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Immunology of asthma and chronic

obstructive pulmonary disease
Peter J.Barnes
Abstract | Asthma and chronic obstructive pulmonary disease (COPD) are both obstructive
airway diseases that involve chronic inflammation of the respiratory tract, but the type of
inflammation is markedly different between these diseases, with different patterns
of inflammatory cells and mediators being involved. As described in this Review, these
inflammatory profiles are largely determined by the involvement of different immune cells,
which orchestrate the recruitment and activation of inflammatory cells that drive the
distinct patterns of structural changes in these diseases. However, it is now becoming clear
that the distinction between these diseases becomes blurred in patients with severe
asthma, in asthmatic subjects who smoke and during acute exacerbations. This has
important implications for the development of new therapies.

Chronic obstructive
pulmonary disease
(COPD). A group of diseases
characterized by the
pathological limitation of
airflow in the airway, including
chronic obstructive bronchitis
and emphysema. It is most
often caused by tobacco
smoking, but can also be
caused by other airborne
irritants, such as coal dust, and
occasionally by genetic
abnormalities, such as
1-antitrypsin deficiency.
Atopic (extrinsic) asthma
The commonest form of
asthma in which the patients
are atopic (as indicated by a
positive skin-prick test and the
presence of IgE to common
inhalant allergens, such as
house-dust mites) and have
allergic inflammation of the
airways.
Airway Disease Section,
National Heart and Lung
Institute, Imperial College
London, Dovehouse Street,
London SW3 6LY, UK.
e-mail:
p.j.barnes@imperial.ac.uk
doi:10.1038/nri2254
Published online
15 February 2008
Asthma and chronic obstructive pulmonary disease
(COPD) are both very common and their incidence
is increasing globally, placing an increasing burden
on health services in industrialized and developing
countries13. Both diseases are characterized by airway
obstruction, which is variable and reversible in asthma
but is progressive and largely irreversible in COPD.
In both diseases, there is chronic inflammation of the
respiratory tract, which is mediated by the increased
expression of multiple inflammatory proteins, including
cytokines, chemokines, adhesion molecules, inflamma-
tory enzymes and receptors. In both diseases there are
acute episodes or exacerbations, when the intensity of
this inflammation increases. The similarity between
these airway diseases prompted the suggestion in the
1960s that asthma and COPD are different forms of
a common disease (chronic obstructive lung disease),
and this came to be known as the Dutch hypothesis.
This was countered by the British hypothesis, which
maintained that these diseases were separate entities;
the debate continues today, with evidence both for and
against these two views4,5.
Despite the similarity of some clinical features of
asthma and COPD, there are marked differences in the
pattern of inflammation that occurs in the respiratory
tract, with different inflammatory cells recruited, dif-
ferent mediators produced, distinct consequences of
inflammation and differing responses to therapy. In
addition, the inflammation seen in asthma is mainly
located in the larger conducting airways, and although
small airways can also be affected in more severe forms
of the disease, the lung parenchyma is not affected. By
contrast, COPD predominantly affects the small airways
and the lung parenchyma, although similar inflamma-
tory changes can also be found in larger airways6,7. These
differences in disease distribution may partly reflect the
distribution of inhaled inciting agents, such as allergens
in asthma and tobacco smoke in COPD. In both dis-
eases, there are different clinical phenotypes recognized.
Most patients with asthma are atopic (extrinsic asthma),
but a few patients are non-atopic (intrinsic asthma), and
these patients often have a more severe form of the dis-
ease8. There is a range of asthma severity, which tends
to be maintained throughout life9. Approximately 5%
of patients have severe asthma that is difficult to con-
trol with maximal inhaler therapy and for whom new
therapeutic approaches are needed. The main types of
COPD are the development of small-airway obstruction
and emphysema, which can occur alone or together, but
which both involve progressive airflow limitation and
are usually caused by tobacco smoke.
The differences in inflammation between asthma
and COPD are linked to differences in the immuno-
logical mechanisms that underlie these two diseases
(FIGS1,2). There have been several recent important
advances in our understanding of the immunopathol-
ogy of asthma and COPD, and these are discussed in
this Review. Tcells have a crucial role in both asthma
and COPD and it is now recognized that different sub-
sets are involved in orchestrating inflammation in these
two diseases, resulting in different inflammatory and
structural consequences. Bcells also have an important

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REVIEWS

Inhaled allergens at the airway surface and activated Tcells. There are
characteristic structural changes, with collagen deposi-
tion under the epithelium that is sometimes described
as basement-membrane thickening and is found in
Epithelial cells all patients with asthma, and thickening of the airway
CCL11 smooth-muscle cell layer as a result of hyperplasia and
hypertrophy, which is more commonly seen in patients
SCF
with severe asthma14. Epithelial cells are often shed from
Mast cell
asthmatic patient biopsies compared to normal control
TSLP biopsies, as they are friable and more easily detach from
the basement membrane during the biopsy procedure.
Histamine, cysteinyl Dendritic
leukotrienes and
CCL17 and
cell In addition, there is an increase in the number of blood
IL-9 CCL22
prostaglandin D2 vessels (angiogenesis) in response to increased secre-
CCR4 tion of vascular-endothelial growth factor (VEGF)15.
Smooth-muscle Mucus hyperplasia is commonly seen in biopsies from
cell IgE asthmatic patients, with an increase in the number of
mucus-secreting goblet cells in the epithelium and an
TH2 cell TReg cells?
Bronchoconstriction increase in the size of submucosal glands16.
