clin. Immunol. 2006;117:1321–1327.
[PubMed: 16750993]
[289]. Sutcliffe A. Kaur D. Page S. Woodman L. Armour C.L. Baraket M. Bradding P. Hughes J.M.
Brightling C.E. Mast cell migration to Th2 stimulated airway smooth muscle from asthmatics.
Thorax 2006;61:657–662. [PubMed: 16601090]
[290]. Scott K. Bradding P. Human mast cell chemokines receptors: implications for mast cell tissue
localization in asthma. Clin. Exp. Allergy 2005;35:693–697. [PubMed: 15969654]
[291]. Dahlen S.E. Kumlin M. Monitoring mast cell activation by prostaglandin D2 in vivo. Thorax
2004;59:453–455. [PubMed: 15170020]

[292]. Holgate S.T. Davies D.E. Puddicombe S. Richter A. Lackie P. Lordan J. Howarth P.
Mechanisms of airway epithelial damage: epithelial–mesenchymal interactions in the
pathogenesis of asthma. Eur. Respir. J. 2003;(Suppl. 44):24s–29s.
[293]. Bush A. How early do airway inflammation and remodeling occur? Allergol. Int. 2008;57:11–
19. [PubMed: 18209503]
[294]. Sumi Y. Hamid Q. Airway remodeling in asthma. Allergol. Int. 2007;56:341–348. [PubMed:
Sponsored Document
17965577]
[295]. Saglani S. Molyneux C. Gong H. Rogers A. Malmstrom K. Pelkonen A. Makela M. Adelroth E.
Bush A. Payne D.N. Jeffery P.K. Ultrastructure of the reticular basement membrane in asthmatic
adults, children and infants. Eur. Respir. J. 2006;28:505–512. [PubMed: 16641125]
[296]. Saglani S. Payne D.N. Zhu J. Wang Z. Nicholson A.G. Bush A. Jeffery P.K. Early detection of
airway wall remodeling and eosinophilic inflammation in preschool wheezers. Am. J. Respir.
Crit. Care Med. 2007;176:858–864. [PubMed: 17702968]
[297]. Holgate S.T. Davies D.E. Lackie P.M. Wilson S.J. Puddicombe S.M. Lordan J.L. Epithelial–
mesenchymal interactions in the pathogenesis of asthma. J. Allergy Clin. Immunol.
2000;105:193–204. [PubMed: 10669837]
[298]. Holgate S.T. Epithelium dysfunction in asthma. J. Allergy Clin. Immunol. 2007;120:1233–
1244. [PubMed: 18073119]
[299]. Laprise C. Laviolette M. Boutet M. Boulet L.P. Asymptomatic airway hyperresponsiveness:
relationships with airway inflammation and remodelling. Eur. Respir. J. 1999;14:63–73.
[PubMed: 10489830]
[300]. Boulet L.P. Turcotte H. Carrier G. Boutet M. Laviolette M. Increased maximal airway response
Sponsored Document
to methacholine during seasonal allergic rhinitis in nonasthmatic subjects: relationships with

airway wall thickness and inflammation. Eur. Respir. J. 1995;8:913–921. [PubMed: 7589377]
[301]. Ward C. Walters H. Airway wall remodelling: the influence of corticosteroids. Curr. Opin.
[302]. Kariyawasam H.H. Aizen M. Barkans J. Robinson D.S. Kay A.B. Remodeling and airway
hyperresponsiveness but not cellular inflammation persist after allergen challenge in asthma. Am.
J. Respir. Crit. Care Med. 2007;175:896–904. [PubMed: 17272787]
[303]. Bjermer L. Evaluating combination therapies for asthma: pros, cons, and comparative benefits.
Ther. Adv. Respir. Dis. 2008;2:149–161. [PubMed: 19124367]
[304]. Tamesis G.P. Krawiec M.E. Heterogeneity in response to asthma medications. Curr. Opin.
[305]. Barnes P.J. Current issues for establishing inhaled corticosteroids as the antiinflammatory
agents of choice in asthma. J. Allergy Clin. Immunol. 1998;101:S427–S433. [PubMed: 9563367]
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Fig. 1.
Gene environment interactions in asthma. Asthma is an inflammatory disorder of profound
heterogeneity with strong genetic and environmental components. Local airway
susceptibility factors together with allergen-specific immune polarisation interact both in the
induction and subsequent expression of the disease phenotype. Key: EpC, epithelial cell.
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Fig. 2.
Immune cells and the inflammatory cascade in asthma. Initial exposure(s) to allergen leads
to the activation of allergen-specific Th2 cells and IgE synthesis (sensitisation). Subsequent
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allergen exposures cause inflammatory-cell recruitment, activation and mediator release.

