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FIGURE 1 | Allergic mechanisms.

In predisposed individuals, initial exposure(s) of professional antigen-presenting cells (APCs)

to allergen leads mainly to the activation of allergen-specific T helper 2 (TH2) cells and IgE
synthesis, which is known as allergic sensitization. Subsequent exposures to allergen cause
inflammatory-cell recruitment and activation and mediator release, which are responsible for
early (acute) allergic responses and late allergic responses. In the early allergic response,
within minutes of contact with allergen, IgE-sensitized mast cells degranulate, releasing both
pre-formed and newly synthesized mediators in sensitized individuals. These include
histamine, cysteinyl leukotrienes and cytokines, which promote vascular permeability,
smooth-muscle contraction and mucus production. Chemokines released by mast cells and
other cell types direct the recruitment of inflammatory cells that contribute to the late
allergic response, which is characterized by an influx of eosinophils and TH2 cells. Eosinophils
release a large number of pro-inflammatory mediators, including cysteinyl leukotrienes and
basic proteins (cationic proteins, eosinophil peroxidase, major basic protein and eosinophil-
derived neurotoxin), and they might be an important source of pro-inflammatory cytokines
such as interleukin-3 (IL-3), IL-5 and IL-13. There is now evidence that TH1-cell responses
might also be responsible for some of the pathogenic features in patients suffering from
chronic forms of atopy, including epithelial apoptosis and smooth-muscle-cell activation.
Regulatory T (TReg) cells are another important subset of CD4+ T cells with implications for
the suppression of TH2-cell responses in humans involving the inhibitory cytokines IL-10 and
transforming growth factor- (TGF). Another newly identified CD4+ T-cell subset, known as
TH17 cells on the basis of secretion of IL-17A and IL-17F, seems to be specifically associated
with the neutrophilic inflammatory events that occur during disease exacerbation and in
tissue remodelling. FceRI, high-affinity receptor for IgE; IFN, interferon-; TCR, T-cell receptor;
TNF, tumour-necrosis factor.

Inflammatory and remodelling responses in asthma with activation of the epithelial
mesenchymal unit
The airways in asthma show characteristics of a chronic wound with evidence of ongoing
epithelial injury and repair. As in any wound, responses to tissue injury create the
necessary stimuli to recruit the underlying mesenchyme to participate in the repair
process through the release of various growth factors and cytokines. Interleukin-13 (IL-
13) is a key cytokine in this process, driving goblet-cell metaplasia and myofibroblast
differentiation, and supporting immunoglobulin class-switching to IgE. Both in human
asthma and in mouse models of allergen-induced remodelling, epidermal growth factors
(EGFs), transforming growth factor- (TGF), fibroblast growth factor 2 (FGF2) and FGF7
(KGF), insulin-like growth factor 1 (IGF1), platelet-derived growth factor AA (PDGFAA)
and PDGFBB, vascular endothelial growth factor (VEGF) and IL-5 are all implicated. The
epithelium is more susceptible to oxidant stress and to injury by prematurely entering
into apoptosis. Impaired wound repair leads to the increased production of growth
factors by damaged epithelium, activated structural cells and infiltrating inflammatory
cells. In asthma this leads to myofibroblast activation, mesenchymal hyperplasia,
mucous metaplasia and the induction of structural changes throughout the airway wall.
The ongoing eosinophil- and mast-cell-driven inflammatory responses are responsible
for the maintenance and progression of tissue injury and repair. The activation of T
helper 1 (TH1)-cell pathways is also important for tissue inflammation and remodelling
through the release of interferon- (IFN, which induces epithelial apoptosis and the
recruitment of further T cells into the lesion) and tumour-necrosis factor (TNF, which
elicits the proliferation and activation of myofibroblasts and fibroblasts and induces a
hypercontractile phenotype in airway smooth muscle cells). APC, antigen-presenting
cell; GM-CSF, granulocyte/macrophage colony-stimulating factor.