IL-13
Antibody IL-5 In biopsies of the bronchial airways, small airways and
production IL-4
lung parenchyma from patients with COPD, there is no
CCR3 evidence for mast-cell activation, but there is an infiltra-
Eosinophil tion of Tcells and increased numbers of neutrophils,
particularly in the airway lumen17. Subepithelial fibrosis
B cell Eosinophilic inflammation is not apparent, but fibrosis does occur around small air-
Figure 1 | Inflammatory and immune cells involved in asthma. Inhaled allergens ways and is thought to be a main factor that contributes
activate sensitized mast cells by crosslinking surface-bound IgE molecules to the irreversible airway narrowing that is characteristic
Nature Reviewsto| Immunology
release
several bronchoconstrictor mediators, including cysteinyl leukotrienes and of this disease18. The airway smooth-muscle cell layer is
prostaglandin D2. Epithelial cells release stem-cell factor (SCF), which is important for not usually increased in COPD patients compared with
maintaining mucosal mast cells at the airway surface. Allergens are processed by myeloid normal airways, and airway epithelial cells may show
dendritic cells, which are conditioned by thymic stromal lymphopoietin (TSLP) secreted pseudostratification as a result of chronic irritation from
by epithelial cells and mast cells to release the chemokines CCchemokine ligand 17 inhaled cigarette smoke or other irritants and the release
(CCL17) and CCL22, which act on CCchemokine receptor 4 (CCR4) to attract T helper 2
of epithelial-cell growth factors. As in biopsies from
(TH2) cells. TH2 cells have a central role in orchestrating the inflammatory response in
allergy through the release of interleukin4 (IL4) and IL13 (which stimulate Bcells to
asthma patients, there is mucus hyperplasia and increased
synthesize IgE), IL5 (which is necessary for eosinophilic inflammation) and IL9 (which expression of mucin genes in biopsies from patients
stimulates mast-cell proliferation). Epithelial cells release CCL11, which recruits with COPD19. A marked difference between COPD and
eosinophils via CCR3. Patients with asthma may have a defect in regulatory T(TReg) cells, asthma is the destruction of alveolar walls (emphysema)
which may favour further TH2-cell proliferation. that occurs in COPD as a result of protease-mediated
degradation of connective tissue elements, particularly
elastin, and apoptosis of typeI pneumocytes and pos-
role, although this remains poorly understood in COPD. sibly endothelial cells20,21. In addition, the production
The appreciation that similar immune mechanisms are of elastolytic enzymes, such as neutrophil elastase and
involved in both asthma and COPD has important particularly several matrix metalloproteinases (MMPs),
implications for the development of new therapies for is increased in the lungs of COPD patients22, and there
these troublesome diseases. may be a reduction in the levels of antiproteinases, such
as 1-antitrypsin, as seen in a rare form of emphysema
Non-atopic (intrinsic)
asthma Inflammatory cells and mediators caused by a congenital deficiency of 1-antitrypsin23.
An uncommon form of asthma There are many differences between mild asthma and
that is more likely to be severe COPD in the type of inflammation that occurs in the lungs, Mast cells. Mast cells have a key role in asthma through
and characterized by negative with a different range of inflammatory cells and mediators the release of several bronchoconstrictors, including
skin-prick tests. The airway
inflammation is similar to that
being implicated10,11. However, many of the cytokines and histamine, which is preformed and stored in granules,
of atopic asthma and may be chemokines that are secreted in both asthma and COPD and the lipid mediators leukotriene C4, leukotriene D4,
mediated by local rather than are regulated by the transcription factor nuclear factor-B leukotriene E4 and prostaglandin D2, which are synthe-
systemic IgE production. (NF-B), which is activated in airway epithelial cells and sized following mast-cell activation. The release of these
macrophages in both diseases, and may have an important mediators may account for the variable bronchocon-
Emphysema
Destruction of the alveolar role in amplifying airway inflammation12,13. striction seen in asthma, as these mediators are released
walls, resulting in decreased by various environmental triggers, such as allergens, and
gas exchange and contributing Histopathology. The histological appearance of airways an increase in plasma osmolality as a result of increased
to airflow limitation by loss of from asthmatic individuals is very different from the ventilation during exercise. Mucosal mast cells are
alveolar attachments to the
small airways that serve to
changes that are observed in patients with COPD (FIG.3). recruited to the surface of the airways by stem-cell factor
keep the airways open during Bronchial biopsies from asthmatic subjects reveal an (SCF; also known as KIT ligand) released from epithelial
expiration. infiltration of eosinophils, activated mucosal mast cells cells, which acts on KIT receptors expressed by the

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Pseudostratification
Increased proliferation of
airway epithelial cells in chronic
obstructive pulmonary disease,
as a result of the release of
epithelial-cell growth factors,
which lead to increased
thickness of the epithelial-cell
layer.
TypeI pneumocytes
Flat alveolar cells that make up
most of the epithelial-cell layer
of the alveolar wall and that are
responsible for gas exchange in
the alveoli.
Bronchoconstrictor
An agent that induces
contraction of airway smooth
muscle and thereby narrows
the airways, thus reducing the
flow of air.
Epithelial cells
TGF
Fibroblast TH1 cell
mast cells24. Mast cells also release cytokines that are
linked to allergic inflammation, including interleukin4
(IL4), IL5 and IL13 (Ref.25). The presence of mast
cells in the airway smooth muscle has been linked to
airway hyper-responsiveness in asthma26, as patients with
eosinophilic bronchitis have a similar degree of eosino
philic inflammation to that found in asthmatics and
also have subepithelial fibrosis, but they do not show
airway hyper-responsiveness, which is the physiological
hallmark of asthma. By contrast, mast cells do not seem
to have a role in COPD, which may explain the lack of
variable bronchoconstriction in this disease.
Granulocytes. The inflammation that occurs in asthma is
often described as eosinophilic, whereas that occurring
in COPD is described as neutrophilic. These differences
reflect the secretion of different chemotactic factors in
these diseases. In asthma, eosinophil chemotactic factors,
such as CCchemokine ligand 11 (CCL11; also known
as eotaxin1) and related CCchemokines, are mainly
secreted by airway epithelial cells. The functional role of
Cigarette smoke
(and other irritants)
CXCL9, CXCL10 Macrophage
and CXCL11
CCL2
CXCL1
and CXCL8
CXCR2
CXCR3
TC1 cell Neutrophil Monocyte
eosinophils in asthma is not clear and the evidence that
links their presence to airway hyper-responsiveness has
been questioned by the finding that the administration of
IL5-specific blocking antibodies that markedly reduce
the number of eosinophils in the blood and sputum
does not reduce airway hyper-responsiveness or asthma
symptoms27,28. As discussed above, eosinophilic bronchi-
tis is not associated with airway hyper-responsiveness,
but subepithelial fibrosis does occur, which suggests a
role for eosinophils in airway fibrosis. Interestingly, the
presence of eosinophils seems to be a good marker of
steroid responsiveness29.