IgE-sensitised mast cells expressing the high affinity IgE receptor (FcɛRI) degranulate,
releasing both pre-formed and newly synthesized mediators including histamine,
leukotrienes and cytokines, which promote vascular permeability, smooth muscle
contraction and mucus production. Chemokines released by inflammatory and resident cells
direct recruitment of inflammatory cells characterised eosinophils and Th2 cells. Eosinophils
release an array of pro-inflammatory mediators, including leukotrienes and basic proteins
and mediators such as, IL-5. Key: APC, antigen-presenting cell; ASM, airway smooth
muscle; EpC, epithelial cell; GM-CSF, granulocyte monocyte colony stimulating factor;
MHC, major histocompatibility; TCR, T cell receptor; TSLP, thymic stromal lymphopoietin.

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Fig. 3.
Th2 effector cells and asthma pathogenesis. Th2 cells have a central role in orchestrating the
allergen-induced inflammatory response. Th2 derived IL-4 and IL-13 stimulate B cells to
synthesise IgE whilst IL-5 is necessary for eosinophilic inflammation. Th2 cytokines are
also involved in mast cell proliferation and allergic airway remodelling. Key: Eφ, eosinophil;
EpC, epithelial cell; EMTU, epithelial to mesenchymal tropic unit; ASM, airway smooth
muscle; AHR, airway hyperreactivity.
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Fig. 4.
Airway remodelling in asthma. Activation of airway epithelium by aeroallergens and
pollutants leads to downstream effects including inflammation, dysregulated repair,
activated EMTU and tissue remodelling. Key: ASM, airway smooth muscle; ECM,
extracellular matrix; EMTU, epithelial to mesenchymal trophic unit; Epc, EpC, epithelial
cell; TGF-β, transforming growth factor-β.
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Chronic inﬂammation and asthma

Article in Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis · September 2009

Jenna Murdoch Clare M Lloyd

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Chronic inflammation and asthma

Jenna R. Murdoch and Clare M. Lloyd⁎

Â© 2010 Elsevier B.V.

1.1 Airway hyper-responsiveness

2 Immunopathogenesis of chronic asthma

Published as: Mutat Res. 2010 August 07; 690(1-2): 24–39.

variety of evolutionarily ancient germline-encoded receptor families, known as pattern-

of microbes, helps drive the development of allergic reactions to a common household

There is now compelling evidence in support of the crucial role played by DC in

Published as: Mutat Res. 2010 August 07; 690(1-2): 24–39.

4 The inflammatory cascade—multi-cellular and fundamental to the

By virtue of their capacity to release a wide range of pro-inflammatory mediators, affinity

Published as: Mutat Res. 2010 August 07; 690(1-2): 24–39.

characterised by mucus secretion and vasodilatation prior to the recruitment of inflammatory

The importance of mast cells in atopic asthma became somewhat overshadowed by

Granulocytic eosinophils typically predominate the atopic allergic inflammatory infiltrate

Published as: Mutat Res. 2010 August 07; 690(1-2): 24–39.

4.2 The Th2 lymphocyte response in the immunopathogenesis of asthma

Published as: Mutat Res. 2010 August 07; 690(1-2): 24–39.

importance of Th2 cells during allergic sensitisation and propagation [106,108].

to promote allergic immunopathology is amplified by production of a range of mediators

producing Th9 subset [105,123]. An overview of the main immunopathological features

4.3 Emerging T lymphocytes in the immunopathogenesis of asthma

Published as: Mutat Res. 2010 August 07; 690(1-2): 24–39.

4.4 Non-classical lymphocytes in the immunopathogenesis of asthma

pathological contribution to both development and maintenance of allergic airway disease

4.5 iNKT cells

Published as: Mutat Res. 2010 August 07; 690(1-2): 24–39.

4.6 γδT cells

αβTh2 driven response by an anti-inflammatory γδT cell population elicited in response to

5 Regulation and resolution of allergic inflammation

Published as: Mutat Res. 2010 August 07; 690(1-2): 24–39.

5.1 Regulatory processes

Altered chemokine production is a feature of allergic airway inflammation and responsible

therapeutic intervention possibilities.

5.2 Regulatory T cells

Published as: Mutat Res. 2010 August 07; 690(1-2): 24–39.

regulatory function by a variety of mechanisms including modulation of APC function [215]

5.3 Regulatory cytokines

Although considered to be a pro-fibrotic cytokine, TGF-β also has potent anti-inflammatory

Exploiting the body's own endogenous counter-regulatory mechanisms offers therapeutic

evidence of structural alterations to the airway architecture in asthmatics [232], which is

Published as: Mutat Res. 2010 August 07; 690(1-2): 24–39.

There is an increasing recognition that alterations to ECM composition play an important

key participants in airway remodelling [246], the mechanisms underlying myofibroblast

disturbance of the EMTU [260].

6.1 Transforming growth factor-β: a key player in airway remodelling

Published as: Mutat Res. 2010 August 07; 690(1-2): 24–39.

6.2 Other important contributors to airway remodelling

differentiation, proliferation and function of lung structural cells [78,277]. Allergen

7 Airway inflammation and remodelling: parallel or sequential events

corticosteroids and administration of beta(2)-agonists, anti-leukotrienes [294], and cannot

7.1 Future considerations for airway remodelling

Published as: Mutat Res. 2010 August 07; 690(1-2): 24–39.

implications of these structural changes are only beginning to be understood, it is thought