Anti-inflammatory actions of corticosteroids
Corticosteroids enter the cell, bind to the glucocorticoid receptor (GR) in the
cytoplasm and translocate to the nucleus, where the transcription of target genes
is initiated. Many genes contain glucocorticosteroid response elements (GREs) in
their promoters. Through transactivation, binding of the activated glucocorticoid
receptor homodimer to a GRE in the promoter region of steroid-sensitive genes
leads to the transcription of genes encoding anti-inflammatory mediators such as
annexin-1 (lipocortin-1), secretory leukoprotease inhibitor (SLPI), interleukin-10
(IL-10) and the inhibitor of nuclear factor-B (IB). Through transrepression, the
glucocorticoid receptorcorticosteroid complex interacts with large co-activator
molecules with intrinsic histone acetyltransferase (HAT) activity (such as cyclic
AMP response element binding protein, CBP), which are activated by pro-
inflammatory transcription factors (such as NF-B and AP1), thus switching off
expression of the inflammatory genes that are activated by these transcription
factors. RNA pol II, RNA polymerase II.

Effects of allergen-specific immunotherapy
(SIT) on immune parameters
SIT modifies cellular and humoral responses to allergen. The ratio of T helper
1 (TH1)-cell cytokines to TH2-cell cytokines is increased after SIT, and
functional regulatory T (TReg) cells are induced. The production of
interleukin-10 (IL-10) by monocytes, macrophages, B cells and T cells is
increased. The production of transforming growth factor- (TGF) is increased
and, together with IL-10, TGF might contribute to TReg-cell function and
immunoglobulin class-switching to IgA, IgG1 and IgG4. These
immunoglobulins compete with IgE for allergen binding, thereby decreasing
the allergen capture and presentation that is facilitated by IgE in complex
with the high-affinity receptor for IgE (FcRI) or the low-affinity receptor for
IgE (FcRII, CD23). In addition, SIT decreases the number of mast cells and the
ability of mast cells to release mediators. The recruitment of eosinophils and
neutrophils to sites of allergen exposure is also decreased.

The effects of targeting IgE on allergic responses
The monoclonal IgE-specific antibody omalizumab can decrease free IgE levels and
decrease the amount of IgE binding to both high-affinity (FcRI) and low-affinity (FcRII)
IgE receptors, resulting in an attenuation of allergic reactions. In addition to inhibiting
the binding of IgE to mast cells, basophils and eosinophils, omalizumab downregulates
the expression of FcRI. This will also decrease the amplification of the inflammatory
response mediated by T helper cells to prevent IgE-dependent allergen presentation.

Cytokine-based therapies in asthma
Allergic inflammation has been characterized as a mainly T helper 2 (TH2)-cell disease; therefore,
efforts to alter the TH2TH1-cell balance in asthma have been aggressively pursued, either by
inhibiting TH2-cell cytokines (in particular, interleukin-4 (IL-4), IL-13 and IL-5) or promoting TH1-cell
responses (interferon- (IFN) and IL-12). Inhibition of the allergic component of atopic asthma can also
be achieved using IgE-specific monoclonal antibodies. APC, antigen-presenting cell; FceRI, high-affinity
receptor for IgE; rh, recombinant human; TCR, T-cell receptor.

Potential new cytokine therapeutic targets in allergy and asthma
Airway inflammation in asthma
Asthma is a complex and interactive process involving many cell types,
mediators and target-organ responses. Furthermore, the process can
involve a progression from acute events (a) such as allergen-induced
activation of mast cells to release pro-inflammatory cytokines and
mediators, leading to acute bronchoconstriction and airway
obstruction, to chronic inflammation (b) characterized by activation of
T helper (TH) 2 cells and macrophages, and recruitment and
degranulation of eosinophils. The changes in the airway cause not only
airflow obstruction but also an increase in airway responsiveness.
Finally, in some subjects, there is a further progression of the
inflammatory changes towards airway remodelling (c). The remodelling
changes can lead to permanent alterations in the airway architecture
such that obstructive events are irreversible. IgE, immunoglobulin E; IL-
4, interleukin 4; TH1, T helper 1 cells; TNF-, tumour necrosis factor .