Neutrophils are increased in the sputum of patients
with COPD and this correlates with disease severity30.
The increase in neutrophils is related to an increase
in the production of CXC-chemokines, such as CXC-
chemokine ligand 1 (CXCL1; also known as GRO) and
CXCL8 (also known as IL8), which act on CXCR2 that
is expressed predominantly by neutrophils.
Macrophages. Macrophage numbers are increased in the
lungs of patients with asthma and COPD, but their num-
bers are far greater in COPD than in asthma. These mac-
rophages are derived from circulating monocytes, which
migrate to the lungs in response to chemoattractants such
as CCL2 (also known as MCP1) acting on CCR2, and
CXCL1 acting on CXCR2 (Ref.31). There is increasing
evidence that lung macrophages orchestrate the inflam-
mation of COPD through the release of chemokines that
attract neutrophils, monocytes and Tcells and the release
of proteases, particularly MMP9 (Ref.32).
The pattern of inflammatory cells found in the res-
CCR2 piratory tract therefore differs in patients with asthma
and those with COPD and some of these contrasts
may be explained by differences in the immunological
mechanisms that drive these two diseases.

Proteases (such as neutrophil

elastase and MMP9)
Smooth- Alveoli
muscle Goblet
cell
cell
Fibrosis Alveolar wall destruction
(small airways) (emphysema)
Figure 2 | Inflammatory and immune cells involved in chronic obstructive
pulmonary disease (COPD). Inhaled cigarette smoke and other Natureirritants
Reviewsactivate
| Immunology
epithelial cells and macrophages to release several chemotactic factors that attract
inflammatory cells to the lungs, including CCchemokine ligand 2 (CCL2), which acts on
CCchemokine receptor 2 (CCR2) to attract monocytes, CXC-chemokine ligand 1
(CXCL1) and CXCL8, which act on CCR2 to attract neutrophils and monocytes (which
differentiate into macrophages in the lungs) and CXCL9, CXCL10 and CXCL11, which act
on CXCR3 to attract T helper 1 (TH1) cells and type1 cytotoxic T(TC1) cells. These
inflammatory cells together with macrophages and epithelial cells release proteases,
such as matrix metalloproteinase 9 (MMP9), which cause elastin degradation and
emphysema. Neutrophil elastase also causes mucus hypersecretion. Epithelial cells and
macrophages also release transforming growth factor (TGF), which stimulates
fibroblast proliferation, resulting in fibrosis in the small airways.
Immune responses
Airway
epithelial The immune mechanisms that drive the different inflam-
cell matory processes of asthma and COPD are mediated by
different types of immune cell, in particular by different
Mucus Tcell subsets. An understanding of which immune cells
are involved is now emerging and may lead to the devel-
opment of new and more-specific therapies for airway
diseases in the future (FIGS1,2).
Mucus gland
Tcells. In asthmatic patients, there is an increase in the
Mucus number of CD4+ Tcells in the airways and these are pre-
hypersecretion
dominantly T helper 2 (TH2) cells, whereas in normal air-
ways TH1 cells predominate33. By secreting the cytokines
IL4 and IL13, which drive IgE production by Bcells,
IL5, which is solely responsible for eosinophil differen-
tiation in the bone marrow, and IL9, which attracts and
drives the differentiation of mast cells34, TH2 cells have a
central role in allergic inflammation and therefore their
regulation is an area of intense research.
The transcription factor GATA3 (GATA-binding pro-
tein 3) is crucial for the differentiation of uncommitted
naive Tcells into TH2 cells and it also regulates the secre-
tion of TH2-type cytokines35,36. Accordingly, there is an
increase in the number of GATA3+ Tcells in the airways

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Airway hyper-
responsiveness
Increased narrowing of the
airways, initiated by exposure
to a defined stimulus that
usually has little or no effect
on airway function in normal
individuals. This is a defining
physiological characteristic of
asthma.
TH2 cells
(T helper 2 cells). The definition
of a CD4+ Tcell that has
differentiated into a cell that
produces the cytokines
interleukin4 (IL4), IL5 and
IL13, thereby supporting
humoral immunity and
counteracting TH1-cell
responses. An imbalance of
TH1TH2-cell responses is
thought to contribute to the
pathogenesis of various
infections, allergic responses
and autoimmune diseases.
TH1 cells
(T helper 1 cells). The definition
of a CD4+ Tcell that has
differentiated into a cell that
produces the cytokines
interferon and tumour-
necrosis factor, thereby
promoting cell-mediated
immunity.
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Asthma COPD
Inflammation
Airway smooth muscle
Basement membrane
Fibrosis
Alveolar disruption
Inflammation +++ +++
Airway smooth muscle +++ +
Basement membrane ++
Fibrosis + (subepithelial) +++ (peribronchiolar)
Alveolar disruption +++
Airway vessels ++ No change
Mast cells ++ (and activated) Normal
Dendritic cells ++ ND
Eosinophils ++ Normal
Neutrophils Normal ++
Lymphocytes TH2 type TH1 and TC1 type
Epithelium Often shed Pseudostratified
Goblet cells ++ ++
Figure 3 | Contrasting histopathology of asthma and chronic obstructive pulmonary disease (COPD). A small airway
from a patient who died from asthma and a similar sized airway from a patient with severe COPD are shown. There is an
Nature Reviews | Immunology
infiltration of inflammatory cells in both diseases. The airway smooth-muscle cell layer is thickened in asthma but only to
a minimal degree in COPD. The basement membrane is thickened in asthma due to collagen deposition (subepithelial
fibrosis) but not in COPD, whereas in COPD collagen is deposited mainly around the airway (peribronchiolar fibrosis). The
alveolar attachments are intact in asthma, but disrupted in COPD as a result of emphysema. Images courtesy of Dr J. Hogg
(Vancouver, Canada). Other differences in the cellular infiltrate in the two diseases are also shown. ND, not determined;
TC1, type 1 cytotoxic T; TH1, T helper 1.
of asthmatic subjects compared with normal subjects37,38. TH1-type cytokines, which then act to further inhibit
Following simultaneous ligation of the Tcell receptor GATA3 expression42. In turn, GATA3 inhibits the pro-
(TCR) and co-receptor CD28 by antigen-presenting duction of TH1-type cytokines by inhibiting STAT4, the
cells, Tcell GATA3 is phosphorylated and activated key transcription factor activated by the Tbet-inducing
by the mitogen-activated protein kinase (MAPK) p38. cytokine IL12 (Ref.43) (FIG.4). Nuclear factor of activated
Activated GATA3 then translocates from the cytoplasm Tcells (NFAT) is a Tcell-specific transcription factor
to the nucleus, where it activates gene transcription39. and appears to enhance the transcriptional activation of
GATA3 expression in Tcells is regulated by the tran- GATA3 by targeting the IL4 promoter44. Finally, IL33, a
scription factor STAT6 (signal transducer and activator newly discovered member of the IL1 family of cytokines,
of transcription 6), which is in turn regulated by IL4 seems to promote TH2-cell differentiation by translocat-
receptor activation. ing to the nucleus and regulating transcription through
For TH1-cell differentiation and secretion of the TH1- an effect on chromatin structure45, but it also acts as a
type cytokine interferon (IFN), the crucial transcrip- selective chemoattractant of TH2 cells by binding the sur-
tion factor is Tbet. Consistent with the prominent role face receptor IL1-receptor-like 1 (also known as ST2),
of TH2 cells in asthma, Tbet expression is reduced in which is specifically expressed by these cells46.
Tcells from the airways of asthmatic patients compared In contrast to asthma, the CD4+ Tcells that accumu-
with non-asthmatic subjects40. When phosphorylated, late in the airways and lungs of patients with COPD are
Tbet can associate with and inhibit the function of mainly TH1 cells. TH1 cells express the chemokine recep-
GATA3, by preventing it from binding to its DNA target tor CXCR3 (Ref.47) and may be attracted to the lungs by
sequences41. Tbet-deficient mice show increased expres- the IFN-induced release of the CXCR3 ligands CXCL9
sion of GATA3 and production of TH2-type cytokines, (also known as MIG), CXCL10 (also known as IP10)
confirming that Tbet is an important regulator of and CXCL12 (also known as ITAC), which are present
GATA3 (Ref.40). GATA3 expression is also regulated by at high levels in COPD airways48,49. However, there is
IL27, a recently identified member of the IL12 family, some evidence that TH2 cells are also increased in lavage
which downregulates GATA3 expression and upregu- fluid of patients with COPD50; likewise, in patients with
lates Tbet expression, thereby favouring the production more severe asthma, TH1 cells are activated, as well as
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Regulatory Tcells
A specialized type of CD4+
Tcells that can suppress the
responses of other Tcells.
These cells provide a crucial
mechanism for the
maintenance of peripheral self-
tolerance and a subset of these
cells is characterized by
expression of CD25 and the
transcription factor forkhead
box P3 (FOXP3).
Allergic rhinitis
Allergic inflammation that is
caused by the pollen of specific
seasonal plants, such as
grasses (causing hay fever), and
house dust (causing perennial
rhinitis) in people who are
allergic to these substances. It
is characterized by sneezing,
and a runny and blocked nose.
TH17 cells
(T helper 17 cells). A subset of
CD4+ T helper cells that
produce interleukin17 (IL17)
and that are thought to be
important in inflammatory and
autoimmune diseases. Their
generation involves IL23 and
IL21, as well as the
transcription factors RORt
(retinoic-acid-receptor-related
orphan receptor-t) and STAT3
(signal transducer and activator
of transcription 3).
Invariant natural killer T
(iNKT)cells
Lymphocytes that express
a particular variable gene
segment, V14 (in mice) and
V24 (in humans), precisely
rearranged to a particular J
(joining) gene segment to yield
Tcell receptor -chains with an
invariant sequence. Typically,
these cells co-express cell-
surface markers that are
encoded by the natural killer
(NK) locus, and they are
activated by recognition of
CD1d, particularly when
galactosylceramide is bound
in the groove of CD1d.
Type 1 cytotoxic T (TC1) and
TC2 cells
A designation that is used to
describe subsets of CD8+
cytotoxic Tcells. TC1 cells
typically secrete interferon
and granulocyte/macrophage
colony-stimulating factor, and
have strong cytotoxic capacity,
whereas TC2 cells secrete
interleukin4 (IL4) and IL10 CXCR3 ligands suppress signalling through CCR3, the
and are less effective killers.
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TH2 cells51, making the distinction between the THcell
patterns in these two diseases less clear. (also known as RANTES), which attracts CD4+ and CD8+
Other subtypes of CD4+ Tcells that may have an
important role in airway diseases are regulatory Tcells,
which have a suppressive effect on other CD4+ Tcells
and may have a role in regulating TH2-cell function
in asthma33,52. There is evidence that the numbers of
CD4+CD25+ regulatory Tcells that express the tran-
scription factor forkhead box P3 (FOXP3) are reduced
in individuals with allergic rhinitis (hay fever) compared
with non-atopic individuals, and this may be important
in enabling high numbers of TH2 cells to develop in aller-
gic disease53. However, by contrast, asthmatic patients
seem to have an increase in FOXP3-expressing regula-
tory Tcells compared with patients with mild asthma,
at least among circulating cells54. Analysis of sputum
from COPD patients suggests that the numbers of
CD4+CD25+FOXP3+ regulatory Tcells are reduced, but
similar changes are also seen in people who smoke but do
not have airflow obstruction55. So, the role of regulatory
Tcells in asthma and COPD remains unclear and fur-
ther research is therefore needed, particularly in defining
the role of different types of regulatory Tcells56.