Possible relationships between respiratory syncytial virus
infection, wheezing in infancy, and asthma
Respiratory syncytial virus (RSV) bronchiolitis is associated with an increased risk of
recurrent wheezing and asthma in childhood, but the nature of this association has not yet
been clearly defined. It is possible that this is a causal relationship, and that RSV
bronchiolitis alters immune responses or lung development to promote allergy or asthma.
Alternately, RSV infection could be an early stimulus for wheezing in children who have a
predisposition for allergies and asthma. These possibilities are not mutually exclusive, and
are currently under investigation in longitudinal clinical studies.

The 'hygiene hypothesis'
According to this theory, the immune
system at birth is immature and is skewed
towards T helper (TH) 2-like cytokine
production. Certain stimuli, such as
infections with helminths or viruses
(contracted from siblings or peers in day
care centres), can help immunological
development towards a healthy balance of
TH1 and TH2-like cytokine responses. In
the absence of these stimuli (that is,
children who do not have contact with
other children, or who live in relatively
'sterile' urban environments), the
immature TH2-like pattern of cytokine
production persists, leading to an
increased risk of asthma and other atopic
diseases. LPS, lipopolysaccharide.

Mechanisms of virus-induced airway inflammation
Viral replication in airway epithelial cells
induces the secretion of chemokines
such as interleukin (IL)-8 and RANTES
(regulated on activation, normal T cell
expressed and secreted); (CCL5), which
recruit mononuclear cells and
neutrophils into the airway. The
recruited leukocytes, together with pre-
existing eosinophils in allergic airways,
contribute to the inflammatory milieu
through the secretion of additional
cytokines and mediators. Epithelial cells
that are damaged by viral infection or
airway inflammation are shed and,
together with transudated plasma
proteins and secreted mucus,
contribute to airway obstruction. IFN-,
interferon ; TNF-, tumour necrosis factor

Susceptibility genes for asthma and asthma-related traits
Summary of the genes that were found to be associated with asthma and/or asthma-
related phenotypes in at least five independent reports of candidate-gene association or
positional-cloning studies (these are underlined). Genes were identified by searching the
public databases using the keyword 'association' together with each of the following
terms: asthma, bronchial hyper-responsiveness, atopic dermatitis or IgE. Genes are
ordered by their chromosomal location. Selected gene variants commonly associated with
relevant phenotypes are shown. The information is updated to December 2007.
References for studies published before 2006 are listed in Ref. 4. The references for the
studies published in 2006 and 2007 are provided as Supplementary information S1 (table).
ACE, angiotensin I converting enzyme 1 (also known as peptidyl-dipeptidase A); ADAM33,
a disintegrin and metalloproteinase domain 33; ADRB2, 2 adrenergic receptor; CC16, Clara
cell-specific 16 kD protein (also known as SCGB1A1); CCL11, CC-chemokine ligand 11 (also
known as eotaxin-1); CCL5, CC-chemokine ligand 5 (also known as RANTES); CD14,
monocyte differentiation antigen 14; CMA1, chymase 1, mast cell; CTLA4, cytytoxic T-
lymphocyte antigen 4; FCERIB, high-affinity Fc receptor for IgE -chain; FLG, filaggrin; GPRA,
G-protein-coupled receptor for asthma susceptibility (also known as NPSR1, and
GPRA154); GSTM1, glutathione S-transferase M1; GSTP1, glutathione S-transferase P1;
GSTT1: glutathione S-transferase T1; HAVCR1, hepatitis A virus cellular receptor 1 (also
known as TIM1); IL, interleukin; IL4R, interleukin-4 receptor (-chain); LTA, lymphotoxin-
(also known as TNF); LTC4S, leukotriene C4 synthase; NAT2, N-acetyltransferase 2; NOS1,
nitric oxide synthase 1 (neuronal); SPINK5, serine protease inhibitor, Kazal-type, 5; STAT6,
signal transducer and activator of transcription 6; TBXA2R, thromboxane A2 receptor;
TGFB1, transforming growth factor-1; TNF, tumour necrosis factor.