Another subset of CD4+ Tcells, known as TH17 cells,
has recently been described and shown to have an
important role in inflammatory and autoimmune dis-
eases57,58. Little is known about the role of TH17 cells in
asthma or COPD, but increased concentrations of IL17
(the predominant product of T H17 cells) have been
reported in the sputum of asthma patients59. IL17 and
the closely related cytokine IL17F have been linked to
neutrophilic inflammation by inducing the release of
CXCL1 and CXCL8 from airway epithelial cells60 (FIG.5).
As well as IL17, TH17 cells also produce IL21, which
is important for the differentiation of these cells and
thus acts as a positive autoregulatory mechanism, but
it also inhibits FOXP3 expression and regulatory Tcell
development61,62. Another cytokine IL22 is also released
by these cells and stimulates the production of IL10 and
acute-phase proteins63. However, more work is needed
to understand the role and regulation of TH17 cells in
asthma and COPD, as they may represent important
new targets for future therapies.
A subset of CD4+ Tcells termed invariant natural killer T
(iNKT) cells, which secrete IL4 and IL13, has been shown
to account for 60% of all CD4+ Tcells in bronchial biop-
sies from asthmatic patients64, but this has been disputed
in another study that failed to show any increase in iNKT-
cell numbers in bronchial biopsies, bronchoalveolar lavage
or sputum of either asthma or COPD patients65. The role
of iNKTcells in asthma is currently uncertain as there
appears to be a discrepancy between the data from murine
models of asthma and humans with the disease33.
CD8+ Tcells predominate over CD4+ Tcells in the
airways and lung parenchyma of patients with COPD66,
but their role in disease pathogenesis is not yet certain.
Type1 cytotoxic T (TC1) cells, which secrete IFN, predomi-
nate and express CXCR3, suggesting that they are attracted
to the lungs by CXCR3-binding chemokines47,49. These
via STAT1. This demonstrates the complex interplay of
receptor for CCL11, suggesting that they might suppress
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eosinophilic inflammation67. The production of CCL5
Tcells via CCR5, is also increased in the sputum of COPD
patients compared with controls and may also be involved
in Tcell recruitment49. TC1 cells release granzyme B and
perforins, which are also present at higher levels in the
sputum of COPD patients than normal control subjects
who also smoke68, and may induce apoptosis of type1
pneumocytes, thereby contributing to the development of
emphysema20. TC1- and TH1-cell-driven inflammation is
likely to be self-perpetuating as IFN stimulates the release
of CXCR3 ligands, which then attract more TH1 and TC1
cells into the lungs (FIG.6). TC2 cells, which secrete IL4,
have also been described in COPD50. In asthma, CD8+
Tcells are present in patients with more severe disease
and irreversible airflow obstruction69 and these cells may
be of either the TC1 or TC2 type70.
Bcells. Bcells have an important role in allergic diseases,
including asthma, through the release of allergen-specific
IgE which binds to high-affinity Fc receptors for IgE
(FcRI) expressed by mast cells and basophils, and to
low-affinity Fc receptors for IgE (FcRII) expressed by
other inflammatory cells, including Bcells, macrophages
and possibly eosinophils71. The TH2-type cytokines IL4
and IL13 induce Bcells to undergo immunoglobulin class
switching to produce IgE. Blocking IgE with the mono-
clonal antibody omalizumab reduces the response to
allergens, airway inflammation and asthma exacerba-
tions, indicating that IgE drives allergic inflammation in
asthma72. In both atopic asthma and non-atopic asthma,
IgE may be produced locally by Bcells in the airways73.
Interestingly, IgE secretion is not observed in patients
with COPD, but in the peripheral airways of patients
with more severe disease there is a marked increase in
the number of Bcells, which are organized into lym-
phoid follicles that are surrounded by Tcells18. The
class of immunoglobulin they secrete and how they
IL-27 IL-12 IL-4 IL-33
STAT1 STAT4 STAT6
TH1 cells T-bet GATA3 TH2 cells
TH1-type cytokines TH2-type cytokines
(IL-2 and IFN) (IL-4, IL-5, IL-9 and IL-13)
Allergic inflammation
Figure 4 | Interactions between TH1 and TH2 cells in
asthma. The transcription factor GATA3 (GATA-binding
Nature Reviews
protein 3) is regulated by interleukin4 | Immunology
(IL4) via STAT6
(signal transducer and activator of transcription 6) and
regulates the expression of IL4, IL5, IL9 and IL13 from
Thelper 2 (TH2) cells and also inhibits the expression of
Tbet via inhibition of STAT4. IL33 enhances the actions of
GATA3. Tbet regulates T helper 1 (TH1)-cell secretion of IL2
and interferon (IFN) and also has an inhibitory action on
GATA3. Tbet is regulated by IL12 via STAT4 and by IL27
cytokines and transcription factors in asthma.
REVIEWS
Immunoglobulin class
switching
The somatic-recombination
process by which the class of
immunoglobulin expressed by
activated Bcells is switched
from IgM to IgG, IgA or IgE.
Corticosteroids
Anti-inflammatory drugs that
are derived from cortisol
secreted by the adrenal cortex
and that are effective in
suppressing inflammation
in asthma but not in chronic
obstructive pulmonary disease.
FEV1
(Forced expiratory volume in
1 second). The amount of air
that can be forcibly exhaled in
1 second, measured in litres.
It is used as a measurement of
airway obstruction in asthma
and chronic obstructive
pulmonary disease.
188 | march 2008 | volume 8 www.nature.com/reviews/immunol
IL-6
IL-23
TGF
?
ROR t
TH17 cell
STAT3
TNF
IL-22
IL-17 and
IL-6 IL-17F
CD8+ T cell
CXCL1 and IL-10
CXCL8 Epithelial cells Acute-phase
Neutrophils proteins
Figure 5 | TH17 cells and airway inflammation. T helper17
(TH17) cells are a newly described subset of CD4+ Tcells
that may have a role in chronic obstructive pulmonary
Nature Reviews | Immunology
disease (COPD) and severe asthma. These cells release
interleukin17 (IL17) and IL17F, which act on airway
epithelial cells to release CXC-chemokine ligand 1 (CXCL1)
and CXCL8, which attract neutrophils, and IL6, which
enhances the activation of TH17 cells. TH17 cells also release
IL21, which promotes TH17-cell differentiation via a
positive autoregulatory loop involving the transcription
factor STAT3 (signal transducer and activator of
transcription 3) and IL22, which induces the release of
IL10 and acute-phase proteins. The regulation of TH17 cells
is predominantly via IL23 through the activation of the
transcription factor retinoic-acid-receptor-related orphan
receptor-t (RORt), whereas transforming growth factor
(TGF) may have an inhibitory effect in human cells.
TNF, tumour-necrosis factor.
are regulated is currently unknown, but they might be
activated by bacterial or viral antigens as a consequence
of the chronic bacterial colonization or latent viral infec-
tion in the airways of these patients. Alternatively, it has
been suggested that COPD might have an autoimmune
component characterized by the development of new
antigenic epitopes as a result of the tissue damage induced
by cigarette smoking, oxidative stress or chronic bacte-
rial infection21,74. CD4+ Tcells isolated from the lungs of
patients with severe emphysema are oligoclonal, which is
consistent with antigenic stimulation by infective organ-
isms or autoimmunity75. Indeed, in a mouse model of
emphysema induced by tobacco smoke, an autoimmune
mechanism has been proposed with a role for antibodies
specific for neutrophil elastase76.
Dendritic cells. Dendritic cells (DCs) have an impor-
tant role in asthma as regulators of T H2 cells and in
the presentation of processed peptides from inhaled
allergens to TH2 cells77. They are not only involved in
the initial sensitization to allergens, but also in driving
the chronic inflammatory response in the lungs, and
therefore provide a link between allergen exposure and
allergic inflammation in asthma. The cytokine thymic
stromal lymphopoietin (TSLP), which is secreted in large
amounts by epithelial cells and mast cells of asthmatic
patients78,79, might have a critical role in the maturation
2008 Nature Publishing Group
of myeloid DCs and the recruitment of TH2 cells to the
airways by inducing the release of CCL17 (also known as
TARC) and CCL22 (also known as MDC), which bind to
CCR4 that is selectively expressed by TH2 cells80.
Cigarette smoking is associated with an expansion
IL-21
of the DC population and with a marked increase in
the number of mature DCs in the airways and alveolar
walls of people who smoke81. However, the role of DCs
in COPD is currently unclear as there are no obvious
antigenic stimulants, apart from glycoprotein, which
is isolated from tobacco and known to have a powerful
immunostimulatory effect82. However, a recent electron
microscopy study has demonstrated a decrease in DCs
in the airways of patients with COPD who smoke com-
pared to smokers without airway obstruction, suggesting
that they do not have a key role in COPD83.
Similarities between asthma and COPD
Although the inflammatory and immune mechanisms of
asthma and COPD described above are markedly differ-
ent, there are several situations where they become more
similar and the distinction between asthma and COPD
becomes blurred (TABLE1).
Severe asthma. Although only about 5% of the asthmatic
population develop severe disease, such cases account for
more than half of the healthcare spending in asthma and
they are poorly controlled by currently available thera-
pies84. The inflammatory pattern that occurs in cases of
severe asthma, contrary to mild asthma, is more similar
to that which occurs in COPD, with increased numbers
of neutrophils in the sputum and increased amounts of
CXCL8 and tumour-necrosis factor85, increased oxidative
stress and a poor response to corticosteroids as is observed
in patients with COPD (TABLE1). Moreover, whereas in
mild asthma TH2 cells predominate, in more severe
asthmatic disease there is a mixture of TH1 and TH2
cells present in bronchial biopsies, as well as more CD8+
Tcells and this more closely resembles the immune-cell
infiltration seen in COPD51,69,70. The neutrophilic inflam-
mation seen in cases of severe asthma may be induced by
IL17 production by TH17 cells, which induces the release
of the neutrophilic chemokine CXCL8 from airway epi-
thelial cells59,60. A neutrophilic pattern of inflammation,
with high levels of CXCL8, is also found in the sputum
of asthmatic individuals who smoke86. Similar to patients
with severe disease or COPD, these individuals also have
a poor response to corticosteroids, even if given orally at
high doses.
Reversible COPD.Approximately 10% of patients with
COPD have a reversibility of bronchoconstriction, show-
ing greater than 12% improvement in lung function as
assessed by forced expiratory volume in 1 second (FEV1),
and therefore behave more like asthmatics. Furthermore,
compared with most patients with COPD, these patients
more frequently have eosinophils in their sputum, an
increase in exhaled nitric oxide and respond better to
corticosteroid treatment, all of which are characteristic
features of asthma87,88. It therefore seems likely that these
patients have concomitant asthma and COPD.

Theophylline
A drug that is used at high
doses as a bronchodilator in
the treatment of asthma and
chronic obstructive pulmonary
disease. However, it is now less
widely used as the high doses
can have side effects, including
nausea, headaches, cardiac
arrhythmias and seizures.
More recently, it has been
shown to have anti-
inflammatory effects at lower
doses and may reverse
corticosteroid resistance by
increasing the activity of
histone deacetylase.
Cyclosporin A and
tacrolimus
Calcineurin inhibitors that are
used to prevent transplant
rejection and that function by
inhibiting nuclear factor of
activated Tcells (NFAT).
Rapamycin
An immunosuppressive drug
that, in contrast to calcineurin
inhibitors, does not prevent
Tcell activation but blocks
interleukin2-mediated clonal
expansion by blocking mTOR
(mammalian target of
rapamycin).