Phases of asthmatic responses
Asthma can be divided into two distinct
phases. The early phase occurs quite rapidly on
exposure to allergen, inducing mast cell
degranulation, which causes mediator release
and subsequent changes in airway function.
Mediators released during the early phase and
allergen-specific immune responses cause
subsequent progression into the late-phase
response. The late-phase response is often
more severe and is characterized by the
accumulation of mononuclear cells
(monocytes and lymphocytes) as well as
eosinophils. The cell populations that
accumulate during the late-phase response are
associated with prolonged airway dysfunction
and damage. IgE, immunoglobulin E.

Chemokine-induced migration of eosinophils in lungs
Eosinophil migration from the vascular supply
to the airway is probably dependent on
sequential chemokine gradients, which allow
the cells to extravasate through the various
compartments of the lung. There are several
eosinophil-active chemokines that are
produced primarily by activated macrophages
in the interstitium. These include macrophage
inflammatory protein-1 (MIP-1)/CCL3,
monocyte chemoattractant protein 3 (MCP-
3)/CCL7 and macrophage-derived chemokine
(MDC)/CCL22. Other chemokines, such as
eotaxin/CCL11 and RANTES (regulated on
activation, normal T-cell expressed and
secreted)/CCL5, are highly expressed in
epithelial cells of the airway. The localized
responses of these particular chemokines
would allow the eosinophils to migrate to the
airway using different chemokine receptors,
therefore avoiding desensitization of migratory

TH2 cytokine-induced responses
The T helper (TH) type 2 cytokines interleukin
(IL)-4 and IL-13 induce the production of
specific chemokines through STAT6 signal-
activated pathways. This group of chemokines,
which includes macrophage-derived
chemokine (MDC)/CCL22, T-cell activation 3
(TCA3)/CCL1 and eotaxin/CCL11, induces
migration of TH2 lymphocytes through specific
receptors (CCR4, CCR8 and CCR3, respectively).
Some of these chemokines, for example,
eotaxin, have also been shown to be potent
eosinophil chemoattractants. The continued
activation of these cell populations promotes
the chronic pathophysiological dysfunction
observed during asthma, including mucous
production, peribronchial thickening and
fibrosis. These pathways might be initiated and
maintained through chronic allergen exposure.

Differential expression of CCRs on TH subsets
The expression of chemokine receptors on T
helper (TH) lymphocytes seems to be related
to the differentiation state of cells. Naive cells
express CCR7 and CxCR4, two receptors that
participate in entry of the lymph node through
the high endothelial venule (HEV). Short-term
or newly activated cells seem to maintain CCR7
expression, but also express CCR5 and CxCR3.
Continued antigenic (Ag) stimulation in vitro in
the presence of TH type 1- (IL-12) or TH type 2-
(IL-4) cytokines significantly alters the
chemokine receptor patterns. CCR7, the HEV-
related receptor, is downregulated and the
differential expression of CCR5 and CxCR3 on
TH1-type cells and CCR3, CCR4, CCR8 and
CxCR4 on TH 2-type cells are induced.
Although the in vivo relevance of these
preferential patterns is unknown, these in vitro
analyses allow a better understanding of
chemokine receptor regulation in specific
cytokine environments.

Chemokines and their receptors
Standardized nomenclature for chemokines and their receptors
Present prospective chemokine targets in asthma
Direct and indirect effects of LIGHT signaling in chronic asthma
Doherty et al.4 show that the TNF family
member LIGHT, which is expressed by
activated B and T lymphocytes, can bind and
signal through HVEM or LTR, which is
expressed on many cell types. Effects of LIGHT
during chronic asthma may result from its
direct interactions with fibroblasts, smooth
muscle cells (SMCs) and epithelial cells. The
effects of LIGHT on these cells may also be
amplified indirectly via TGF- and IL-13, which
are induced in macrophages and eosinophils,
respectively, thereby facilitating subepithelial
fibrosis, smooth muscle hypertrophy and
hyperplasia, epithelial-mesenchymal transition
(EMT) and airway hyper-reactivity.