Mycophenolate mofetil
An immunosuppressant that
inhibits purine synthesis and
has an inhibitory effect on
Tcells and Bcells. It is
currently used to treat
transplant rejection and
rheumatoid arthritis.
nature reviews | immunology volume 8 | march 2008 | 189
f o c u s o n a l l er g Y a n d RAs
Acute exacerbations. Acute exacerbations (worsening of
symptoms) occur in patients with asthma and COPD,
and are a major cause of patient suffering and medical
expenditure89,90. Exacerbations in asthmatic individuals
are usually triggered by upper respiratory tract infections,
such as with rhinoviruses, and less commonly by inhaled
allergens and air pollutants, whereas exacerbations in
patients with COPD are usually triggered by either bacte-
rial or viral infections. In both diseases, exacerbations are
associated with a further increase in airway inflamma-
tion, increased numbers of cells infiltrating the lungs and
higher concentrations of inflammatory mediators than are
present in the steady state. However, there may also be
changes in the pattern of inflammation. In exacerbations
of asthma triggered by viruses, there can be increases in
the numbers of neutrophils, as well as of eosinophils89,
whereas in COPD exacerbations, particularly those due to
viruses, there may be an increase in eosinophil numbers91.
So, during episodes of disease exacerbation, the pattern of
inflammation becomes similar in COPD and asthma.
Implications for therapy
In view of the different inflammatory and immune
patterns of asthma and COPD, it is not surprising that
they should respond differently to anti-inflammatory
therapies.
Corticosteroid responsiveness. Asthma is usually highly
responsive to corticosteroid therapy and inhaled cor-
ticosteroids have become the mainstay of disease
management. Corticosteroids suppress inflammation
by inducing the recruitment of the nuclear enzyme
histone deacetylase 2 (HDAC2) to multiple activated
inflammatory genes, which leads to deacetylation of the
hyperacetylated genes, thereby suppressing inflamma-
tion92. By contrast, patients with COPD respond poorly
to corticosteroid treatment, and even high doses of
inhaled or oral corticosteroids fail to suppress inflam-
mation. This appears to be related to decreased activity
and expression of HDAC2 in the inflammatory cells and
peripheral lungs of COPD patients93. This is the result of
increased oxidative and nitrative stress, which together
generate peroxynitrite that nitrates tyrosine residues
in HDAC2, impairing enzyme activity and decreasing
expression93,94. The poor response to corticosteroid treat-
ment seen in patients with severe asthma, in asthmatics
who smoke and during acute exacerbations may also
reflect a reduction in HDAC2 protein levels and func-
tion, as oxidative and nitrative stress are also increased
in these situations95. So, patients with severe asthma have
a relative corticosteroid resistance, and this is linked to
impaired HDAC2 function96,97. Reversal of corticosteroid
resistance may therefore be a useful therapeutic strategy
in the future for patients with COPD and severe asthma.
Interestingly, low concentrations of the drug theophylline,
which was previously used at high doses as a bronchodi-
lator in the treatment of asthma and COPD, are able to
restore HDAC2 activity invitro to normal levels and
granzyme B, induce apoptosis of typeI pneumocytes,
have been shown to reverse corticosteroid resistance in
cells from COPD patients, so may provide a means of
restoring corticosteroid responsiveness clinically98.
2008 Nature Publishing Group
E VtIh
EmWa
S
Immunomodulation. Specific immunotherapy to inhibit
allergic responses has been successful in treating individ-
uals with hay fever, in which there is a single type of aller-
gen involved, but so far such an approach has not proved
to be very effective for treating asthma and, because it
is potentially dangerous through triggering anaphylactic
responses, it is not recommended in current treatment
guidelines. More effective and safer immunotherapy for
asthma using DNA vaccines, Tcell peptides and sublin-
gual immunotherapy is currently under investigation99.
Suppression of Tcells may be a useful therapeutic
approach in the treatment of asthma and COPD, given
their role in driving inflammation in both diseases.
Cyclosporin A, a non-selective inhibitor of Tcells, although
early studies showed it had some clinical benefit100, it has
subsequently been found to be of little benefit to asthmat-
ics in several clinical trials and is now not recommended
as a therapy, particularly in view of its toxicity101. Less-
toxic immunomodulators, such as tacrolimus, rapamycin
and mycophenolate mofetil (CellCept; Roche), which are
currently used in the prevention of transplantation rejec-
tion, have not been tested in clinical studies of asthma
and there are no studies assessing the efficacy of immuno
suppressants in patients with COPD. More specific
immunomodulators that selectively inhibit TH2 cells have
been sought for the treatment of asthma, as yet without
success. Suplatast tosilate (IPD; Taiho Pharmaceutical)
is a drug that apparently inhibits TH2 cells and TH2-type
cytokine release102, but its mechanisms of action are not
known. It has only weak clinical effects and is currently
only available in Japan. In COPD patients, treatments
that target CD8+ Tcells might be more appropriate.
IFN
Epithelial cells Macrophage
CXCL9, CXCL10 and CXCL11
CXCR3
TH1 cell TC1 cell
Emphysema
Perforin and (apoptosis of type I
granzyme B pneumocytes)
Figure 6 | CD8+ Tcells in chronic obstructive
pulmonary disease (COPD). Epithelial cells and
macrophages are stimulated by interferon (IFN) to
Nature Reviews
release the chemokines CXC-chemokine ligand| Immunology
9 (CXCL9),
CXCL10 and CXCL11, which together act on CXC-
chemokine receptor 3 (CXCR3) expressed on T helper 1
(TH1) cells and type1 cytotoxic T (TC1) cells to attract them
into the lungs. TC1 cells, through the release of perforin and
thereby contributing to emphysema. IFN released by TH1
and TC1 cells then stimulates further release of CXCR3
ligands, resulting in a persistent inflammatory activation.
REVIEWS

Table 1 | Comparison between patterns of inflammation in asthma and COPD

Asthma COPD Refs
Mild Severe Exacerbation Mild Severe Exacerbation
Neutrophils 0 ++ ++++ ++ +++ ++++ 7
Eosinophils + ++ +++ 0 0 + 110,111
Mast cells ++ +++ +++? 0 0 ? 7,26,112
Macrophages + + ? +++ ++++ ++++ 113
T cells TH2 cells: ++ TH1 cells: + ? TC1 cells: + TC1 cells: +++ ? 18,66,114
iNKT cells: ? TH2 cells: + TH1 cells: +++
TC1 cells: + TH17 cells: ?
TC2 cells: +?
TH17 cells: ?
B cells IgE producing IgE producing ? + +++ ? 18,73
Dendritic cells + ? ? +? +? ? 115
Chemokines CCL11: + CXCL8: + CXCL8: ++ CXCL8: + CXCL8: ++ CXCL8: +++ 116
CXCL1: +
CCL2: +
Cytokines IL-4: ++ TNF: ++ ? TNF: + TNF: ++ TNF: +++ 117,118
IL-5: ++
IL-13: ++
Lipid mediators LTD4: ++ LTB4: ++ ? LTB4: + LTB4: ++ LTB4: +++ 10,11
PGD2: + PGD2: +
Oxidative stress 0 ++ +++ ++ +++ ++++ 119122
Steroid response ++++ ++ + 0 0 0 92
0, no response; + to ++++, magnitude scale; ?, uncertain. CCL, CC-chemokine ligand; COPD, chronic obstructive pulmonary disease; CXCL, CXC-chemokine ligand;
iNKT, invariant natural killer T; LTB4, leukotriene B4; LTD4, leukotriene D4; PGD2, prostaglandin D2; TC1, type 1 cytotoxic T; TH, T helper; TNF, tumour-necrosis factor.

Given the role of Bcells in both asthma and COPD,
non-selective Bcell inhibitors, such as the CD20-
specific monoclonal antibody rituximab (Rituxan;
Genentech, Inc. and Biogen Idec) might be beneficial,
as it is in rheumatoid arthritis and other autoimmune
diseases103. However, there are concerns about the safety
of using rituximab, particularly in COPD patients who
are susceptible to recurrent bacterial infections, as the
airways of patients with more severe disease are often
colonized by bacteria.
Other novel therapeutic approaches. Several novel
therapeutic approaches are currently in development
for treating inflammation in asthma and COPD104,105,
for example, one type of therapy involves targeting spe-
cific transcription factors that are known to be active in
these diseases106. In both airway diseases, NFB acti-
vation appears to be important for activating multiple
but different inflammatory genes, so inhibition of this
transcription factor using small molecule inhibitors of
IKK2 (inhibitor of NFB kinase 2) would be a logical
approach. For the treatment of asthma, inhibition of
GATA3 function and therefore TH2-type cytokine pro-
duction may be a more specific approach and this might
be possible using inhibitors of the GATA3-activating
kinase p38 MAPK39. Indeed, downregulation of p38
MAPK expression using an antisense oligonucleotide
has proved to be effective in inhibiting TH2-type cytokine
production in a mouse model of asthma107. For the treat-
ment of COPD, inhibition of the TH1-cell-inducing tran-
scription factor Tbet would be more appropriate and
this could be achieved by blocking STAT4 activity, but
no such drugs have so far been developed.
Given that chemokines are crucial mediators in
the recruitment of inflammatory cells to the lungs of
patients with asthma and COPD, antagonism of spe-
cific chemokine receptors would be a logical approach
for treating these diseases108,109. In asthma, chemokine
receptors on eosinophils (CCR3) and TH2 cells (CCR4,
CCR8 and CXCR4) are the main targets, whereas in
COPD, receptors on neutrophils (CXCR2), monocytes
(CXCR2 and CCR2), TH1 cells (CXCR3) and TC1 cells
(CXCR3) are the major foci of drug development. Small
molecule inhibitors for all of these receptors are now
in development.
Conclusions and future perspectives
Although both COPD and asthma involve chronic
inflammation of the respiratory tract, the pattern of
inflammation is markedly different between these two
diseases. Mild asthma is characterized by eosinophilic
inflammation driven by TH2 cells and DCs, and is asso-
ciated with mast-cell sensitization by IgE, and by the
release of multiple bronchoconstrictors. By contrast,
COPD is characterized by neutrophilic inflammation
that can be driven by a marked increase in the number
of lung-resident macrophages, which also attract CD4+
and CD8+ Tcells to the lungs. This lymphocytic infil-
tration can also be driven by chronic stimulation by
viral and bacterial antigens or by autoantigens released
following lung injury. Mast cells and DCs, which have
such a key role in asthma, have little or no known

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involvement in COPD. However, these distinctions
between asthma and COPD may not be as clear as
previously believed, as in patients with severe asthma
and in asthmatic individuals who smoke there is a
neutrophilic pattern of inflammation, and acute exac-
erbations of asthma and of COPD have similar inflam-
matory features. The role of TH17 cells in severe asthma
and COPD as a driving mechanism of neutrophilic
inflammation is not yet fully understood and deserves
more research; understanding these mechanisms may
lead to new therapeutic approaches.
New therapeutic approaches may also stem from a
greater understanding and appreciation of the similarities
between asthma and COPD. Although there are highly
effective treatments for mild asthma, severe asthma and
asthma in people who smoke are poorly treated with cur-
rent therapies and because of the similarities with COPD,
it is likely that new anti-inflammatory treatments that
are effective in COPD may also be effective in refractory
asthma. Whether therapies based on the immune mecha-
nisms will be safe and effective in treating airway diseases
also deserves further research.

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DATABASES
Entrez Gene: http://www.ncbi.nlm.nih.gov/entrez/query.
fcgi?db=gene
CCR2 | CCR3 | CCR4 | CXCR2 | CXCR3 | CXCR4 | GATA3 |
IFN| IL4 | IL5 | IL-6 | IL-9 | IL13 | IL17 | IL33 | p38 | TSLP
FURTHER INFORMATION
Peter Barness homepage: http://www1.imperial.ac.uk/
medicine/people/p.j.barnes.html
All links are active in the online pdf